Two-year clinical and radiographic results with combination etanerceptmethotrexate therapy versus monotherapy in early rheumatoid arthritisA two-year double-blind randomized study.

ARTHRITIS & RHEUMATISM
Vol. 62, No. 3, March 2010, pp 674–682
DOI 10.1002/art.27268
© 2010, American College of Rheumatology
Two-Year Clinical and Radiographic Results With Combination
Etanercept–Methotrexate Therapy Versus Monotherapy in
Early Rheumatoid Arthritis
A Two-Year, Double-Blind, Randomized Study
Paul Emery,1 Ferdinand Breedveld,2 Désirée van der Heijde,2 Gianfranco Ferraccioli,3
Maxime Dougados,4 Deborah Robertson,5 Ronald Pedersen,5 Andrew S. Koenig,5 and
Bruce Freundlich,5 for the Combination of Methotrexate and Etanercept in
Early Rheumatoid Arthritis Trial Group
Objective. To evaluate how continuation of and
alterations to initial year 1 combination etanercept–
methotrexate (MTX) therapy and MTX monotherapy
regimens affect long-term remission and radiographic
progression in early, active rheumatoid arthritis.
Methods. Subjects were randomized at baseline
for the entire 2-year period; those who completed 1 year
of treatment with combination or MTX monotherapy
entered year 2. The original combination group either
continued combination therapy (the EM/EM group; n ⴝ
111) or received etanercept monotherapy (the EM/E
group; n ⴝ 111) in year 2; the original MTX monotherapy group either received combination therapy (the
M/EM group; n ⴝ 90) or continued monotherapy (the
M/M group; n ⴝ 99) in year 2. Efficacy end points
included remission (a Disease Activity Score in 28 joints
[DAS28] <2.6) and radiographic nonprogression
(change in the modified Sharp/van der Heijde score
<0.5) at year 2. A last observation carried forward
analysis from the modified intention-to-treat population
(n ⴝ 398) and a post hoc nonresponder imputation
(NRI) analysis (n ⴝ 528) were performed for remission.
Results. At year 2, DAS28 remission was achieved
by 62/108, 54/108, 51/88, and 33/94 subjects in the
EM/EM, EM/E, M/EM, and M/M groups, respectively
(P < 0.01 for the EM/EM and M/EM groups versus the
M/M group). This effect was corroborated by a more
conservative post hoc 2-year NRI analysis, with remission observed in 59/131, 50/134, 48/133, and 29/130 of
the same respective groups (P < 0.05 for each of the
EM/EM, EM/E, and M/EM groups versus the M/M
group). The proportions of subjects achieving radiographic nonprogression (n ⴝ 360) were 89/99, 74/99,
59/79, and 56/83 in the EM/EM (P < 0.01 versus each of
ClinicalTrials.gov identifier: NCT00195494.
Supported by Wyeth Pharmaceuticals, a wholly owned subsidiary of Pfizer Inc. Dr. Emery is an Arthritis Research Campaign
Professor of Rheumatology.
1
Paul Emery, MA, MD, FRCP: University of Leeds, Leeds,
UK; 2Ferdinand Breedveld, MD, Désirée van der Heijde, MD, PhD:
Leiden University Medical Center, Leiden, The Netherlands; 3Gianfranco Ferraccioli, MD: Catholic University of the Sacred Heart–CIC,
Rome, Italy; 4Maxime Dougados, MD: Hôpital Cochin, Assistance
Publique Hôpitaux de Paris, and René Descartes University, Paris,
France; 5Deborah Robertson, RD, MS, Ronald Pedersen, MS, Andrew S. Koenig, DO, Bruce Freundlich, MD: Pfizer Inc., Collegeville,
Pennsylvania.
Dr. Emery has received consulting fees, speaking fees, and/or
honoraria from Wyeth Pharmaceuticals (less than $10,000) and research grants from Wyeth Pharmaceuticals, and was the primary
investigator in this trial. Dr. Breedveld has received consulting fees,
speaking fees, and/or honoraria from Wyeth Pharmaceuticals (less
than $10,000) and research grants from Wyeth Pharmaceuticals, and
was an investigator in this trial. Dr. van der Heijde has received
consulting fees, speaking fees, and/or honoraria from Abbott, Amgen,
Centocor, Wyeth Pharmaceuticals, UCB, Roche, Pfizer, Novartis,
Bristol-Myers Squibb, and Schering-Plough (less than $10,000 each)
and research grants from Wyeth Pharmaceuticals. Dr. Ferraccioli has
received consulting fees, speaking fees, and/or honoraria from Wyeth
Pharmaceuticals (less than $10,000) and research grants from Wyeth
Pharmaceuticals, and was an investigator in this trial. Dr. Dougados
has received consulting fees, speaking fees, and/or honoraria from
Wyeth Pharmaceuticals (less than $10,000) and research grants from
Wyeth Pharmaceuticals, and was an investigator in this trial. Ms
Robertson, Mr. Pedersen, and Drs. Koenig and Freundlich own stock
or stock options in Pfizer Inc.
Address correspondence and reprint requests to Paul Emery,
MA, MD, FRCP, Leeds Institute of Molecular Medicine, Chapel
Allerton Hospital, Chapeltown Road, Leeds LS4 7SA, UK. E-mail:
p.emery@leeds.ac.uk.
Submitted for publication June 25, 2009; accepted in revised
form November 3, 2009.
674
BENEFITS OF COMBINATION ETANERCEPT–MTX THERAPY OVER TWO YEARS
the other groups), EM/E, M/EM, and M/M groups,
respectively. No new safety signals or between-group
differences in serious adverse events were seen.
Conclusion. Early sustained combination
etanercept–MTX therapy was consistently superior to
MTX monotherapy. Combination therapy resulted in
important clinical and radiographic benefits over 2
study years, without significant additional safety risk.
Over the past decade, strategies for the management of rheumatoid arthritis (RA) have changed substantially with the introduction of goal-driven intensive
treatment, the use of potent biologic agents, and the
recognition of the importance of earlier treatment (1–4).
Although conventional treatment with diseasemodifying antirheumatic drugs (DMARDs) is effective
in providing clinical and functional benefits in some
patients, it may not always be sufficient to halt radiographic progression of joint destruction (1,5–8). In several RA trials, joint damage, as evidenced by radiographic
lesions, was found to progress despite intensive conventional DMARD therapy (7–9). Clinical criteria alone may
be inadequate measures of remission, which would explain
the discrepancy between clinical improvement and progression of joint damage observed in these trials.
Because joint damage has been shown to continue to progress among patients with very limited
disease activity, remission is increasingly defined by both
clinical and radiographic evidence of disease control.
New treatment strategies consist of earlier, more intensive regimens with combination therapy of several traditional DMARDs or a traditional DMARD and an
anti–tumor necrosis factor (anti-TNF) agent to produce
the desired clinical responses and prevent joint damage
(10). The Finnish Rheumatoid Arthritis Combination
Therapy (FIN-RACo) study found that combination
DMARD therapy provided better sustainability of remission than did single DMARD use in patients with
early RA, with sustained remission being associated with
less radiographic progression (11). Similarly, combination strategy is supported by the Trial of Etanercept and
Methotrexate with Radiographic Patient Outcomes
(TEMPO) study, in which a significantly higher percentage of subjects who received 3 years of combination
therapy with etanercept plus methotrexate (MTX) had
clinical remission of their disease than did those receiving either etanercept or MTX given as monotherapy;
moreover, both combination therapy and etanercept
monotherapy had significantly greater radiographic efficacy than did MTX monotherapy (12).
The aim of the Combination of Methotrexate and
Etanercept in Early Rheumatoid Arthritis (COMET)
675
trial was to evaluate the effects of early intensive therapy
with combined treatment on clinical remission (Disease
Activity Score in 28 joints [DAS28; see ref. 13] ⬍2.6)
and radiographic progression in subjects with early
active RA, merging the combination drug strategy with
the concept of early intervention. In the first year of this
2-year, double-blind, randomized study, significantly
greater improvements were observed in both disease
activity and radiographic outcomes after 52 weeks of
combination therapy compared with MTX monotherapy
(14). In this report, results are presented from the
second year of the COMET trial, which determined how
continuation of and alterations to the initial combination
and monotherapy regimens affected long-term clinical
and radiographic outcomes. A list of COMET investigators is shown in Appendix A.
SUBJECTS AND METHODS
Subjects. The COMET study design has been described previously in detail (14). All subjects who completed 1
year of treatment in the COMET study were eligible for
enrollment in the second year of the study. At the baseline of
year 1, subjects who had never received MTX and who
had active RA with a disease duration of 3–24 months (early
RA) were randomly assigned to 1 of 4 treatment groups, as
follows: 1) combination etanercept plus MTX treatment in
year 1 followed by continued combination treatment in year 2
(EM/EM), 2) combination treatment in year 1 followed by
etanercept alone in year 2 (EM/E), 3) MTX monotherapy in
year 1 followed by combination treatment in year 2 (M/EM), or
4) MTX monotherapy in year 1 followed by continued MTX
monotherapy in year 2 (M/M).
Protocol. Subjects were randomly assigned to a treatment group only once, at the baseline of the study, with no
rerandomization occurring at the end of year 1. Treatment was
allocated with a computerized randomization and enrollment
system that masked both participants and investigators at
original baseline and during the transition from year 1 to year
2. Investigators, study team members, and subjects remained
blinded to treatment assignment until the end of year 2.
Participants received 50 mg etanercept by subcutaneous injection or placebo injection once weekly. Oral MTX or placebo
was administered once weekly. In subjects receiving MTX or
oral placebo in both study years, the same dosage was maintained; no reduction in MTX or oral placebo was permitted in
year 2, except in the EM/E group. In that group, MTX was
discontinued according to a prespecified blinded downward
titration schedule over the first 4 weeks of year 2. Procedures
related to usage of corticosteroids, nonsteroidal antiinflammatory drugs, and folic acid supplementation have been described
previously (14). Administration of parenteral corticosteroids
was permitted after week 52, with a limit of 1 injection every 8
weeks.
This study was done in accordance with the ethical
principles of the Declaration of Helsinki. The protocol and its
amendments received independent ethics committee or institutional review board approval and regulatory review and
676
approval before site initiation and recruitment of subjects. All
elements of informed consent were explained to eligible subjects, and adequate time was allowed for questions and for
subjects to make voluntary decisions. No subject underwent
procedures specific to the protocol until he or she had signed
and dated an approved informed consent form.
End points. The co–primary end points of the percentage of subjects with disease in remission according to the
DAS28 and radiographic nonprogression at week 52 have been
reported previously (14). For study year 2, clinical efficacy end
points included the proportions of subjects in the 4 treatment
groups achieving DAS28 remission at week 104, the proportions of subjects in the 4 treatment groups meeting the
American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) (15) or achieving an
ACR50 or ACR70 response at week 104, and changes in the
mean DAS28 and 28-swollen-joint count in the 4 treatment
groups from week 52 to week 104.
Joint space narrowing and joint erosion were assessed,
and the modified Sharp/van der Heijde score (SHS; range
0–448) (16–18) was calculated for all groups. Radiographic
end points included the proportion of subjects achieving
radiographic nonprogression at week 104 (change from week
52 in SHS ⱕ0.5 [18]) and the rate of change in the SHS from
baseline to week 52 and from week 52 to week 104. Two
separate physicians who were masked to the treatment regimens and sequence of films read the digitized radiographic
images (BioImaging Technologies, Newtown, PA) for all participants in a randomized sequence (the interrater correlation
was 0.935–0.961). Functional improvement was measured using the disability index of the Health Assessment Questionnaire (HAQ DI) (19), and the proportion of subjects in each
group who achieved a normal HAQ DI score (ⱕ0.5 [20,21])
was evaluated. A post hoc analysis of the proportions of
subjects who achieved DAS28 remission, radiographic nonprogression, and a normal HAQ DI score was performed at week
104; subjects who had missing data at week 104 were considered to be nonresponders for this composite end point.
Statistical analysis. Power determinations for year 2
assumed 2-sided testing at the 0.05 significance level. Based on
the expected percentages of subjects discontinuing participation in the study at 1 year of 20% in the combination therapy
group and 30% in the MTX monotherapy group, 216 subjects
(108 subjects in both the combination therapy and etanercept
monotherapy groups) and 189 subjects (94–95 subjects in the
combination and MTX monotherapy groups), respectively,
were expected to enter year 2 of the study. On the assumption
of a difference between the latter groups of 1.21 to 1.85 and an
SD of 4.5, there was 80% power to detect a significant
difference in the SHS change from week 52 to week 104.
Statistical comparisons for clinical and radiographic
efficacy end points tested the null hypotheses that there were
no differences between the EM/EM and EM/E groups,
EM/EM and M/EM groups, EM/EM and M/M groups, and
M/EM and M/M groups. The proportions of subjects achieving
DAS28 remission and radiographic nonprogression were compared using Fisher’s exact test. The mean SHS changes from
year 2 baseline (week 52) to week 104 were compared between
treatment groups using analysis of covariance on the rank of
the change scores, averaged over readers, with the rank of
baseline scores as covariate.
The modified intention-to-treat (ITT) population for
EMERY ET AL
clinical efficacy analyses included all enrolled subjects who
received at least 1 dose of the year 2 test article, for whom
baseline DAS28 results were reported for year 2, and for whom
DAS28 results while receiving therapy were reported at least
once from week 52 to week 104. The radiographic modified
ITT population included subjects who received at least 1 dose
of year 2 test article and provided valid radiographs at baseline
of year 1, at week 52 (baseline of the year 2 analysis), and at
week 104 or early termination. For radiographic analyses,
annualized progression rates were used for radiographs obtained before the week 104 visit. As prespecified for both
clinical and radiographic analyses, missing values were imputed using the last observation carried forward (LOCF)
method. A post hoc statistical analysis of DAS28 remission was
subsequently performed using nonresponder imputation
(NRI) at week 104, with subjects who discontinued at any point
during the 2-year study counted as nonresponders. A post hoc
observed analysis of the proportion of subjects who achieved a
DAS28 ⬍2.6, an HAQ DI score ⱕ0.5, and a change in the SHS
ⱕ0.5 over the second year of the study was also performed on
those subjects with year 2 radiographs. A number-needed-totreat analysis, recommended in rheumatology (22), was conducted for DAS28 remission and radiographic nonprogression
in the EM/EM group compared with the M/M group. Safety
analyses included all subjects who entered year 1 and received
at least 1 dose of year 1 test article (n ⫽ 542) and those subjects
who continued into year 2 and received at least 1 dose of year
2 test article (n ⫽ 411).
RESULTS
A total of 411 subjects completed 1 year of either
combination therapy or MTX monotherapy and continued into year 2 of this trial as originally randomized
(Figure 1). Of these, 398 subjects were valid for evaluation of clinical efficacy, and all 411 subjects were valid
for evaluation of safety. Overall, 64 subjects (15.6%)
discontinued participation in the study from week 52 to
week 104; subjects in the EM/EM treatment group were
significantly less likely to discontinue treatment due to
lack of efficacy than subjects in other treatment groups
(P ⬍ 0.01). The mean weekly doses of MTX from week
52 to week 104 in the EM/EM, EM/E, M/EM, and M/M
groups were 16.2 mg, 16.3 mg (MTX placebo), 17.8 mg,
and 18.0 mg, respectively; the maximum allowable dosage was 20 mg/week, based on the standard of care at the
time the protocol was written. A total of 360 subjects
were included in the year 2 radiographic analysis (99
subjects in the EM/EM group, 99 in the EM/E group, 79
in the M/EM group, and 83 in the M/M group). Demographics and baseline disease characteristics are summarized in Table 1. In a post hoc NRI analysis over 104
weeks, 528 subjects were evaluated for DAS28 remission.
Efficacy. After 2 years of treatment (LOCF
method), the proportions of subjects achieving DAS28
remission in the EM/EM and M/EM groups (62/108
BENEFITS OF COMBINATION ETANERCEPT–MTX THERAPY OVER TWO YEARS
677
Figure 1. Study design and subject disposition. EM/EM ⫽ combination etanercept plus methotrexate
(MTX) treatment in year 1 followed by continued combination treatment in year 2; EM/E ⫽ combination
treatment in year 1 followed by etanercept alone in year 2; M/EM ⫽ MTX monotherapy in year 1 followed
by combination treatment in year 2; M/M ⫽ MTX monotherapy in year 1 followed by continued MTX
monotherapy in year 2. ⴱ ⫽ 1 subject discontinued at final visit of year 1 but received 1 dose of study drug
in period 2 (included in period 2 population); † ⫽ overall P ⫽ 0.003, by 2-tailed Fisher’s exact test.
[57%] and 51/88 [58%], respectively) were significantly
greater than that in the M/M group (33/94 [35%]) (P ⫽
0.002 for EM/EM group versus M/M group; P ⫽ 0.003
for M/EM group versus M/M group) but not significantly greater than that in the EM/E group (54/108
[50%]). Based on the NRI analysis, significantly greater
proportions of subjects in the EM/EM (59/131 [45%]),
EM/E (50/134 [37%]), and M/EM (48/133 [36%])
groups were similarly shown to have achieved DAS28
remission after 2 years compared with the M/M group
(29/130 [22%]) (P ⬍ 0.001 for EM/EM group versus
M/M group; P ⫽ 0.010 for EM/E group versus M/M
group; P ⫽ 0.015 for M/EM group versus M/M group)
(Figure 2). To achieve 1 DAS28 remission during a
period of 2 years, 4.5 persons (95% confidence interval
[95% CI] 2.7, 12.7) would have to be treated with the
EM/EM regimen rather than the M/M regimen. The
mean DAS28 was maintained at 2.7 at weeks 52 and 104
in the EM/EM group. Subjects in the M/EM group
demonstrated improvement in the mean DAS28 from
3.3 at week 52 to 2.8 at week 104 (P ⬍ 0.001 versus the
M/M group). Worsening of the mean DAS28 was observed from weeks 52 to 104 in the EM/E group (from
2.6 to 3.1; P ⬍ 0.05 versus the EM/EM group), and
minimal change was seen in the M/M group (from 3.4 to
3.5).
The percentages of subjects in the EM/EM,
EM/E, M/EM, and M/M groups who achieved an
ACR20 response at week 104 were 86%, 80%, 81%, and
61%, respectively. Statistically significant differences
were noted at week 104 in the M/EM group compared
with the M/M group (P ⫽ 0.004) and in the EM/EM
group compared with the M/M group (P ⬍ 0.001). For
the ACR50 response, the percentages of responders in
the EM/EM, EM/E, M/EM, and M/M groups were 70%,
64%, 66%, and 46%, respectively. Statistically significant
differences were found in the M/EM group compared
with the M/M group (P ⫽ 0.007) and in the EM/EM
group compared with the M/M group (P ⬍ 0.001). An
ACR70 response was achieved in 57%, 44%, 48%, and
32% of the EM/EM, EM/E, M/EM, and M/M groups,
respectively, with statistically significant differences be-
678
EMERY ET AL
Table 1. Demographics at the year 1 baseline and disease characteristics at the year 2 baseline for the year 2 modified intention-to-treat
population*
Treatment group
Age, years
Women, no. (%)
White, no. (%)
Disease duration, months
DAS28
Swollen joint count, 0–68
Tender joint count, 0–71
HAQ disability index score
ESR, mm/hour
Anti-CCP positive, no. (%)
CRP level, mg/liter
EM/EM
(n ⫽ 108)
EM/E
(n ⫽ 108)
M/EM
(n ⫽ 88)
M/M
(n ⫽ 94)
Total
(n ⫽ 398)
52.4 ⫾ 14.3
78 (72.2)
94 (87.0)
8.4 ⫾ 5.7
2.7 ⫾ 1.2
2.7 ⫾ 6.1
3.9 ⫾ 7.3
0.6 ⫾ 0.6
15.8 ⫾ 12.4
72 (67.3)
6.0 ⫾ 5.0
52.2 ⫾ 14.6
82 (75.9)
95 (88.0)
9.1 ⫾ 5.6
2.6 ⫾ 1.2
1.5 ⫾ 3.1
3.7 ⫾ 7.9
0.6 ⫾ 0.7
15.3 ⫾ 12.8
74 (68.5)
7.6 ⫾ 13.9
55.6 ⫾ 13.1
52 (59.1)
78 (88.6)
9.1 ⫾ 6.0
3.3 ⫾ 1.4
3.9 ⫾ 6.4
6.5 ⫾ 10.2
0.7 ⫾ 0.7
22.5 ⫾ 15.9
63 (72.6)
10.0 ⫾ 13.8
53.2 ⫾ 12.5
77 (81.9)
83 (88.3)
8.7 ⫾ 5.4
3.4 ⫾ 1.4
3.1 ⫾ 4.4
6.1 ⫾ 7.9
0.8 ⫾ 0.7
22.7 ⫾ 17.8
64 (69.6)
10.5 ⫾ 14.6
53.2 ⫾ 13.7
289 (72.6)
350 (87.9)
8.8 ⫾ 5.7
3.0 ⫾ 1.4
2.7 ⫾ 5.2
4.9 ⫾ 8.4
0.6 ⫾ 0.7
18.8 ⫾ 15.1
273 (69.1)
8.3 ⫾ 12.4
* Except where indicated otherwise, values are the mean ⫾ SD. EM/EM ⫽ combination etanercept plus methotrexate (MTX) treatment in year 1
followed by continued combination treatment in year 2; EM/E ⫽ combination treatment in year 1 followed by etanercept alone in year 2; M/EM ⫽
MTX monotherapy in year 1 followed by combination treatment in year 2; M/M ⫽ MTX monotherapy in year 1 followed by continued MTX
monotherapy in year 2; DAS28 ⫽ Disease Activity Score in 28 joints; HAQ ⫽ Health Assessment Questionnaire; ESR ⫽ erythrocyte sedimentation
rate; anti-CCP ⫽ anti–cyclic citrullinated peptide; CRP ⫽ C-reactive protein.
tween the M/EM and the M/M groups (P ⫽ 0.034) and
between the EM/EM and the M/M groups (P ⬍ 0.001).
During year 2, radiographic nonprogression
(LOCF method; SHS ⱕ0.5) was demonstrated in a
significantly higher proportion of subjects in the EM/EM
group (89/99 [90%]) than in the EM/E (74/99 [75%]),
M/EM (59/79 [75%]), and M/M (56/83 [67%]) groups
(P ⫽ 0.008 for the EM/EM group versus the EM/E
group; P ⫽ 0.009 for the EM/EM group versus the
M/EM group; P ⬍ 0.001 for the EM/EM group versus
the M/M group) (Figure 3). The estimated number of
persons who would need to be treated with the EM/EM
regimen rather than the M/M regimen for 2 years to
achieve radiographic nonprogression was 4.5 (95% CI
2.8, 10.4). The mean SHS changes from week 52 to week
104 were –0.02 (95% CI –0.32, 0.29), 0.11 (95% CI
–0.54, 0.77), 0.78 (95% CI –0.06, 1.61), and 2.07 (95% CI
0.42, 3.72) for the EM/EM, EM/E, M/EM, and M/M
groups, respectively; the change in the EM/EM group was
significantly less than the change in the EM/E group (P ⫽
0.006). From week 52 to week 104, improvements from 1.7
to 1.3 and from 2.6 to 1.3 were achieved in the mean
28-swollen-joint counts in the EM/EM and M/EM groups,
respectively, compared with worsening from 1.1 to 1.7 and
from 2.4 to 2.9 in the EM/E and M/M groups, respectively
(P ⫽ 0.001 for the M/EM group versus the M/M group).
The proportions of subjects achieving normal
HAQ DI scores at week 52 differed significantly between the EM/EM and M/M groups (57% and 43%,
respectively; P ⫽ 0.048). The addition of etanercept to
MTX produced significant within-group improvement in
the raw mean score for change from week 52 to week
Figure 2. Proportions of subjects achieving clinical remission (a Disease Activity Score in 28 joints [DAS28] ⬍2.6) at week 104, based on
last observation carried forward (LOCF) and nonresponder imputation (NRI) analyses. See Figure 1 for other definitions.
Figure 3. Proportions of subjects achieving radiographic nonprogression (a change in the modified Sharp/van der Heijde score ⱕ0.5) at
week 104, based on last observation carried forward analysis. See
Figure 1 for definitions.
BENEFITS OF COMBINATION ETANERCEPT–MTX THERAPY OVER TWO YEARS
679
Table 2. Safety summary in the year 1 and year 2 safety populations*
Year 1 treatment group
Any treatment-emergent
adverse event
Serious adverse events
Death†
Malignancy‡
Serious infection
Year 2 treatment group
EM
(n ⫽ 274)
M
(n ⫽ 268)
Total
(n ⫽ 542)
EM/EM
(n ⫽ 111)
EM/E
(n ⫽ 111)
M/EM
(n ⫽ 90)
M/M
(n ⫽ 99)
Total
(n ⫽ 411)
246 (89.8)
241 (89.9)
487 (89.9)
91 (82.0)
89 (80.2)
71 (78.9)
79 (79.8)
330 (80.3)
8 (7.2)
0 (0)
0 (0)
1 (0.9)
10 (9.0)
0 (0)
1 (0.9)
2 (1.8)
11 (12.2)
0 (0)
5 (5.6)
1 (1.1)
12 (12.1)
1 (1.0)
3 (3.0)
2 (2.0)
41 (10.0)
1 (0.2)
9 (2.2)
6 (1.5)
33 (12.0)
1 (⬍0.1)
4 (1.5)
5 (1.8)
34 (12.7)
0 (0)
4 (1.5)
8 (3.0)
67 (12.4)
1 (⬍0.1)
8 (1.5)
13 (2.4)
* Values are the number (%) of subjects. EM ⫽ combination etanercept plus methotrexate (MTX) treatment; M ⫽ MTX monotherapy (see Table
1 for other definitions).
† One subject in the EM/E group died of pneumonia during year 1. One subject in the M/M group died during year 2; pneumonia and
adenocarcinoma of the lungs with metastasis were reported as the cause of death.
‡ Nine malignancies were reported: 1 case each of gastrointestinal cancer, bladder cancer, rectal melanoma with metastasis to the lung, and prostate
cancer in the M/EM group; 1 case each of pancreatic cancer and cancer of the chest wall and lungs in the M/M group; 1 case of basal cell cancer
in each of the EM/E, M/EM, and M/M groups.
104 (mean ⫾ SD change 0.17 ⫾ 0.42) (P ⫽ 0.0007);
mean changes in scores for the other treatment groups
did not reach statistical significance. Comparing the
proportions of subjects with normal HAQ DI scores,
statistically significant differences were noted at week
104 only between the EM/EM and M/M groups (62%
and 44%, respectively; P ⫽ 0.011).
A post hoc completers’ analysis of the proportions of subjects who achieved DAS28 remission
(DAS28 ⬍2.6), radiographic nonprogression (change in
the SHS ⱕ0.5 from week 52 to week 104), and a normal
HAQ DI score (ⱕ0.5) at week 104 demonstrated a trend
toward higher percentages of responders in the groups
that included etanercept in the therapy regimen during
year 2. Thirty-nine percent of the EM/EM group, 32%
of the EM/E group, and 36% of the M/EM group
achieved all 3 responses, while only 18% of the M/M
group achieved this composite outcome.
Safety. During this 2-year study, combination
therapy was well tolerated, with no new safety signals
identified and no significant differences among groups
(Table 2). No cases of opportunistic infection, tuberculosis, or demyelinating diseases were reported.
DISCUSSION
In recent years, the use of MTX and combination
DMARD therapy for RA has begun to address the
underlying joint destruction that resulted in deformities
and disability. However, new research suggests that
radiographic progression may continue in patients receiving treatment, even when clinical remission is
achieved (7–9). The most robust evidence of joint damage prevention is derived from clinical trials of anti-TNF
agents, which have been shown to be particularly effec-
tive when used in combination with high-dose MTX in
RA (23–25). This is especially the case for early RA
(26–28), which is important because studies have demonstrated a rapid progression of radiographic damage in
the first few years of disease (29–33), potentially representing the beginning of a lifetime of cumulative destruction. A “therapeutic window of opportunity” has
been proposed in which treatment administered early
may modify the underlying disease processes, halt the
destruction of joints, and prevent a base level of joint
damage (34–37).
To begin to explore this possibility, subjects with
early RA in the first year of the COMET study were
treated with combination therapy or MTX alone. At 1
year, the percentage of subjects in the combination
group achieving DAS28 remission was nearly twice that
in the MTX monotherapy group (50% versus 28%; P ⬍
0.0001), and the percentage of subjects with no radiographic progression was also considerably higher (80%
versus 59%; P ⬍ 0.0001) (14). The second year of the
COMET study determined whether these important
effects of combination therapy could be maintained
compared with MTX monotherapy without sacrificing
safety.
Sustained combination therapy was consistently
more effective than continuous MTX monotherapy in
improving clinical and radiographic outcomes. This was
reflected in the greater numbers of subjects who withdrew from the M/M group due to lack of efficacy, both
in year 1 (9 in the EM group versus 24 in the M group;
P ⫽ 0.007) and in year 2 (none in the EM/EM group
versus 7 in the M/M group; P ⫽ 0.003). The EM/EM
regimen was associated with significantly higher rates of
DAS28 remission, ACR response, and SHS nonprogres-
680
sion than was the M/M regimen. Importantly, the M/M
group had a mean progression of 2.07 SHS units compared with a decrease of –0.02 for combination therapy
(EM/EM)–treated subjects during year 2. This represents continued underlying joint destruction in the M/M
group as opposed to the EM/EM group.
The second year of this study also evaluated the
effect of switching to combination therapy after 1 year of
MTX monotherapy switching to the M/EM regimen was
significantly more effective than continuing MTX monotherapy (the M/M regimen) in providing DAS28 remission. Similar percentages of subjects in the M/EM and
EM/EM groups achieved DAS28 remission at 2 years
(58% and 57%, respectively; P not significant [NS]),
according to the LOCF analysis. A more conservative
post hoc 2-year NRI analysis, which accounted for the
greater number of dropouts in the MTX treatment arm
during year 1, revealed a numerically higher percentage
of subjects with disease in remission in the EM/EM
group than in the M/EM group (45% versus 36%; P NS).
Furthermore, delaying combination therapy until year 2
of the study resulted in a significantly lower percentage
of subjects attaining radiographic nonprogression compared with early and sustained combination therapy
(75% versus 90%; P ⫽ 0.009). These findings suggest
that delaying the addition of etanercept to an MTX
regimen for 1 year creates a potential “trade off.”
Although, on a group level, the cost of deferred combination therapy is lower compared with that of early
combination therapy, this delay may result in failure to
achieve clinical remission and in residual radiographic
damage.
We also assessed the effects of a step down from
the EM regimen in year 1 to the EM/E regimen in year
2. This regimen was numerically less effective than
continuous combination therapy in providing DAS28
remission (50% versus 57%; P NS) and significantly less
effective in producing nonprogression (75% versus 90%;
P ⫽ 0.008). Outcomes at year 2 (LOCF method) in the
EM/E group were numerically, but not statistically,
superior to those in the M/M group in terms of both
DAS28 remission (50% versus 35%; P NS) and radiographic nonprogression (75% versus 68%; P NS), demonstrating the importance of MTX as an adjunct to
etanercept for optimizing clinical and radiographic outcomes in early RA. Nevertheless, the efficacy of the
step-down approach may be an encouraging finding for
patients who do not tolerate MTX or otherwise need to
discontinue treatment with this agent. It is of note that
none of the 111 subjects who had received combination
therapy for the full 2 years of the study and only 1 of 90
who switched to combination therapy for the second
EMERY ET AL
Figure 4. Radiographic progression over 2 years. Shown are mean
changes in modified Sharp/van der Heijde score (mTSS) from week 0
to week 104, based on last observation carried forward analysis.
ETN ⫽ etanercept; MTX ⫽ methotrexate. See Subjects and Methods
for descriptions of groups. ⴱ ⫽ 1 subject did not have a valid
radiograph at week 52 but did at baseline and week 104; change from
week 52 to week 104 cannot be assessed.
year dropped out due to lack of efficacy compared with
7 of the 99 subjects who had received MTX monotherapy for 2 years and 7 of 111 who continued receiving
etanercept only in the second year. On NRI analysis,
both the M/EM and EM/E therapy regimens led to
similar DAS28 responses.
The addition of etanercept to MTX at week 52
altered the rate of change in SHS, so that the continued
progression over the second year of the study more
closely resembled that of the EM/E group. However, the
total SHS for the M/M group was observed to be greater
than that of the EM/E group at week 104, due to the
residual radiographic damage from year 1 (Figure 4).
This again suggests that the early use of combination
therapy protects against joint damage and subsequent
loss of function over time. Additionally, the initial year
of combination therapy appeared to support achievement of the composite outcome of DAS28 remission,
radiographic nonprogression, and a normal HAQ DI
score. In the EM/EM, EM/E, and M/EM groups, the
proportions of subjects who achieved all 3 results (39%,
32%, and 36%, respectively) approximated the rate of
this response seen in the first year of the COMET trial
(35%) (14), while the proportion in the M/M group
(18%) was considerably lower.
The results of this trial further address whether
the benefits of combination therapy in early RA outweigh the potential side effects of long-term administration. Combination therapy continued to be well
tolerated over the second year of observation, with no
new safety signals reported during year 2, suggesting
that early and sustained intensive therapy can improve
long-term outcomes for subjects with early RA without
posing an additional safety risk.
This study had several limitations, which included
BENEFITS OF COMBINATION ETANERCEPT–MTX THERAPY OVER TWO YEARS
potential distribution disparities since the 2-year end
points were reported only for those subjects who completed year 1 of the study and did not account for the
greater number of discontinuations in the M/M group in
year 1. Randomization to the year 2 treatment groups
occurred at study entry (baseline of year 1); hence, not
all subjects randomized to year 2 groups were present in
the year 2 efficacy population, due to withdrawals during
year 1. For these reasons, an NRI analysis was performed. In contrast to subjects treated in clinical practice, COMET participants were not permitted to reduce
the dosage of their primary medication unless required
due to adverse events, which does not reflect current
practice. Furthermore, the 20-mg maximal dose of MTX
might not be considered sufficiently aggressive by some
clinicians today, although this was the state of the art
when the COMET study was designed. Modifications in
MTX dosages (either up or down) or other therapeutic
interventions based on clinical response or DAS28 might
have yielded different outcomes. Also, treatment group
means were analyzed in this study, so these results need
to be interpreted with caution when considering individual patients. Finally, for purposes of simplicity, this study
did not have a fifth step-down treatment arm in which
etanercept was discontinued following the combination
EM regimen in year 1. The results of this study, however,
have generated interest in further exploring etanercept
step-down therapy regimens for patients who achieve
remission of disease with combination therapy, with the
possibility of drug-free remission as a goal for some RA
patients.
In conclusion, the final results of the COMET
trial underscore a growing body of evidence that demonstrates the important sustained clinical benefits of
intensive therapy in early RA. Combination therapy with
etanercept and MTX led to DAS28 remission in approximately half of the subjects at year 2, with 90% of
subjects showing no radiographic progression. Even
though 3 alternative regimens led to good responses compared with those achieved with treatment in past decades,
the combination regimen for 2 years appeared to produce
the optimal results with no compromise in safety.
ACKNOWLEDGMENTS
We thank the COMET trial investigators, their staff,
and their subjects for participation in this clinical trial; Theresa
Mscsiz, RN (of Pfizer Inc.), who was the lead clinical scientist
for this trial; and J. R. Foehl, PhD (of Pfizer Inc.) and Donna
McGuire (of On Assignment, a contractor for Pfizer Inc.) for
assistance with preparation of the manuscript.
681
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Emery had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Emery, Breedveld, van der Heijde,
Dougados, Robertson, Pedersen, Freundlich.
Acquisition of data. Emery.
Analysis and interpretation of data. Emery, Breedveld, van der Heijde,
Ferraccioli, Dougados, Robertson, Pedersen, Koenig, Freundlich.
Clinical project team leader. Robertson.
Study medical monitor. Koenig.
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APPENDIX A: COMET INVESTIGATORS
In addition to several of the authors (P. Emery, F. Breedveld,
D. van der Heijde, G. Ferraccioli, and M. Dougados), COMET
investigators included the following: S. Hall (Victoria, Australia), N.
Nanolios (Westmead, Australia), P. Nash (Queensland, Australia), R.
Will (Victoria Park, Australia), W. Ebner (Wien, Austria), R.
Westhovens (Leuven, Belgium), M. Malaise (Liege, Belgium), J.-P.
Devogelaer (Bruxelles, Belgium), M. Barros Bértolo (São Paulo,
Brazil), J. C. Tavares Brenol (Porto Alegre, Brazil), S. Jacobsen
(Copenhagen, Denmark), P. Holck (Silkeborg, Denmark), M.
Leirisalo-Repo (Helsinki, Finland), A. Karjalainen (Oys, Finland), J.
Sibilia (Strasbourg, France), T. Schaeverbeke (Bordeaux, France), X.
Puechal (Le Mans, France), A. Cantagrel (Toulouse, France), B.
Combe (Montpellier, France), C. Jorgensen (Montpellier, France), L.
Euller-Ziegler (Nice, France), X. Le Loët (Rouen, France), O. Meyer
(Paris, France), B. Pallot Prades (St. Etienne, France), J. Kekow
(Vogelsang, Germany), H.-P. Tony (Würzburg, Germany), S. Wassenberg (Ratingen, Germany), M. Gaubitz (Muenster, Germany), M.
Aringer (Dresden, Germany), G. Burmester (Berlin, Germany), O.
Schröder (Kiel, Germany), U. v. Hinüber (Hildesheim, Germany),
K.-H. Göttl (Passau, Germany), H. Moutsopoulos (Athens, Greece),
A. Andonopoulos (Patras, Greece), P. Geher (Budapest, Hungary), O.
Fitzgerald (Dublin, Ireland), M. Molloy (Wilton, Cork, Ireland), M.
Carrabba (Milano, Italy), S. de Vita (Udine, Italy), C. Montecucco
(Pavia, Italy), F. Trotta (Ferrara, Italy), M. Cantini (Prato, Italy), R.
Foti (Catania, Italy), C. Ferri (Modena, Italy), A. Fraga (Mexico City,
Mexico), J. M. Miranda (Mexico City, Mexico), R. Allaart (Leiden,
The Netherlands), M. Hoekstra (Erchede, The Netherlands), R.
Landewé (Maastricht, The Netherlands), H. K. Ronday (Den Haag,
The Netherlands), T. K. Kvien (Oslo, Norway), O. Bjorneboe (Bærum
Postterminal, Norway), F. Viana Queiroz (Lisboa, Portugal), V.
Rodriguez Valverde (Santander, Spain), I. Mateo Bernardo (Madrid,
Spain), F. Navarro (Sevilla, Spain), R. Oding (Västerås, Sweden), A.
Kataja Knight (Uppsala, Sweden), A. Kai-Lik So (Lausanne, Switzerland), C.-T. Chou (Taipei, Taiwan), D.-M. Chang (Taipei, Taiwan), H.
Yazici (Istanbul, Turkey), H. Direskeneli (Istanbul, Turkey), D.
Walker (Tyne, UK), T. Sheeran (Cannock, England, UK), D. Scott
(Norwich, Norfold, UK), R. Moots (Liverpool, UK), A. Gough (North
Yorkshire, UK), M. Schiff (Denver, Colorado, US).