The purpose of this study is to determine the long-term effectiveness and safety of CP-690,550 for the treatment of rheumatoid arthritis. Subjects are only eligible for this study after they have completed participation in another \"qualifying\" study of CP-690,550.
BACKGROUND/PURPOSE: Tofacitinib has previously shown efficacy and a manageable safety profile in 12-week (wk) randomized Phase 2 (P2) studies for the treatment of rheumatoid arthritis (RA) in Japan. Here we compare the safety and efficacy of tofacitinib in a long-term extension (LTE) study for Japanese pts with RA who received tofacitinib either as monotherapy or with background methotrexate (bkMTX). METHOD: This LTE study (NCT00661661) recruited pts completing P2 studies of tofacitinib either as monotherapy (NCT00687193) or with bkMTX (NCT00603512). LTE pts received tofacitinib 5 mg twice daily (BID) and could change or stop background DMARDs including MTX; inadequate responders could increase to tofacitinib 10 mg BID. For the purposes of this analysis pt groups were defined as follows: pts entering LTE on 'MTX' (N=113) or 'monotherapy' (N=291); pts receiving tofacitinib '10 mg BID' for >12 wks (N=66), or all others, i.e. receiving tofacitinib '5 mg BID' (N=338). RESULT: Results are presented for 404 pts whose tofacitinib exposure ranged from 8 months (mo) through 3 years (y). Efficacy was maintained over the long term in all pts (Figure 1a). Treatment with tofacitinib monotherapy for 1-2 y and with bkMTX for 2-3 y provided similar long-term efficacy. In both populations, the ACR20 response rate was maintained (Figure 1b). In total, 16% (66/404) pts received tofacitinib 10 mg BID for at least 12 wks. An increase in ACR20 response rate was apparent in those pts (Figure 1c). There was no relationship between length of participation in the study and incidence of adverse events (AEs). Rates of discontinuation (DC) for AEs, DC for serious AEs (SAEs) and DC for serious infections (SIEs) also appeared stable over time (Table). The most common AEs were infections such as nasopharyngitis (42.8%) and herpes zoster (9.9%). The most common AEs leading to DC were herpes zoster (1.5%), pneumonia (1.0%), and elevations in aspartate aminotransferase (0.5%) and alanine aminotransferase (1.0%) for which the protocol defined 3-fold elevation over the normal range as mandating treatment DC. SIEs were the category of SAEs most frequently leading to DC; the most common SIE was herpes zoster (1.5%). CONCLUSION: Tofacitinib demonstrated sustained efficacy in the treatment of Japanese pts with RA when administered as monotherapy for 1-2 y or with bkMTX for 2-3 y. ACR response rates were similar in pts receiving tofacitinib as monotherapy or with bkMTX. The safety profile of tofacitinib, with or without bkMTX, was generally tolerable and consistent with that from P2 studies.
OBJETIVO: Describir la seguridad a largo plazo y el perfil de eficacia de tofacitinib en pacientes con artritis reumatoide moderada a severa activa (RA).
MÉTODOS: Se combinaron los datos de 2 estudios abiertos (NCT00413699, NCT00661661) con pacientes que habían participado en la fase de calificación de E, estudios de índice II o III de tofacitinib. Los datos de seguridad incluyen más de 60 meses de observación; datos de eficacia se reportan hasta 48 meses. El tratamiento se inició con tofacitinib 5 o 10 mg dos veces al día. Criterios de valoración primarios fueron los eventos adversos (EA) y los datos de seguridad del laboratorio. Los objetivos secundarios incluyeron Colegio Americano de Reumatología (ACR) las tasas de respuesta, y la actividad de la enfermedad Puntuación (28 articulaciones) (DAS28) -4 [velocidad de sedimentación globular (VSG)] y la Salud Evaluación Índice Cuestionario-Discapacidad (HAQ-DI) evaluaciones.
RESULTADOS: En total, 4.102 pacientes fueron tratados por 5.963 pacientes-año; duración media del tratamiento (como máximo) fue 531 (1.844) días; 20,8% de los pacientes interrumpieron el tratamiento durante 60 meses. La AE más comunes fueron nasofaringitis (12,7%) y la infección del tracto respiratorio superior (10,5%). Grave AE se informó en 15,4% de los pacientes con una tasa de incidencia de la exposición-estimado de 11.1 eventos / 100 pacientes-año. Las infecciones graves se registraron en el 4,5% de los pacientes con una tasa de incidencia exposición estimada de 3,1 eventos / 100 pacientes-año (IC del 95%: 2,66 a 3,55). Los valores medios de las variables de laboratorio se mantuvieron estables en el tiempo y en consonancia con la fase II y III. Eficacia persistente se demostró a través Mes 48, medida por la tasa de respuesta ACR (ACR20 / 50/70) DAS28-4-ESR y HAQ-DI. La seguridad y eficacia fueron similares para los pacientes que recibieron tofacitinib en monoterapia o con el fondo fármacos antirreumáticos modificadores de la enfermedad no biológicos.
CONCLUSIÓN: tofacitinib demostrado la seguridad y eficacia consistente persistente más de 48 meses en los pacientes con AR.
OBJETIVO: Determinar la tasa de infección y mortalidad por cualquier causa a través de tofacitinib fase II, fase III, y la extensión a largo plazo (LTE) estudios en pacientes con moderada a severamente activa de la artritis reumatoide (AR).
Se analizaron los datos combinados de los estudios de tofacitinib en pacientes con AR: MÉTODOS. En estos estudios, tofacitinib fue administrado como monoterapia o en combinación con metotrexato u otros fármacos antirreumáticos modificadores de la enfermedad no biológicos. La fecha límite para la inclusión de los datos fue 19 de abril 2012.
RESULTADOS: Al otro lado de la fase II, fase III, y los estudios de LTE, 4.789 pacientes recibieron tofacitinib (8.460 pacientes-años de exposición). La tasa global de infección seria era 3,09 eventos por 100 pacientes-año (95% intervalo de confianza [IC 95%] 2,73-3,49), y las tasas se mantuvieron estables en el tiempo. Un modelo de riesgos proporcionales de Cox mostró que la edad, la dosis de corticosteroides, la diabetes, y la dosis tofacitinib estaban relacionados de forma independiente con el riesgo de infección grave. Recuento de linfocitos de <0,5 × 10 (3) / mm (3) fueron rara pero se asocia con un mayor riesgo de infección tratada y / o grave. En general, todas las causas de mortalidad fueron las tasas de 0,30 eventos por 100 pacientes-año (IC del 95%: 0,20 hasta 0,44).
CONCLUSIÓN: El riesgo general de infección (incluyendo infección grave) y mortalidad en los pacientes con AR tratados con tofacitinib parecen ser similares a los observados en los pacientes con AR tratados con agentes biológicos. Las tasas de infección grave se mantuvieron estables en el tiempo.
Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives: To report tofacitinib safety, tolerability, and durability of response up to 72 months (mo) in long-term extension (LTE) studies. Methods: Data were from 2, open-label studies: A3921024 (NCT00413699 [ongoing; database unlocked as of April 2014 data cut-off]) and A3921041 (NCT00661661). Patients (pts) had RA and participated in randomised Phases (P)1/2/3 tofacitinib studies. Treatment was initiated with tofacitinib 5 or 10 mg BID as monotherapy or with background DMARDs; data for both doses ± background DMARDs were pooled. Primary endpoints: AEs and laboratory safety. Confirmed data are reported for decreased haemoglobin (HgB), neutrophil, and lymphocyte counts, and increases >50% from baseline (BL) in creatinine. Secondary endpoints: ACR responses, DAS28-4(ESR), and HAQ-DI. Safety data were included over 84 mo and efficacy up to Mo 72 (n≤29 pts, post-Mo 72). Results: 4858 pts were treated (mean [max] duration: 918 [2535] days). BL data were from index studies for 91% of pts. Total tofacitinib exposure was 12 359 ptyears (py). In total, 1747 pts (36.0%) discontinued (AEs: 882 [18.2%]; insufficient clinical response: 133 [2.7%]). Most common classes of AEs: infections and infestations (63.4%), musculoskeletal/connective tissue disorders (33.9%), and GI disorders (29.9%). Most frequently reported AEs: nasopharyngitis (16.3%), upper respiratory tract infection (14.5%), and urinary tract infection (10.3%). SAEs occurred in 23.0% of pts (incidence rate [IR] 9.9/100 py [95% confidence interval [CI]; 9.4, 10.5]) and serious infections in 7.2% (IR 2.9/100 py [95% CI; 2.6, 3.2]). Malignancies (excluding NMSC) were reported in 2.5% of pts (IR 1.0/100 py [95% CI; 0.8, 1.2]). IRs for SAEs, serious infections, and malignancies up to Mo 84 did not increase vs previously reported data (Mo 72).1 Decreased Hgb (>2g/dL change from BL or Hgb <8 g/dL) occurred in 6.1% of pts and increased aminotransferases (>3× ULN) in 1.6% (ALT) and <1.0% (AST) of pts. Moderate to severe neutropenia (absolute neutrophil count [ANC] 0.5-1.5×103/mm3) was reported in 1.3% of pts. No pts had ANC <0.5×103/mm3. Absolute lymphocyte counts <0.5×103/mm3 were reported in 1.1% of pts. Increases >50% from BL in creatinine occurred in 3.1% of pts. ACR20, ACR50 and ACR70 response rates for tofacitinib were sustained to Mo 72 (80.8%, 61.5% and 35.9%). Mean DAS28-4(ESR) was 6.29 at BL, 3.74 at LTE Mo 1 and 3.32 at Mo 72. Mean HAQ-DI score was 1.42 at BL, 0.81 at LTE Mo 1 and 0.77 at Mo 72. Conclusions: A consistent safety profile and sustained efficacy up to 72 mo was observed in pts with RA receiving tofacitinib 5 or 10 mg BID in LTE studies.
OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme.
METHODS: Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies.
RESULTS: Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA.
CONCLUSIONS: The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented.
METHODS: Study A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate. Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID. Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted. Primary endpoints were adverse events, laboratory parameters and vital signs. Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Safety and efficacy data were assessed throughout the study.
RESULTS: A total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study. Median (range) duration of treatment in this extension study was 1185 (5-2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity. The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %). For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer). Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib. ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion.
CONCLUSIONS: Tofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis. The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population.
TRIAL REGISTRATION: Clinicaltrials.gov NCT00661661 . Registered 7 February 2008.
OBJECTIVES: To evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib.
METHODS: Phase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA programme were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (≤0.01), medium (>0.01 to ≤0.05) and high (>0.05).
RESULTS: We identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)).
CONCLUSIONS: Within the global tofacitinib RA development programme, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint destruction. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. This post hoc analysis assessed the safety of tofacitinib in Latin American (LA) patients with RA versus the Rest of World (RoW) population.
METHODS: Data were pooled from 14 clinical studies of tofacitinib: six Phase 2, six Phase 3 and two long-term extension studies. Incidence rates (IRs; patients with events/100 patient-years of treatment exposure) were calculated for safety events of special interest combined across tofacitinib doses. 95% confidence intervals (CI) for IRs were calculated using the maximum likelihood method. Descriptive comparisons were made between LA and RoW (excluding LA) populations.
RESULTS: This analysis included data from 984 LA patients and 4687 RoW patients. IRs for safety events of special interest were generally similar between LA and RoW populations, with overlapping 95% CIs. IRs for discontinuation due to adverse events, serious infections, tuberculosis, all herpes zoster (HZ), serious HZ, malignancies (excluding non-melanoma skin cancer) and major adverse cardiovascular events were numerically lower for LA versus RoW patients; IR for mortality was numerically higher. No lymphoma was reported in the LA population versus eight cases in the RoW population. Exposure (extent and length) was lower in the LA population (2148.33 patient-years [mean = 2.18 years]) versus RoW (10515.68 patient-years [mean = 2.24 years]).
CONCLUSION: This analysis of pooled data from clinical studies of tofacitinib in patients with RA demonstrates that tofacitinib has a consistent safety profile across LA and RoW patient populations.
OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the efficacy and safety of tofacitinib 5 or 10 mg twice daily (BID), in patients with moderate to severe RA, aged ≥65 and <65 years.
METHODS: Data were pooled from five Phase 3 trials and, separately, from two open-label long-term extension (LTE) studies (data cut-off April, 2012). Patients received tofacitinib, or placebo (Phase 3 only), with/without conventional synthetic DMARDs (mainly methotrexate). Clinical efficacy outcomes from Phase 3 studies were evaluated at Month 3. Safety evaluations using pooled Phase 3 data (Month 12) and pooled LTE data (Month 24) compared exposure-adjusted incidence rates (IRs; with 95% confidence intervals [CIs]), in older versus younger patients.
RESULTS: In Phase 3 and LTE studies, 15.3% (475/3111) and 16.1% (661/4102) of patients, respectively, were aged ≥65 years. Consequently, exposure to tofacitinib was lower in older versus younger patients in Phase 3 (259.2 vs. 1554.9 patient years [pt-yrs]) and LTE (962.1 vs. 5071.7 pt-yrs) studies. Probability ratios for ACR responses and HAQ-DI improvement from baseline ≥0.22 (Month 3) favoured tofacitinib and were similar in older and younger patients, with overlapping CIs. IRs for SAEs and discontinuations due to AEs were generally numerically higher in older versus younger patients, irrespective of treatment.
CONCLUSIONS: Older patients receiving tofacitinib 5 or 10 mg BID had a similar probability of ACR20 or ACR50 response and, due to comorbidities, a numerically higher risk of SAEs and discontinuations due to AEs compared with younger patients.
The purpose of this study is to determine the long-term effectiveness and safety of CP-690,550 for the treatment of rheumatoid arthritis. Subjects are only eligible for this study after they have completed participation in another \"qualifying\" study of CP-690,550.
