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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Objective

To assess 2-year golimumab efficacy/safety in patients with active rheumatoid arthritis (RA) who had never taken methotrexate (MTX).

Methods

RA patients who had never taken MTX (n = 637) were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4) every 4 weeks. Nonresponders based on week 28 swollen/tender joint counts changed treatment as follows: group 1 added golimumab 50 mg, group 2 added MTX, group 3 increased golimumab to 100 mg, and group 4 had no change. Most group 1 patients (85%) initiated golimumab 50 mg + MTX at week 28 or subsequently at week 52. After the last patient completed week 52 and blinding was broken, the investigator could escalate golimumab to 100 mg and/or adjust MTX. The co–primary end points (week 24 American College of Rheumatology criteria for 50% improvement [ACR50] response and week 52 change in Sharp/van der Heijde score [SHS]) have been published previously. We now detail week 52 major secondary end points (Health Assessment Questionnaire [HAQ] disability index [DI] scores and SHS among patients with a baseline C-reactive protein [CRP] level >1.0 mg/dl) and week 104 findings.

Results

At week 52 for combined groups 3 and 4 versus group 1, the respective proportions of patients achieving ACR20 and ACR50 responses were 63.2% versus 51.9% (P = 0.017) and 45.3% versus 35.6% (P = 0.044). Respective week 52 mean HAQ DI improvements were 0.70 versus 0.58 (P = 0.053); mean SHS changes were 0.41 versus 1.37 (P = 0.006) among all patients and 0.74 versus 2.16 (P = 0.003) in patients with a CRP level >1.0 mg/dl. Improvements were maintained through week 104. Golimumab + MTX for 2 years yielded statistically less radiographic progression than initial MTX or golimumab 100 mg monotherapy. Golimumab safety profiles through weeks 24, 52, and 104 were generally consistent with those observed in other golimumab studies.

Conclusion

In RA patients who had never taken MTX, up to 2 years of golimumab + MTX yielded sustained improvements in clinical signs/symptoms, physical function, and radiographic progression.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Because of the role of proinflammatory cytokine overproduction in rheumatoid arthritis (RA) ([1]), inhibition of tumor necrosis factor α (TNFα) is an effective therapy for this chronic and debilitating autoimmune disorder ([2-12]). Golimumab is a human anti-TNF monoclonal antibody that reduced RA signs/symptoms, with a safety profile consistent with other TNF inhibitors, in the phase III GO-BEFORE study ([13]).

GO-BEFORE is an ongoing 5-year, phase III, multicenter, randomized, controlled study of subcutaneous golimumab in RA patients who had never taken methotrexate (MTX). The co–primary end points at 1 year were change in the Sharp/van der Heijde score (SHS) from baseline to week 52 (controlled study period) and the proportion of patients achieving ≥50% improvement in the American College of Rheumatology criteria (ACR50) at week 24. As reported, golimumab + MTX inhibited radiographic progression (mean SHS change of 0.41) significantly better than MTX alone (mean SHS change of 1.37; P = 0.006) ([14]), but the other co–primary end point in the study, i.e., ACR50 response at week 24, was not met ([13]). Other prespecified secondary efficacy measures demonstrated that golimumab + MTX was significantly better than, and golimumab alone was similar to, MTX alone in reducing RA signs/symptoms in patients who had never taken MTX ([13]). Additional 1-year and 2-year findings of GO-BEFORE are reported herein.

Box 1. Significance & Innovations

  • Golimumab + methotrexate (MTX) through 1 year yielded significant improvement in the signs and symptoms of active rheumatoid arthritis, as well as significant reductions in radiographic progression, relative to MTX-only therapy; these improvements were sustained with up to 2 years of golimumab + MTX therapy.
  • The golimumab + MTX safety profiles through 1 year and 2 years of therapy were generally consistent with those observed during the controlled study period, as well as with those observed in other golimumab studies in rheumatic indications.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Patients

Patient inclusion/exclusion criteria have been described previously ([13]). Eligible patients had active RA ([15]) for ≥3 months before initial study agent administration and had not received biologic agents or >3 weekly doses of oral MTX for RA. Concurrent use of stable doses of nonsteroidal antiinflammatory drugs, other analgesics for RA, and oral corticosteroids (≤10 mg of prednisone or equivalent per day) was allowed. Patients with evidence of active tuberculosis (TB) were excluded. Patients with a history of latent TB at screening, i.e., positive tuberculin skin and/or whole blood interferon-γ–based QuantiFERON-TB testing, could participate if treatment for latent TB was started before or simultaneously with the first study agent injection.

Study design

This phase III multicenter study in patients with active RA who had never taken MTX comprised a 52-week, randomized, double-blind, placebo-controlled phase followed by a 4-year extension period. The study was conducted according to the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice. The protocol was reviewed and approved by each site's institutional review board or ethics committee. All patients provided written informed consent before undergoing any study-related procedures.

As described previously ([13]), eligible patients were randomly (1:1:1:1) assigned to receive placebo subcutaneous injection + MTX capsules (group 1), golimumab 100 mg subcutaneous injection + placebo capsules (group 2), golimumab 50 mg subcutaneous injection + MTX capsules (group 3), or golimumab 100 mg subcutaneous injection + MTX capsules (group 4). Golimumab and placebo were supplied as sterile liquid for subcutaneous injection and active/placebo MTX was supplied as double-blinded, identical opaque capsules by Janssen Biotech. Subcutaneous injections were administered at week 0 and then every 4 weeks. MTX was initiated at 10 mg/week and titrated to 20 mg/week by week 8.

Patients with <20% improvement from baseline in both swollen and tender joint counts entered early escape any time after week 24; patients in group 1 switched from placebo to golimumab 50 mg, group 2 switched from placebo to MTX capsules, and group 3 escalated the golimumab dose from 50 to 100 mg. Patients in group 4 continued to receive golimumab 100 mg + MTX through week 48. At week 52, patients in group 1 (placebo + MTX) with ≥1 tender or swollen joint began receiving golimumab 50 mg + MTX if they had not early escaped after week 24. Following the week 52 database lock and study unblinding, MTX and corticosteroids could be adjusted and the golimumab dose could be escalated at the investigator's sole discretion. Patients who continued to receive MTX monotherapy could receive golimumab 50 mg + MTX and those receiving golimumab 50 mg + MTX could receive golimumab 100 mg + MTX during the open-label study extension period.

Study end points

The 2 co–primary study end points were ACR50 response at week 24 and change from baseline to week 52 in SHS. Methodology and findings pertaining to these end points have been reported previously ([13, 14]).

Major secondary study end points included the change from baseline to week 52 in the disability index of the Health Assessment Questionnaire (HAQ) disability index (DI) ([16]), ACR20 response ([17]) at week 24 (previously reported) ([13]), the change from baseline in the SHS at week 52 in patients with an elevated baseline C-reactive protein (CRP) level, and the proportion of patients with an elevated baseline CRP level at baseline who achieved an ACR50 response at week 24 (previously reported) ([13]).

Radiographic images of the hands and feet were obtained at baseline, week 28, week 52, and week 104. Baseline, week 28, and week 52 images comprised reading session 1, the results of which have been published previously ([14]); baseline, week 52, and week 104 images comprised reading session 2, the results of which are reported herein. Centrally digitized images were scored using the SHS method ([18]) by 2 independent primary readers (plus an adjudicator for reading session 1 images) in random order and without knowledge of assessment time point, patient identity, or treatment assignment.

ACR responses, as well as the 28-joint Disease Activity Score employing the CRP level (DAS28-CRP), were also assessed; the DAS28-CRP was used to determine the proportions of patients achieving a European League Against Rheumatism (EULAR) response (good/moderate ratings) ([19]) and/or a DAS28-CRP score <2.6 ([20, 21]). Major clinical response was defined as achievement of an ACR70 response continuously for ≥6 months. The proportions of patients achieving clinical remission according to the Simplified Disease Activity Index (SDAI) ([22]), i.e., a score ≤3.3, and the Clinical Disease Activity Index (CDAI) ([23, 24]), i.e., a score ≤2.8, were calculated in post hoc analyses. The presence/absence of antibodies to golimumab was also determined ([25]), and safety was primarily assessed via documentation of adverse events (AEs).

Statistical analyses

Details of the planned sample size and statistical methods for the analyses of the co–primary end points have been published previously ([13, 14]). Treatment group differences at week 52 were assessed with a 2-sided Cochran-Mantel-Haenszel test for discrete variables and an analysis of variance on the van der Waerden normal scores test for continuous parameters stratified by screening CRP level (<1.5 or ≥1.5 mg/dl). Additional details of the statistical analyses are shown in Supplementary Appendix A (available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22072/abstract).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Patient disposition and baseline characteristics

Data were collected for this report between December 12, 2005 and May 21, 2009, at which time all patients completed the study through week 104. Of the 637 randomized patients, 634 received ≥1 dose of the study agent. By week 104, 140 patients had discontinued the subcutaneous study agent, including 38 (23.8%) in group 1, 33 (20.8%) in group 2, 30 (18.9%) in group 3, and 39 (24.5%) in group 4 (Figure 1). AEs were the most common reason for patient discontinuation.

image

Figure 1. Patient disposition through week 104 for the randomized patients. MTX = methotrexate; EE = early escape; CO = crossover; LTE = long-term extension; * = includes patients who crossed over at week 52 to week 104; DE = dose escalation; † = includes patients who may have early escaped after week 24 or crossed over at week 52 to receive golimumab 50 mg + MTX and then dose escalated to golimumab 100 mg + MTX during the LTE through week 104; Discon. SC = discontinuation of the subcutaneous study agent.

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Overall, 89 patients met the early escape criteria at week 28, including 28 (17.5%) in group 1, 22 (13.8%) in group 2, 20 (12.6%) in group 3, and 19 (11.9%) in group 4. Through week 104, 108 group 1 patients (67.5%) crossed over to golimumab 50 mg + MTX (Figure 1), and 33 group 1 patients (20.6%), 58 group 2 patients (36.5%), and 17 group 3 patients (10.7%) were determined by the investigator to be eligible for dose escalation to 100 mg (groups 1 and 3) or crossover from placebo to MTX capsules (group 2) (Figure 1). Baseline demographics and disease characteristics were generally well balanced across the randomized groups and indicated the majority of patients had relatively early disease of moderate to severe intensity, with median durations of RA ranging from 1.0–1.8 years across the treatment groups (Table 1).

Table 1. Baseline patient characteristics*
 Group 1, placebo + MTXGroup 2, golimumab 100 mg + placeboGroup 3, golimumab 50 mg + MTXGroup 4, golimumab 100 mg + MTXCombined groups 3 and 4, golimumab + MTX
  1. Values are the mean ± SD (median) unless indicated otherwise. MTX = methotrexate; RA = rheumatoid arthritis; RF = rheumatoid factor; HAQ = Health Assessment Questionnaire; DI = disability index; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; DAS28-CRP = 28-joint Disease Activity Score employing the CRP level; SF-36 = Short Form 36 health survey; PCS = physical component summary; MCS = mental component summary; SHS = Sharp/van der Heijde score.

  2. a

    N = 159.

Patients randomized, no.160159159159318
Women, no. (%)134 (83.8)134 (84.3)135 (84.9)125 (78.6)260 (81.8)
Age, years48.6 ± 12.9 (50.0)48.2 ± 12.9 (49.0)50.9 ± 11.3 (51.0)50.2 ± 11.9 (50.0)50.6 ± 11.6 (51.0)
Duration of RA, years2.9 ± 4.8 (1.2)4.1 ± 5.6 (1.8)3.5 ± 5.6 (1.0)3.6 ± 6.1 (1.3)3.6 ± 5.9 (1.1)
RF positive, no. (%)130 (81.8)a129 (81.1)121 (76.1)127 (79.9)248 (78.0)
Swollen joint count (range 0–66)14.9 ± 10.0 (11.0)15.2 ± 10.1 (12.0)16.0 ± 10.0 (13.0)15.8 ± 10.3 (14.0)15.9 ± 10.2 (13.0)
Tender joint count (range 0–68)27.3 ± 16.2 (25.5)27.3 ± 15.4 (24.5)29.2 ± 17.1 (26.0)27.4 ± 14.7 (26.0)28.3 ± 15.9 (26.0)
HAQ DI score (range 0–3)1.5 ± 0.6 (1.5)1.6 ± 0.7 (1.8)1.5 ± 0.7 (1.5)1.5 ± 0.6 (1.6)1.5 ± 0.6 (1.5)
CRP level, mg/dl2.6 ± 3.3 (1.4)2.6 ± 3.4 (1.3)2.4 ± 3.0 (1.3)2.4 ± 2.9 (1.3)2.4 ± 3.0 (1.3)
ESR, mm/hour45.2 ± 30.0 (37.5)46.1 ± 31.2 (40.0)45.8 ± 27.6 (40.0)43.7 ± 27.9 (36.0)44.8 ± 27.7 (38.0)
DAS28-CRP score (range 0–10)5.6 ± 1.1 (5.6)5.8 ± 1.1 (5.8)5.7 ± 1.1 (5.6)5.7 ± 1.1 (5.7)5.7 ± 1.1 (5.7)
SF-36     
PCS score (range 0–100)29.4 ± 7.4 (28.6)28.9 ± 8.1 (28.0)29.4 ± 8.1 (28.6)30.2 ± 7.5 (29.1)29.8 ± 7.8 (29.0)
MCS score (range 0–100)41.1 ± 11.7 (39.2)41.3 ± 11.3 (39.5)43.1 ± 10.7 (42.6)41.7 ± 12.4 (39.8)42.4 ± 11.6 (41.4)
Total SHS, reading session 2 (range 0–448)15.2 ± 25.3 (4.5)16.3 ± 25.4 (4.8)13.3 ± 24.4 (3.5)14.4 ± 32.7 (3.5)13.8 ± 28.7 (3.5)

Efficacy results

Results of the prespecified intent-to-treat analysis of ACR50 response at week 24 (co–primary end point) ([13]) and of the second of the 2 co–primary end points of the study, i.e., change from baseline to week 52 in total SHS, were previously reported ([14]). We now report the results of additional major secondary end points, which included the assessment of changes from baseline to week 52 in the total SHS (reading session 1) among the 354 patients with baseline CRP levels >1.0 mg/dl. Results of these analyses indicated that significantly less disease progression was observed among patients treated with golimumab + MTX (SHS mean change of 0.74; P = 0.003) than with placebo + MTX (SHS mean change of 2.16) (Table 2). Also at week 52, significantly higher proportions of patients had no radiographic progression (SHS ≤0) both in combined groups 3 and 4 (66.3%; P = 0.015) and in group 3 (71.4%; P = 0.003) versus group 1 (53.9%) (Table 2). Similar findings were observed for the proportions of patients with no new joints exhibiting erosion or joint space narrowing (data not shown). See Figure 2 for a cumulative probability plot of individual changes in total SHS from baseline to week 52.

Table 2. Summary of clinical and radiographic efficacy and patient-reported outcomes at week 52*
 Group 1, placebo + MTXaGroup 2, golimumab 100 mg + placebobGroup 3, golimumab 50 mg + MTXbGroup 4, golimumab 100 mg + MTXCombined groups 3 and 4, golimumab + MTX
  1. Values are the number (percentage) of randomized patients unless indicated otherwise. Data were analyzed using the intent-to-treat population, i.e., all randomized patients, according to assigned treatment group. For patients who met the early escape criteria, week 28 values were carried forward to week 52 (i.e., last observation carried forward), except for radiograph data, for which linear extrapolation was employed, and major clinical response, for which such patients were considered nonresponders. MTX = methotrexate; ACR20/50/70 = American College of Rheumatology 20%/50%/70% improvement criteria; EULAR = European League Against Rheumatism; DAS28-CRP = 28-joint Disease Activity Score employing the C-reactive protein (CRP) level; CDAI = Clinical Disease Activity Index; SDAI = Simplified Disease Activity Index; HAQ = Health Assessment Questionnaire; DI = disability index; SHS = Sharp/van der Heijde score; SDC = smallest detectable change.

  2. a

    Includes patients who early escaped at week 28 to receive golimumab 50 mg + MTX.

  3. b

    Includes patients who early escaped at week 28 to receive golimumab 100 mg + MTX.

  4. c

    Major secondary end point.

  5. d

    Linear extrapolation was employed for missing SHS data imputation and for patients who entered early escape.

  6. e

    Co–primary end point.

  7. f

    Major secondary end point. Based on reading session 1 data.

  8. g

    Based on reading session 1 data.

Patients randomized, no.160159159159318
ACR20 response83 (51.9)85 (53.5)95 (59.7)106 (66.7)201 (63.2)
P vs. group 1 0.780.160.0070.017
ACR50 response57 (35.6)61 (38.4)67 (42.1)77 (48.4)144 (45.3)
P vs. group 1 0.610.240.0210.044
ACR70 response35 (21.9)35 (22.0)45 (28.3)50 (31.4)95 (29.9)
P vs. group 1 0.970.190.0540.064
Major clinical response (ACR70 continuously for ≥6 months)11 (6.9)9 (5.7)24 (15.2)18 (11.4)42 (13.3)
P vs. group 1 0.680.0180.160.036
EULAR response (good/moderate)98 (61.3)103 (64.8)115 (72.3)122 (76.7)237 (74.5)
P vs. group 1 0.510.0350.0030.003
DAS28-CRP <2.656 (35.0)50 (31.4)70 (44.0)73 (45.9)143 (45.0)
P vs. group 1 0.510.1000.0470.037
CDAI ≤2.826 (16.3)21 (13.2)40 (25.2)35 (22.0)75 (23.6)
P vs. group 1 0.440.0500.190.06
SDAI ≤3.324 (15.0)22 (13.8)37 (23.3)37 (23.3)74 (23.3)
P vs. group 1 0.770.060.060.035
HAQ DI score, mean ± SD improvementc0.58 ± 0.690.62 ± 0.720.66 ± 0.680.75 ± 0.670.70 ± 0.67
P vs. group 1 0.690.290.0230.053
HAQ DI score improvement ≥0.25100 (62.5)92 (57.9)104 (65.4)112 (70.4)216 (67.9)
P vs. group 1 0.400.590.130.23
Total SHSd     
Reading session 1, mean ± SD changee1.37 ± 4.5551.25 ± 6.1550.74 ± 5.2330.07 ± 1.8330.41 ± 3.929
P vs. group 1 0.270.0150.0250.006
Total SHS among patients with baseline CRP level >1.0 mg/dl, no.f95908683169
Mean ± SD change2.16 ± 5.6422.19 ± 7.9671.29 ± 6.9910.16 ± 2.1950.74 ± 5.235
P vs. group 1 0.550.0100.0140.003
Total SHS, change ≤0, no./total (%)g76/141 (53.9)82/137 (59.9)100/140 (71.4)85/139 (61.2)185/279 (66.3)
P vs. group 1 0.460.0030.240.015
Total SHS, change greater than SDC (3.82), no./total (%)g17/141 (12.1)12/137 (8.8)9/140 (6.4)3/139 (2.2)12/279 (4.3)
P vs. group 1 0.480.120.0010.004
image

Figure 2. Probability plot for change in radiographic score at week 52. SHS = Sharp/van der Heijde; SDC = smallest detectable change; MTX = methotrexate.

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For the additional major secondary end point evaluated at week 52, i.e., improvement in HAQ DI score, patients in group 1 (mean improvement from baseline to week 52 of 0.58), group 2 (mean improvement of 0.62), and combined groups 3 and 4 (mean improvement of 0.70) experienced clinically meaningful improvement in the HAQ DI score. Substantial proportions of patients achieved a ≥0.25-unit improvement in the HAQ DI score, including 62.5% of group 1, 57.9% of group 2, and 67.9% of combined groups 3 and 4 patients (Table 2).

Regarding clinical response at week 52, significantly higher proportions of patients in combined groups 3 and 4 achieved an ACR20 response (63.2%; P = 0.017), an ACR50 response (45.3%; P = 0.044), a EULAR (good/moderate) response (74.5%; P = 0.003), and a DAS28-CRP <2.6 (45.0%; P = 0.037) versus group 1 (51.9%, 35.6%, 61.3%, and 35.0%, respectively) (Table 2). Also, greater proportions of patients achieved a major clinical response in the combined groups 3 and 4 (13.3%; P = 0.036) and group 3 (15.2%; P = 0.018) versus group 1 (6.9%) (Table 2). When remission at week 52 was assessed using the CDAI, a trend toward a higher remission rate with golimumab therapy was observed (23.6% of combined groups 3 and 4 patients versus 16.3% of group 1 patients; P = 0.06). The difference in SDAI-defined remission was statistically significant (23.3% of combined groups 3 and 4 patients versus 15.0% of group 1 patients; P = 0.035) (Table 2).

The improvements in clinical efficacy, physical function, and radiographic progression, including ACR20/50/70 and EULAR (good/moderate) responses and changes in HAQ DI and SHS scores, observed through week 52 were maintained or enhanced through week 104. More than one-third of golimumab + MTX–treated patients achieved remission according to the CDAI and SDAI criteria at week 104 (Table 3).

Table 3. Summary of clinical and radiographic efficacy and patient-reported outcomes at week 104*
 Group 1, placebo + MTX ([RIGHTWARDS ARROW] golimumab + MTX)aGroup 2, golimumab 100 mg + placebobGroup 3, golimumab 50 mg + MTXcGroup 4, golimumab 100 mg + MTXCombined groups 3 and 4, golimumab + MTX
NValueNValueNValueNValueNValue
  1. Values are the number (percentage) of randomized patients unless indicated otherwise. Observed clinical data were used for all analyses, with no imputation for missing data or patients who entered early escape. Last observation carried forward methodology was employed for missing week 104 total radiographic scores, and missing baseline total scores were imputed using the median baseline total score for all patients. MTX = methotrexate; ACR20/50/70 = American College of Rheumatology 20%/50%/70% improvement criteria; EULAR = European League Against Rheumatism; DAS28-CRP = 28-joint Disease Activity Score employing the C-reactive protein (CRP) level; CDAI = Clinical Disease Activity Index; SDAI = Simplified Disease Activity Index; HAQ = Health Assessment Questionnaire; DI = disability index; SHS = Sharp/van der Heijde score; SDC = smallest detectable change.

  2. a

    Includes patients who early escaped at week 28 or crossed over at week 52 to receive golimumab 50 mg + MTX or dose escalated after week 52 database lock to receive golimumab 100 mg + MTX.

  3. b

    Includes patients who early escaped at week 28 to receive golimumab 100 mg + MTX or received MTX after week 52 database lock.

  4. c

    Includes patients who early escaped at week 28 or dose escalated after week 52 database lock to receive golimumab 100 mg + MTX.

  5. d

    Includes patients who had ≥1 SHS after week 52.

  6. e

    Missing imputation rules were applied.

  7. f

    One patient in this group underwent foot surgery between week 52 and week 104 that, due to analytical rules imputing the worst score for all joints in the foot, resulted in a very large increase in SHS (change of 133.5) for this patient and elevated the mean change in SHS for this treatment group.

Patients randomized160 159 159 159 318 
ACR response criteria125 125 131 125 256 
ACR20 108 (86.4) 102 (81.6) 113 (86.3) 101 (80.8) 214 (83.6)
ACR50 81 (64.8) 71 (56.8) 84 (64.1) 77 (61.6) 161 (62.9)
ACR70 54 (43.2) 50 (40.0) 60 (45.8) 56 (44.8) 116 (45.3)
EULAR response (good/moderate)123119 (96.7)123116 (94.3)129120 (93.0)120111 (92.5)249231 (92.8)
DAS28-CRP <2.612354 (43.9)12351 (41.5)12969 (53.5)12057 (47.5)249126 (50.6)
CDAI ≤2.812536 (28.8)12431 (25.0)13043 (33.1)12248 (39.3)25291 (36.1)
SDAI ≤3.312335 (28.5)12231 (25.4)12841 (32.0)12046 (38.3)24887 (35.1)
HAQ DI score improvement ≥0.25125106 (84.8)12497 (78.2)130104 (80.0)124100 (80.6)254204 (80.3)
Randomized patients included in reading session 2d          
Total SHS, mean ± SD changee1310.94 ± 4.241282.54 ± 13.77f133−0.03 ± 1.93127−0.20 ± 1.98260−0.11 ± 4.10
Total SHS (patients with baseline CRP level >1.0 mg/dl), mean ± SD changee780.29 ± 3.07672.42 ± 16.36710.73 ± 6.8763−0.14 ± 1.341340.32 ± 5.09
Total SHS, change ≤0, no./total (%)e 71/125 (56.8) 67/124 (54.0) 86/130 (66.2) 84/125 (67.2) 170/255 (66.7)
Total SHS, change greater than SDC (5.10), no./total (%)e 8/125 (6.4) 9/124 (7.3) 3/130 (2.3) 1/125 (0.8) 4/255 (1.6)

Patients treated with golimumab + MTX for 2 years had numerically less radiographic progression through week 104 (SHS mean changes from baseline to week 104 of −0.03 for golimumab 50 mg + MTX and −0.20 for golimumab 100 mg + MTX) than patients who started the trial receiving placebo + MTX (SHS mean change of 0.94) or golimumab 100 mg + placebo (SHS mean change of 2.54) (Table 3). One patient receiving golimumab 100 mg + placebo had foot surgery between weeks 52 and 104 that, due to analytical rules imputing the worst score for all foot joints, yielded a very large SHS increase (133.5) and elevated the treatment group's mean change in SHS.

During the study extension period (week 52 to week 104), 27 patients had the golimumab dose escalated from 50 mg to 100 mg at the discretion of the investigator and had ≥12 weeks of followup. Mean DAS28-CRP and HAQ DI scores were already improved from baseline to week 52 (from 5.0 to 3.3 and 1.5 to 1.0, respectively) among these patients, and dose escalation resulted in average improvements from before to 12 weeks after dose escalation of only ∼8.5% for DAS28-CRP and ∼6.5% for HAQ DI scores. Albeit limited, this further improvement was observed despite the fact that among patients with dose escalation, approximately half (22 [44%] of 50) already had achieved a relatively low level of disease activity (i.e., a DAS-CRP score <3.2) and approximately one-quarter (12 [24%] of 50) already had achieved a DAS-CRP score <2.6 before dose escalation.

AEs

The proportions of patients with ≥1 AE were comparable between patients who received placebo + MTX (134 [84.3%] of 159) and all patients treated with golimumab + MTX (329 [89.4%] of 368) through week 52, as well as with the proportion of all golimumab-treated patients with AEs through week 104 (545 [89.3%] of 610) (Table 4). Common AEs included upper respiratory tract infection, nausea, increased alanine aminotransferase (ALT), and bronchitis (Table 4).

Table 4. Summary of safety through week 52 and week 104*
 AEs through week 52AEs through week 104
Placebo + MTXAll golimumab + MTXPlacebo + MTXGolimumab 100 mg + placeboGolimumab 50 mg + MTXGolimumab 100 mg + MTXAll golimumab + MTXAll golimumab
  1. Values are the number (percentage) unless indicated otherwise. AE = adverse event; MTX = methotrexate; ALT = alanine aminotransferase; AST = aspartate aminotransferase; SC = subcutaneous; 95% CI = 95% confidence interval.

  2. a

    Patients may appear in more than one column.

  3. b

    Absolute numbers and percentages of patients with ≥1 adverse event reported in ≥10% of patients in any treatment group. The Medical Dictionary for Regulatory Activities preferred terms are sorted by decreasing frequency in the “all golimumab” group.

  4. c

    Injection-site reactions were defined as any adverse reaction at an SC study agent injection site.

Patients treated with placebo/golimumab, no.a159368160157293312537610
Followup, mean weeks45.146.250.475.066.364.473.684.1
Total patient-years of followup137.8327.3155.1226.4373.7386.5760.1986.6
AEs134 (84.3)329 (89.4) 134 (85.4)245 (83.6)240 (76.9)451 (84.0)545 (89.3)
Common AEsb     
Upper respiratory tract infection   29 (18.5)43 (14.7)51 (16.3)89 (16.6)117 (19.2)
Nausea   13 (8.3)43 (14.7)52 (16.7)95 (17.7)108 (17.7)
ALT increased   11 (7.0)49 (16.7)33 (10.6)80 (14.9)91 (14.9)
Bronchitis   17 (10.8)29 (9.9)26 (8.3)54 (10.1)69 (11.3)
Cough   17 (10.8)21 (7.2)23 (7.4)44 (8.2)61 (10.0)
AST increased   7 (4.5)35 (11.9)19 (6.1)53 (9.9)60 (9.8)
Injection-site erythema   16 (10.2)12 (4.1)20 (6.4)31 (5.8)47 (7.7)
Discontinuation of SC study agent due to AE6 (3.8)28 (7.6)16 (10.2)23 (7.8)30 (9.6)53 (9.9)69 (11.3)
Serious AEs22 (13.8)44 (12.0)19 (12.1)40 (13.7)48 (15.4)88 (16.4)106 (17.4)
Death0 (0.0)3 (0.8)0 (0.0)2 (1.3)4 (1.4)2 (0.6)6 (1.1)8 (1.3)
Incidence/100 patient-years (95% CI)0.00 (0.00–2.17)0.64 (0.13–1.88)0.00 (0.00–1.93)0.88 (0.11–3.19)1.07 (0.29–2.74)0.52 (0.06–1.87)0.79 (0.29–1.72)0.81 (0.35–1.60)
Malignancy3 (1.9)4 (1.0)3 (1.9)1 (0.6)6 (2.1)4 (1.3)9 (1.7)11 (1.8)
Incidence/100 patient-years (95% CI)2.18 (0.45–6.36)0.86 (0.23–2.20)1.93 (0.40–5.65)0.44 (0.01–2.46)1.61 (0.59–3.49)1.04 (0.28–2.65)1.18 (0.54–2.25)1.11 (0.56–1.99)
Infections83 (52.2)195 (53.0)89 (56.7)161 (54.9)164 (52.6)310 (57.7)386 (63.3)
Serious infections6 (3.8)18 (4.9)4 (2.5)5 (3.2)16 (5.5)24 (7.7)40 (7.5)45 (7.4)
Incidence/100 patient-years (95% CI)4.36 (1.60–9.48)5.50 (3.26–8.69)2.58 (0.70–6.61)2.21 (0.72–5.15)4.28 (2.45–6.95)6.21 (3.98–9.24)5.26 (3.76–7.17)4.56 (3.33–6.10)
Injection-site reactionsc       
Reactions to golimumab0 (0.0)30 (8.2) 26 (16.6)15 (5.1)27 (8.7)41 (7.6)66 (10.8)
Reactions to placebo2 (1.3)21 (5.7) 9 (5.7)10 (3.4)13 (4.2)23 (4.3)32 (5.2)

Through week 52, 28 golimumab + MTX–treated patients (7.6%) discontinued the subcutaneous study agent because of an AE compared with 6 placebo + MTX–treated patients (3.8%). Through week 104, 69 (11.3%) of all golimumab-treated patients discontinued the subcutaneous study agent because of an AE, most commonly infections (Table 4).

Through week 52, serious AEs were reported for 12.0% of golimumab + MTX–treated patients (44 of 368) versus 13.8% of placebo + MTX–treated patients (22 of 159). At week 104, 17.4% of golimumab-treated patients (106 of 610) had reported serious AEs, most commonly serious infections (45 [7.4%] of 610). When expressed per 100 patient-years of followup, the incidences of serious infections through week 104 were 2.58 (95% confidence interval [95% CI] 0.70–6.61) for placebo + MTX, 2.21 (95% CI 0.72–5.15) for golimumab 100 mg monotherapy, 4.28 (95% CI 2.45–6.95) for golimumab 50 mg + MTX, and 6.21 (95% CI 3.98–9.24) for golimumab 100 mg + MTX (Table 4).

Despite screening for latent/active TB and the requirement for concurrent treatment for latent TB, 11 patients (2, 4, and 5 patients receiving golimumab 100 mg + placebo, golimumab 50 mg + MTX, and golimumab 100 mg + MTX, respectively) had active TB reported through week 104, including 3 patients with active TB through week 52 and an additional 8 patients with active TB during open-label treatment from week 52 to week 104. Eight patients had extrapulmonary involvement, with or without pulmonary disease, including pleural, peritoneal, ileal, pericardial, and bone involvement. There were no reported cases of disseminated TB, and no deaths were due to TB. Note that the patients with active TB were mostly enrolled by sites in endemic countries, including the Philippines (n = 5 patients), Chile (n = 2), Singapore (n = 1), Thailand (n = 1), and Ukraine (n = 1). Of the 106 patients who required treatment for latent TB at baseline, 2 developed active TB during the trial. One case involved a 57-year-old woman in Thailand, and another involved a 49-year-old woman in the Philippines. Both of these countries have high background incidences of TB. In both cases, the active TB was diagnosed several months (7 and 13 months, respectively) after completion of 9 months of isoniazid therapy and therefore likely represented new infections.

Eight patients died through week 104, including 2 patients receiving golimumab 100 mg + placebo (unknown cause and cardiac arrest), 4 patients receiving golimumab 50 mg + MTX (self-induced hypoglycemic coma, lung cancer, septic shock, and non–small cell lung carcinoma), and 2 patients receiving golimumab 100 mg + MTX (tramadol overdose and unknown cause). The incidences of death per 100 patient-years were 0.00 (95% CI 0.00–1.93) for placebo + MTX, 0.88 (95% CI 0.11–3.19) for golimumab 100 mg + placebo, 1.07 (95% CI 0.29–2.74) for golimumab 50 mg + MTX, and 0.52 (95% CI 0.06–1.87) for golimumab 100 mg + MTX (Table 4).

Fourteen patients had malignancies documented through week 104, including 3 patients receiving placebo + MTX (1 patient with breast cancer and 2 patients with squamous cell skin cancer), 1 patient receiving golimumab 100 mg + placebo (breast cancer), 6 patients receiving golimumab 50 mg + MTX (1 patient each with adenocarcinoma, breast cancer, lung cancer, and thyroid cancer, and 2 patients with non–small cell lung cancer), and 4 patients receiving golimumab 100 mg + MTX (1 patient each with adenocarcinoma, basal cell carcinoma, Hodgkin's lymphoma, and breast cancer). The malignancy incidences per 100 patient-years of followup were 1.93 (95% CI 0.40–5.65) for placebo + MTX, 0.88 (95% CI 0.11–3.19) for golimumab 100 mg + placebo, 1.61 (95% CI 0.59–3.49) for golimumab 50 mg + MTX, and 0.78 (95% CI 0.16–2.27) for golimumab 100 mg + MTX (Table 4).

Reactions to subcutaneous golimumab injections, most commonly injection-site erythema, occurred in 10.8% of golimumab-treated patients (66 of 610) through week 104 (Table 4). Reactions to golimumab injections were more common with all golimumab 100 mg + placebo (16.6%) than with golimumab + MTX (7.6%) (Table 4). No injection-site reaction was severe; only 1 patient had a serious injection-site reaction (moderate injection-site erythema) resulting in discontinuation of the study agent, occurring 1 day following the week 52 visit. This patient was treated with golimumab 100 mg + MTX and tested positive for antibodies to golimumab. No patient experienced anaphylactic or serum sickness–like reactions through week 104.

Antibodies to golimumab

Antibodies to golimumab were detected in 6.0% (21 of 351) and 7.1% of patients receiving golimumab (42 of 588) with appropriate samples through week 52 and week 104, respectively. Through week 104, patients receiving golimumab 100 mg + placebo appeared to have a higher incidence of antibodies to golimumab (9.2%) than patients receiving golimumab + MTX since week 0 (5.5%). Most patients testing negative for antibodies to golimumab at week 52 maintained this status at week 104 (471 [98.7%] of 477) (data not shown). Injection-site reactions were observed in 7 (16.7%) of 42 patients who tested positive and 57 (10.4%) of 546 patients who tested negative for antibodies to golimumab. The number of patients testing positive for antibodies to golimumab was too small to support any conclusions regarding the impact of antibody status on efficacy or safety.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

We evaluated the efficacy of golimumab 50 mg and 100 mg administered subcutaneously every 4 weeks in combination with MTX and golimumab 100 mg every 4 weeks without MTX versus MTX alone in patients with active RA who had never taken MTX or biologic agents. Results of this ongoing phase III multicenter GO-BEFORE study pertaining to the co–primary end points of the study, i.e., ACR50 response at week 24 ([13]) and change in SHS at week 52 ([14]), have been reported previously. Two of the major secondary end points of the current study, i.e., improvement in the HAQ DI score from baseline to week 52 and change in the SHS from baseline to week 52 among patients with a baseline CRP level >1.0 mg/dl, along with other efficacy and safety data through week 104, are reported herein.

Physical function as assessed by the HAQ DI score was restored to normal in substantial proportions of patients treated with MTX monotherapy, golimumab 100 mg monotherapy, and golimumab 50 mg or 100 mg + MTX. The study was not powered for major secondary end points, including overall improvement in patient quality of life, which may have contributed to the lack of statistical significance for the difference in HAQ DI improvement between the MTX monotherapy and golimumab + MTX groups at 1 year. When compared with previous trials of other TNF inhibitors in a population that had never taken MTX with an active MTX control group ([5, 9, 12]), the GO-BEFORE trial had the smallest number of patients per treatment group. In addition, as discussed previously ([13]), the study patients exhibited lower disease activity than has been observed in previous studies of biologic agents in patients who had never taken MTX, which may have led to smaller treatment differences between the golimumab + MTX and MTX monotherapy groups. Calculation of Guyatt's effect size ([26]), defined as the mean change observed with golimumab divided by the SD of the change with placebo + MTX, for HAQ DI score changes yielded effect sizes of 0.84 for placebo + MTX, 0.90 for golimumab 100 mg + placebo, 0.96 for golimumab 50 mg + MTX, and 1.09 for golimumab 100 mg + MTX.

In the assessment of changes from baseline to week 52 in the total SHS among patients with baseline CRP levels >1.0 mg/dl, which was a major secondary study end point, significantly less disease progression was observed for patients treated with golimumab + MTX than placebo + MTX. When compared with the co–primary end point analysis conducted among all randomized patients ([14]), treatment group differences were more pronounced in the subgroup of patients with more inflammation at baseline. These findings were anticipated based on the fact that patients with more inflammation at baseline tend to demonstrate more radiographic progression ([27, 28]), and there is a greater opportunity to demonstrate significant improvement with a strongly efficacious treatment compared with a less effective control treatment when greater radiographic progression will occur in such patients. Also through week 52, when compared with group 1, significantly higher proportions of patients in combined groups 3 and 4 achieved a clinical response (ACR20, ACR50, and EULAR) and a DAS28-CRP <2.6, which were the other major secondary end points of the study.

The benefits of golimumab + MTX in reducing signs and symptoms of active RA observed at week 52 were maintained or enhanced through week 104. Also through week 104, patients treated with golimumab + MTX for 2 years had numerically less radiographic progression from baseline versus patients who started the trial receiving placebo + MTX or golimumab 100 mg + placebo. Numerically higher proportions of these golimumab-treated patients also had no radiographic progression (SHS ≤0) through week 104.

Consistent with findings observed with other TNF inhibitors in patients who had never taken MTX ([12, 29]), efficacy outcomes in GO-BEFORE were enhanced using combination treatment of golimumab + MTX compared with golimumab monotherapy, and were generally similar between golimumab monotherapy and MTX alone ([12]). Superior efficacy for combination therapy with MTX versus without MTX was observed for outcomes of both reducing signs and symptoms and inhibiting radiographic damage. Golimumab is approved for RA when used in combination with MTX. It should be noted, however, that interpretation of efficacy findings in the second year of golimumab treatment is limited by the fact that dose adjustments for MTX and corticosteroids were allowed at the sole discretion of the investigator and observed data were assessed.

The golimumab safety profile was consistent with that reported previously ([13]). The most commonly reported AEs were nausea, increased ALT, and upper respiratory tract infection. At both week 52 and week 104, infections were the most commonly reported AEs. Serious infections were more commonly observed in association with golimumab 100 mg + MTX (6.4%) than with golimumab 50 mg + MTX (2.7%) at week 52 (data not shown), and a smaller but clinically relevant dose-related difference was also evident at week 104 (7.7% versus 5.5%). The incidence of serious infections per 100 patient-years of followup through week 104 was higher in the golimumab 100 mg + MTX group than in the other treatment groups; however, CIs overlapped and the lack of power to detect treatment group differences in individual safety events precludes drawing any definitive conclusions. Most of the active TB cases observed through week 104 of the GO-BEFORE trial, which occurred in geographic areas with high TB incidence rates and occurred after 1 year of treatment, were generally regarded as new infections. These findings are consistent with those observed in an analysis of 1-year safety data pooled across 5 phase III golimumab trials, including the GO-BEFORE trial. Results of that analysis suggested that the comprehensive TB screening program employed in the golimumab phase III program, which included skin, whole blood, and radiographic evaluations, was effective in limiting the number of active TB cases despite patient enrollment in TB-endemic areas ([30]). These cases of active TB documented through week 104, however, underscore the need for ongoing close observation of patients receiving anti-TNF therapy, especially in endemic countries ([31]).

Eight patients died through week 104, including 2 patients treated with golimumab 100 mg + placebo, 4 patients treated with golimumab 50 mg + MTX, and 2 patients treated with golimumab 100 mg + MTX; no patients receiving MTX + placebo died. Fourteen patients developed malignancies through week 104, including 3 patients treated with placebo + MTX, 6 patients treated with golimumab 50 mg + MTX, and 5 patients treated with golimumab 100 mg ± MTX. When reported as incidence per 100 patient-years of followup, golimumab in combination with MTX did not appear to increase the occurrence of death or malignancy when compared with receipt of placebo + MTX.

Reactions to subcutaneous injections of golimumab occurred infrequently and generally comprised injection-site erythema. Injection-site reactions appeared less common in patients receiving combination therapy with MTX and were more commonly observed in association with golimumab 100 mg + MTX than with golimumab 50 mg + MTX at week 52; however, this dose-related difference was diminished by week 104. No injection-site reaction was severe, and only 1 patient had a serious reaction (injection-site erythema resulting in discontinuation of the study agent). No patient experienced anaphylactic or serum sickness–like reactions through week 104. The proportion of patients who developed antibodies to golimumab through week 104 was low.

These longer-term results of the GO-BEFORE study indicate that through 2 years, golimumab 50 mg and 100 mg administered subcutaneously every 4 weeks in combination with MTX reduced signs and symptoms of active RA, improved physical function, and inhibited radiographic progression in patients with active RA who had not previously received MTX or biologic anti-TNF therapy. The golimumab efficacy and safety profiles generally have been stable over time, and further monitoring will continue in this 5-year trial.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

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, Park, Weichun Xu, Hsia.

Acquisition of data. Emery, Fleischmann, Doyle, Strusberg, Durez, Nash, Amante, Churchill, Park, Pons-Estel, Weichun Xu, Hsia.

Analysis and interpretation of data. Emery, Fleischmann, Doyle, Durez, Weichun Xu, Stephen Xu, Wu, Hsia.

ROLE OF THE STUDY SPONSORS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Janssen Research and Development, LLC and Merck/Schering-Plough provided funding for this trial. Authors who are/were Janssen employees had a role in the study design, data collection, data analysis, and/or writing of the manuscript, as well as approval of the content of the submitted manuscript. Publication of this article was contingent on the approval of all authors, some of whom are/were Janssen employees.

Acknowledgments

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

The authors would like to thank Mahboob U. Rahman, MD (a former Janssen employee who is now employed by Pfizer), for his work pertaining to the GO-BEFORE clinical trial, as well as Michelle L. Perate, MS, and Mary H. Whitman, PhD, of Janssen (Spring House, Pennsylvania) for assisting with manuscript preparation and submission. The list of investigators who participated in the GO- BEFORE study has been provided ([14]). Please note the following corrected investigator names: Pedro Claudio Miranda Cabezas, MD, Ana Maria Flores Torterolo, MD, and Maria Loreto Massardo Vega, MD.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSORS
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

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