This study will test if CP-690,550 is safe and effective in rheumatoid arthritis patients taking methotrexate who have an inadequate response to tumor necrosis factor inhibitor treatment.
Conferencia»American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting Chicago, Illinois (Published in: Arthritis & Rheumatism 2011;63(Suppl 10):S279)
BACKGROUND/PURPOSE: Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor investigated as a targeted immunomodulator for rheumatoid arthritis (RA). This study was designed to compare efficacy and safety of tofacitinib vs placebo (PBO) in pts with active RA with inadequate response to tumor necrosis factor (TNF)-inhibitors. METHODS: In this 6-month (Mo) study (NCT00960440), pts with inadequate response or lack of tolerance to >=1 TNF inhibitor and on concomitant treatment with a stable (>6 weeks) dose of methotrexate (MTX; 7.5–25 mg/week) were randomized 2:2:1:1 to one of four sequences: tofacitinib 5 mg twice daily (BID); tofacitinib 10 mg BID; PBO advanced to 5 mg BID; PBO advanced to 10 mg BID (at Mo 3 all PBO patients were advanced to tofacitinib 5 or 10 mg according to randomization at baseline; for analyses PBO sequences were combined into one group). Primary endpoints included ACR20 responder rate, change from baseline in HAQ-DI, and rate of pts achieving a DAS28-4(ESR) <2.6, all at Mo 3. RESULTS: 399 pts were randomized and treated: 5 mg BID (n=133); 10 mg BID (n=134); PBO to 5 mg (n=66); PBO to 10 mg (n=66). Mean baseline values were comparable across treatment sequences: age, 54.3–55.4 years; disease duration, 11.3–13 years; HAQ-DI, 1.50–1.66; DAS28-4(ESR), 6.29–6.64; rheumatoid factor (RF) positive, 60.6–70.8%; anti-CCP positive, 68.5–77.8%; >=2 prior anti-TNFs, 32.1–36.6%. Both doses of tofacitinib were statistically superior to PBO for all primary efficacy endpoints at Mo 3 and were maintained to Mo 6 (end of study) (Table). Onset of efficacy as measured by significant ACR20 responses vs PBO was seen by Week 2. Key safety endpoints are summarized in the table. Most AEs were mild; most frequently reported were infections and infestations. There was 1 death due to pulmonary emboli in the 10 mg BID dose group. No serious infectious events were reported in Mo 0–3, and 2 (5 mg BID), 2 (10 mg BID), and 1 (PBO to 5 mg) were reported in Mo 3–6. There were no opportunistic infections. Decreases in neutrophils, increases in LDL and HDL, and small increases in serum creatinine were seen with tofacitinib. CONCLUSION: This was the first Phase 3 study of tofacitinib in combination with MTX in pts with active RA with an inadequate response to TNF-inhibitors. In this treatment refractory patient population, tofacitinib demonstrated rapid, significant, and clinically meaningful improvements in the signs and symptoms of RA, physical function, and disease activity over 6 mo of study treatment. No new safety signals were detected.
ANTECEDENTES: La artritis reumatoide es una enfermedad crónica heterogénea, y ningún agente terapéutico se ha identificado que es universalmente eficaz y persistente en todos los pacientes. Hemos investigado la eficacia de tofacitinib (CP-690550), un nuevo inhibidor oral de la quinasa Janus, como un inmunomodulador específico y la terapia modificadora de la enfermedad para la artritis reumatoide.
MÉTODOS: Realizamos un 6-meses, doble ciego, fase de grupos paralelos 3 a 82 centros en 13 países, incluyendo América del Norte, Europa y América Latina. 399 pacientes de 18 años o mayores con moderada a severa la artritis reumatoide y la respuesta inadecuada a los inhibidores del factor de necrosis tumoral (TNFi) fueron asignados aleatoriamente en una proporción 2: 2: 1: 1 con una internet o teléfono sistema automatizado para recibir dos veces al tratamiento de día con: tofacitinib 5 mg (n = 133); tofacitinib 10 mg (n = 134); o placebo (n = 132), todas con metotrexato. Al mes 3, los pacientes que recibieron placebo avanzaron a cualquiera tofacitinib 5 mg dos veces al día (n = 66) o 10 mg dos veces al día (n = 66). Criterios de valoración primarios incluyeron Colegio Americano de Reumatología (ACR) Tasa de respuesta de 20, el cambio desde la línea base en el Índice de Discapacidad Cuestionario-evaluación de la salud (HAQ-DI) significa, y las tasas de actividad de la enfermedad (DAS) 28-4 (ESR) a menos de 2 · 6 (referido como DAS28 <2 · 6), todo a 3 meses. El grupo completo de análisis para el análisis primario incluyó todos los pacientes aleatorizados que recibieron al menos una dosis de la medicación del estudio y que tenían al menos una evaluación posterior a la línea de base. Este ensayo se ha registrado en www.ClinicalTrials.gov, número NCT00960440.
RESULTADOS: En el mes 3, las tasas de respuesta ACR20 fueron 41 · 7% (55 de 132 [IC del 95% frente a placebo 6 · 06-28 · 41]; p = 0 · 0024) para tofacitinib 5 mg dos veces al día y 48 · 1 % (64 de 133; [12 · 45-34 · 92]; p <0 · 0001) para tofacitinib 10 mg dos veces al día en comparación con 24 · 4% (32 de 131) para el placebo. Las mejoras de la línea de base en HAQ-DI eran -0 · 43 ([-0 · 36--0 · 15]; p <0 · 0001) de 5 mg dos veces al día y -0 · 46 ([-0 · 38 a - 0 · 17]; p <0 · 0001) para 10 mg dos veces al día tofacitinib frente -0 · 18 para placebo; DAS28 <2 · 6 tasas fueron 6 · 7% (ocho de 119 [0-10 · 10]; p = 0 · 0496) de 5 mg dos veces al día y tofacitinib 8 · 8% (11 de 125 [1 · 66 -12 · 60]; p = 0 · 0105) para 10 mg dos veces al día tofacitinib frente a 1 · 7% (dos de 120) para el placebo. La seguridad fue consistente con la fase 2 y 3 estudios. Los eventos adversos más comunes en los meses 0-3 fueron diarrea (13 de 267; 4 · 9%), nasofaringitis (11 de 267; 4 · 1%), cefalea (11 de 267; 4 · 1%), y del tracto urinario infección (ocho de 267; 3 · 0%) en todos los grupos tofacitinib, y náuseas (nueve de 132; 6 · 8%) en el grupo placebo.
En conclusión, en esta población refractaria al tratamiento, tofacitinib con metotrexato tuvo mejoras rápidas y clínicamente significativos en los signos y síntomas de la artritis reumatoide y la función física de más de 6 meses con la seguridad manejable. Tofacitinib podría proporcionar una opción de tratamiento eficaz en los pacientes con una respuesta inadecuada a TNFi.
FINANCIACIÓN: Pfizer.
Introduction: Small increases in mean serum creatinine (SCr) were observed in studies of rheumatoid arthritis patients during tofacitinib treatment. These SCr changes were investigated and potential mechanisms explored.Methods: SCr values and renal adverse event data were pooled from five Phase 3 and two long-term extension (LTE) studies. Dose-response relationships and association with inflammation (C-reactive protein (CRP)) were explored using Phase 2 data and confirmed with Phase 3 data.Results: In Phase 3, least squares mean SCr differences from placebo at Month 3 were 0.02 and 0.04 mg/dl for tofacitinib 5 and 10 mg twice daily (BID) (P <0.05), respectively. During Months 0 to 3, confirmed SCr ≥33% increases over baseline were reported in 17 (1.4%; 5 mg BID) and 23 (1.9%; 10 mg BID) patients. Generally, elevations plateaued and remained within normal limits throughout Phase 3 and LTE studies. Exposure-response modeling demonstrated small, reversible effects of tofacitinib on mean SCr, and significant (P <0.05) effects of CRP on model parameters. Phase 3 data confirmed that patients with higher baseline CRP or greater CRP decreases following tofacitinib treatment had the largest increases in SCr. Across Phase 3 and LTE studies, 22 tofacitinib-treated patients had clinical acute renal failure (ARF), predominantly in the setting of concurrent serious illness.Conclusions: Tofacitinib treatment was associated with small, reversible mean increases in SCr that plateaued early. The mechanism behind these SCr changes remains unknown, but may involve effects of tofacitinib on inflammation. ARF occurred infrequently, was associated with concurrent serious illness, and was unrelated to prior SCr increases.
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.
OBJECTIVE: To assess patient-reported outcomes (PROs) for tofacitinib, an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), in a 6-month, phase III, randomized controlled trial.
METHODS: Patients ages ≥18 years with active RA with an inadequate response to ≥1 tumor necrosis factor inhibitor (TNFi) and receiving stable background methotrexate were randomized 2:2:1:1 to tofacitinib 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib 5 mg or 10 mg twice daily at month 3. PROs measured at month 3 included patient global assessment of disease activity (PtGA), pain, Health Assessment Questionnaire (HAQ) disability index (DI), Medical Outcomes Study (MOS) Short Form 36 Health Survey version 2 (SF-36v2; acute), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and MOS Sleep Scale.
RESULTS: Patients received tofacitinib 5 mg (n = 133) or 10 mg (n = 134) or placebo advanced to tofacitinib 5 mg (n = 66) or 10 mg (n = 66). HAQ DI (reported previously), PtGA (P < 0.0001), and SF-36v2 physical and mental component summary (P < 0.05) scores were improved for both tofacitinib doses versus placebo. Furthermore, improvements greater than or equal to the minimum clinically important difference were more frequently reported by tofacitinib-treated patients versus placebo for PtGA (P < 0.05), pain (P < 0.0001), HAQ DI (P < 0.05), SF-36v2 physical and mental component summary scores (P < 0.05), and FACIT-F (P < 0.001 for 5 mg twice daily). No statistical differences were observed in the MOS Sleep Scale.
CONCLUSION: Tofacitinib treatment resulted in significant, clinically meaningful improvements in multiple PROs versus placebo over 3 months of treatment in patients with active RA and a previous inadequate response to TNFi.
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.
OBJECTIVES: Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR).
METHODS: Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed.
RESULTS: 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs).
CONCLUSIONS: Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations.
TRIAL REGISTRATION NUMBERS: (NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).
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.
OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The aim of this analysis was to characterize changes in haematological parameters following tofacitinib treatment, and to compare changes in haemoglobin with markers of disease activity, fatigue and vitality.
METHODS: Changes in neutrophil counts, lymphocyte counts and haemoglobin levels were analysed in patients with RA from six phase 3 randomized controlled trials (n = 4271) of tofacitinib 5 or 10 mg bd, placebo or active comparators of up to 24 months' duration, and two long-term extension (LTE) studies (n = 4858) of tofacitinib of up to 84 months' duration. Disease activity markers included CRP and ESR. Fatigue and vitality were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Short Form Health Survey-36 vitality domain scores.
RESULTS: In phase 3 studies, mean neutrophil and lymphocyte counts decreased and mean haemoglobin levels increased in all tofacitinib treatment groups. Haemoglobin levels and neutrophil counts stabilized in the LTE studies, while lymphocyte count decreases stabilized at approximately month 48. Increased haemoglobin was associated with decreased ESR and CRP levels. Clinically meaningful reductions in haemoglobin levels (⩾3 g/dl from baseline or haemoglobin ⩽7 g/dl) occurred in <1.0% of patients in all treatment groups. FACIT-F and Short Form Health Survey-36 vitality scores were weakly correlated with haemoglobin levels.
CONCLUSION: Small changes in haematological parameters were seen with tofacitinib treatment, which stabilized over time in the LTE studies. Changes in haemoglobin levels, although associated with changes in ESR and CRP, were not associated with fatigue or vitality.
Objetivo. Tofacitinib es un inhibidor oral de la quinasa Janus para el tratamiento de la artritis reumatoide (AR). Este análisis evaluó la eficacia y la seguridad de tofacitinib en la subpoblación Latinoamericana (LA) de los estudios fase 3 y de extensión a largo plazo (ELP). Materiales y métodos. Se agruparon datos de pacientes de Latinoamérica con AR y una respuesta inadecuada a agentes modificadores de la enfermedad (DMARD) de 5 estudios fase 3. Los pacientes en estos estudios recibieron tofacitinib 5 o 10mg/2 veces al día (bid), adalimumab o placebo; los pacientes en el estudio de seguridad recibieron tofacitinib 5 o 10mg/bid; los tratamientos se administraron en monoterapia o con DMARD sintéticos convencionales. La eficacia se reporta hasta 12 (fase 3) y 36 meses (ELP) mediante las tasas de respuesta del Colegio Americano de Reumatología (ACR) 20/50/70, el índice de actividad de la enfermedad (DAS)28-4 ESR (tasa de sedimentación globular [ESR]) y el índice de discapacidad del cuestionario de evaluación de la salud (HAQ-DI). Se reportan las tasas de incidencia (IR: pacientes con evento/100 pacientes/año) de eventos adversos (EA) de interés especial. Resultados. Los estudios fase 3, incluyeron 496 pacientes de LA, el ELP reclutó 756 pacientes de fase 2 y fase 3. En los estudios de fase 3, los pacientes que recibieron tofacitinib 5 y 10mg/bid presentaron mejorías vs placebo al mes 3 en las respuestas ACR20 (68,9% y 75,7% vs 35,6%), ACR50 (45,8% y 49,7% vs 20,7%) y ACR70 (17,5% y 23,1% vs 6,9%), en cambio, desde el valor basal en el escore HAQ-DI (−0,6 y −0,8 vs −0,3) y en el escore DAS28-4(ESR) (−2,3 y −2,4 vs −1,4); estas mejorías fueron sostenidas hasta el mes 36, último mes de evaluación en el estudio de ELP. En los pacientes con tofacitinib 5 o 10mg/bid y placebo, las tasas de incidencia de SAE fueron de 7,99, 6,57 y 9,84, mientras que la incidencia de descontinuaciones por EA fueron de 3,87, 5,28 y 3,26, respectivamente. Las IR de EA de interés especial en pacientes de LA fueron similares a la población global. Conclusión. En los pacientes de LA con AR de estudios fase 3 y ELP, tofacitinib demostró eficacia hasta por 36 meses con un perfil de seguridad manejable hasta por 60 meses, en los pacientes de LA con AR, datos consistentes con el de la población global de los estudios de tofacitinib (AU)
This study will test if CP-690,550 is safe and effective in rheumatoid arthritis patients taking methotrexate who have an inadequate response to tumor necrosis factor inhibitor treatment.
País»Australia,Austria,Belgium,Brazil,Canada,France,Germany,Ireland,Italy,Korea, Republic of,Puerto Rico,Spain,United States
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
