This randomized, double-blind, parallel group study will assess the safety, disease remission, and prevention of structural joint damage in patients with early moderate to severe rheumatoid arthritis treated with tocilizumab as monotherapy or in combination with methotrexate, versus methotrexate alone. Patients will be randomized to receive either (A) tocilizumab (8 mg/kg iv every 4 weeks) plus placebo, (B) tocilizumab (8 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), (C) tocilizumab (4 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), or (D) placebo plus methotrexate (7.5-20 mg po weekly). Patients in groups C and D who have not achieved low disease activity at week 52 can receive tocilizumab 8 mg/kg iv every 4 weeks. Anticipated time on study treatment is 104 weeks.
ANTECEDENTES: Las recomendaciones recientes apoyan el tratamiento intensivo de pts con AR temprana para lograr la remisión o la enfermedad bajo activity.1-3 TCZ no fue estudiado previamente exclusivamente en una población de la AR temprana. OBJETIVOS: Evaluar la eficacia y seguridad del tratamiento con TCZ {+/-} MTX frente a MTX en pts MTX-ingenuos con AR temprana (definida como [& le;] 2 y desde el diagnóstico). MÉTODOS: Pts fueron aleatorizados 1: 1: 1: 1 (doble simulación, doble-ciego) para recibir TCZ 8 mg / kg (TCZ8) + MTX (intervención primaria), TCZ8 monoterapia, TCZ 4 mg / kg (TCZ4) + MTX o MTX durante 104 semanas. Pts recibió IV TCZ Q4w, y MTX a partir de 7,5 mg qw, escalada a 20 mg qw por sem 8. Los criterios de inclusión incluyeron RA para [& le;] 2 y, DAS28> 3,2, MTX ingenuo, VSG elevada o la PCR y la presencia de anticuerpos o la erosión radiográfica (s) de RF o anti-CCP. El punto final primario fue la proporción de puntos que alcanzan la remisión DAS28 (DAS28-VSG <2,6) a las 24 semanas. Criterios de valoración secundarios clave incluyen cambios medios desde la línea de base (BL) WK 52 de van der Heijde modificado puntuación total de Sharp (MTSS) y la mejora de la función física (HAQ-DI usando). Una jerarquía de la prueba estadística se llevó a cabo para controlar la tasa de error de tipo 1 para la multiplicidad. Este ensayo está en curso; Datos de 52 sem se reportan aquí. RESULTADOS: La población por intención de tratar (ITT) consistieron en 1.157 pts. BL características fueron similares en todos los grupos de tratamiento: duración media de la RA, 0,4-0,5 y; significa DAS28, 06.06 a 06.07; mTSS, 5,66-7,72. Estadísticamente significativa mayor proporción de TCZ8 + MTX que la remisión DAS28 pts MTX logrado y ACR20 / 50/70 respuestas a las 24 semanas y 52 (p <0,05); estadísticamente mejoras significativas en la media mTSS y HAQ-DI, también se observaron en la semana 52 (p <0,05; Tabla). TCZ8 monoterapia también se reunió con el criterio principal de valoración (p <0,05). Tanto la monoterapia TCZ8 y TCZ4 + MTX mostraron numéricamente mayores mejoras en comparación con MTX a través de criterios de valoración secundarios clave. Eventos adversos observados (AA) con TCZ fueron consistentes con el perfil de seguridad conocido. La incidencia de acontecimientos adversos y acontecimientos adversos graves fueron similares entre los grupos de tratamiento, mientras que las infecciones graves fueron más altas en puntos en la terapia de combinación (Tabla). En general, se observaron 9 muertes en todos los grupos de tratamiento; las causas subyacentes de la muerte fueron variables. CONCLUSIONES: TCZ fue eficaz como terapia de combinación y la monoterapia en pts MTX-ingenuos con AR temprana activa. TCZ tratamiento resultó en mejoras de BL en los signos, los síntomas y la función física y en la inhibición del daño articular estructural en todos los grupos de tratamiento. De los 3 grupos de tratamiento TCZ, respuestas de eficacia de TCZ frente a MTX fueron consistentemente mayor en el grupo de TCZ8 + MTX. La seguridad general de TCZ era coherente con su perfil conocido.
BACKGROUND/PURPOSE: Treatment with tocilizumab (TCZ) in combination with MTX or as monotherapy (Mono) in MTX-naive patients (pts) with early RA resulted in improved signs and symptoms and inhibition of joint damage at wk 52 of the 104-wk, double-blind, placebo-controlled trial FUNCTION.1 Results to wk 104 are presented. METHODS: Pts were randomized 1:1:1:1 to TCZ 8 mg/kg (TCZ8) + MTX, TCZ8 Mono, TCZ 4 mg/kg (TCZ4) + MTX, or MTX for 104 wks. Pts received IV TCZ q4w, with MTX escalated from 7.5 mg qw to 20 mg qw by wk 8. Inclusion criteria have been described.1 At wk 52, TCZ4 + MTX and MTX pts who had not achieved low disease activity (DAS28 ≤3.2) switched to blinded escape therapy with TCZ8 + MTX. Efficacy end points (DAS28, ACR responses, and van der Heijde–modified Total Sharp Score) were assessed in the intent-to-treat (ITT) population, and a subgroup analysis was performed for postescape data. Adverse events (AEs) were evaluated under the treatment group in which the AE occurred. Wk 104 analyses were exploratory; no statistical testing was performed. RESULTS: At wk 52, 95/290 (33%) TCZ4 + MTX pts and 142/289 (49%) MTX pts switched to TCZ8 + MTX escape therapy. Baseline characteristics of escape pts were consistent with those of the full ITT population.1 Clinical efficacy was maintained through wk 104 in the TCZ8 groups, with similar proportions at wks 52 and 104 achieving ACR20/50/70 responses and DAS28, ACR/EULAR Boolean/Index, and Clinical Disease Activity Index criteria remission. Inhibition/slowing of radiographic progression was also maintained. In TCZ4 + MTX and MTX pts who switched to escape with TCZ8 + MTX at wk 52, further improvement in efficacy from the point of escape was generally seen at wk 104. Despite the inhibition of structural joint damage after escape, joint damage was numerically greater than in pts who received TCZ8 Mono or TCZ8 + MTX throughout (Table). TCZ serum levels were similar with both Mono and combination TCZ treatment. AE rates were similar across groups, with serious AE and serious infection rates numerically higher in the TCZ groups (Table). There were 14 deaths (9 reported earlier1); 5 occurred in year 2. Underlying causes varied and included 4 due to infection (2 MTX; 2 TCZ4 + MTX), 3 due to malignancy (1 TCZ8 + MTX; 2 TCZ8 Mono), and 2 due to cardiovascular disease (1 TCZ4 + MTX; 1 TCZ8 Mono). CONCLUSION: Pts with early RA who received TCZ8 + MTX or TCZ8 Mono for the duration of the study had sustained improvement in disease activity and maintained joint damage inhibition over 104 wks. Efficacy improved further in pts receiving MTX or TCZ4 + MTX who switched to escape with TCZ8 + MTX at wk 52; the overall degree of joint damage (though generally minor) was greater than that in pts who received TCZ8 for the entire study, highlighting the importance of early initiation of optimal therapy. Safety was consistent with the known safety profile of TCZ.
OBJECTIVES: The efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA).
METHODS: In a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX)-naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28-erythrocyte sedimentation rate (ESR) <2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52.
RESULTS: The intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde-modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, -0.81 vs -0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group.
CONCLUSIONS: TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA.
TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT01007435.
OBJECTIVE: Investigate whether the efficacy and safety of intravenous tocilizumab (TCZ) demonstrated at week 52 in patients with early rheumatoid arthritis (RA) are maintained to week 104.
METHODS: Methotrexate (MTX)-naive patients with early progressive RA were randomly assigned to double-blind 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo or placebo+MTX for 104 weeks. Patients not receiving 8 mg/kg TCZ and not achieving Disease Activity Score-28 joints (DAS28-erythrocyte sedimentation rate (ESR)) ≤3.2 at week 52 switched to escape therapy (8 mg/kg TCZ+MTX). Analyses were exploratory.
RESULTS: Intent-to-treat and safety populations included 1157 and 1153 patients, respectively. DAS28-ESR remission (<2.6) rates were maintained from weeks 52 to 104 (eg, 8 mg/kg TCZ+MTX, 49.3% to 47.6%). Placebo+MTX and 4 mg/kg TCZ+MTX escape patients' week 104 response rates were 51.4% and 30.5%, respectively. Inhibition of radiographic progression was maintained with 8 mg/kg TCZ (eg, 8 mg/kg TCZ+MTX mean (SD) change from baseline in modified total Sharp score: 0.13 (1.28), week 52; 0.19 (2.08), week 104). The safety profile of TCZ was consistent with that of previous reports.
CONCLUSIONS: Patients with early RA treated with TCZ monotherapy or TCZ+MTX maintained clinical benefits during their second year of treatment with no new safety signals.
TRIAL REGISTRATION NUMBER: NCT01007435; Results.
This randomized, double-blind, parallel group study will assess the safety, disease remission, and prevention of structural joint damage in patients with early moderate to severe rheumatoid arthritis treated with tocilizumab as monotherapy or in combination with methotrexate, versus methotrexate alone. Patients will be randomized to receive either (A) tocilizumab (8 mg/kg iv every 4 weeks) plus placebo, (B) tocilizumab (8 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), (C) tocilizumab (4 mg/kg iv every 4 weeks) plus methotrexate (7.5-20 mg po weekly), or (D) placebo plus methotrexate (7.5-20 mg po weekly). Patients in groups C and D who have not achieved low disease activity at week 52 can receive tocilizumab 8 mg/kg iv every 4 weeks. Anticipated time on study treatment is 104 weeks.
