This is a comparative study of CP 690,550, Humira (adalimumab) and placebo on background methotrexate in patients with Rheumatoid Arthritis. The study is intended to provide evidence of the efficacy and safety of CP 690,550 when dosed 5 mg and 10 mg twice a day on background methotrexate in adult patients with moderate to severe Rheumatoid Arthritis. It is intended to confirm the benefits of CP-690,550 in improving signs and symptoms and physical function that were observed in Rheumatoid Arthritis. An active comparator, adalimumab, is also included.
ANTECEDENTES: tofacitinib (CP-690,550) es un nuevo inhibidor oral de la quinasa Janus de que está siendo investigado para el tratamiento de la artritis reumatoide.
MÉTODOS: En este 12 meses, ensayo de fase 3, 717 pacientes que recibían dosis estables de metotrexato fueron asignados al azar a 5 mg de tofacitinib dos veces al día, 10 mg de tofacitinib dos veces al día, 40 mg de adalimumab vez cada 2 semanas, o placebo . Al mes 3, los pacientes del grupo placebo que no tenían una reducción del 20% respecto al valor basal en el número de articulaciones inflamadas y dolorosas fueron conmutadas de manera ciega a cualquiera de 5 mg o 10 mg de tofacitinib dos veces al día; en el mes 6, todos los pacientes que recibieron placebo todavía se cambiaron a tofacitinib de una manera ciega. Las tres medidas de resultado primarias fueron una mejora del 20% en el mes 6 en el Colegio Americano de Reumatología escala (ACR 20); el cambio desde el inicio hasta el mes 3 en la puntuación en el Índice de Evaluación de la Salud Cuestionario-Discapacidad (HAQ-DI) (que va de 0 a 3, con las puntuaciones más altas indican mayor discapacidad); y el porcentaje de pacientes de 6 meses que tenía un índice de actividad de la enfermedad durante 28-articulares recuentos basados en el tipo de sedimentación globular (DAS28-4 [ESR]) de menos de 2,6 (con puntuaciones que van desde 0 hasta 9,4 y una puntuación más alta que indica una mayor actividad de la enfermedad).
RESULTADOS: Al mes 6, ACR 20 las tasas de respuesta fueron mayores entre los pacientes que recibieron 5 mg o 10 mg de tofacitinib (51,5% y 52,6%, respectivamente) y entre los que recibieron adalimumab (47,2%) que entre los que recibieron placebo (28,3%) ( P <0,001 para todas las comparaciones). También hubo una mayor reducción en la puntuación de HAQ-DI en 3 meses y un mayor porcentaje de pacientes con un DAS28-4 (ESR) por debajo de 2,6 a 6 meses en los grupos de tratamiento activo que en el grupo placebo. Los eventos adversos fueron más frecuentes con tofacitinib que con placebo, y la tuberculosis pulmonar desarrollado en dos pacientes en el grupo de tofacitinib 10 mg. Tofacitinib se asoció con un aumento en los niveles tanto de baja densidad y de colesterol de lipoproteína de alta densidad y con reducciones en los recuentos de neutrófilos.
Conclusiones: En los pacientes con artritis reumatoide que recibieron metotrexato fondo, tofacitinib fue significativamente superior al placebo y fue numéricamente similar a adalimumab en la eficacia. (Financiado por Pfizer;. ORAL Número estándar ClinicalTrials.gov, NCT00853385).
Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis (RA). Objectives To compare the effects of tofacitinib 5 and 10 mg twice daily (BID), and active control adalimumab, with placebo (PBO) on patient reported outcomes (PROs) in patients (pts) with active RA and an inadequate response to methotrexate (MTX). Methods Pts in this 12-month (Mo), phase 3, randomised control trial (RCT) with RA (≥6 TJC/SJC; ESR >28 mm/h or CRP >7 mg/L) and prior MTX failure were randomised (4:4:4:1:1) to 5 treatment sequences: tofacitinib 5 mg or 10 mg BID; adalimumab 40 mg subcutaneous (SC) injections once every two weeks (Q2W); PBO advanced to tofacitinib 5 mg BID; and PBO advanced to tofacitinib 10 mg BID, all with MTX. Pts on PBO with <20% improvement in TJC and SJC after 3 months were blindly advanced to tofacitinib 5 or 10 mg BID at that time, and all other PBO pts after 6 months. We analysed changes from Baseline to Mo 6 based on the Full Analysis Set (all pts who received ≥1 dose of study drug) using a mixed-effect longitudinal model for the following PROs (secondary endpoints): PtGA [VAS]; pain (VAS); physical function (HAQ-DI); HR-QoL (SF-36); fatigue (FACIT-F), and sleep (MOS Sleep Scale). Results At Mo 6, treatment with tofacitinib 5 and 10 mg BID, and adalimumab 40 mg Q2W, resulted in statistically significant improvements from baseline vs placebo in all PROs (see Table): (Table presented) Conclusions In this phase 3 RCT in pts with RA with incomplete responses to MTX, the efficacy of tofacitinib 5 or 10 mg BID in improving PROs was significantly superior to placebo and numerically similar to adalimumab.
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.
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA.
METHODS: Analyses included patients treated with adalimumab 40 mg once every 2 weeks or tofacitinib 10 mg twice daily (BID) with background methotrexate (MTX) in a 12-month randomized study (NCT00853385), who subsequently received tofacitinib 10 mg BID (with/without background MTX) in an open-label extension (NCT00413699). Patients with treatment-related serious adverse events (AEs) and serious or recurrent infections in the index study were excluded from the extension study. Exposure-adjusted incidence rates of safety-related events were assessed in 3-month and 12-month periods in the year before and in the year after switching. Efficacy was assessed 3 months before, at the time of, and 3 months after switching.
RESULTS: There were 233 (107 adalimumab to tofacitinib 10 mg BID, 126 blinded to open-label tofacitinib 10 mg BID) patients included in these analyses. Patients in both treatment sequences had similar incidence rates (per 100 patient-years) of discontinuation due to AEs, serious AEs, and serious infections in the year before and in the year after switching. Incidence rates of AEs were increased in the first 3 months after switching compared with the last 3 months before switching in both treatment groups. Switching from either blinded adalimumab or tofacitinib to open-label tofacitinib resulted in numerically higher incidence of responders for signs and symptoms of disease and improved physical function.
CONCLUSIONS: Treatment can be directly switched from adalimumab to tofacitinib. A similar safety and efficacy profile was seen when patients received open-label tofacitinib after receiving either blinded adalimumab or tofacitinib.
TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00853385 , registered 27 February 2009; NCT00413699 , registered 18 December 2006.
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.
OBJECTIVE: To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX.
METHODS: In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep).
RESULTS: At month 3, tofacitinib 10 mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ⩾minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5 mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ⩾minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10 mg BID and similar between tofacitinib 5 mg BID and adalimumab.
CONCLUSION: Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10 mg BID and adalimumab that were significantly superior to placebo.
Background: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). In a Phase 3, 12-month (Mo) study (ORAL Standard) including RA patients (pts) on stable background methotrexate (MTX), tofacitinib and adalimumab (ADA) demonstrated significant improvements in efficacy outcomes compared with placebo (PBO).1 Objectives: To evaluate the efficacy of tofacitinib and ADA based upon American College of Rheumatology (ACR) component scores in a post-hoc analysis of ORAL Standard. Methods: ORAL Standard (NCT00853385) was a randomised, multicentre, Phase 3 study investigating the efficacy of oral tofacitinib 5 and 10 mg twice daily (BID) or ADA 40 mg administered subcutaneously (SC) every two weeks vs PBO in MTX inadequate responders. All pts received background MTX. Effects of tofacitinib 5 mg BID vs ADA 40 mg SC were evaluated in exploratory, post-hoc analyses at Mo 3, 6, 9 and 12 of the proportion of pts achieving ACR 20/50/70 response as well as the change from baseline in each of the following ACR components: Health Assessment Questionnaire-Disability Index (HAQ-DI), tender and swollen joint counts (TJC and SJC), Patient's Global Assessment (PtGA), erythrocyte sedimentation rate (ESR), Physician's Global Assessment (PGA), C-reactive protein (CRP) and Pain. For ACR response rates, pts who withdrew before Mo 12 were considered non-responders from that visit onward. The normal approximation approach to binomial proportions was used to analyse the ACR response. A mixed-effect model was applied to analyse the change from baseline data. Treatment differences for tofacitinib 5 mg BID vs ADA 40 mg SC were reported along with 95% confidence intervals. All analyses were descriptive and were not adjusted for multiplicity. Results: Overall, ACR20/50/70 response rates were numerically higher for tofacitinib 5 mg BID vs ADA over the 12 mo. At Mo 6 ACR20/50/70 rates for tofacitinib were 60.6%, 38.9%, 19.7% vs 57.9%, 28.9%, 9.1%, for ADA. At Mo 12 ACR20/50/70 rates for tofacitinib were 59.6%, 43.5%, 24.9%, vs 61.4%, 38.6%, 16.8% for ADA. Comparable changes from baseline were reported for tofacitinib vs ADA in HAQ-DI, ESR, TJC, SJC, CRP, PtGA, PGA and Pain over time, with numerically higher improvements observed for tofacitinib in the majority of ACR components (Table). Previously published safety data from this study showed that infections and infestations were the most frequent AEs reported over 12 mo in both tofacitinib and ADA treatment groups.1 Serious infection events were more frequent in tofacitinib 5 and 10 mg BID treatment groups (3.4% and 4.0%, respectively) compared with ADA (1.5%), over 12 Mo.1 Conclusions: These post-hoc analyses show that efficacy was generally similar in comparing tofacitinib with ADA, with numerical differences in favour of tofacitinib in some efficacy parameters. The ORAL Standard study was not designed or powered for statistical comparisons between ADA and tofacitinib. Prospective studies to investigate the effect of tofacitinib compared with ADA are under way. (Table Presented).
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).
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.
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)
Objetivos: Tofacitinib es un inhibidor de la cinasa Janus para el tratamiento de la artritis reumatoide (AR). Se evaluaron la eficacia y la seguridad de tofacitinib en pacientes mexicanos a partir de los estudios fase 3 y de extensión a largo plazo (ELP) de AR. Métodos: Datos de pacientes mexicanos con AR y respuesta inadecuada a fármacos antirreumáticos modificadores de la enfermedad (FARME) fueron tomados de 4 estudios fase 3 y de un estudio abierto de ELP de tofacitinib. Los pacientes recibieron tofacitinib 5 o 10mg 2 veces al día, adalimumab (en un estudio fase 3) o placebo (en 4 estudios fase 3) como monoterapia o en combinación con FARME sintético convencional. Se evaluó la eficacia al mes 12 (fase 3) y al mes 36 (ELP) por medio de las tasas de respuesta del Colegio Americano de Reumatología 20/50/70, el puntaje de actividad de la enfermedad (DAS) 28-4, velocidad de sedimentación globular y el índice de discapacidad del cuestionario de evaluación de la salud (HAQ-DI). Se evaluó la seguridad a través de los estudios, incluyendo tasas de incidencia (IR; pacientes con evento/100 pacientes-año). Resultados: Ciento diecinueve y 212 pacientes mexicanos fueron incluidos en el análisis de los estudios fase 3 y de extensión a largo plazo, respectivamente. Pacientes tratados con tofacitinib en los estudios fase 3, numéricamente, tuvieron una mayor mejoría en las respuestas de eficacia en comparación con el placebo al mes 3. La eficacia fue sostenida en los estudios fase 3 y de extensión a largo plazo. Las tasas de incidencia de los eventos adversos de especial interés fueron similares a aquellas con tofacitinib en la población global y latinoamericana. Conclusiones: En pacientes mexicanos del programa global de tofacitinib en AR, la eficacia de tofacitinib se demostró hasta el mes 12 en los estudios fase 3 y hasta el mes 36 en el estudio de extensión a largo plazo, con un perfil de seguridad consistente con el de la población global de los estudios de tofacitinib
OBJECTIVE: Optimal targeted treatment in rheumatoid arthritis requires early identification of failure to respond. This post hoc analysis explored the relationship between early disease activity changes and the achievement of low disease activity (LDA) and remission targets with tofacitinib.
METHODS: Data were from 2 randomized, double-blind, phase III studies. In the ORAL Start trial, methotrexate (MTX)-naive patients received tofacitinib 5 or 10 mg twice daily, or MTX, for 24 months. In the placebo-controlled ORAL Standard trial, MTX inadequate responder patients received tofacitinib 5 or 10 mg twice daily or adalimumab 40 mg every 2 weeks, with MTX, for 12 months. Probabilities of achieving LDA (using a Clinical Disease Activity Index [CDAI] score ≤10 or the 4-component Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] ≤3.2) at months 6 and 12 were calculated, given failure to achieve threshold improvement from baseline (change in CDAI ≥6 or DAS28-ESR ≥1.2) at month 1 or 3.
RESULTS: In ORAL Start, 7.2% and 5.4% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to show improvement in the CDAI ≥6 at month 3; of those who failed, 3.8% and 28.6%, respectively, achieved month 6 CDAI-defined LDA. In ORAL Standard, 18.8% and 17.5% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to improve CDAI ≥6 at month 3; of those who failed, 0% and 2.9%, respectively, achieved month 6 CDAI-defined LDA. Findings were similar when considering improvements at month 1 or DAS28-ESR thresholds.
CONCLUSION: In patients with an inadequate response to MTX, lack of response to tofacitinib after 1 or 3 months predicted a low probability of achieving LDA at month 6. Lack of an early response may be considered when deciding whether to continue treatment with tofacitinib.
This is a comparative study of CP 690,550, Humira (adalimumab) and placebo on background methotrexate in patients with Rheumatoid Arthritis. The study is intended to provide evidence of the efficacy and safety of CP 690,550 when dosed 5 mg and 10 mg twice a day on background methotrexate in adult patients with moderate to severe Rheumatoid Arthritis. It is intended to confirm the benefits of CP-690,550 in improving signs and symptoms and physical function that were observed in Rheumatoid Arthritis. An active comparator, adalimumab, is also included.
