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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

Objective

To assess the safety and efficacy of golimumab in methotrexate (MTX)–naive patients with active rheumatoid arthritis (RA).

Methods

MTX-naive patients with RA (n = 637) were randomized 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). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1).

Results

An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P = 0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P = 0.049) and between group 3 (40.5%; P = 0.038) but not group 4 (36.5%; P = 0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound −5.2%; predefined delta value for noninferiority −10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively.

Conclusion

Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns.

Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disorder, is believed to be partially mediated by overproduction of cytokines such as tumor necrosis factor α (TNFα) (1). Inhibition of TNFα has emerged as an effective therapy for RA (2–13) and several other related immune-mediated inflammatory diseases (14).

Golimumab, a new human anti-TNFα monoclonal antibody, inhibits TNFα bioactivity by binding with high affinity and specificity to soluble and transmembrane TNFα. Preclinical studies demonstrate that neutralization of human TNFα can be achieved with lower concentrations of golimumab versus infliximab (15). Results of a phase II trial in patients with active RA despite methotrexate (MTX) therapy indicated that golimumab administered by subcutaneous (SC) injection reduced the signs and symptoms of RA within 2 weeks of the first dose, with no unexpected safety concerns (16). We present golimumab efficacy and safety data through week 24 from an ongoing, multicenter, phase III study in MTX-naive patients with RA. The overall study encompasses a 52-week, randomized, double-blind, placebo-controlled phase followed by an open-label extension through 5 years.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

Patients.

Eligible study participants were adults who had RA, according to the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) criteria (17), for at least 3 months before administration of the initial study agent and had not received more than 3 weekly doses of oral MTX as treatment of RA. Patients had active RA, with at least 4 swollen joints and at least 4 tender joints at both screening and baseline, and met at least 2 of the following criteria at screening and/or baseline: 1) C-reactive protein (CRP) level of ≥1.5 mg/dl or erythrocyte sedimentation rate (ESR) of ≥28 mm/hour according to the Westergren method, 2) morning stiffness lasting 30 minutes or longer, 3) bone erosion by radiography and/or magnetic resonance imaging prior to initiation of treatment with the study agent, or 4) anti–cyclic citrullinated peptide antibody positivity or rheumatoid factor positivity. Eligible patients met the prespecified tuberculosis (TB) screening criteria. Patients with positive results for TB skin and/or whole blood interferon-γ–based QuantiFERON-TB testing could participate but had to start prophylaxis for latent TB before or simultaneously with administration of the first dose of the study agent.

Concurrent use of nonsteroidal antiinflammatory drugs (NSAIDs), other analgesics for RA, and oral corticosteroids (≤10 mg of prednisone/day or equivalent) was allowed if doses were stable for ≥2 weeks prior to initiation of treatment with the study agent and during the study. Patients who had previously received infliximab, etanercept, adalimumab, rituximab, natalizumab, or cytotoxic agents, including chlorambucil, cyclophosphamide, nitrogen mustard, and other alkylating agents, were excluded. Patients receiving anakinra could participate 4 weeks after receiving the last dose, patients receiving alefacept or efalizumab could participate 3 months after receiving the last dose, and patients receiving an experimental agent could participate after the equivalent of 5 half-lives of the agent.

Study design.

This multicenter phase III study in MTX-naive patients with active RA has a 52-week, randomized, double-blind, placebo-controlled phase followed by an open-label 5-year extension. The co-primary end points of the study are an ACR 50% improvement (ACR50) response (18) at week 24 and a change from baseline in the modified Sharp/van der Heijde score (19) at week 52. This report presents clinical data through 24 weeks. The study was conducted according to the Declaration of Helsinki and the International Committee on Harmonisation Good Clinical Practices. The protocol was reviewed and approved by the institutional review board or ethics committee at each site. All patients provided written informed consent before undergoing study-related procedures. The investigators who participated in the Golimumab Before Employing Methotrexate as the First-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset (GO-BEFORE) study are shown in Appendix A.

An interactive voice response system (IVRS) was used to randomly assign eligible patients to 1 of 4 treatment groups in approximately equal proportions: placebo by SC injection plus MTX capsules (group 1), golimumab 100 mg by SC injection plus placebo capsules (group 2), golimumab 50 mg by SC injection plus MTX capsules (group 3), or golimumab 100 mg by SC injection plus MTX capsules (group 4). Randomization was stratified by investigational site and the patient's screening CRP level (<1.5 mg/dl or ≥1.5 mg/dl).

Golimumab and placebo were supplied as sterile liquid (aqueous medium of histidine, sorbitol, and polysorbate 80 [pH 5.5] with or without golimumab) for SC injection. Active and placebo MTX were supplied as double-blinded, identical opaque capsules (filled with microcrystalline cellulose with or without MTX). All study agents were provided by Centocor (Malvern, PA). Injections were administered subcutaneously at week 0 and then every 4 weeks. The dosage of MTX started at 10 mg/week at week 0 and escalated by 2.5 mg every 2 weeks to 20 mg/week by week 8.

Study end points.

The primary end point was the difference in the ACR50 response at week 24 between groups 3 and 4 combined (combined group) versus group 1 and a pairwise comparison (group 3 or group 4 versus group 1). ACR20, ACR70, and ACR90 responses were also measured. Additional efficacy assessments included the numeric index of the ACR response (ACR-N) (20, 21) and the Disease Activity Score using 28 joints (DAS28) (22). Both versions of the DAS28 composite score, i.e., using the CRP or the ESR, were used to determine the DAS28 response (good and moderate ratings according to the European League Against Rheumatism) and remission (DAS28 of <2.6) (22–24). An independent assessor at each study center, who had no access to patient records and no other role in the study, performed the joint assessments. The functional status of patients was assessed using the disability index of the Health Assessment Questionnaire (25). Changes in hemoglobin levels were assessed in patients with baseline anemia.

Safety assessments included adverse events (including injection-site reactions) and routine laboratory analyses (including antinuclear antibodies [ANAs] and, if the patient was ANA positive, antibodies to double-stranded DNA [dsDNA]). Antibodies to golimumab were also determined (16).

Statistical analysis.

In the primary efficacy analysis, data from all randomized patients (all of those who were entered in the IVRS for randomization regardless of receipt of study treatment) were analyzed by assigned treatment group using an intent-to-treat (ITT) approach. Patients for whom all week 24 (the primary end point visit) ACR component data were missing were considered nonresponders, as were patients meeting predefined treatment failure criteria related to prohibited concomitant medications or discontinuation of the SC study agent due to lack of efficacy. Actual week 24 data were used for patients who discontinued the study agent for reasons other than lack of efficacy but returned for clinical evaluations, but these patients were considered nonresponders if they met any of the treatment failure criteria. These rules also applied to the categorical major secondary end points. A post hoc modified ITT analysis of patients receiving at least 1 study treatment (excluding 3 “randomized” patients who were never treated) was also performed for the primary end point only. An additional post hoc ITT analysis of ACR50 responses at week 24 was undertaken, whereby a value of 0.15 mg/dl rather than 0.3 mg/dl was assigned to all CRP values <0.3 mg/dl in the analysis of the primary end point. All other efficacy analyses were prespecified. Safety analyses included all treated patients according to actual treatment received.

Treatment group differences were assessed with a 2-sided Cochran-Mantel-Haenszel test for discrete variables and an analysis of variance on the normal van der Waerden scores for continuous parameters stratified by the CRP level at the time of screening (<1.5 mg/dl or ≥1.5 mg/dl). A 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 primary efficacy end points, wherein the comparison between the combined group and group 1 was made first. If there was a significant difference between the combined group and group 1, pairwise comparisons between group 3 versus group 1 and group 4 versus group 1 were performed. If a statistically significant difference was observed for at least 1 of these pairwise comparisons, group 2 and group 1 were compared for noninferiority, with a prespecified lower limit of a 1-sided 95% confidence interval (95% CI) for the difference between group 2 and group 1 of −10%. The primary end point was considered to be met if the combined group as well as group 3 or group 4 had statistically significantly higher proportions of patients achieving an ACR50 response at week 24 versus group 1.

The planned sample size (n = 600) provided >98% power to detect a difference in the ACR50 response between the combined group and group 1 (α = 0.05) at week 24, assuming that 50% of the overall patient population would have a screening CRP level of <1.5 mg/dl, and also that the following proportions of patients within the subgroups defined by the screening CRP level would achieve ACR50 responses: for group 1, 25% (CRP level <1.5 mg/dl) and 40% (CRP level ≥1.5 mg/dl); for group 3, 40% (CRP level <1.5 mg/dl) and 60% (CRP level ≥1.5 mg/dl); for group 4, 45% (CRP level <1.5 mg/dl) and 65% (CRP level ≥1.5 mg/dl). The >98% power for the primary analysis was a result of providing ∼85% power to claim noninferiority of group 2 versus group 1 (α = 0.05 by 1-sided noninferiority test), providing a balanced sample size with sufficient power for both tests.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

Patient disposition and baseline characteristics.

Data for this report were collected between December 12, 2005 and October 1, 2007 (when all patients completed the first 24 weeks of the study). Six hundred thirty-seven patients, enrolled at 90 investigational sites in Europe/Australia/New Zealand (n = 34), Asia (n = 25), North America (n = 21), and Latin America (n = 10), were randomized; 634 of these patients received at least 1 study treatment. At baseline, the majority of patients had relatively early disease of severe intensity, with the median duration of RA ranging from 1 year to 1.8 years across groups 1–4 (Table 1). Of note, 444 (69.7%), 387 (60.8%), and 291 (45.7%) randomized patients had RA for ≤3 years, ≤2 years, and ≤1 year, respectively. Similar proportions of patients across treatment groups discontinued SC treatment with the study agent (5.0–6.3%) and completed the study through week 24 (93.1–95.0%) (Figure 1).

Table 1. Baseline characteristics of the patients*
CharacteristicGroup 1, placebo plus MTX (n = 160)Group 2, golimumab 100 mg plus placebo (n = 159)Group 3, golimumab 50 mg plus MTX (n = 159)Group 4, golimumab 100 mg plus MTX (n = 159)Groups 3 and 4 combined (n = 318)
  • *

    Except where indicated otherwise, values are the mean ± SD (median). Study medication was administered by subcutaneous injection. MTX = methotrexate; RA = rheumatoid arthritis; VAS = visual analog scale; HAQ = Health Assessment Questionnaire; DAS28 = Disease Activity Score in 28 joints; ESR = erythrocyte sedimentation rate; DMARDs = disease-modifying antirheumatic drugs.

Female sex, no. (%)134 (83.8)134 (84.3)135 (84.9)125 (78.6)260 (81.8)
Age, years48.6 ± 12.91 (50.0)48.2 ± 12.85 (49.0)50.9 ± 11.32 (51.0)50.2 ± 11.87 (50.0)50.6 ± 11.58 (51.0)
Race, no. (%)     
 White114 (71.3)111 (69.8)119 (74.8)117 (73.6)236 (74.2)
 Black6 (3.8)4 (2.5)1 (0.6)1 (0.6)2 (0.6)
 Asian25 (15.6)31 (19.5)30 (18.9)31 (19.5)61 (19.2)
 Other15 (9.4)13 (8.2)9 (5.7)10 (6.3)19 (6.0)
Duration of RA, years2.9 ± 4.80 (1.2)4.1 ± 5.60 (1.8)3.5 ± 5.65 (1.0)3.6 ± 6.09 (1.3)3.6 ± 5.86 (1.1)
 ≤3 years, no. (%)116 (72.5)101 (63.5)116 (73.0)111 (69.8)227 (71.4)
 ≤2 years, no. (%)99 (61.9)86 (54.1)102 (64.2)100 (62.9)202 (63.5)
 ≤1 years, no. (%)73 (45.6)64 (40.3)81 (50.9)73 (45.9)154 (48.4)
No. of swollen joints, range 0–6614.9 ± 10.01 (11.0)15.2 ± 10.08 (12.0)16.0 ± 9.98 (13.0)15.8 ± 10.34 (14.0)15.9 ± 10.15 (13.0)
No. of tender joints, range 0–6827.3 ± 16.16 (25.5)27.3 ± 15.40 (24.5)29.2 ± 17.05 (26.0)27.4 ± 14.70 (26.0)28.3 ± 15.92 (26.0)
Patient's assessment of pain, 0–10-cm  VAS6.3 ± 2.12 (6.7)6.5 ± 2.14 (6.8)6.4 ± 2.11 (6.5)6.2 ± 2.20 (6.5)6.3 ± 2.15 (6.5)
Patient's global assessment of disease  activity, 0–10-cm VAS5.9 ± 2.32 (5.9)6.4 ± 2.40 (6.8)6.1 ± 2.21 (6.2)6.1 ± 2.26 (6.0)6.1 ± 2.23 (6.1)
Physician's global assessment of disease  activity, 0–10-cm VAS6.0 ± 1.72 (6.0)6.4 ± 1.75 (6.3)6.2 ± 1.63 (6.2)6.1 ± 1.75 (6.2)6.2 ± 1.69 (6.2)
HAQ disability index, range 0–31.5 ± 0.64 (1.5)1.6 ± 0.72 (1.7)1.5 ± 0.66 (1.5)1.5 ± 0.64 (1.6)1.5 ± 0.65 (1.5)
C-reactive protein level, mg/dl2.6 ± 3.28 (1.4)2.6 ± 3.43 (1.3)2.4 ± 3.02 (1.3)2.4 ± 2.90 (1.3)2.4 ± 2.95 (1.3)
DAS28 using C-reactive protein level,  range 0–105.0 ± 1.01 (5.0)5.2 ± 0.98 (5.1)5.1 ± 0.99 (5.1)5.1 ± 1.0 (5.1)5.1 ± 0.99 (5.1)
DAS28 using ESR, range 0–106.2 ± 1.17 (6.1)6.3 ± 1.19 (6.4)6.3 ± 1.11 (6.3)6.3 ± 1.11 (6.3)6.3 ± 1.11 (6.3)
Previous medications, no. (%)     
 DMARDs83 (51.9)93 (58.5)80 (50.3)91 (57.2)171 (53.8)
  Hydroxychloroquine26 (16.3)43 (27.0)33 (20.8)40 (25.3)73 (23.0)
  Sulfasalazine51 (31.9)54 (34.0)36 (22.6)49 (30.8)85 (26.7)
  Leflunomide12 (7.5)15 (9.4)13 (8.2)11 (6.9)24 (7.5)
  Other DMARDs26 (16.3)32 (20.1)29 (18.2)28 (17.6)57 (17.9)
 Anakinra0 (0.0)0 (0.0)0 (0.0)1 (0.6)1 (0.3)
 Immunosuppressive agents3 (1.9)6 (3.8)2 (1.3)9 (5.7)11 (3.5)
 Systemic corticosteroids109 (68.1)101 (63.5)111 (69.8)104 (65.4)215 (67.6)
 Nonsteroidal antiinflammatory drugs153 (95.6)156 (98.1)156 (98.1)156 (98.1)312 (98.1)
MTX dosage, mg/week     
 Week 010.1 ± 1.31 (10.0)0.0 ± 0.00 (0.0)10.0 ± 0.85 (10.0)10.1 ± 0.71 (10.0)
 Week 2319.1 ± 2.73 (20.0)0.1 ± 1.71 (0.0)19.2 ± 2.35 (20.0)19.1 ± 3.31 (20.0)
thumbnail image

Figure 1. Disposition of randomized patients through week 24. MTX = methotrexate; RA = rheumatoid arthritis.

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Between October 2006 and February 2007, clinical supply distribution to some sites was interrupted due to delays in study agent labeling/packaging. Therefore, 3 (1.9%), 12 (7.6%), 2 (1.3%), and 4 (2.5%) treated patients in groups 1, 2, 3, and 4, respectively, missed at least 1 SC dose of the study drug during the impacted time frame. Among these patients, 3 in group 2 and 1 in group 4 missed the week 20 SC injection. Data for these patients were not handled differently in the statistical analysis.

Efficacy results.

ACR response.

Using the prespecified ITT analysis, the primary end point, i.e., an ACR50 response at week 24 in the combined group versus group 1 (122 [38.4%] of 318 patients and 47 [29.4%] of 160 patients, respectively; P = 0.053), was not met (Figure 2). Results of a post hoc modified ITT analysis (excluding 3 randomized but untreated patients) of the primary end point resulted in a statistically significant difference between the combined group versus group 1 (122 [38.5%] of 317 patients and 47 [29.4%] of 160 patients, respectively; P = 0.049) (Table 2). In this modified ITT analysis, group 3 (golimumab 50 mg plus MTX; 64 [40.5%] of 158 patients [P = 0.038]) was statistically superior to group 1 (29.4%), while group 4 (golimumab 100 mg plus MTX; 58 [36.5%] of 159 patients [P = 0.177]) was not.

thumbnail image

Figure 2. Proportions of randomized patients achieving an American College of Rheumatology 20% response (ACR20) (A), an ACR50 response (B), an ACR70 response (C), or an ACR90 response (D), from baseline through week 24. MTX = methotrexate.

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Table 2. Efficacy results at week 24*
 Group 1, placebo plus MTX (n = 160)Group 2, golimumab 100 mg plus placebo (n = 159)Group 3, golimumab 50 mg plus MTX (n = 159)Group 4, golimumab 100 mg plus MTX (n = 159)Groups 3 and 4 combined (n = 318)
  • *

    Except where indicated otherwise, values are the number of patients/number of patients analyzed (%). Study medication was administered by subcutaneous injection. All P values are versus placebo plus methotrexate (MTX). Except where indicated otherwise, all analyses were prespecified. ACR50 = American College of Rheumatology 50% improvement criteria; ACR-N = numeric index of the ACR response; DAS = Disease Activity Score in 28 joints; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; Hgb = hemoglobin.

  • Modified intent-to-treat analysis.

  • Abnormal C-reactive protein (CRP) level defined as >1.0 mg/dl at baseline.

  • §

    Among patients who were anemic at baseline, based on the following sex- and age-specific normal ranges: for females ages 12–65 years, 11.6–16.2 gm/dl; for females ages 66–110 years, 11.0–16.1 gm/dl; for males ages 18–65 years, 13.0–17.5 gm/dl; for males ages 66–110 years, 12.6–17.7 gm/dl. Patients who received intravenous iron, recombinant human erythropoietin, or a blood transfusion through week 24 were excluded.

ACR50 response, all randomized patients [P]47 (29.4)52 (32.7)64 (40.3) [0.042]58 (36.5) [0.177]122 (38.4) [0.053]
 Patients with CRP level <1.5 mg/dl at screening21/83 (25.3)30/80 (37.5)33/82 (40.2)24/82 (29.3)57/164 (34.8)
 Patients with CRP level ≥1.5 mg/dl at screening26/77 (33.8)22/79 (27.8)31/77 (40.3)34/77 (44.2)65/154 (42.2)
ACR50 response, post hoc analysis of all treated patients [P]47/160 (29.4)52/157 (33.1)64/158 (40.5) [0.038]58/159 (36.5) [0.177]122/317 (38.5) [0.049]
ACR50 response, all randomized patients with abnormal baseline CRP level [P]34/95 (35.8)26/90 (28.9)38/86 (44.2) [0.250]37/83 (44.6) [0.240]75/169 (44.4) [0.178]
ACR50 response, all randomized patients with CRP level <0.3 mg/dl assigned to 0.15 mg/dl instead of 0.3 mg/dl, post hoc analysis [P]47 (29.4)53 (33.3)64 (40.3) [0.042]60 (37.7) [0.114]124 (39.0) [0.039]
ACR20 response, all randomized patients [P]79 (49.4)82 (51.6)98 (61.6) [0.028]98 (61.6) [0.028]196 (61.6) [0.011]
ACR70 response, all randomized patients [P]25 (15.6)22 (13.8)38 (23.9) [0.064]29 (18.2) [0.535]67 (21.1) [0.155]
ACR90 response, all randomized patients [P]5 (3.1)5 (3.1)15 (9.4) [0.021]12 (7.5) [0.080]27 (8.5) [0.027]
ACR-N, median % improvement [P]18.2021.6033.30 [0.015]27.80 [0.095]32.45 [0.017]
DAS28 using CRP level, good or moderate response [P]97 (60.6)105 (66.0)120 (75.5) [0.005]120 (75.5) [0.004]240 (75.5) [<0.001]
DAS28 using ESR, good or moderate response [P]98 (61.3)107 (67.3)116 (73.0) [0.027]122 (76.7) [0.003]238 (74.8) [0.002]
DAS28 using CRP level, remission [P]45 (28.1)40 (25.2)61 (38.4) [0.050]60 (37.7) [0.069]121 (38.1) [0.031]
DAS28 using ESR, remission [P]18 (11.3)25 (15.7)40 (25.2) [0.001]31 (19.5) [0.040]71 (22.3) [0.003]
Median % improvement from baseline [P]     
 Swollen joint count66.7066.7075.60 [0.127]71.40 [0.293]75.00 [0.133]
 Tender joint count57.1057.1067.20 [0.023]66.70 [0.088]66.70 [0.020]
 Patient's assessment of pain44.3538.3052.15 [0.028]51.65 [0.038]52.05 [0.013]
 Patient's assessment of disease activity36.7034.7049.55 [0.042]51.55 [0.005]50.40 [0.005]
 Physician's assessment of disease activity63.0057.0566.70 [0.206]63.50 [0.480]64.70 [0.257]
 CRP level42.9025.0057.10 [0.002]62.50 [0.014]57.60 [0.001]
 HAQ disability index36.9531.0543.65 [0.141]48.55 [0.006]45.85 [0.014]
Increase in Hgb level of ≥1 gm/dl from baseline [P]§13/37 (35.1)7/43 (16.3)20/34 (58.8) [0.040]16/37 (43.2) [0.583]36/71 (50.7) [0.145]

In noninferiority testing, the lower bound of the 95% CI for the difference in the ACR50 response at week 24 between groups 1 and 2 was −5.2% (delta value for noninferiority −10%). The noninferiority criterion was met, suggesting that the proportions of patients achieving an ACR50 response at week 24 were similar in group 1 (29.4%) and group 2 (33.1%) (Table 2).

Because patient randomization was stratified by the baseline CRP level, the proportions of patients with a baseline CRP level of ≥1.5 mg/dl and those with a level of <1.5 mg/dl were uniformly distributed among the treatment arms. The ACR50 response rates were similar among patients in groups 3 and 4 with a baseline CRP level of ≥1.5 mg/dl. However, the ACR50 response rate was lower among patients in group 4 with a CRP level of <1.5 mg/dl than among those in group 3 with a CRP level of <1.5 mg/dl. Also, although the proportions of patients with a baseline CRP level of <1.5 mg/dl were similar between groups 3 and 4, the median CRP levels were 0.5 mg/dl and 0.3 mg/dl in the lowest quartiles of groups 3 and 4, respectively. Of note, because the lower limit of quantitation (LLOQ) of the CRP assay used was 0.3 mg/dl, any CRP values <0.3 mg/dl could not be measured, and a value of 0.3 mg/dl was conservatively assigned to all values <0.3 mg/dl.

A higher proportion of patients in group 4 than in group 3 had baseline CRP levels <0.3 mg/dl and had no possibility of showing improvement in the CRP level, which could have impacted the overall ACR and DAS28 responses. To evaluate the extent of such an impact on preplanned analyses, an alternative post hoc analysis, which was considered less conservative but more equitable, was implemented whereby a value of 0.15 mg/dl was assigned to all CRP values <0.3 mg/dl in the analysis of the primary end point utilizing the ITT population. In this post hoc analysis, a significant P value of 0.039 was achieved for the comparison of the ACR50 response at week 24 between the combined group (39.0%) versus group 1 (29.4%) (Table 2). A prespecified analysis of patients with abnormal CRP levels at baseline, i.e., CRP levels >1.0 mg/dl, was also performed. Although the absolute ACR50 response rates were generally higher in this subgroup of patients (35.8%, 44.2%, and 44.6% in groups 1, 3, and 4, respectively), the numbers of patients in each treatment group with an abnormal CRP level were insufficient to draw firm conclusions from formal statistical testing.

The ACR20, ACR70, and ACR90 response rates are shown in Figure 2. Significantly greater proportions of patients in group 3 (98 of 159 [61.6%]) and group 4 (98 of 159 [61.6%]) achieved an ACR20 response at week 24 compared with group 1 (79 of 160 patients [49.4%]; P = 0.028 for both). Significantly higher proportions of patients in group 3 (15 of 159 patients [9.4%]; P = 0.021), but not group 4 (12 of 159 patients [7.5%]; P = 0.080), achieved an ACR90 response at week 24 compared with group 1 (5 of 160 patients [3.1%]) (Table 2). In addition, significantly greater proportions of patients in group 3 (55 of 158 patients [34.8%]; P = 0.010) and group 4 (65 of 158 patients [41.1%]; P < 0.001) achieved an ACR20 response as early as week 4 compared with group 1 (35 of 160 patients [21.9%]). In addition, the proportion of patients with early RA, corresponding to disease durations of 1 year or less or fewer than 3 years, who achieved ACR20 and ACR50 responses are shown in Table 3.

Table 3. Summary of ACR20 and ACR50 responses and the DAS28 using ESR at week 24 among all randomized patients with early rheumatoid arthritis*
 Group 1, placebo plus MTXGroup 2, golimumab 100 mg plus placeboGroup 3, golimumab 50 mg plus MTXGroup 4, golimumab 100 mg plus MTXGroups 3 and 4 combined
  • *

    Except where indicated otherwise, values are the number of patients/number of patients analyzed (%). Study medication was administered by subcutaneous injection. All P values are versus placebo plus MTX. See Table 2 for definitions.

Disease duration ≤1 year     
 No. of patients randomized73648173154
 ACR20 response36/71 (50.7)35/56 (62.5)56/79 (70.9)40/70 (57.1)96/149 (64.4)
 ACR50 response21/71 (29.6)21/56 (37.5)40/79 (50.6)23/70 (32.9)63/149 (42.3)
 DAS28 using ESR, good or moderate response [P]46 (63.0)41 (64.1)66 (81.5) [0.012]53 (72.6) [0.222]119 (77.3) [0.029]
 DAS28 using ESR, remission [P]9 (12.3)9 (14.1)24 (29.6) [0.007]16 (21.9) [0.121]40 (26.0) [0.017]
Disease duration ≤3 years     
 No. of patients randomized116101116111227
 ACR20 response58/112 (51.8)50/91 (54.9)78/112 (69.6)66/106 (62.3)144/218 (66.1)
 ACR50 response38/112 (33.9)33/91 (36.3)54/112 (48.2)44/106 (41.5)98/218 (45.0)
 DAS28 using ESR, good or moderate response [P]73 (62.9)66 (65.3)88 (75.9) [0.040]82 (73.9) [0.082]170 (74.9) [0.026]
 DAS28 using ESR, remission [P]14 (12.1)16 (15.8)33 (28.4) [0.001]23 (20.7) [0.071]56 (24.7) [0.005]
Other measures of arthritis.

The median percent improvement in the ACR-N and the proportions of patients achieving a DAS28 response and DAS28 remission at week 24 are shown in Table 2. Statistical comparisons of the combined group versus group 1 and group 3 versus group 1 were significant for these parameters, while those for group 4 versus group 1 did not achieve significance for the ACR-N and DAS28 (using the CRP) remission (Table 2).

The median percent improvements from baseline at week 24 in the ACR components were generally higher in the combined group as well as group 3 and group 4 individually compared with group 1, with statistical significance being achieved in several cases (Table 2). Improvement in the swollen and tender joint counts and CRP levels as a result of golimumab plus MTX therapy was observed as early as week 4 (the first efficacy evaluation after the start of study drug administration). Among patients with anemia at baseline (i.e., a hemoglobin level less than the sex- and age-specific lower limit of the normal range), the proportion of patients with at least a 1-gm/dl increase in the hemoglobin level from baseline at week 24 was significantly higher in group 3 compared with group 1, but not for the combined group versus group 1 or group 4 versus group 1 (Table 2).

Safety results.

Adverse events.

Overall, 72.5% (116 of 160), 68.2% (107 of 157), 81.6% (129 of 158), and 76.1% (121 of 159) of patients in groups 1, 2, 3, and 4, respectively, had 1 or more adverse events through week 24. The most frequently reported adverse events across both golimumab plus MTX groups were nausea, upper respiratory tract infection, increased aspartate aminotransferase (AST) level, increased alanine aminotransferase (ALT) level, dyspepsia, and headache (Table 4). More patients in groups 3 and 4 discontinued both SC and oral study agents compared with group 1 or group 2 (Table 4).

Table 4. Summary of safety results through week 24*
 Group 1, placebo plus MTX (n = 160)Group 2, golimumab 100 mg plus placebo (n = 157)Group 3, golimumab 50 mg plus MTX (n = 158)Group 4, golimumab 100 mg plus MTX (n = 159)
  • *

    Except where indicated otherwise, values are the number (%). Study medication was administered by subcutaneous injection. MTX = methotrexate; TB = tuberculosis.

  • Absolute number (%) of patients with ≥1 adverse event reported in ≥3% patients in any treatment group.

  • Defined as any adverse reaction at the site of injection of either placebo or golimumab.

  • §

    Any markedly abnormal postbaseline value through week 24 (for alanine aminotransferase [ALT] and aspartate aminotransferase [AST], at least 100% increase and value >150 IU/liter; for total bilirubin, at least 100% increase and value >1.5 mg/dl).

  • Using a titer of ≥1:160 for positivity and among patients who were negative for antinuclear antibodies at baseline.

  • #

    Among patients for whom appropriate samples were available.

Average duration of followup, weeks23.423.724.023.5
Adverse events116 (72.5)107 (68.2)129 (81.6)121 (76.1)
Common adverse events    
 Nausea16 (10.0)11 (7.0)22 (13.9)24 (15.1)
 ALT increased10 (6.3)7 (4.5)20 (12.7)12 (7.5)
 AST increased6 (3.8)6 (3.8)13 (8.2)10 (6.3)
 Upper respiratory tract infection14 (8.8)9 (5.7)13 (8.2)19 (11.9)
 Dyspepsia7 (4.4)5 (3.2)10 (6.3)8 (5.0)
 Headache10 (6.3)7 (4.5)6 (3.8)11 (6.9)
 Injection-site erythema0 (0.0)11 (7.0)8 (5.1)9 (5.7)
 Upper abdominal pain1 (0.6)6 (3.8)9 (5.7)5 (3.1)
 Hypertension3 (1.9)4 (2.5)8 (5.1)6 (3.8)
 Rash7 (4.4)6 (3.8)8 (5.1)5 (3.1)
 Nasopharyngitis4 (2.5)8 (5.1)9 (5.7)3 (1.9)
 Influenza7 (4.4)3 (1.9)4 (2.5)7 (4.4)
 Vomiting3 (1.9)2 (1.3)4 (2.5)7 (4.4)
 Dizziness1 (0.6)3 (1.9)7 (4.4)3 (1.9)
 Fatigue6 (3.8)10 (6.4)2 (1.3)8 (5.0)
 Insomnia1 (0.6)4 (2.5)4 (2.5)6 (3.8)
Discontinuation of study agent due to  adverse event    
 Subcutaneous study agent2 (1.3)1 (0.6)6 (3.8)7 (4.4)
 Oral study agent3 (1.9)1 (0.6)6 (3.8)9 (5.7)
Serious adverse events11 (6.9)5 (3.2)10 (6.3)10 (6.3)
Malignancies2 (1.3)0 (0)1 (0.6)1 (0.6)
Infections52 (32.5)55 (35.0)54 (34.2)50 (31.4)
Serious infections3 (1.9)2 (1.3)2 (1.3)7 (4.4)
Injection-site reactions3 (1.9)17 (10.8)7 (4.4)14 (8.8)
Elevated ALT§2 (1.3)0 (0.0)10 (6.3)7 (4.4)
 Patients receiving TB prophylaxis1 (0.6)0 (0.0)2 (1.3)1 (0.6)
Elevated AST§0 (0.0)0 (0.0)1 (0.6)3 (1.9)
 Patients receiving TB prophylaxis0 (0.0)0 (0.0)0 (0.0)0 (0.0)
Elevated total bilirubin§1 (0.6)1 (0.6)1 (0.6)3 (1.9)
Antinuclear antibodies2/53 (3.8)7/49 (14.3)13/57 (22.8)12/60 (20.0)
Antibodies to golimumab#14/104 (13.5)4/107 (3.7)2/104 (1.9)

Serious adverse events were reported for 6.9% (11 of 160), 3.2% (5 of 157), 6.3% (10 of 158), and 6.3% (10 of 159) of patients in groups 1, 2, 3, and 4, respectively. Each serious adverse event occurred in 1 patient, with the exception of pneumonia (2 patients in group 4) and anemia (2 patients in group 2). More patients in group 4 had serious infections (7 of 159 [4.4%]) as compared with group 1 (3 of 160 [1.9%]), group 2 (2 of 157 [1.3%]), or group 3 (2 of 158 [1.3%]). In a 64-year-old woman in group 3, TB of the spine was diagnosed 33 days after she received golimumab at week 8. The patient discontinued the study agent as a result of this serious adverse event and received TB treatment and also underwent spinal surgery. This patient had back pain and radiographic evidence of spinal involvement prior to study entry. Although the diagnosis was not confirmed by acid-fast bacilli staining, culture, or polymerase chain reaction testing, the surgical tissue showed caseating granulomas.

Two patients died during the 24-week study period. One patient in group 3 committed suicide by taking a large amount of her husband's insulin on day 113 (last golimumab dose on day 84). A second patient, in group 4, experienced cardiorespiratory arrest after gluteal abscess evacuation surgery on day 34 (last golimumab dose on day 1). Malignancies developed in 4 patients; 2 patients (groups 1 and 3) had breast cancer, 1 patient (group 4) had Hodgkin's lymphoma, and 1 patient (group 1) had lip squamous cell skin cancer.

Reactions to SC administration of the study agent, most commonly erythema, occurred in 1.9% (3 of 160), 10.8% (17 of 157), 4.4% (7 of 158), and 8.8% (14 of 159) of patients in groups 1, 2, 3, and 4, respectively. No injection-site reaction was severe, serious, or resulted in discontinuation of the study agent. No patient experienced anaphylactic or serum sickness reactions.

Laboratory values.

In general, there was no difference in hematology and chemistry values between the golimumab and placebo groups (data not shown), with the exception of a few patients in groups 1, 3, and 4 having elevated ALT and/or AST values on 1 or more occasions (Table 4). ALT and total bilirubin levels were the only chemistry parameters that were markedly abnormal on more than 1 occasion for any patient; each abnormality was observed in 1 patient in group 3 and 1 patient in group 4.

Although some trends were noted for an increased incidence of ALT and/or AST abnormalities among patients who were treated for latent tuberculosis versus those who were not treated, these trends were not consistent across all treatment groups (Table 4). There was no suggestion that concomitant golimumab and isoniazid treatment increased the risk of serious ALT or AST abnormalities (data not shown).

The proportions of patients with newly positive ANAs at week 24 were higher in group 3 (13 of 57 [22.8%]) and group 4 (12 of 60 [20.0%]) than in group 1 (2 of 53 [3.8%]) and group 2 (7 of 49 [14.3%]) (Table 4). However, there appeared to be no clinical significance of these findings, and a lupus-like syndrome did not develop in any patient. No patient in any treatment group had newly positive anti-dsDNA antibodies at week 24.

Antibodies to golimumab.

Antibodies to golimumab were detected in 6.3% (20 of 315) of patients receiving golimumab who had appropriate samples. Patients receiving golimumab 100 mg without MTX appeared to have a higher incidence of antibodies to golimumab (14 of 104 [13.5%]) than those receiving MTX with either golimumab 50 mg (4 of 107 [3.7%]) or golimumab 100 mg (2 of 104 [1.9%]).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

We evaluated the efficacy of golimumab administered subcutaneously every 4 weeks, with and without MTX versus MTX 20 mg/week in patients with active RA who were naive to MTX and anti-TNF agents. At baseline, patients had severely active RA of relatively short duration (median duration 1–1.8 years). However, study patients exhibited lower disease activity, as assessed by both the baseline ACR core components and the DAS28, than was observed in previous studies of biologic agents in MTX-naive patients (5, 10, 13). In recent years, there has been a trend toward earlier and more aggressive treatment of early-stage RA (26), suggesting that our study population may be more reflective of patients currently seen in clinical practice who are candidates for therapy with biologic agents compared with patients enrolled in previously conducted clinical trials.

The overall study results indicated that subcutaneously administered golimumab (with or without MTX) effectively reduces the signs and symptoms of active RA in patients who are naive to MTX. Although the primary end point (ITT analysis of the ACR50 response at week 24) was not achieved, results of a post hoc modified ITT analysis that excluded 3 untreated patients indicated a significant difference for this end point. Both analyses, however, resulted in borderline P values. Although the ACR50 response rates were clinically relevant, the size of the overall sample studied may not have been large enough to reach robust statistical significance. In this study, each treatment group had ∼150 patients, while previous studies in similar populations had larger treatment groups (5, 13, 27, 28).

Although the validity of comparing results across clinical trials is debatable, the differences in the clinical response rates (ACR and DAS28) for patients receiving golimumab plus MTX or golimumab alone in this MTX-naive population, compared with the rates for patients receiving MTX alone, were modest but generally comparable with those observed in previous studies conducted in similar patient populations (5, 13, 27).

Significantly greater proportions of patients treated with golimumab (50 mg or 100 mg) plus MTX achieved an ACR20 response at week 24 compared with patients treated with placebo plus MTX, and a significantly higher proportion of patients receiving golimumab at a dose of 50 mg (but not 100 mg) plus MTX achieved an ACR90 response at week 24 compared with patients treated with placebo plus MTX. Statistical significance was not achieved for the ACR70 response with either dose of golimumab. The benefit of golimumab plus MTX versus placebo plus MTX was also observed when evaluated by the ACR-N (only golimumab 50 mg plus MTX), the proportions of patients achieving a DAS28 response or remission (both doses, except only golimumab 50 mg plus MTX for DAS28 remission calculated using the CRP), and the ACR core components, with statistically significant improvements between golimumab plus MTX versus placebo plus MTX observed for the tender joint count (only 50 mg plus MTX), patient's assessment of pain, patient's assessment of disease activity, and the CRP level (both doses). Among patients with anemia at baseline, treatment with golimumab 50 mg, but not 100 mg, plus MTX was superior to treatment with placebo plus MTX in raising hemoglobin levels a minimum of 1 gm/dl from baseline to week 24.

The response observed with golimumab 100 mg plus MTX may have been impacted by the slight imbalances in baseline CRP levels between the 2 groups receiving golimumab plus MTX, with a higher proportion of patients in the group receiving golimumab 100 mg plus MTX having CRP levels below the LLOQ (0.3 mg/dl). Despite stratification of patients according to the baseline CRP level and the fact that the proportion of patients with a CRP level <1.5 mg/dl was similar in the groups receiving golimumab 50 mg plus MTX and the group receiving golimumab 100 mg plus MTX, the median CRP levels were 0.5 mg/dl and 0.3 mg/dl in the lowest quartiles of those groups, respectively. It is noteworthy that the LLOQ of the CRP assay was 0.3 mg/dl, and that for the purpose of the analysis, a CRP level of <0.3 mg/dl was considered to be equal to 0.3 mg/dl. Thus, patients with CRP levels of ≤0.3 mg/dl at baseline would not be able to show an improvement from baseline in this ACR component.

The impact of baseline CRP is highlighted by the analysis of patients with a baseline CRP level of >1.0 mg/dl, the results of which indicated nearly identical ACR50 response rates at week 24 in the group receiving golimumab 50 mg plus MTX (44.2%) and the group receiving golimumab 100 mg plus MTX (44.6%). The group receiving golimumab 100 mg plus MTX also showed a higher ACR50 response rate within the stratum of patients with a CRP level of ≥1.5 mg/dl as part of the primary analysis. Furthermore, in a post hoc analysis in which CRP values of ≤0.3 mg/dl were assigned a value of 0.15 mg/dl rather than 0.3 mg/dl as used in the primary analysis, a P value of 0.039 was achieved. It is also noteworthy that the group receiving golimumab 100 mg plus MTX was not statistically superior to the group receiving MTX alone when evaluated by the DAS28 remission criteria using the CRP but did show statistical superiority when evaluated by the DAS28 remission criteria using the ESR. In this study, however, even when taking these factors into consideration, the regimen of golimumab 100 mg plus MTX did not appear to provide greater efficacy than the regimen of golimumab 50 mg plus MTX.

Golimumab was generally well tolerated, with no unexpected safety issues. The incidence of serious adverse events and serious infections was low and similar across treatment groups, with the exception of a seemingly higher incidence of serious infections with golimumab 100 mg plus MTX (4.4%) versus the other treatments (1.3–1.9%). It is noteworthy that the relatively small number of patients evaluated and the lack of power to detect treatment group differences in individual safety events preclude drawing definitive conclusions regarding these isolated safety findings. Two patients died during the 24-week study period (1 receiving golimumab 50 mg plus MTX and 1 receiving golimumab 100 mg plus MTX). In 1 patient in the golimumab 50 mg plus MTX group, TB of the spine was diagnosed 33 days after that patient received the third (week 8) golimumab dose. A review of that patient's record indicated that the spinal lesion was present prior to study entry.

Injection-site reactions were most common in patients receiving golimumab 100 mg plus placebo (10.8%), followed by those receiving golimumab 100 mg plus MTX (8.8%), golimumab 50 mg plus MTX (4.4%), and placebo plus MTX (1.9%). No injection-site reaction was severe, serious, or resulted in permanent discontinuation of the study agent. The overall incidence of antibodies to golimumab was low (6.3%). The number of antibody-positive patients was too small to ascertain the impact of these antibodies on efficacy or safety.

The totality of study data through week 24, which includes a comparison of golimumab with or without MTX versus placebo plus MTX across a wide range of clinical response parameters, indicates that golimumab administered subcutaneously at a dosage of 50 mg or 100 mg every 4 weeks plus MTX reduces signs and symptoms of active RA in patients who had not previously received MTX or biologic anti-TNF therapy. Although the golimumab 100 mg plus MTX regimen provided no additional benefit compared with golimumab 50 mg plus MTX, it did appear to increase the risk of serious infection and injection-site reactions. Golimumab 100 mg without MTX also reduced signs and symptoms of RA and was statistically noninferior to MTX at a dosage of 20 mg/week. The golimumab safety profile appeared similar to that of other anti-TNFα agents.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

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, Moreland, Hsia, Park, Rahman.

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

Analysis and interpretation of data. Emery, Fleischmann, Moreland, Hsia, Nash, Amante, Doyle, Visvanathan, Xu, Rahman.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

Centocor Research and Development, Inc. and Schering-Plough Research Institute, Inc. sponsored this study. The steering committee (Paul Emery, MA, MD, FRCP, Roy M. Fleischmann, MD, Larry W. Moreland, MD, Elizabeth C. Hsia, MD, MSCE, and Mahboob U. Rahman, MD, PhD) assisted Centocor scientists with the study design and conduct. 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 a medical writer, 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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

We thank the patients, investigators, and study personnel who made this trial possible. Michelle Perate, MS, Mary Whitman, PhD, and Kirsten Schuck of Centocor Ortho Biotech, Inc. assisted in preparing and submitting the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A
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APPENDIX A

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. APPENDIX A

THE GO-BEFORE INVESTIGATORS

The investigators who participated in the GO-BEFORE study, in addition to the authors, are as follows: J. C. Barreira, A. Berman, M. A. Lazaro, G. A. Tate, O. Hübscher (Argentina); S. Hall (Australia); K. Machold (Austria); F. A. E. Houssiau, M. Malaise (Belgium); H. El-Gabalawy, M. Khraishi, G. Thomson (Canada); P. C. M. Cabezas, A. M. F. Torterolo, M. L. M. Vega (Chile); L. Hodinka, P. Keszthelyi, L. Nafradi (Hungary); V. S. C. Mouli, S. Chandrashekara, R. Misra (India); C. Salvarani (Italy); G. S. Chyn, H. Hussein, A. B. Rosman (Malaysia); D. W. T. Ching, P. J. Gow, G. P. Singh (New Zealand); J. M. Antigua, M. Y. Barba, J. J. T. Lichauco, S. T. G. Victorio-Navarra (Philippines); J. Brzezicki, M. S. Brzosko, Z. A. Mencel, A. Filipowicz-Sosnowska, H. Chwalińska-Sadowska, J. A. Pazdur, S. J. Sierakowski (Poland); I. Bokarev, E. Nasonov, A. Rebrov, N. Shilkina (Russia); F. K. Yong (Singapore); S. C. Bae, S. W. Kang, S. H. Park, C. H. Suh (South Korea); E. R. Gieb, E. M. Mola, F. N. Sarabia, V. R. Valverde, J. A. R. Ivorra (Spain); C. M. Haung, J. L. Lan, H. Y. Lin, W. C. Tsai (Taiwan); P. Asavatanabodee, W. Louthrenoo, K. Nantiruj, S. Nilganuwong (Thailand); O. Dyadyk, G. V. Dzyak, O. Grishyna, V. Kovalenko (Ukraine); B. Kirkham (UK); J. D. Anderson, A. Hou, E. P. Boling, J. Del Giudice, G. DiVittorio, J. E. Ervin, R. Kipnis, K. M. Latinis, S. D. Mathews, M. Miniter, F. T. Murphy, E. G. Moreta-Freire, B. R. Rubin, M. A. Stern, M. Weitz, C. Wiesenhutter (US).