The purpose of this study is to evaluate the efficacy and safety of golimumab, alone or in combination with methotrexate, as compared to methotrexate alone in rheumatoid arthritis subjects who have not been previously treated with methotrexate.
OBJETIVO: Evaluar la eficacia y seguridad de golimumab en metotrexato (MTX) sin tratamiento previo con pacientes con artritis reumatoide activa (AR). MÉTODOS: MTX-ingenuos pacientes con AR (n = 637) fueron aleatorizados para recibir placebo más MTX (grupo 1), golimumab 100 mg y placebo (grupo 2), golimumab 50 mg + MTX (grupo 3), o golimumab 100 mg, más MTX (grupo 4). Las inyecciones subcutáneas de golimumab o placebo se administró cada 4 semanas. La dosis de MTX / cápsulas de placebo se inició a 10 mg / semana y se intensificó a 20 mg / semana. El punto final primario, la proporción de pacientes que cumplen el American College of Rheumatology criterios de mejora de 50% (el logro de una respuesta ACR50) en la semana 24, requeridos diferencias significativas entre los grupos 3 y 4 combinados (grupo mixto) frente al grupo 1 y las diferencias significativas en una de comparación de pares (grupo de 3 o 4 frente al grupo 1). RESULTADOS: La intención de tratar (ITT), el análisis de la respuesta ACR50 en la semana 24 no mostraron una diferencia significativa entre el grupo combinado y el grupo 1 (38,4% y 29,4%, respectivamente, p = 0,053), mientras que un post hoc análisis ITT modificada (con exclusión de 3 pacientes no tratados) de la respuesta ACR50 mostró diferencias estadísticamente significativas entre el grupo combinado y el grupo 1 (38,5% frente a 29,4%, p = 0,049) y entre el grupo 3 (40,5%, p = 0,038) del grupo, pero no 4 (36,5%, p = 0,177) y el grupo 1. El grupo 2 fue inferior en el grupo 1 de la respuesta ACR50 en la semana 24 (33,1%, 95% intervalo de confianza límite inferior -5,2%; valor predefinido de no inferioridad del delta -10%). La combinación de golimumab más MTX demostraron una respuesta significativamente mejor en comparación con placebo más MTX en la mayoría de los parámetros de eficacia, incluyendo la respuesta / remisión de acuerdo con el Disease Activity Score 28, en las articulaciones. Los acontecimientos adversos graves se produjeron en el 7%, 3%, 6% y el 6% de los pacientes en los grupos 1, 2, 3 y 4, respectivamente. CONCLUSIÓN: Aunque el punto final primario no se cumplió, el análisis por ITT modificada del punto final primario y otras medidas de eficacia predefinidos demostrado que la eficacia de golimumab más MTX es mejor que el, y la eficacia de golimumab por sí sola es similar a la eficacia de la MTX solo en la reducción de los signos y síntomas de la AR en pacientes sin tratamiento previo con MTX, sin problemas de seguridad inesperados.
OBJETIVO: Evaluar los efectos de golimumab en la progresión radiográfica en pacientes con artritis reumatoide (AR).
MÉTODOS: El metotrexato (MTX) pacientes -naive (en el golimumab antes de emplear metotrexato como thefirst-Line opción en el tratamiento de la artritis reumatoide de inicio temprano estudio [GO-ANTES]; n = 637) y pacientes con AR activa a pesar del tratamiento con MTX ( en el golimumab en Active artritis reumatoide A pesar de la terapia con metotrexato estudio [GO-FORWARD]; n = 444) fueron asignados al azar para recibir placebo más MTX (grupo 1), golimumab 100 mg más (grupo 2) placebo, golimumab 50 mg más MTX ( grupo 3), o golimumab 100 mg más MTX (grupo 4). Orplacebo golimumab se administró por vía subcutánea cada 4 semanas. Las radiografías de las manos y los pies se tomaron al inicio del estudio, la semana 28 y la semana 52 en el estudio-GO ANTES y al inicio del estudio, la semana 24 (semana 16 para los pacientes que ingresaron a escapar antes de tiempo), y la semana 52 en el estudio de seguir adelante. Las radiografías fueron anotados por 2 lectores independientes en cada estudio utilizando el van der Heijde modificación del índice de Sharp.
Resultados: En el estudio-GO ANTES, la media ± SD cambios en el índice de Sharp modificado desde la línea base hasta la semana 52 (período de control) fueron 1,4 ± 4,6 en el grupo 1, 1,3 ± 6,2 en el grupo 2 (p = 0,266), 0.7 ± 5,2 en el grupo 3 (P = 0,015), y 0,1 ± 1,8 en el grupo 4 (P = 0,025). En el estudio de ir hacia adelante, los cambios desde el inicio hasta la semana 24 (período de control) fueron 0,6 ± 2,4 en el grupo 1, 0,3 ± 1,6 en el grupo 2 (p = 0,361), 0,6 ± 2,7 en el grupo 3 (P = 0,953), y 0,2 ± 1,3 en el grupo 4 (P = 0,293).
CONCLUSIÓN: El golimumab en combinación con MTX inhibe la progresión radiográfica significativamente mejor que hizo MTX solo en el estudio-GO ANTES. La progresión radiográfica en el estudio-GO FORWARD fue mínima en todos los grupos de tratamiento, lo que impide una evaluación adecuada del efecto de golimumab en la progresión radiográfica en este estudio.
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.
Objectives To assess golimumab (GLM) treatment effect in patients with rheumatoid arthritis (RA) naïve to methotrexate (MTX) therapy with severe, active and progressive disease. Methods The GO-BEFORE trial studied GLM 50mg and 100mg + MTX in MTX-naïve patients. In the overall GO-BEFORE study population, patients exhibited lower disease activity (baseline ACR components and DAS28) than was observed in previous studies of biologic agents in MTX-naive patients1. This is a retrospective analysis of GO-BEFORE wk 52 data which compares efficacy outcomes in subsets of RA patients with severe, active disease to the overall study population. 637 MTX-naïve pts were randomized to PBO+MTX (Grp 1), GLM 100mg+PBO (Grp 2), GLM 50mg+MTX (Grp 3), or GLM 100mg+MTX (Grp 4). GLM/PBO received injections q4wks. Pts with 5.1, and CRP ≥3 mg/dL. Treatment effect for each subset and the overall population was defined as the differences between GLM 50mg or 100mg +MTX and MTX-alone in ACR50, DAS28 (CRP) remission, change in HAQ ≥0.25 and total vdHS score ≤0. Differences in the treatment effect between each subset of severe, active and progressive RA and the overall population was examined. Results Greater proportions of patients achieved the efficacy endpoints in the GLM+MTX groups versus MTX-alone and the difference between the treatment groups (tx effect) was generally larger in the severe, active and progressive subsets compared with the overall population (Table). Conclusions Overall, treatment effect in the efficacy parameters between GLM 50mg +MTX and GLM 100mg +MTX versus MTX-alone was greater for the severe, active and progressive subsets versus the overall population. (Table Presented).
Objectives To assess the impact of golimumab (GLM) on physical function and employability in patients with rheumatoid arthritis (RA) with various prior treatment histories, after 5 years of therapy. Methods The efficacy and safety of GLM were assessed in methotrexate (MTX)-naïve RA patients (GO-BEFORE, N=637), patients with inadequate response to MTX (GO-FORWARD, N=444), and patients previously treated with TNF-inhibitors (TNFi, GO-AFTER, N=445). Patients with active RA were randomized to placebo (PBO), GLM 100mg+PBO (GO-BEFORE and GO-FORWARD), or GLM (50 or 100mg), q4w. Patients in GO-BEFORE and GO-FORWARD could receive concomitant MTX or no MTX and crossed-over to GLM after wk24 (GO-FORWARD) OR wk52 (GO-BEFORE), while patients in GO-AFTER were on background (with or without) MTX and crossed-over to GLM after wk24. Clinical remission was defined as DAS28 (ESR) <2.6. Physical function was measured using Health Assessment Questionnaire (HAQ) and employability was defined as being employed or being able to work if job was available (Yes/No). 5 year data were presented by 3 patient populations. Results At baseline, the percent of patients with disability (HAQ-DI score >0.5) in each of 3 RA populations were 90.9% in patients who were MTX-naïve, 87.6% in patients who were MTX-inadequate responders and 92.3% in patients who were TNFi-experienced. Among the analyzed patient population for employability (not retired and age<65 years), the percent of patients unemployable due to their RA at baseline were 9% in MTX-naïve patients, 8.1% in MTX-inadequate responders and 13.1% in TNF-experienced patients. After treatment with GLM, among those who had disability at baseline, 46.8% of MTX-naive patients, 37.5% of MTX-inadequate responders and 27.5% of TNFi-experienced patients had no disability (HAQ-DI score≤0.5) at wk256; among patients unemployable at baseline, 29.5% of MTX-naive patients, 28.6% of MTX-inadequate responders and 5.4% of TNFi-experienced patients regained employability at wk256. Similar trends of better outcomes on disability and employability of MTX-naïve patients were observed among those who achieved remission at wk256: 65.1% in MTX- naive patients, 54.4% in MTX-inadequate responders and 53.1% in TNFi-experienced patients achieved no disability; and 73.3% in MTX-naive patients, 50% in MTX-inadequate responders and 50.0% in TNFi-experienced patients regained employability. Conclusions This analysis indicates that effective treatment at an early stage may result in reduction in disability and improvement in employability over the long-term.
OBJECTIVE: To evaluate the safety and efficacy of golimumab through 5 years in adults with active rheumatoid arthritis (RA) who had not previously received methotrexate (MTX).
METHODS: In the GO-BEFORE study, 637 MTX-naive adult patients with active RA 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). Inadequate responders in groups 1, 2, and 3 entered early escape at week 28 to golimumab 50 mg + MTX, golimumab 100 mg + MTX, or golimumab 100 mg + MTX, respectively; remaining patients in group 1 could cross over to golimumab 50 mg + MTX at week 52. Assessments included the American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) response, the Disease Activity Score in 28 joints (DAS28) using C-reactive protein (CRP) level, and the modified Sharp/van der Heijde score (SHS). Efficacy was analyzed using an intent-to-treat (ITT) analysis. Pharmacokinetics and immunogenicity were evaluated at selected visits.
RESULTS: A total of 422 patients completed golimumab treatment through week 256. At week 256, 72.8%, 54.6%, and 38.0% of all patients in the full ITT population (n = 637) had an ACR20/50/70 response, respectively; 84.1% had a good or moderate DAS28-CRP response; and 72.7% had a clinically meaningful improvement in physical function. Radiographic progression was minimal in all treatment groups through week 256, and the overall mean change from baseline in SHS was 1.36. Serum trough golimumab concentrations were approximately dose proportional and maintained through week 256. Antibodies to golimumab occurred in 9.6% of patients through week 256. Infections were the most common type of adverse event (AE); 204 of 616 patients (33.1%) had ≥1 serious AE.
CONCLUSION: Clinical efficacy with golimumab treatment was maintained through week 256 of the GO-BEFORE trial of MTX-naive RA patients. No unexpected AEs occurred; safety results through 5 years are consistent with earlier reports.
OBJECTIVE: To evaluate the construct validity of the rheumatoid arthritis MRI score (RAMRIS) erosion evaluation as structural damage end point and to assess the potential impact of incorporation in clinical trials.
METHODS: In a randomised trial of early methotrexate-naïve RA (GO-BEFORE), RAMRIS scores were determined from MRIs and van der Heijde-Sharp (vdHS) scores from radiographs, at baseline, week 12, week 24 and week 52. Progression in damage scores was defined as change >0.5. Associations of X-ray and MRI outcomes with clinical features were evaluated for convergent validity. Iterative Wilcoxon rank sum tests and tests of proportion estimated the sample size required to detect differences between combination therapy (methotrexate+golimumab) and methotrexate-monotherapy arms in (A) change in damage score and (B) proportion of patients progressing.
RESULTS: Patients with early MRI progression had higher DAS28, C reactive protein (CRP) and vdHS at baseline, and higher 2-year HAQ. Associations were similar to those with 1-year vdHS progression. Differences in change in structural damage between treatment arms achieved significance with fewer subjects when 12-week or 24-week MRI erosion score was the outcome (150 patients; 100 among an enriched sample with baseline-synovitis >5) compared with the 52-week vdHS (275 patients). Differences in the proportion progressing could be detected in 234 total subjects with 12-week MRI in an enriched sample whereas 1-year X-ray required between 468 and 1160 subjects.
CONCLUSIONS: Early MRI erosion progression is a valid measure of structural damage that could substantially decrease sample size and study duration if used as structural damage end point in RA clinical trials.
PURPOSE: We assessed whether MRI measures of synovitis, osteitis and bone erosion were associated with patient-reported outcomes (PROs) in a longitudinal clinical trial setting among patients with rheumatoid arthritis (RA).
METHODS: This longitudinal cohort of 291 patients with RA was derived from the MRI substudy of the GO-BEFORE randomised controlled trial of golimumab among methotrexate-naïve patients. Correlations between RAMRIS scores (synovitis, osteitis, bone erosion) and physical function (Health Assessment Questionnaire (HAQ)), pain and global patient scores were determined at 0, 12, 24 and 52 weeks. Correlations between interval changes were also assessed. Multivariable regression models using robust generalised estimating equations evaluated associations over all time-points and their relationship to other clinical disease activity measures.
RESULTS: Greater synovitis, osteitis and bone erosion scores were positively associated with HAQ at all time-points (all p<0.05) and with pain and patient global scores at 24 and 52 weeks. Over all visits, synovitis was associated with HAQ, pain and patient global scores (p≤0.03) independent of clinical disease activity measures. Improvements in synovitis and bone erosion were also associated with improvements in PROs. Less improvement in synovitis and progression in MRI erosion at 52 weeks were both independently associated with worsening in all PROs at 52 weeks while progression on X-ray was not associated. Similar associations were observed across treatment groups.
CONCLUSIONS: MRI measures of inflammation and structural damage correlate independently with physical function, pain and patient global assessments. These observations support the validity of MRI biomarkers.
TRIAL REGISTRATION NUMBER: NCT00264537; Post-results.
The purpose of this study is to evaluate the efficacy and safety of golimumab, alone or in combination with methotrexate, as compared to methotrexate alone in rheumatoid arthritis subjects who have not been previously treated with methotrexate.
