OBJECTIVES: To report 5-year efficacy and safety in rheumatoid arthritis (RA) patients with active disease treated with tocilizumab.
METHODS: LITHE was a 2-year, randomised, placebo-controlled study of tocilizumab in RA patients (ClinicalTrials.gov, NCT00106535), with an additional 3-year, open-label extension. Patients were randomly assigned to tocilizumab (4 or 8 mg/kg IV) or placebo every 4 weeks + methotrexate. They could receive rescue with tocilizumab from week 16; after week 52, patients could switch to open-label tocilizumab 8 mg/kg. Radiographs were analysed by randomized treatment using the Genant-modified Total Sharp Score (GmTSS). Patients with at least baseline, week 104 and post-week 104 radiographs were included. Clinical and safety data were pooled for all patients who received ≥1 dose of tocilizumab; results are presented from the first tocilizumab dose.
RESULTS: 1,149 patients were included with 4,380 patient-years of exposure; 34% received 5 years of treatment. Mean 5-year change in GmTSS revealed greater inhibition of radiographic progression in tocilizumab patients than placebo patients (1.34 vs. 3.02), with the greatest annualised progression rate in year 1. Overall, 53% of tocilizumab and 35% of placebo patients experienced no progression (GmTSS ≤0). Clinical benefit was maintained - determined by ACR response, DAS28-ESR <2.6, EULAR good/moderate response and Boolean remission - as was physical function. The safety profile over 5 years was similar to that over 2 years.
CONCLUSIONS: Over 5 years, tocilizumab + MTX inhibited radiographic progression and maintained improvements in signs and symptoms and physical function in MTX-inadequate responders with active disease; no new safety signals occurred.
Background: LITHE was a 2-year, randomized, double-blind study of tocilizumab (TCZ) in patients (pts) with moderate to severe RA who were inadequate responders to MTX, with an additional 3 years of open-label (OL) extension. Methods: 1190 pts were randomized (1:1:1) to TCZ (4 mg/kg [TCZ4] or 8 mg/kg [TCZ8]) or placebo every 4 weeks+MTX (10-25 mg/week). Pts could receive rescue TCZ from week 16; after week 52, pts could switch to OL TCZ8. Radiographs were analysed by Genant-modified Total Sharp Score (GmTSS). Data were pooled for all pts who received ≥1 dose of TCZ (All TCZ). The proportions of pts who maintained efficacy responses consecutively for ≥24 weeks are summarized (Table 1). Results: 1149 pts received ≥1 dose of TCZ with 4379.6 patient-years (PY) of exposure, and 34% received 5 years of treatment (All TCZ). Mean duration in the All TCZ population was 3.81 years with half the pts participating for ≥4.69 years. The mean change in GmTSS over 5 years showed a 56% greater inhibition of joint damage in pts randomized to TCZ vs placebo, with greatest annualized progression rate (APR) in year 1. 53% of TCZ pts had no progression (GmTSS≤0) during the 5 years vs 35% of placebo pts (placebo pts may have switched to TCZ as early as week 16). Clinical benefit was maintained, as measured by ACR response, DAS28-ESR remission and EULAR good/moderate response. Overall rates/100PY of serious adverse events and serious infections were 11.67 and 3.42, respectively. Conclusion: During long-term treatment, TCZ+MTX continued to inhibit radiographic progression. Improvements in signs and symptoms and in physical function were maintained with continued TCZ treatment. The safety profile at 5 years was similar to that previously observed. (Table presented).
OBJETIVO: Evaluar la progresión radiográfica, la función física, la actividad de la enfermedad clínica y seguridad en pacientes con artritis reumatoide (AR) que tenían una respuesta inadecuada a metotrexato (MTX), y que fueron tratados con tocilizumab-MTX o MTX durante el Año 2 de 2- estudio de años.
MÉTODOS: Durante el año 1, los pacientes fueron asignados al azar a placebo-MTX, 4 mg / kg de tocilizumab-MTX u 8 mg / kg de tocilizumab-MTX. Durante el año 2, los pacientes continuaron el tratamiento doble ciego inicial o cambiaron a abrir etiqueta 8 mg / kg de tocilizumab-MTX. Criterios de valoración co-primarios en la semana 104 fueron el cambio medio desde el inicio en el modificado Genant puntuación total de Sharp (GmTSS) y el área media ajustada bajo la curva (AUC) para el cambio desde la línea base en el Índice de Discapacidad Cuestionario-Evaluación de la Salud (HAQ-DI). También se evaluaron los signos y síntomas de la AR y la seguridad.
RESULTADOS: En la semana 104, el cambio del valor inicial en GmTSS significan fue significativamente menor para los pacientes inicialmente asignados al azar a tocilizumab-MTX 4 mg / kg (0,58; p = 0,0025) u 8 mg / kg (0,37; p <0,0001) que para los pacientes inicialmente aleatorizados a placebo MTX (1,96). AUC medio ajustado de cambio desde el inicio en el HAQ-DI también fue significativamente menor en los pacientes inicialmente asignados al azar a tocilizumab-MTX 4 mg / kg (-287,5; p <0,0001) u 8 mg / kg (-320,8; p <0,0001) que en pacientes inicialmente asignados al azar a placebo-MTX (-139,4). Los signos y síntomas de la AR se mantuvieron o mostraron una mejoría. No se observaron nuevas señales de seguridad.
CONCLUSIÓN: En comparación con placebo MTX, tocilizumab-MTX, inhibió el daño articular estructural y mejorar la función física en pacientes con AR que antes no tenían respuesta inadecuada a MTX. Una extensión de este estudio continúa y proporcionará datos de eficacia y seguridad a largo plazo adicionales. Ensayos clínicos Registro Nacional NCT00106535.
Background LITHE was a 2-y, randomised, double-blind, placebo-controlled study of TCZ in pts with moderate to severe RA who were inadequate responders to methotrexate (MTX) with an additional 3 y of open-label extension. Objectives To report radiographic, efficacy and safety data in RA pts treated with TCZ in LITHE at 5 y of follow up. Methods In LITHE, 1190 pts were randomised (1:1:1) to receive TCZ (4 mg/kg [TCZ4] or 8 mg/kg [TCZ8]) or placebo every 4 wks + MTX (10-25 mg/wk). Mean duration of RA at study entry was 8.96 to 9.43 y in the 3 arms. Pts could receive rescue with TCZ from wk 16; after wk 52, pts could switch to open-label TCZ8. Radiographs were analysed by Genant-modified Total Sharp Score (GmTSS) at baseline (BL) and at wks 52, 104, 152, 200 and 260 by original randomised group. Pts with at least BL, wk 104 and post-wk 104 radiographs were included in the analysis; linear extrapolation was used to impute any additional missing time points. Signs and symptoms and safety data were pooled for all pts who received ≥1 dose of TCZ (All TCZ) with data presented from the first dose of TCZ. LOCF was used for missing tender and swollen joint counts; no imputation was used for missing HAQ-DI score, CRP, ESR and VAS assessments. The proportions of pts who maintained an ACR20/50/70, DAS28-ESR, EULAR or HAQ-DI response consecutively for ≥24 wks at any time point during the study were summarised (Table). Results 1149 pts received ≥1 dose of TCZ with 4379.6 pt-y (PY) of exposure, and 34% received 5 y of treatment (All TCZ). Mean duration in the All TCZ population was 3.81 y with half the pts participating for ≥4.69 y. Radiographic data were assessed in 803 pts: 545 initially assigned to TCZ and 258 initially assigned to placebo. The mean change in GmTSS over 5 y showed a 56% greater inhibition of joint damage in pts randomised to TCZ vs those initially randomised to placebo, with greatest APR in y 1 (Table). 53% of TCZ pts had no progression (GmTSS≤0) during the 5 y vs 35% of placebo pts (placebo pts might have switched to TCZ as early as wk 16). Clinical benefit was maintained, as measured by maintenance of ACR response, DAS28-ESR remission and EULAR good/moderate response (Table). Overall rates/100PY of serious adverse events and serious infections were 11.67 and 3.42, respectively. The safety profile at 5 y was similar to that observed at 2 y.1 Conclusions During long-term treatment, TCZ + MTX continued to inhibit radiographic progression. Improvements in signs and symptoms and in physical function were maintained with continued TCZ treatment. The safety profile of TCZ at 5 y was similar to that previously observed.1 (Figure Presented).
Background RA characterized by poly-articular and synovial inflammation, cartilage loss and erosion of subchondral bone. It is critical to diagnose and effectively treat the disease early to suppress inflammation and prevent destruction of the joint. Thus, identification of the patients most likely to respond to a given intervention may be pursued for optimal benefits for both patients and payers. Objectives To investigate early changes in biomarkers of bone, cartilage, synovium and inflammation as an effect of tocilizumab (TCZ) treatment, and to identify profiles associated with responders and non-responders. Methods The LITHE study (Roche WA17823) is a 2-year phase III, 3-arm randomized, double-blind, placebo-controlled, parallel group, with moderate/severe active RA, inadequate response to MTX. 1196 patients were randomized to the 3 treatment groups: TCZ8mg/kg (TCZ8), TCZ4mg/kg or placebo. Every 4 weeks, patients received an infusion of TCZ8 mg/kg or 4mg/kg placebo for a total of up to 13 infusions in 52 weeks. Escape patients was defined as those who experienced <20% improvement in both swollen (SJC) and tender joint counts (TJC) at week 16. These patients were designated non-responders in current sub-study. The sub-study only the TCZ8 group was investigate and fasted serum was analyzed baseline and week 4weeks. Following biomarkers were measured: C2M (cartilage degradation), C3M (synovial inflammation), MMP3, total CRP, CRPM (MMP-degraded CRP), VICM (Citrullinated and MMP degraded Vimentin), ICTP (MMP destroyed type I collagen), osteocalcin (bone formation) and CTX-I (Bone resorption). The sub-study consisted of 102 responders and 33 non-responders. Data is shown as percentage change from baseline (Mann-Whitney test). Results Cartilage degradation - C2M - was reduced to 90.4% of baseline levels upon treatment with TCZ8 in the responder group, whereas the level of C2M was increased to 111% of baseline level in the non-responder group (p=0.0031). Synovial tissue turnover, C3M, was decreased to 77.3% of baseline in the responder group, compared to 90.5% in the non-responder group (p=0.0034). MMP-3, ICTP and Citrullinated vimentin decreased to approx. 85% of baseline and there were no difference between the groups. The general inflammatory marker hsCRP was decreased in both responders and non-responders to approx. 35%, with no significant ability to separate these groups. In contrast, there was a significant difference between the level of MMP cleaved CRP, CRPM (p=0.031). The level of CRPM was decreased to 75.9% in the responder group and only to 85.9% in non-responder group. There were only minimal significant differences in the bone resorption and bone formation markers. Conclusions The novel biomarkers of cartilage and synovial turnover were able to discriminate between responders and non-responders to IL-6 intervention, in contrast to traditional CRP and bone markers. Whether the markers may reflect the same response and power for prediction to other biological interventions need to be investigated. TCZ strongly inhibited cartilage degradation and inflammation mediated tissue turnover which may explain the clinical benefits of this biological intervention.
OBJETIVO: Evaluar la eficacia y seguridad de tocilizumab más metotrexato (MTX) versus MTX solo en la prevención del daño articular estructural y mejorar la función física y la actividad de la enfermedad en los pacientes con respuestas artritis reumatoide y la insuficiencia moderada a severa a MTX.
MÉTODOS: Un total de 1.196 pacientes fueron incluidos en un estudio de 2 años, aleatorizado, doble ciego, controlado con placebo. Los pacientes recibieron tocilizumab (8 mg / kg o 4 mg / kg) o placebo cada 4 semanas más MTX. Tratamiento de rescate estaba disponible desde la semana 16. Los resultados del año 1 se presentan.
RESULTADOS: La media de cambio en la puntuación total de Sharp modificado Genant fue de 0,29 y 0,34 con tocilizumab 8 mg / kg más MTX y 4 mg / kg más MTX, respectivamente, frente a 1,13 con placebo más MTX (p <0,0001 para ambas comparaciones). Análisis de varianza del área bajo la curva para el cambio desde la línea base en el índice de discapacidad del Cuestionario de Evaluación de Salud mostró una mayor disminución con tocilizumab 8 mg / kg y 4 mg / kg (-144,1 y -128,4 unidades, respectivamente) que con placebo ( -58,1 unidades; P <0,0001 para ambas comparaciones). Las proporciones de pacientes con American College of Rheumatology 20%, 50% y 70% de mejora y con actividad de la enfermedad Puntuación en 28 articulaciones remisión fueron superiores en los que recibieron 8 mg / kg de tocilizumab que en los que recibieron placebo (P <0.0001 para todas las comparaciones) . El perfil de seguridad de tocilizumab fue consistente con los perfiles en los estudios anteriores. Infecciones fueron los acontecimientos adversos y adversos graves más comunes.
CONCLUSIÓN: Los resultados de este estudio muestran que tocilizumab resultados MTX más en una mayor inhibición del daño articular y la mejoría en la función física que hace MTX solo. El tocilizumab tiene un perfil de seguridad bien caracterizado.
Background: Patients with moderate to severe RA who remained on methotrexate (MTX) despite inadequate response were treated with TCZ in a double‐blind, randomized, controlled phase 3 trial. Results of a 2‐year planned analysis from this study are presented. Methods: Patients were randomized to treatment with TCZ 4 mg/ kg+MTX (TCZ4), TCZ 8 mg/kg+MTX (TCZ8) or placebo+MTX (CON) every 4 weeks. If patients failed to respond (<20% improvement in swollen and tender joint count; SJC and TJC) then stepwise rescue therapy could begin at week 16. Patients with >=70% improvement in SJC and TJC could continue the blinded therapy at the end of year 1 to week 104. For all other patients, open‐label TCZ8 was initiated at week 52. Change from baseline in Genant‐modified total Sharp score (GmTSS) and physical function (AUC of change from baseline in HAQDI) were the primary 2‐year end points. Linear extrapolation (GmTSS) or standardization (change in HAQ‐DI) was used for missing data. The impact of 2 years of treatment was examined by assessing efficacy end points over time for patients randomized to TCZ8, with the last observation carried forward for SJC and TJC in patients who received rescue therapy or withdrew. Results: The intention to treat population consisted of 398 TCZ8, 399 TCZ4 and 393 CON patients. At 2 years, exposure rates in patientyears (PY) were 1320.0, 521.9 and 284.8 in TCZ8, TCZ4 and CON patients, respectively. At year 2, patients in the TCZ8 group had 81% less radiographic progression vs CON patients (based on linear extrapolation of mean change in GmTSS). Significantly more TCZ8 patients had no radiographic progression vs CON patients (P<=0.0001). AUC of change from baseline in HAQ‐DI showed significant improvement in physical function in TCZ4 and in TCZ8 vs CON patients (P<=0.0025). In patients initially randomized to TCZ8, a low disease activity score (LDAS; DAS28 <3.2) was seen in >60% of patients and the DAS28 remission (DAS28 <2.6) rate was 48% at week 52 and continued to increase to week 104. By week 52, patients treated with TCZ8 had clinically significant improvements in SJC that were maintained through week 104. Rates per 100 PY for adverse events (AEs) were higher in TCZ8 and TCZ4 (263.6, 275.4) vs CON patients (251.4) while rates for serious AEs were comparable (11.4, 12.1, 10.9, respectively). Rates per 100 PY of AEs leading to withdrawal (7.4, 32.5, 4.8) and treatment modification (8.4, 30.7, 20.4) were higher in TCZ8 and TCZ4 vs CON patients, respectively and death rates were comparable (0.6, 0.2, 0.4). Conclusions: Treatment with TCZ‐MTX inhibits radiographic progression over 2 years and improves physical function as shown by DAS28 remission, LDAS and low SJC, with a manageable safety profile.
Purpose: Results of the TCZ clinical development program have shown that for most endpoints, the 8 mg/kg dose is more effective than the 4 mg/kg dose. In the US, TCZ 4 mg/kg has been approved as the starting dose with a subsequent escalation to 8 mg/kg based on clinical response. This analysis evaluated the effect of increasing the TCZ dose from 4 to 8 mg/kg on inhibition of radiographic progression and safety in the LITHE study. Methods: RA pts with inadequate responses to MTX were randomly assigned to TCZ 4 or 8 mg/kg (TCZ4 or TCZ8) or placebo Q4W + MTX. From wk 16, blinded first-step rescue was allowed if pts had <20% improvement in SJC and TJC (eg, pts on placebo went to TCZ4, pts on TCZ4 or TCZ8 went to TCZ8). If <20% improvement persisted after 3 doses of blinded first-step rescue, pts received second-step rescue with TCZ8. At wk 52, pts were treated with open-label (OL) TCZ8 except those with >=70% improvement in SJC and TJC, who could continue blinded therapy to wk 104. X-rays were performed at baseline and wks 24, 52, 80, and 104. Data were analyzed in pts whose dose increased from TCZ4 to TCZ8. Data from this TCZ dose-escalation analysis must be interpreted with caution because 78 pts who withdrew (44 for safety, 8 for insufficient response, 26 for other reasons) from the study before dose escalation are not included. In addition, criteria for dose escalation and/or dose continuation were based on efficacy results that were predetermined per study protocol. Safety data are provided for all randomly assigned pts who received >=1 TCZ dose and who had at least 1 post-randomization safety assessment. Results: Of 1190 pts (393, 399, and 398 randomly assigned to placebo, TCZ4, and TCZ8, plus MTX, respectively), 451 pts increased their dose from TCZ4 to TCZ8. In these 451 pts, annualized rate of progression of Genant-modified Total Sharp Score, erosion, and joint space narrowing slowed after the dose increased from TCZ4 to TCZ8 (Table A). Rates/100 patient-years (PY) of serious adverse events (AEs) and serious infections were lower than previously reported (Kremer et al, EULAR 2010) before dose escalation but increased to rates comparable to those of the TCZ pooled groups (TCZ4, n =597, includes pts who received TCZ4 as initial or rescue therapy; TCZ8, n=983 pts, includes those who received TCZ8 as initial and/or rescue and/or OL therapy) after dose escalation (Table B). The low predose escalation event rates for the TCZ4 group are influenced by a selection bias-ie, pts who withdrew while on TCZ4 do not contribute safety data to the analysis of the switching group but continue to contribute to the rates in the TCZ4 pooled analysis. Conclusions: For this analysis of pts who increased dose, the annualized rate of progression was reduced after pts increased their TCZ dose from 4 to 8 mg/kg; safety in these pts after dose escalation was comparable to that in the TCZ pooled groups. (Table presented).
Purpose: To report results of a 2-yr planned analysis of a double-blind, randomized controlled, phase 3 trial of TCZ in pts with moderate to severe RA who remained on MTX despite inadequate response. Method: Pts were randomized (1:1:1) to receive TCZ + MTX (4 mg/kg [TCZ4] or 8 mg/kg [TCZ8]) or placebo + MTX (control [CON]) every 4 wks. Stepwise rescue therapy starting at wk 16 was allowed if pts did not respond (<20% improvement in SJC and TJC). At wk 52, all pts were required to initiate open-label TCZ8 for yr 2, unless they had achieved >= 70% improvement in SJC and TJC, allowing them to continue the blinded therapy they were receiving at the end of yr 1 to wk 104. Primary 2-yr end points were change from baseline in Genant-modified Total Sharp Score (GmTSS) and physical function (AUC of change from baseline in HAQ-DI). Linear extrapolation (GmTSS) or standardization (change in HAQ-DI) was used for missing data (post-rescue data set to missing). To examine impact of 2 yrs of treatment, efficacy end points were assessed over time for pts randomized to TCZ8, with LOCF for SJC and TJC for pts who received rescue therapy or withdrew from that time point. Results: The ITT population consisted of 398 TCZ8, 399 TCZ4, and 393 CON pts. At 2 yrs, exposure rate per pt-yrs (PY) were 1320, 521.9, and 284.8 in TCZ8, TCZ4, and CON pts. More CON pts required rescue vs TCZ pts, and more TCZ pts remained on initial randomized therapy (Table A). At yr 2, pts in the TCZ8 group had significantly less radiographic progression (81% inhibition) vs CON pts (based on linear extrapolation of mean change in GmTSS on initial treatment for post-rescue data). Significantly more TCZ8 pts had no radiographic progression vs CON pts (p<=0.0001). AUC of change from baseline in HAQ-DI showed significant improvement in physical function in TCZ4 and TCZ8 vs CON pts (Table A). In pts initially randomized to TCZ8, low disease activity score (LDAS; DAS28 <=3.2) was seen in >60%, and DAS28 remission (DAS28 <2.6) rates were ∼50% at wk 52 and continued to increase to wk 104 (Table B). By wk 52, in pts treated with TCZ8, clinically significant improvements in SJC occurred (-10) that were maintained through wk 104. Rates/100PY for adverse events (AEs) were higher in TCZ8 and TCZ4 (263.6, 275.4) vs CON pts (251.4) while rates for serious AEs were comparable (11.4, 12.1, 10.9). Rates per 100PY of AEs leading to withdrawal and treatment modification were higher in TCZ8 and TCZ4 (7.4 and 32.5; 8.4 and 30.7) vs CON pts (4.8 and 20.4) and rates for death were comparable (0.6, 0.2, 0.4). Conclusion: TCZ + MTX continues to inhibit radiographic progression and improve physical function with a clinical effect, as evidenced by improving DAS28 remission, LDAS, and SJC at 2 yrs and with a manageable safety profile. (Table presented).
To report 5-year efficacy and safety in rheumatoid arthritis (RA) patients with active disease treated with tocilizumab.
METHODS:
LITHE was a 2-year, randomised, placebo-controlled study of tocilizumab in RA patients (ClinicalTrials.gov, NCT00106535), with an additional 3-year, open-label extension. Patients were randomly assigned to tocilizumab (4 or 8 mg/kg IV) or placebo every 4 weeks + methotrexate. They could receive rescue with tocilizumab from week 16; after week 52, patients could switch to open-label tocilizumab 8 mg/kg. Radiographs were analysed by randomized treatment using the Genant-modified Total Sharp Score (GmTSS). Patients with at least baseline, week 104 and post-week 104 radiographs were included. Clinical and safety data were pooled for all patients who received ≥1 dose of tocilizumab; results are presented from the first tocilizumab dose.
RESULTS:
1,149 patients were included with 4,380 patient-years of exposure; 34% received 5 years of treatment. Mean 5-year change in GmTSS revealed greater inhibition of radiographic progression in tocilizumab patients than placebo patients (1.34 vs. 3.02), with the greatest annualised progression rate in year 1. Overall, 53% of tocilizumab and 35% of placebo patients experienced no progression (GmTSS ≤0). Clinical benefit was maintained - determined by ACR response, DAS28-ESR <2.6, EULAR good/moderate response and Boolean remission - as was physical function. The safety profile over 5 years was similar to that over 2 years.
CONCLUSIONS:
Over 5 years, tocilizumab + MTX inhibited radiographic progression and maintained improvements in signs and symptoms and physical function in MTX-inadequate responders with active disease; no new safety signals occurred.
