[show abstract][hide abstract] ABSTRACT: To assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials.
Golimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naïve, methotrexate-experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naïve), with early escape at wk 16 (wk 28, methotrexate-naïve); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo-controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial.
Across five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for ≥156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma.
SC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow-up up to year 5 continues.
Annals of the rheumatic diseases 12/2013; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective. To evaluate the effect of golimumab on haemoglobin levels in patients with RA, PsA or AS.Methods. Secondary analysis was performed on integrated data from five randomized controlled studies: three RA, one PsA and one AS (2303 patients total). Golimumab 50 or 100 mg was injected s.c. every 4 weeks with or without MTX. Control groups received placebo injections plus MTX or background therapy. Patients with haemoglobin levels below the age- and sex-specific normal ranges were considered to have anaemia. Ferritin levels were used to distinguish anaemia of mixed aetiology (≥15 and <60 ng/ml) and anaemia of inflammation (≥60 ng/ml). Changes from baseline to weeks 14 and 24 in haemoglobin level were compared between treatment groups using an analysis of variance on the van der Waerden normal scores.Results. At baseline, 21% of RA patients, 9% of PsA patients and 15% of AS patients had anaemia. Of these, 24%, 57% and 25%, respectively, had anaemia of inflammation. The median increase from baseline to week 14 in the haemoglobin level of anaemic patients was 0.3 g/dl in the control group and 0.9 g/dl in the golimumab group (P < 0.001). Haemoglobin levels improved within the subgroups of patients with anaemia of mixed aetiology (control, 0.4 g/dl vs golimumab, 0.7 g/dl) (P = 0.305) and with anaemia of inflammation (0.2 vs 1.4 g/dl, respectively) (P < 0.001).Conclusion. Compared with the control group, patients receiving golimumab treatment had significantly improved haemoglobin levels, particularly among patients with anaemia of inflammation.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To evaluate radiographic progression in patients with ankylosing spondylitis (AS) receiving two different doses of the tumour necrosis factor antagonist golimumab. METHODS: 356 patients with AS were randomly assigned to placebo, or golimumab 50 mg or 100 mg every 4 weeks (wks). At wk16, patients with inadequate response early escaped with blinded dose adjustments (placebo→golimumab 50 mg, 50 mg→100 mg). At wk24, patients still receiving placebo crossed over to golimumab 50 mg. Lateral view radiographs of the cervical/lumbar spine were obtained at wk0, wk104 and wk208, and scored (two blinded readers, modified Stoke AS Spine Score (mSASSS)). Observed data were used for wk104 analyses; missing wk208 scores were linearly extrapolated. RESULTS: Wk104 changes from baseline in mSASSS averaged 1.6±4.6 for placebo crossover, 0.9±2.7 for 50 mg and 0.9±3.9 for 100 mg. By wk208, following golimumab therapy for 3.5-4 years, mean changes in mSASSS were 2.1±5.2 for placebo crossover, 1.3±4.1 for 50 mg and 2.0±5.6 for 100 mg. Less than a third of patients (placebo crossover, 19/66 (28.8%); 50 mg, 29/111 (26.1%); 100 mg, 35/122 (28.7%)) had a definitive change from baseline mSASSS (>2). Less radiographic progression was observed through wk208 in patients without baseline syndesmophytes (0.2 vs 2.8 in patients with ≥1 syndesmophyte; p<0.0001) and with baseline C-reactive protein (CRP) levels ≤1.5 mg/dl (0.9 vs 2.9 with CRP >1.5 mg/dl; p=0.0004). CONCLUSIONS: No difference in mSASSS change was observed between golimumab 50 mg and 100 mg. The radiographic progression rate remained stable at years 2 and 4, suggesting no acceleration of new bone formation over time. Golimumab-treated AS patients with no syndesmophytes and less systemic inflammation at baseline had considerably less radiographic progression.
Annals of the rheumatic diseases 05/2013; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective. To compare the abilities of three enthesitis indices to detect improvement in entheseal tenderness with the TNF antagonist golimumab in AS.Methods. Adult patients with active AS were randomly assigned to receive s.c. injections of placebo or golimumab (50 or 100 mg) every 4 weeks. Patients with inadequate week 16 responses were switched (blinded) from placebo to golimumab 50 mg or from golimumab 50 mg to 100 mg. At week 24, all patients still receiving placebo crossed over to golimumab 50 mg. Enthesitis data through week 52 are reported herein. Enthesitis was measured by a trained, independent assessor who recorded the presence or absence of tenderness in 27 entheses, which allowed simultaneous determination of three different indices [12-point Berlin Index, 17-point University of California, San Francisco (UCSF) Index and 13-point Maastricht AS Enthesitis Score (MASES)].Results. Three hundred and fifty-six AS patients were randomized to placebo (n = 78), golimumab 50 mg (n = 138) or golimumab 100 mg (n = 140); 355 had enthesitis data available for analysis. Using the UCSF Index, significant improvement from baseline vs placebo was observed for golimumab 100 mg at weeks 14 and 24. Using the MASES, significant improvement for golimumab 100 mg vs placebo at week 14 and a trend toward improvement at week 24 were observed. Using the Berlin Index, significant improvement for golimumab 100 mg vs placebo at week 14 was observed. Effect size determinations for changes to weeks 14, 24 and 52, respectively, in the Berlin (-0.27, -0.34, -0.42), UCSF (-0.44, -0.61, -0.55) and MASES (-0.30, -0.55, -0.39) indices suggested small to moderate effect sizes.Conclusion. In patients with active AS, the UCSF Index appeared most sensitive in detecting the effect of golimumab 100 mg vs placebo on enthesitis.Trial registration. http://www.clinicaltrials.gov, NCT00265083.
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: To investigate the relationship between MRI inflammation and measures of clinical disease activity as well as treatment responses in patients with ankylosing spondylitis (AS) treated with a tumour necrosis factor inhibitor. METHODS: MRI at baseline (n=221), 24 (n=158) and 102 weeks (n=179) were scored for inflammation/activity (MRIa, Berlin scoring system). Treatment responses according to the AS disease activity score (ASDAS), Bath AS disease activity index (BASDAI) and assessment of spondyloarthritis 20 (ASAS20) criteria were calculated. For each treatment response criterion, subgroups of responders and non-responders changes in MRIa scores were compared. RESULTS: Higher baseline ASDAS and C-reactive protein (CRP) values were associated with higher baseline MRIa scores and with greater decreases in MRIa scores at follow-up. ASDAS and CRP improvements correlated with MRIa improvement. Stronger correlations were observed for CRP. Differences in MRIa change scores between responders and non-responders were greater when subgroups were defined according to ASDAS response than according to BASDAI or ASAS20 response. CONCLUSIONS: MRIa correlates better with CRP than with other measures of disease activity. By including both CRP and patient-reported outcomes in its formula, ASDAS has the advantage of providing combined information on objective and subjective measures. As a status and response measure ASDAS better reflects the spinal inflammatory disease process in AS than other composite measures.
Annals of the rheumatic diseases 08/2012; · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti-tumor necrosis factor (TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase 3 Program (3 rheumatoid arthritis, 1 psoriatic arthritis, and 1 ankylosing spondylitis) through 1 year among 2210 golimumab-exposed patients. METHODS: Data from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy. RESULTS: No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients by week 52 (2 patients by week 24); all had negative screening TB tests (per local guidelines), and resided in countries with high background rates of TB. No deaths were due to TB. Across all groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times upper limit normal). CONCLUSION: A comprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB endemic regions. Treatment for latent TB infection appeared effective, as no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti-TB medication was generally well-tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF blockers, as prompt diagnosis and treatment can improve outcomes.
[show abstract][hide abstract] ABSTRACT: To investigate the relationship between MRI inflammation at the vertebral unit and the formation and growth of syndesmophytes at the same vertebral unit.
An 80% random sample of the ASSERT database was analysed. MRI were scored using the ankylosing spondylitis (AS) spinal MRI activity score (at baseline, 24 and 102 weeks) and spinal x-rays were scored using the modified Stoke AS spine score (at baseline and 102 weeks). Data were analysed at the patient level and the vertebral unit level using a multilevel approach to adjust for within-patient correlation.
There was a slightly increased probability of developing syndesmophytes in vertebral units with MRI activity, which was maintained after adjustment for within-patient correlation (per vertebral unit level) and treatment, and after further adjustment for potential confounders, resulting in significant OR ranging from 1.51 to 2.26. Growth of existing syndesmophytes at the vertebral unit level was not associated with MRI activity. At the patient level only a trend for an association was observed.
MRI inflammation in a vertebral unit slightly increases the propensity to form a new syndesmophyte in the same vertebral unit, but does not predict the growth of already existing syndesmophytes. Despite this association, the large majority of new syndesmophytes developed in vertebral units without inflammation. The subtle association at the vertebral unit level did not translate into an association at the patient level.
Annals of the rheumatic diseases 03/2012; 71(3):369-73. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the performance of an interferon-γ release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti-tumor necrosis factor therapy in patients with autoimmune inflammatory diseases.
This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test.
In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157-0.279; P=0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guérin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P=0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P=0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported.
In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST.
[show abstract][hide abstract] ABSTRACT: To evaluate golimumab's effect on MRI-detected spinal inflammation in ankylosing spondylitis (AS).
Patients were randomly assigned to subcutaneous injections of placebo (n=78), golimumab 50 mg (n=138), or golimumab 100 mg (n=140) every 4 weeks. An MRI substudy comprising 98 patients (placebo n=23, 50 mg n=37, 100 mg n=38) at eligible MRI substudy sites had serial spine MRI scans (sagittal plane, 1.5T scanners, T1 and short tau inversion recovery sequences) at baseline and weeks 14 and 104. Two blinded (treatment, image order) readers independently evaluated MRI spinal inflammation using AS spine MRI-activity (ASspiMRI-a) scores; reader scores were averaged. Changes from baseline to weeks 14 and 104 were compared among treatment groups using analysis of variance on van der Waerden normal scores both with (post-hoc) and without (prespecified) adjustment for baseline ASspiMRI-a scores.
Median baseline ASspiMRI-a scores were lower in the 100 mg (3.5) than placebo (6.8) and 50 mg (7.8) groups. Median decreases in activity scores from baseline to week 14 were -0.5 for placebo, -3.5 for 50 mg (p=0.047 vs placebo), and -1.5 for 100 mg (p=0.14 vs placebo). After adjusting for baseline ASspiMRI-a score imbalance, significant improvements were observed with both 50 mg (p=0.011) and 100 mg (p=0.002) versus placebo. ASspiMRI-a scores improvement achieved with golimumab was maintained at week 104. Improvement in ASspiMRI-a scores correlated with improvement in the recently developed AS disease activity score (ASDAS) and C-reactive protein (CRP) levels but not with other key AS clinical outcomes.
Golimumab significantly reduced MRI-detected spinal inflammation of AS; improvements were sustained to week 104 and correlated with improvement in ASDAS and CRP.
Annals of the rheumatic diseases 11/2011; 71(6):878-84. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the efficacy and safety of golimumab over 104 weeks in patients with active ankylosing spondylitis.
At baseline, patients with active ankylosing spondylitis (n=356) were randomly assigned (1:1.8:1.8) to subcutaneous injections of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3) every 4 weeks. At week 16, patients in groups 1 and 2 with <20% improvement in total back pain and morning stiffness entered early escape to 50 or 100 mg, respectively. At week 24, patients still receiving placebo crossed over to golimumab 50 mg. Findings through week 24 were previously reported; those through week 104 are presented herein.
At week 104, 38.5%, 60.1% and 71.4% of patients in groups 1, 2 and 3, respectively, had at least 20% improvement in the Assessment in SpondyloArthritis international Society response criteria (ASAS20); 38.5%, 55.8% and 54.3% had an ASAS40 response and 21.8%, 31.9% and 30.7% were in ASAS partial remission. Mean Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores were <3 at week 104 for all the treatment regimens. Golimumab safety through week 104 was similar to that through week 24.
Clinical response that was achieved by patients receiving golimumab through 24 weeks was sustained through 52 and 104 weeks. The golimumab safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.
Annals of the rheumatic diseases 11/2011; 71(5):661-7. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Identify serum biomarkers modulated by golimumab treatment and associated with clinical response in patients with ankylosing spondylitis (AS).
Sera were collected at weeks 0, 4 and 14 from 100 patients with active AS in the GO-RAISE study. Patients were randomly assigned subcutaneous injections of placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks. Samples were tested for select inflammatory, bone and cartilage markers, and protein profiling was also performed.
Golimumab treatment resulted in significant decreases in several serum proteins at weeks 4 and 14 compared with placebo. Patients who achieved clinical response at week 14, as assessed by a ≥20% improvement in the Assessment in SpondyloArthitis international Society response criteria (ASAS 20), demonstrated a distinct biomarker profile with lower levels of acute phase reactants and inflammatory biomarkers compared with patients who did not. Notably, combinations of two or three biomarkers assessed at baseline were predictive of various clinical outcomes (ASAS 20, Bath ankylosing spondylitis disease activity index 50 or Bath ankylosing spondylitis functional index) using a logistic regression analysis, and the overall predictive values for these combined biomarkers were greater than observed for C-reactive protein (CRP) alone.
Golimumab modulated acute phase reactants and inflammatory markers in patients with active AS. Specific combinations of biomarkers at baseline demonstrated a stronger prediction for clinical efficacy than CRP alone. These data provide insights into the mechanism of golimumab on inflammatory processes driving AS pathology, and may have utility in managing the treatment of patients with AS.
Annals of the rheumatic diseases 10/2011; 71(5):674-80. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: To create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease profile of individual patients with ankylosing spondylitis (AS).
ASSERT and GO-RAISE trial data (n=635) were analysed to identify baseline predictors for various disease-state and disease-activity outcome instruments in AS. Univariate, multivariate, receiver operator characteristic and correlation analyses were performed to select final predictors. Their associations with outcomes were explored. Matrix and algorithm-based prediction models were created using logistic and linear regression, and their accuracies were compared. Numbers needed to treat were calculated to compare the effect size of anti-TNF therapy between the AS matrix subpopulations. Data from registry populations were applied to study how a daily practice AS population is distributed over the prediction model.
Age, Bath ankylosing spondylitis functional index (BASFI) score, enthesitis, therapy, C-reactive protein (CRP) and HLA-B27 genotype were identified as predictors. Their associations with each outcome instrument varied. However, the combination of these factors enabled adequate prediction of each outcome studied. The matrix model predicted outcomes as well as algorithm-based models and enabled direct comparison of the effect size of anti-TNF treatment outcome in various subpopulations. The trial populations reflected the daily practice AS population.
Age, BASFI, enthesitis, therapy, CRP and HLA-B27 were associated with outcomes in AS. Their combined use enables adequate prediction of outcome resulting from anti-TNF and conventional therapy in various AS subpopulations. This may help guide clinicians in making treatment decisions in daily practice.
Annals of the rheumatic diseases 03/2011; 70(6):973-81. · 8.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the effect of golimumab on sleep disturbance in patients with active ankylosing spondylitis (AS).
Golimumab was studied in a multicenter, randomized, placebo-controlled study (GO-RAISE). At baseline, 356 patients were randomly assigned in a 1.8:1.8:1 ratio to subcutaneous golimumab 50 mg, 100 mg, or placebo every 4 weeks. Sleep disturbance was assessed using the Jenkins Sleep Evaluation Questionnaire (JSEQ), which was administered at baseline, week 14, and week 24. Treatment effect was evaluated using analysis of variance on the van der Waerden normal scores.
Median JSEQ scores at baseline were 9.0 in the placebo group, 10.0 in the 50-mg group, and 11.0 in the 100-mg group, indicating moderate to severe sleep disturbance. Patients who received golimumab showed significantly greater median improvement from baseline in JSEQ scores compared with placebo at week 14 (-3.0 versus 0.0; P < 0.001) and week 24 (-3.0 versus -1.0; P < 0.001). Changes from baseline in JSEQ scores significantly correlated with changes from baseline in Short Form 36 summary scores, Bath AS Functional Index scores, total back pain, night back pain, and Bath AS Disease Activity Index scores. Multiple regression analyses indicated that improvement in the night back pain score was the most consistent predictor of change in JSEQ score or reduction in sleep disturbance.
Patients with active AS showed significant sleep disturbance at baseline due to underlying pain associated with AS. Treatment with subcutaneous golimumab every 4 weeks significantly reduced sleep disturbance and improved health-related quality of life.
Arthritis care & research. 09/2010; 62(9):1266-71.
[show abstract][hide abstract] ABSTRACT: To evaluate the efficacy and safety of golimumab in patients with ankylosing spondylitis (AS) in the GO-RAISE study.
Patients with active AS, a Bath AS Disease Activity Index (BASDAI) score > or =4, and a back pain score of > or =4 were randomly assigned in a 1.8:1.8:1 ratio to receive subcutaneous injections of golimumab (50 mg or 100 mg) or placebo every 4 weeks. The primary end point was the proportion of patients with at least 20% improvement in the ASsessment in AS (ASAS20) criteria at week 14.
At randomization, 138, 140, and 78 patients were assigned to the 50-mg, 100-mg, and placebo groups, respectively. After 14 weeks, 59.4%, 60.0%, and 21.8% of patients, respectively, were ASAS20 responders (P < 0.001). A 40% improvement in the ASAS criteria at week 24 occurred in 43.5%, 54.3%, and 15.4% of patients, respectively. Patients receiving golimumab also showed significant improvement in the physical and mental component summary scores of the Short Form 36 Health Survey, the Jenkins Sleep Evaluation Questionnaire score, the BASDAI score, and the Bath AS Functional Index score, but not the Bath AS Metrology Index score. Through week 24, 85.6% of golimumab-treated patients and 76.6% of patients in the placebo group had > or =1 adverse event, and 5.4% and 6.5% of patients, respectively, had > or =1 serious adverse event. Eight golimumab-treated patients and 1 placebo-treated patient had markedly abnormal liver enzyme values (> or =100% increase from baseline and a value >150 IU/liter), which were transient.
Golimumab was effective and well tolerated in a large cohort of patients with AS during a 24-week study period.