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The effects of golimumab on radiographic progression in rheumatoid arthritisResults of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy.

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ARTHRITIS & RHEUMATISM
Vol. 63, No. 5, May 2011, pp 1200–1210
DOI 10.1002/art.30263
© 2011, American College of Rheumatology
The Effects of Golimumab on Radiographic Progression in
Rheumatoid Arthritis
Results of Randomized Controlled Studies of Golimumab Before Methotrexate
Therapy and Golimumab After Methotrexate Therapy
Paul Emery,1 Roy Fleischmann,2 Désirée van der Heijde,3 Edward C. Keystone,4
Mark C. Genovese,5 Philip G. Conaghan,1 Elizabeth C. Hsia,6 Weichun Xu,7 Anna Baratelle,8
Anna Beutler,7 and Mahboob U. Rahman9
Objective. To evaluate the effects of golimumab on
radiographic progression in patients with rheumatoid
arthritis (RA).
Methods. Methotrexate (MTX)–naive patients (in
the Golimumab Before Employing Methotrexate as the
First-Line Option in the Treatment of Rheumatoid
Arthritis of Early Onset [GO-BEFORE] study; n ⴝ 637)
and patients with active RA despite MTX therapy (in
the Golimumab in Active Rheumatoid Arthritis Despite
Methotrexate Therapy [GO-FORWARD] study; n ⴝ
444) were randomly assigned to receive placebo plus
MTX (group 1), golimumab 100 mg plus placebo (group
2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Golimumab or
placebo was administered subcutaneously every 4
weeks. Radiographs of the hands and feet were taken at
baseline, week 28, and week 52 in the GO-BEFORE
study and at baseline, week 24 (week 16 for patients who
entered early escape), and week 52 in the GOFORWARD study. Radiographs were scored by 2 independent readers in each study using the van der Heijde
modification of the Sharp score.
Results. In the GO-BEFORE study, the mean ⴞ
SD changes in the modified Sharp score from baseline
to week 52 (control period) were 1.4 ⴞ 4.6 in group 1,
1.3 ⴞ 6.2 in group 2 (P ⴝ 0.266), 0.7 ⴞ 5.2 in group 3
(P ⴝ 0.015), and 0.1 ⴞ 1.8 in group 4 (P ⴝ 0.025). In
the GO-FORWARD study, changes from baseline to
week 24 (control period) were 0.6 ⴞ 2.4 in group 1,
0.3 ⴞ 1.6 in group 2 (P ⴝ 0.361), 0.6 ⴞ 2.7 in group 3
(P ⴝ 0.953), and 0.2 ⴞ 1.3 in group 4 (P ⴝ 0.293).
Supported by Centocor Research and Development, Inc. (a
subsidiary of Johnson & Johnson) and Schering-Plough/Merck Research Institute.
1
Paul Emery, MA, MD, FRCP, Philip G. Conaghan, MB BS,
PhD, FRACP, FRCP: University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK; 2Roy Fleischmann,
MD: University of Texas Southwest Medical Center at Dallas; 3Désirée van der Heijde, MD, PhD: Leiden University Medical Center,
Leiden, The Netherlands; 4Edward C. Keystone, MD, FRCP: University of Toronto and Mount Sinai Hospital, Toronto, Ontario, Canada;
5
Mark C. Genovese, MD: Stanford University, Palo Alto, California;
6
Elizabeth C. Hsia, MD: Centocor Research and Development, Inc.,
Malvern, Pennsylvania, and University of Pennsylvania School of
Medicine, Philadelphia; 7Weichun Xu, PhD, Anna Beutler, MD:
Centocor Research and Development, Inc., Malvern, Pennsylvania;
8
Anna Baratelle, ASRT: Baratelle and Associates, LLC, Springfield,
Pennsylvania; 9Mahboob U. Rahman, MD, PhD: Pfizer, Collegeville,
Pennsylvania.
Dr. Emery has received consulting fees, speaking fees, and/or
honoraria from MSD, Pfizer, Roche, Bristol-Myers Squibb, and Abbott (less than $10,000 each). Dr. Fleischmann has received consulting
fees, speaking fees, and/or honoraria from Centocor (less than
$10,000). Dr. van der Heijde has received consulting fees, speaking
fees, and/or honoraria from Abbott, Amgen, AstraZeneca, BristolMyers Squibb, Centocor, Chugai, Eli Lilly, GlaxoSmithKline, Merck,
Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough/
Merck, UCB, and Wyeth (less than $10,000 each). Dr. Keystone has
received consulting fees, speaking fees, and/or honoraria from Abbott,
Amgen, Bristol-Myers Squibb, Centocor, F. Hoffmann-La Roche,
Genentech, Schering-Plough/Merck, UCB, and Pfizer (less than
$10,000 each) and has received research funding from Abbott, Amgen,
AstraZeneca, Bristol-Myers Squibb, Centocor, F. Hoffmann-La
Roche, Novartis, Schering-Plough/Merck, UCB, and Wyeth. Dr.
Genovese has received grant support from, and served as a consultant
to, Johnson & Johnson. Dr. Conaghan has received consulting fees,
speaking fees, and/or honoraria from AstraZeneca, Roche, Novartis,
MSD, and Bristol-Myers Squibb (less than $10,000 each). Drs. Hsia,
Xu, Beutler, and Rahman own stock or stock options in Johnson &
Johnson.
Address correspondence to Paul Emery, MA, MD, FRCP,
Academic Section of Musculoskeletal Disease, Leeds Institute of
Molecular Medicine, Chapel Allerton Hospital, Chapeltown Road,
Leeds LS7 4SA, UK. E-mail: p.emery@leeds.ac.uk.
Submitted for publication April 16, 2010; accepted in revised
form January 18, 2011.
1200
EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA
Conclusion. Golimumab in combination with
MTX inhibited radiographic progression significantly
better than did MTX alone in the GO-BEFORE study.
Radiographic progression in the GO-FORWARD study
was minimal in all treatment arms, precluding an
adequate assessment of the effect of golimumab on
radiographic progression in this study.
Golimumab is a human monoclonal antibody to
tumor necrosis factor ␣ (TNF␣). The effect of golimumab in rheumatoid arthritis (RA) was evaluated in 3
large, phase III clinical studies that included populations
of patients with different exposures to previous therapies
(1–3). The Golimumab Before Employing Methotrexate
as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset (GO-BEFORE) study
included patients with active RA who were naive to
methotrexate (MTX), the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy (GOFORWARD) study included patients with active RA
despite MTX therapy, and the Golimumab in Patients
with Active Rheumatoid Arthritis After Treatment with
Tumour Necrosis Factor ␣ Inhibitors (GO-AFTER)
study included patients with active RA who had previously received anti-TNF␣ therapy. The primary efficacy
end points were related to signs and symptoms and the
safety results for these studies have been previously
reported (1–3).
Radiographic progression, however, was a coprimary end point in the GO-BEFORE study and a
secondary end point in the GO-FORWARD study; the
GO-AFTER study did not include radiographic evaluations. The objective of the current analysis was to
therefore evaluate the effect of golimumab on radiographic progression in patients with RA who participated in the GO-BEFORE and GO-FORWARD trials.
PATIENTS AND METHODS
The study design and patient inclusion criteria of the
GO-BEFORE (1) and GO-FORWARD (2) studies have been
published previously. The GO-BEFORE population consisted
of 637 patients with RA who were MTX naive (defined as
having taken no more than 3 weekly doses of MTX for RA at
any time), while the GO-FORWARD population consisted of
444 patients who had active RA despite having taken MTX.
These patients were to have tolerated MTX at a dosage of ⱖ15
mg/week for at least 3 months before screening, with receipt of
a stable dosage of 15–25 mg/week during the 4-week period
immediately preceding screening (2). In both studies, active
RA was defined as the presence of ⱖ4 swollen joints (of 66
total joints assessed), ⱖ4 tender joints (of 68 total joints
1201
assessed), and at least 2 of the following 4 features: a
C-reactive protein (CRP) level of ⱖ1.5 mg/dl (normal 0–0.6)
or an erythrocyte sedimentation rate (Westergren) of ⱖ28
mm/hour; morning stiffness of at least 30 minutes’ duration;
presence of bone erosion, as determined by radiograph and/or
magnetic resonance imaging; or presence of anti–cyclic citrullinated peptide antibody or rheumatoid factor (1,2).
In both studies, patients were randomly assigned to
receive placebo injections plus MTX capsules (group 1),
golimumab 100-mg injections plus placebo capsules (group 2),
golimumab 50-mg injections plus MTX capsules (group 3), or
golimumab 100-mg injections plus MTX capsules (group 4).
Golimumab and placebo injections were administered subcutaneously every 4 weeks. In the GO-BEFORE study, group 1
was an active comparator group because all patients were
MTX naive. In the GO-FORWARD study, all patients had
had an inadequate response to MTX therapy, so group 1
served as a placebo comparator. Randomization in the GOBEFORE study was stratified according to the CRP level at
screening (⬍1.5 mg/dl or ⱖ1.5 mg/dl); randomization was not
stratified by the CRP level in the GO-FORWARD study. Both
studies were conducted according to the principles of the
Declaration of Helsinki, and all patients provided written
informed consent before participating in the study.
At week 28 in the GO-BEFORE study and at week 16
in the GO-FORWARD study, patients with ⬍20% improvement in both the tender joint count and the swollen joint count
entered a double-blind early escape phase, during which those
in group 1 received golimumab 50 mg plus MTX, those in
group 2 received golimumab 100 mg plus MTX, and those in
group 3 received golimumab 100 mg plus MTX (Figure 1).
Patients in group 4 who met the criteria for early escape did
not receive study medication adjustments. In the GOFORWARD study, patients in group 1 who did not enter the
early escape phase crossed over to golimumab 50 mg plus
MTX at week 24. Thus, the duration of the placebocomparator portion of the GO-FORWARD study was 24
weeks. The duration of the active-comparator portion of the
GO-BEFORE study was 52 weeks.
Radiographs of the hands and feet were taken at
baseline, week 28, and week 52 in the GO-BEFORE study and
at baseline, week 24 (week 16 for patients who entered early
escape), and week 52 in the GO-FORWARD study (Figure 1).
Baseline radiographs were taken within 4 weeks prior to the
first dose. Patients who discontinued injections had radiographs taken at the time of discontinuation unless radiographs
had been obtained within the previous 8 weeks. In the GOFORWARD study, patients in group 4 who met the criteria for
early escape did not receive medication adjustments, but
radiographs were taken at week 16 for consistency with
patients in the other groups, thus maintaining the blind.
Radiographs were scored by 2 independent readers
(different pairs of readers for the GO-BEFORE and the
GO-FORWARD studies) and an adjudicator, using the Sharp
score as modified by van der Heijde (4). Readers were blinded
to the patient’s identity, the treatment group assignment, and
the time point at which the radiograph was taken. Ten percent
of images were randomly selected and scored a second time in
a blinded manner so that intrareader variability could be
determined.
1202
EMERY ET AL
Figure 1. Study diagram for A, the Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis
of Early Onset (GO-BEFORE) study and B, the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy (GO-FORWARD)
study. Numbers in parentheses are the number of patients with evaluable radiographs at each time point. Radiographs were obtained at baseline,
week 24 or 28, and week 52. In the GO-FORWARD study, patients who entered the double-blind early-escape phase underwent radiography at week
16. In both studies, for patients who met the criteria for early escape, the radiographic scores for subsequent time points were linearly extrapolated.
Intention-to-treat principles were used in the data
analyses. Images that were taken more than 8 weeks before or
after a scheduled visit date or were not taken at all were
considered to be missing. For patients who had missing
modified Sharp scores at the study end point but had scores at
ⱖ2 points before that end point, linear extrapolation was used
to impute the end point score. For patients who met the
criteria for early escape in the GO-BEFORE study, the week
52 radiographic scores were imputed using linear extrapolation
from the baseline and week 28 scores. For patients who met
the criteria for early escape in the GO-FORWARD study, the
week 24 and week 52 scores were imputed using linear
extrapolation from the baseline and week 16 scores. For
patients in group 1 of the GO-FORWARD study who crossed
over from placebo plus MTX to golimumab 50 mg plus MTX
at week 24, the week 52 scores were imputed using linear
extrapolation from the baseline and week 24 scores.
In the GO-BEFORE study, the change in the modified
Sharp score from baseline to week 52 was a co-primary end
point. Results for the study’s other co-primary end point, the
percentage of patients achieving at least 50% improvement
according to the American College of Rheumatology criteria
(ACR50) (5) at week 24, have been reported previously (1). In
the GO-FORWARD study, radiographic outcomes were sec-
ondary end points. Analysis of variance on the van der
Waerden normal scores (a test for data that are not normally
distributed) (6) was used to evaluate differences between
golimumab and control groups for continuous variables, while
Cochran-Mantel-Haenszel methodology was used for categorical variables. We also evaluated the proportion of patients
with a change in the modified Sharp score of ⱕ0 and with a
change in the modified Sharp score that was greater than the
smallest detectable change (SDC) (7).
In both studies, Type I error at the 0.05 level of
significance was preserved with a hierarchical approach to
control for multiplicity when testing each of the efficacy end
points, wherein the comparison between combined groups 3
and 4 versus group 1 was made first. If there was a significant
difference between combined groups 3 and 4 versus group 1,
pairwise comparisons between group 3 and group 1 and
between group 4 and group 1 were performed. Then, if a
statistically significant difference was found for at least 1 of
these pairwise comparisons, group 2 and group 1 were compared. The co-primary end points for the GO-BEFORE study
were considered to have been met if the differences between
combined groups 3 and 4, as well as the differences between at
least one of group 3 or group 4 versus group 1, were statistically
significant. This same approach was applied to the GO-
EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA
1203
Table 1. Baseline clinical characteristics of rheumatoid arthritis patients in the GO-BEFORE and GO-FORWARD studies*
Characteristic
GO-BEFORE study
No. of patients randomized to treatment
No. (%) female
Age, years
Disease duration, years
No. of swollen joints (66 assessed)
No. of tender joints (68 assessed)
HAQ DI score (range 0–3)
CRP, mg/dl
ESR, mm/hour
DAS28-ESR score
No. (%) RF positive
No. (%) anti-CCP antibody positive
No. (%) taking corticosteroids
Prednisone equivalent dosage, mg/day
No. (%) with modified Sharp score ⬎0
GO-FORWARD study
No. of patients randomized to treatment
No. (%) female
Age, years
Disease duration, years
No. of swollen joints (66 assessed)
No. of tender joints (68 assessed)
HAQ DI score (range 0–3)
CRP, mg/dl
ESR, mm/hour
DAS28-ESR score
No. (%) RF positive
No. (%) anti-CCP antibody positive
No. (%) taking corticosteroids
Prednisone equivalent dosage, mg/day
No. (%) with modified Sharp score ⬎0
Golimumab plus MTX
Group 1,
placebo
plus MTX
Group 2,
golimumab 100 mg
plus placebo
Group 3,
golimumab 50 mg
Group 4,
golimumab 100 mg
160
134 (83.8)
50 (40, 57)
1.2 (0.5, 3.2)
11 (7, 19)
26 (14, 38)
1.5 (1.1, 1.9)
1.4 (0.6, 3.3)
37.5 (26.0, 65.0)
6.1 (5.3, 7.1)
130 (81.8)†
121 (75.6)
83 (51.9)
5.0 (5.0, 7.5)
153 (95.6)
159
134 (84.3)
49 (39, 56)
1.8 (0.6, 4.7)
12 (7, 19)
25 (15, 37)
1.8 (1.0, 2.1)
1.3 (0.5, 3.5)
40.0 (26.0, 60.0)
6.4 (5.6, 7.3)
129 (81.1)
125 (78.6)
86 (54.8)‡
5.0 (5.0, 10.0)
153 (96.2)
159
135 (84.9)
51 (45, 58)
1.0 (0.5, 3.3)
13 (9, 21)
26 (15, 40)
1.5 (1.1, 2.0)
1.3 (0.5, 3.1)
40.0 (29.0, 60.0)
6.3 (5.7, 7.0)
121 (76.1)
106 (66.7)
82 (51.6)
5.0 (5.0, 10.0)
154 (96.9)
159
125 (78.6)
50 (41, 58)
1.3 (0.5, 4.3)
14 (8, 20)
26 (15, 35)
1.6 (1.0, 2.0)
1.3 (0.3, 3.4)
36.0 (25.0, 60.0)
6.3 (5.5, 7.1)
127 (79.9)
116 (73.0)
80 (50.3)
5.5 (5.0, 10.0)
152 (95.6)
133
109 (82.0)
52 (42, 58)
6.5 (3.1, 11.9)
12 (8, 19)
21 (14, 34)
1.3 (0.8, 1.8)
0.8 (0.3, 2.0)
34.0 (18.0, 48.0)
6.1 (5.3, 6.6)
108 (81.2)
107 (80.5)
87 (65.4)
7.3 (5.0, 10.0)
118 (88.7)
133
105 (78.9)
51 (42, 59)
5.9 (2.4, 12.2)
11 (8, 17)
22 (14, 32)
1.4 (0.9, 1.9)
0.9 (0.4, 2.5)
36.0 (22.0, 50.0)
6.0 (5.2, 6.8)
111 (83.5)
106 (79.7)
90 (67.7)
7.5 (5.0, 10.0)
122 (91.7)
89
72 (80.9)
52 (43, 57)
4.5 (2.1, 9.7)
13 (8, 22)
26 (16, 39)
1.4 (1.0, 1.9)
1.0 (0.4, 2.8)
37.0 (23.0, 55.0)
6.1 (5.4, 6.9)
77 (86.5)
72 (80.9)
67 (75.3)
7.5 (5.0, 10.0)
81 (91.0)
89
72 (80.9)
50 (45, 56)
6.7 (2.4, 14.3)
12 (8, 18)
23 (15, 33)
1.4 (0.9, 1.9)
0.9 (0.4, 2.4)
34.0 (22.0, 48.0)
5.9 (5.3, 6.8)
75 (84.3)
68 (76.4)
62 (69.7)
7.5 (5.0, 10.0)
77 (86.5)
* Except where indicated otherwise, values are the median (interquartile range). GO-BEFORE ⫽ Golimumab Before Employing Methotrexate as
the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset; GO-FORWARD ⫽ Golimumab in Active Rheumatoid Arthritis
Despite Methotrexate Therapy; MTX ⫽ methotrexate; HAQ ⫽ Health Assessment Questionnaire; DI ⫽ disability index; CRP ⫽ C-reactive protein;
ESR ⫽ erythrocyte sedimentation rate; DAS28-ESR ⫽ Disease Activity Score 28-joint assessment (3-variable) using the ESR; RF ⫽ rheumatoid
factor; anti-CCP ⫽ anti–cyclic citrullinated peptide.
† Of 159 patients tested.
‡ Of 157 patients tested.
FORWARD analyses; however, assessments of structural
damage were secondary end points for the GO-FORWARD
study. All analyses were prespecified in the statistical analysis
plan.
Power calculations for the ACR50 co-primary end
point in the GO-BEFORE study were reported previously (1).
For the modified Sharp score co-primary end point, based on
10,000 simulations, the sample size of 150 patients per treatment group was expected to provide ⬎90% power to detect a
difference in the change from baseline at week 52 in the
modified Sharp score between the combined groups 3 and 4
versus group 1, using a 2-sided t-test on the van der Waerden
normal scores at the level of ␣ ⫽ 0.05, assuming the mean
change from baseline in modified Sharp score was 3.5 for
group 1 and 0.5–1.5 for combined groups 3 and 4. Simulations
were performed using standard deviations ranging from 0.6 to
0.9. Power calculations for the signs and symptoms end points
in the GO-FORWARD study were reported previously (2).
Radiographic end points were not considered in the power
calculations in the GO-FORWARD study.
RESULTS
Baseline demographic and disease characteristics
were well balanced among the treatment groups in each
study (Table 1). As expected, patients in the GOBEFORE study had a shorter median disease duration
than those in the GO-FORWARD study, but had
slightly more active disease and greater physical disability, as indicated by the median CRP levels, the Disease
1204
EMERY ET AL
Table 2. Summary of modified Sharp scores at baseline and changes from baseline to week 24 or 28 and from baseline to week 52 in the
GO-BEFORE and GO-FORWARD studies*
Characteristic
GO-BEFORE study
No. of patients randomized
Baseline score
Mean ⫾ SD
Median (IQR)
Estimated yearly rate of progression†
Change from baseline to week 28
Mean ⫾ SD
Median (IQR)
P
Change from baseline to week 52‡
Mean ⫾ SD
Median (IQR)
P
CRP ⬍1.5 mg/dl at screening
No. of patients
Mean ⫾ SD
Median (IQR)
CRP ⱖ1.5 mg/dl at screening
No. of patients
Mean ⫾ SD
Median (IQR)
Change from baseline to week 52
ⱕ0, no./no. evaluated (%)
P
Change from baseline to week 52
⬎SDC, no./no. evaluated (%)
P
GO-FORWARD study
No. of patients randomized
Baseline score
Mean ⫾ SD
Median (IQR)
Estimated yearly rate of progression†
Change from baseline to week 24
Mean ⫾ SD
Median (IQR)
P
CRP ⬍1.5 mg/dl at screening
No. of patients
Mean ⫾ SD
Median (IQR)
CRP ⱖ1.5 mg/dl at screening
No. of patients
Mean ⫾ SD
Median (IQR)
Change from baseline to week 52
Mean ⫾ SD
Median (IQR)
P
Change from baseline to week 24
ⱕ0, no./no. evaluated
P
Change from baseline to week 24
⬎SDC, no./no. evaluated
P
Golimumab plus MTX
Group 1,
placebo
plus MTX
Group 2,
golimumab 100
mg plus placebo
Group 3,
golimumab 50 mg
Group 4,
golimumab 100 mg
Groups 3 and 4
combined
160
159
159
159
318
19.7 ⫾ 35.4
5.25 (2.00, 18.1)
12.7
20.4 ⫾ 30.9
6.00 (2.50, 26.5)
12.1
18.7 ⫾ 32.4
5.50 (2.00, 19.5)
13.7
18.2 ⫾ 35.5
6.00 (2.50, 18.0)
10.3
18.5 ⫾ 33.9
6.00 (2.00, 18.0)
12.0
1.11 ⫾ 3.88
0.00 (0.00, 1.00)
0.61 ⫾ 3.55
0.00 (0.00, 0.50)
0.054
0.71 ⫾ 3.77
0.00 (0.00, 0.50)
0.065
0.01 ⫾ 1.47
0.00 (0.00, 0.50)
0.003
0.36 ⫾ 2.89
0.00 (0.00, 0.50)
0.005
1.37 ⫾ 4.56
0.00 (0.00, 1.50)
1.25 ⫾ 6.16
0.00 (0.00, 1.00)
0.266
0.74 ⫾ 5.23
0.00 (⫺0.50, 0.50)
0.015
0.07 ⫾ 1.83
0.00 (0.00, 0.50)
0.025
0.41 ⫾ 3.93
0.00 (0.00, 0.50)
0.006
83
0.98 ⫾ 3.990
0.00 (0.00, 0.50)
80
0.02 ⫾ 2.04
0.00 (⫺0.50, 0.25)
82
0.07 ⫾ 1.34
0.00 (⫺0.50, 0.00)
82
0.10 ⫾ 1.17
0.00 (0.00, 0.50)
164
0.08 ⫾ 1.25
0.00 (⫺0.25, 0.25)
77
1.80 ⫾ 5.16
0.50 (0.00, 2.00)
76/141 (53.9)
79
2.50 ⫾ 8.33
0.00 (0.00, 1.81)
82/137 (59.9)
77
1.47 ⫾ 7.35
0.00 (0.00, 0.91)
100/140 (71.4)
77
0.04 ⫾ 2.35
0.00 (0.00, 0.50)
85/139 (61.2)
154
0.75 ⫾ 5.49
0.00 (0.00, 0.70)
185/279 (66.3)
17/141 (12.1)
0.456
12/137 (8.8)
0.003
9/140 (6.4)
0.236
3/139 (2.2)
0.015
12/279 (4.3)
0.475
0.120
0.001
0.004
133
133
89
89
178
36.7 ⫾ 52.1
17.5 (1.5, 49.5)
5.0
37.4 ⫾ 52.5
15.3 (2.5, 49.0)
5.2
29.7 ⫾ 39.3
9.5 (2.0, 49.6)
5.3
39.6 ⫾ 56.1
17.0 (3.0, 47.0)
6.0
34.6 ⫾ 48.5
14.0 (2.5, 49.3)
5.6
0.55 ⫾ 2.35
0.00 (0.00, 0.50)
0.27 ⫾ 1.60
0.00 (0.00, 0.50)
0.361
0.60 ⫾ 2.74
0.00 (0.00, 0.50)
0.953
0.23 ⫾ 1.34
0.00 (0.00, 0.50)
0.293
0.41 ⫾ 2.16
0.00 (0.00, 0.50)
0.551
88
0.39 ⫾ 2.36
0.00 (0.00, 0.50)
82
0.29 ⫾ 1.74
0.00 (0.00, 0.50)
56
0.11 ⫾ 1.12
0.00 (0.00, 0.50)
52
0.35 ⫾ 1.51
0.00 (0.00, 0.50)
108
0.23 ⫾ 1.32
0.00 (0.00, 0.50)
45
0.85 ⫾ 2.34
0.00 (0.00, 1.00)
51
0.24 ⫾ 1.37
0.00 (0.00, 1.00)
33
1.44 ⫾ 4.17
0.00 (0.00, 1.50)
37
0.05 ⫾ 1.07
0.00 (⫺0.50, 0.43)
70
0.70 ⫾ 3.02
0.00 (0.00, 0.90)
1.10 ⫾ 4.68
0.00 (0.00, 1.10)
81/122 (66.4)
0.89 ⫾ 3.37
0.00 (0.00, 1.00)
0.967
85/124 (68.5)
0.93 ⫾ 4.86
0.00 (0.00, 0.50)
0.855
57/86 (66.3)
0.15 ⫾ 1.64
0.00 (0.00, 0.85)
0.221
58/84 (69.0)
0.54 ⫾ 3.64
0.00 (0.00, 0.50)
0.390
115/170 (67.6)
5/122 (4.1)
0.718
5/124 (4.0)
0.986
5/86 (5.8)
0.689
3/84 (3.6)
0.822
8/170 (4.7)
0.979
0.569
0.847
0.804
* In the GO-BEFORE study, patients in group 1 who did not enter the double-blind early escape phase continued to receive placebo plus MTX
through week 52. In the GO-FORWARD study, all patients in group 1 who did not enter the early escape phase crossed over to golimumab 50 mg
plus MTX at week 24. Therefore, there is no placebo comparator after week 24 in the GO-FORWARD study. All P values are versus group 1. IQR ⫽
interquartile range; SDC ⫽ smallest detectable change. See Table 1 for other definitions.
† Mean of the modified Sharp score at baseline divided by the disease duration per patient.
‡ Change in the modified Sharp score from baseline to week 52 was a co-primary end point of the GO-BEFORE study, along with the proportion
of patients who met the American College of Rheumatology 50% improvement criteria at week 24, the results of which were previously reported
(1). All other radiographic outcomes were secondary end points in each study.
EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA
1205
Table 3. Erosion and joint space narrowing scores at baseline and changes from baseline to week 24 or 28 and from baseline to week 52 in the
GO-BEFORE and GO-FORWARD studies*
Characteristic
GO-BEFORE study
Erosion score
Baseline
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
Joint space narrowing score
Baseline
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
GO-FORWARD study
Erosion score
Baseline
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
Joint space narrowing score
Baseline
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
Change from baseline to week
Mean ⫾ SD
Median (IQR)
28
52
28
52
24
52
24
52
Golimumab plus MTX
Group 1,
placebo
plus MTX
Group 2,
golimumab 100 mg
plus placebo
Group 3,
golimumab 50 mg
Group 4,
golimumab 100 mg
Groups 3 and 4
combined
11.3 ⫾ 18.6
4.00 (1.50, 12.1)
11.7 ⫾ 16.3
4.50 (2.00, 16.5)
10.8 ⫾ 17.4
4.50 (1.50, 11.5)
10.5 ⫾ 19.4
4.50 (1.50, 12.0)
10.6 ⫾ 18.4
4.50 (1.50, 11.5)
0.77 ⫾ 2.56
0.00 (0.00, 1.00)
0.55 ⫾ 3.08
0.00 (0.00, 0.50)
0.46 ⫾ 2.12
0.00 (0.00, 0.50)
⫺0.02 ⫾ 1.20
0.00 (⫺0.50, 0.50)
0.22 ⫾ 1.73
0.00 (0.00, 0.50)
0.74 ⫾ 2.82
0.00 (0.00, 0.50)
0.76 ⫾ 3.88
0.00 (⫺0.02, 0.50)
0.48 ⫾ 2.08
0.00 (0.00, 0.50)
0.09 ⫾ 1.39
0.00 (⫺0.50, 0.50)
0.28 ⫾ 1.78
0.00 (0.00, 0.50)
8.37 ⫾ 17.8
1.00 (0.00, 6.75)
8.70 ⫾ 15.7
1.00 (0.00, 10.50)
7.89 ⫾ 16.1
1.50 (0.00, 6.50)
7.75 ⫾ 17.2
1.00 (0.00, 6.50)
7.82 ⫾ 16.7
1.00 (0.00, 6.50)
0.43 ⫾ 2.17
0.00 (0.00, 0.00)
0.13 ⫾ 1.34
0.00 (0.00, 0.00)
0.27 ⫾ 2.10
0.00 (0.00, 0.00)
0.03 ⫾ 0.68
0.00 (0.00, 0.00)
0.15 ⫾ 1.56
0.00 (0.00, 0.00)
0.58 ⫾ 2.26
0.00 (0.00, 0.00)
0.35 ⫾ 1.65
0.00 (0.00, 0.50)
0.23 ⫾ 1.99
0.0 (0.00, 0.00)
0.04 ⫾ 0.88
0.00 (0.00, 0.00)
0.13 ⫾ 1.54
0.00 (0.00, 0.00)
18.7 ⫾ 27.1
5.50 (1.00, 25.0)
19.1 ⫾ 27.2
8.00 (1.50, 25.0)
16.2 ⫾ 22.2
5.75 (1.50, 22.3)
19.7 ⫾ 29.7
7.00 (2.23, 23.5)
17.9 ⫾ 26.2
6.00 (2.00, 22.5)
0.19 ⫾ 0.75
0.00 (0.00, 0.50)
0.01 ⫾ 0.86
0.00 (0.00, 0.23)
0.26 ⫾ 1.63
0.00 (0.00, 0.50)
0.09 ⫾ 0.96
0.00 (0.00, 0.00)
0.18 ⫾ 1.34
0.00 (0.00, 0.00)
0.17 ⫾ 0.77
0.00 (0.00, 0.50)
0.23 ⫾ 1.41
0.00 (⫺0.23, 0.50)
0.29 ⫾ 1.62
0.00 (0.00, 0.50)
0.14 ⫾ 1.41
0.00 (0.00, 0.50)
⫺0.04 ⫾ 1.09
0.00 (0.00, 0.00)
18.0 ⫾ 25.9
4.50 (0.00, 26.0)
18.4 ⫾ 27.1
6.50 (0.00, 25.0)
13.5 ⫾ 18.5
4.00 (0.00, 23.8)
19.9 ⫾ 27.8
9.00 (0.00, 26.0)
16.7 ⫾ 23.7
5.00 (0.00, 25.5)
0.32 ⫾ 1.75
0.00 (0.00, 0.00)
0.23 ⫾ 1.20
0.00 (0.00, 0.00)
0.23 ⫾ 0.85
0.00 (0.00, 0.00)
0.15 ⫾ 0.90
0.00 (0.00, 0.00)
0.19 ⫾ 0.87
0.00 (0.00, 0.00)
0.36 ⫾ 2.34
0.00 (0.00, 0.00)
0.64 ⫾ 2.50
0.00 (0.00, 0.50)
0.22 ⫾ 0.92
0.00 (0.00, 0.23)
0.23 ⫾ 0.94
0.00 (0.00, 0.00)
0.24 ⫾ 0.97
0.00 (0.00, 0.00)
* IQR ⫽ interquartile range. See Table 1 for other definitions.
Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) (8), and the median
scores on the disability index (DI) of the Health Assessment Questionnaire (HAQ) (9). Also, at baseline, ⬃96–
97% of patients in the GO-BEFORE study and ⬃87–
92% of those in the GO-FORWARD study had a
modified Sharp score ⬎0.
In the GO-BEFORE study, intraclass correlation
estimates between the readers were 0.90 for baseline
values and 0.90 for week 52 values. In the GOFORWARD study, the intraclass correlation estimates
were 0.95 for both baseline and week 24. The SDC in the
total modified Sharp score was 2.7 in the GO-BEFORE
study and 1.8 in the GO-FORWARD study.
Radiographic scores at baseline and changes
from baseline to week 24/28 and to week 52 are summarized in Table 2. Baseline radiographic scores were
similar among the treatment groups in the GOBEFORE study. However, in the GO-FORWARD
study, patients in group 3 had lower modified Sharp
scores than those in the other groups. At baseline, the
median modified Sharp scores were greater in the
GO-FORWARD study than in the GO-BEFORE study,
which was expected for a patient population with a
1206
EMERY ET AL
Figure 2. Changes in the modified Sharp scores from baseline to week 24 or 28 and to week 52 in A, the GO-BEFORE study and B, the
GO-FORWARD study. Shown are the mean (solid horizontal line), median (dotted horizontal line), and interquartile range (IQR) (shaded bars)
of the changes in radiographic scores from baseline in each treatment group. GLM ⫽ golimumab. See Figure 1 for other definitions.
longer disease duration. Baseline erosion and joint space
narrowing scores are summarized in Table 3.
The co-primary end point in the GO-BEFORE
study was met. Patients in groups 3 and 4 had significantly less radiographic progression than patients in
group 1 over the 52 weeks, during which there was a
comparator group (Figure 2A and Table 2). No differences in the scores for patients in groups 1 and 2 were
observed. Statistically significant differences between
the combined groups 3 and 4 and group 1 and between
group 4 and group 1 were also observed at week 28
(Table 2). There was a trend toward statistical significance for the difference between group 3 and group 1 at
week 28 (P ⫽ 0.065). The individual radiographic scores
for each patient are given in the probability plot shown
in Figure 3A.
A significantly greater percentage of patients in
combined groups 3 and 4 and in group 3 alone did not
have an increase in the modified Sharp score (i.e.,
change from baseline to week 52 was ⱕ0) as compared
with the patients in group 1; the difference between
these percentages in groups 1 and 4 was not statistically
significant (Table 2). In contrast, the percentage of
patients with a change in the modified Sharp score
greater than the SDC from baseline to week 52 was
significantly higher in combined groups 3 and 4 and in
group 4 alone as compared with group 1; the difference
between group 3 and group 1 was not statistically
significant.
Results of subgroup analyses in the GOBEFORE patients were consistent with the primary end
point results, including the group of patients with a
disease duration ⬎3 years (data not shown). A total of
193 patients (44 in group 1, 58 in group 2, 43 in group 3,
and 48 in group 4) had established RA, with a disease
duration ⬎3 years. Among these patients, those in the
combined groups 3 and 4 had significantly less change in
the modified Sharp score from baseline to week 52
(mean 0.62, median 0.0 [interquartile range (IQR)
–0.12, 0.50]) as compared with those in group 1 (mean
1.41, median 0.0 [IQR 0.00, 1.50]) (P ⫽ 0.029). The
baseline CRP level (mean 2.2 mg/dl, median 1.20 mg/dl
[IQR 0.4, 2.9]), swollen joint count (mean 14.7, median
12.0 [IQR 8.0, 18.0]), and tender joint count (mean 28.8,
median 26.0 [IQR 14.0, 39.0]) for this subgroup were
similar to those in the GO-BEFORE patient population
as a whole. As may be expected given the longer disease
duration, the modified Sharp score at baseline in this
subgroup of GO-BEFORE patients with a disease duration ⬎3 years (mean 39.2, median 22.0 [IQR 6.0, 55.5])
was higher than that in the GO-BEFORE population as
a whole. In another subgroup analysis, mean changes in
the modified Sharp score from baseline to week 52 were
larger, indicating more radiographic progression, in patients with a CRP of ⱖ1.5 mg/dl at screening (1.80 in
group 1 and 0.75 in combined groups 3 and 4) than
in patients with a CRP of ⬍1.5 mg/dl at screening
(0.98 in group 1 and 0.08 in combined groups 3 and 4).
In the GO-FORWARD study, the comparator
phase continued through week 24, and in patients who
entered early escape, their modified Sharp score at week
24 was extrapolated linearly from the baseline and week
16 values. Overall, minimal progression was observed in
all treatment groups during this phase, and the differ-
EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA
1207
Figure 3. Probability plots of changes in the total modified Sharp score from baseline in each patient during the portion of the study that included
a comparator group. A, Changes in radiographic scores from baseline to week 52 in the GO-BEFORE study patients. B, Changes in radiographic
scores from baseline to week 24 in the GO-FORWARD study patients. Upper broken line represents the smallest detectable change for the study
(2.7 in the GO-BEFORE study and 1.8 in the GO-FORWARD study); lower broken line represents 0. Insets show the data at both ends of each
graph in more detail (i.e., only 0–10% and 90–100%). See Figure 1 for definitions.
ences in the changes in modified Sharp scores from
baseline between the golimumab groups and placebo
were not statistically significant (Figure 2B and Table 2).
The individual radiographic scores for each patient are
given in the probability plot shown in Figure 3B. Patients
in groups 1 and 3 with screening CRP levels that were
ⱖ1.5 mg/dl showed slightly more radiographic progression at week 24 than did those with screening CRP levels
that were ⬍1.5 mg/dl. However, patients in group 4 with
a screening CRP level ⱖ1.5 mg/dl had a mean change in
the modified Sharp score of 0.05, as compared with a
mean change of 0.85 in patients in group 1.
Changes in erosion and joint space narrowing
scores compared with baseline are summarized in Table 3.
DISCUSSION
We evaluated radiographic progression in two
studies of patients with RA who received golimumab:
the GO-BEFORE study (in patients who were MTX
naive) and the GO-FORWARD study (in patients who
had active RA despite MTX therapy). The GO-
BEFORE study, which was designed and powered to
evaluate radiographic progression as a co-primary end
point, demonstrated that golimumab therapy in combination with MTX inhibited radiographic progression
significantly better than MTX therapy alone. The difference in radiographic progression between the golimumab monotherapy group and MTX monotherapy
group, however, was not statistically significant. Overall,
the benefits of the combination of golimumab plus MTX
were comparable for the 50-mg and 100-mg dosage
groups.
In the GO-FORWARD study, minimal radiographic progression was observed in all treatment
groups, and no statistically significant differences between the placebo plus MTX group and the golimumab
groups with or without MTX were observed. This may
have been attributable to the following limitations of the
study design and the inclusion/exclusion criteria: first,
because radiographic outcomes were only secondary end
points in this study, they were not considered in the
power calculation assumptions.
Second, an elevated CRP level was not required
1208
for study entry, and only one-third of patients in this
study had CRP levels that were ⱖ1.5 mg/dl. Patients
with low CRP levels are known to have less radiographic
progression over time than those with high CRP levels
(10).
Third, the placebo-comparator portion of this
study continued for only 24 weeks, and the radiographs
for patients who entered early escape (nonresponders)
were taken at week 16. Since the population consisted
mostly of patients whose RA was progressing slowly, the
few patients whose RA was most likely to progress were
those who entered early escape. However, some of these
patients may not have had sufficient progression by week
16 for the readers to detect that progression. Given the
low overall progression rate and the short 16-week time
period, linear extrapolation from week 16 to week 24
may have underestimated the true progression that these
patients would have shown without adjustment in the
medication regimen.
Fourth, patients who were enrolled in this study
generally had less disease activity and radiographic
damage at baseline than those in the earlier studies of
TNF␣ inhibitors in patients with an inadequate response
to MTX (2,11,12). The mean modified Sharp score at
baseline in the GO-FORWARD population was ⬃35, as
compared with ⬃75 in the Anti–Tumor Necrosis Factor
Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study of infliximab (11) and with ⬃68
in the study of adalimumab by Keystone and colleagues
(12). In a more recent study of certolizumab pegol (13),
the mean modified Sharp score at baseline (⬃39) was
similar to that in the current study, suggesting that the
severity of joint damage in the population of patients
with RA from which these studies recruited may be
decreasing over time (14).
Thus, the lack of significant differences between
the GO-FORWARD treatment groups may be explained by the above study limitations, as well as by the
very limited amount of radiographic progression actually
observed in the study population as a whole. We did,
however, observe numerically less radiographic progression in the golimumab 100 mg plus MTX group from
baseline to week 24, although the possibility that this
difference was due to chance cannot be ruled out.
The radiographic score and CRP level at baseline
have been shown to be predictive of radiographic progression over time (10,15,16). It is likely that the baseline
CRP, as a marker of active inflammation in RA, is a
more important predictor of radiographic progression
than the baseline radiographic score, since radiographic
damage is less likely to progress if there is no active
EMERY ET AL
inflammation, regardless of the level of damage at
baseline. As an example of this phenomenon, patients
with RA who had an inadequate response to MTX in the
Rheumatoid Arthritis Prevention of Structural Damage
1 (RAPID 1) study of certolizumab (13) had median
baseline CRP levels of ⬃1.6 mg/dl, as compared with
⬃0.9 mg/dl in the GO-FORWARD study. Despite having similar levels of radiographic damage at baseline
(modified Sharp scores of ⬃35 in the GO-FORWARD
study and 39 in the RAPID 1 study [13]), progression
observed in the control group of the RAPID 1 study was
greater than that seen in group 1 of the GOFORWARD study (mean changes in the modified Sharp
score from baseline to week 24 1.3 versus 0.6). Similarly,
patients in the GO-FORWARD study had more radiographic damage at baseline than those in the GOBEFORE study. However, patients in the GOBEFORE study had higher baseline CRP levels and
greater radiographic progression during the study than
those in the GO-FORWARD study, despite having
lower baseline radiographic damage.
The relationship between higher CRP level and
radiographic progression is further illustrated by the
results of the CRP subgroup analyses performed in the
GO-BEFORE and GO-FORWARD studies, which
generally indicated that more radiographic progression
was observed among patients with screening CRP levels
that were ⱖ1.5 mg/dl versus those with levels that were
⬍1.5 mg/dl. However, while the data discussed herein
are consistent with the hypothesis that CRP is a more
important predictor of radiographic progression than is
the baseline radiographic score, future studies specifically aimed at evaluating this concept are needed.
Unlike previous studies of TNF␣ inhibitors in
MTX-naive patients with RA (17–19), the GOBEFORE study permitted the inclusion of patients
regardless of disease duration. As a result, approximately one-fourth of the patients in the GO-BEFORE
study had disease duration longer than 3 years. This was
similar to the disease duration in patients in the GOFORWARD study and other studies of patients with
more established RA (11,20,21), and the patients also
had a mean modified Sharp score of ⬃39 at baseline that
was similar to the mean baseline score of 35 in the
GO-FORWARD population. However, patients in the
GO-FORWARD study had evidence of minimal inflammation at baseline, as judged by their lower CRP level,
which may have led to minimal radiographic progression
in all treatment groups, including the control group.
The subgroup of GO-BEFORE patients with
disease duration ⬎3 years (more established disease)
EFFECTS OF GOLIMUMAB ON RADIOGRAPHIC PROGRESSION IN RA
had higher CRP concentrations (median 1.2 mg/dl) and
more radiographic progression (mean change in the
modified Sharp score from baseline 1.4) was observed in
the control group relative to the control group of the
GO-FORWARD study (mean change in the modified
Sharp score from baseline 0.6). The higher degree of
radiographic progression in this subgroup of patients in
the GO-BEFORE study allowed the assessment of the
effects of golimumab on radiographic progression in
patients with more established disease. Patients in this
established-disease subgroup of the GO-BEFORE study
who received golimumab plus MTX had statistically less
radiographic progression than did those who received
placebo plus MTX. While both the established-disease
subgroup from the GO-BEFORE study and patients
from the GO-FORWARD study had established disease
and similar radiographic damage at baseline, the baseline level of disease activity (as indicated by CRP level)
was higher in the established-disease subgroup from the
GO-BEFORE study with ⬎3 years of disease duration.
Thus, golimumab effectively inhibited radiographic progression in patients with more established
RA when they had higher disease activity and more
radiographic progression (in the control group). This
again indicates that the minimal progression in the
control group of the GO-FORWARD study may have
precluded the adequate assessment of the effects of
golimumab on radiographic progression. Golimumab
has also been shown to inhibit radiographic progression
in patients with established psoriatic arthritis, another
inflammatory arthritis with similar mechanisms of joint
erosion (22), who had an inadequate response to conventional therapies, including MTX (23).
In conclusion, minimal radiographic progression
was observed in all treatment arms of the GOFORWARD study, which precluded adequate assessment of the effects of golimumab on radiographic
progression in patients with established disease. Results
of the GO-BEFORE study showed that golimumab plus
MTX inhibited radiographic progression not only in
patients with early RA, but also in a subset of patients
with more established disease (⬎3 years).
ACKNOWLEDGMENTS
We thank the patients, investigators, and study personnel who made these trials possible. We also thank Scott
Newcomer (formerly of Centocor Ortho Biotech Inc.) and
Michelle Perate (Centocor Ortho Biotech Inc.) who helped
prepare the manuscript.
1209
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, Fleischmann, van der Heijde,
Keystone, Genovese, Conaghan, Hsia, Xu, Baratelle, Rahman.
Acquisition of data. Emery, Fleischmann, Genovese, Hsia, Xu, Baratelle, Beutler, Rahman.
Analysis and interpretation of data. Emery, Fleischmann, van der
Heijde, Keystone, Genovese, Conaghan, Hsia, Xu, Beutler, Rahman.
ROLE OF THE STUDY SPONSOR
Centocor Research and Development, Inc. (a subsidiary of
Johnson & Johnson) and Schering-Plough/Merck Research Institute,
Inc. sponsored this study. The following steering committee members
who were also authors of this article assisted Centocor scientists with
the study design and conduct: Paul Emery, MA, MD, FRCP, Roy M.
Fleischmann, MD, Edward C. Keystone, MD, FRCP, and Mark C.
Genovese, MD. Data were collected by the investigators and entered
into a Centocor database. Centocor statisticians and programmers
conducted the analyses, and members of the steering committee, with
the assistance of medical writers Scott Newcomer (formerly of Centocor Ortho Biotech Inc.) and Michelle Perate (Centocor Ortho Biotech
Inc., a wholly owned subsidiary of Johnson & Johnson, Inc.), prepared
the manuscript. All authors reviewed and approved the manuscript
content before submission and jointly agreed to submit the final
version of the manuscript. Publication of this study was not contingent
upon approval from Centocor or Schering-Plough/Merck.
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