This Phase 3 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 as monotherapy 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 the Phase 2 Rheumatoid Arthritis studies.
ANTECEDENTES: Tofacitinib (CP-690,550) es un nuevo inhibidor oral de la quinasa Janus que está siendo investigado como un inmunomodulador específico y modificador de la enfermedad como terapia para la artritis reumatoide. MÉTODOS: En este estudio de fase 3, doble ciego, controlado con placebo, de grupos paralelos, de 6 meses, 611 pacientes fueron asignados aleatoriamente en una proporción 4:4:1:1, a 5 mg de tofacitinib dos veces al día, 10 mg de tofacitinib dos veces al día contra placebo durante 3 meses seguidos de 5 mg de tofacitinib dos veces al día o placebo durante 3 meses seguidos de 10 mg de tofacitinib dos veces al día. Los puntos finales primarios, evaluados a los 3 meses, fueron el porcentaje de pacientes con al menos una mejora del 20% en el American College of Rheumatology escala (ACR 20), el cambio desde el inicio de Health Assessment Questionnaire–Disability Index (HAQ-DI) resultados (que van de 0 a 3, con las puntuaciones más altas que indican mayor discapacidad) y el porcentaje de pacientes con Disease Activity Score de 28 puntos basado en la velocidad de sedimentación globular (DAS28-4 [ESR]) de menos de 2,6 (con puntuaciones que van desde 0 hasta 9,4 y puntajes más altos indican mayor actividad de la enfermedad). RESULTADOS: En 3 meses, un porcentaje mayor de pacientes en los grupos tofacitinib que en los grupos tratados con placebo cumplían los criterios de una respuesta ACR 20 (59,8% en el grupo de 5 mg tofacitinib y el 65,7% en el grupo de 10 mg tofacitinib vs 26,7% en los grupos placebo combinados, p <0,001 para ambas comparaciones). Las reducciones desde el inicio de puntuaciones HAQ-DI fueron mayores en los grupos de tofacinib de 5 mg y 10 mg que en el grupo placebo (-0.50 y -0.57 puntos, respectivamente, frente a los puntos de -0,19; P <0,001). El porcentaje de pacientes con una DAS28-4 (ESR) de menos de 2,6 no fue significativamente mayor con tofacitinib que con placebo (5,6% y 8,7% en grupos 5-mg y 10 mg tofacitinib, respectivamente, y 4,4% con placebo , p = 0,62 yp = 0,10 para las dos comparaciones). Infecciones graves se desarrollan en seis pacientes que estaban recibiendo tofacitinib. Reacciones adversas comunes fueron dolor de cabeza e infecciones del tracto respiratorio superior. El tratamiento con Tofacitinib se asoció con elevaciones en los niveles de colesterol de lipoproteinas de baja densidad y reducciones en el recuento de neutrófilos. CONCLUSIONES: En pacientes con artritis reumatoide activa, la monoterapia con tofacitinib se asoció con reducciones en los signos y síntomas de la artritis reumatoide y mejora la función física. (Financiado por Pfizer; ORAL Solo número ClinicalTrials.gov, NCT00814307)
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.
INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.
METHOD: In this 6-month, phase 3, randomized, placebo-controlled trial, 611 patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARD-IR) were randomized 4:4:1:1 to receive: tofacitinib 5 mg BID or tofacitinib 10 mg BID for the duration of the study, or placebo for 3 months followed by tofacitinib 5 mg BID or tofacitinib 10 mg BID. Patient-reported outcomes (PROs) included: Patient Global Assessment of Disease Activity (PtGA); Patient Assessment of Pain (Pain); Health Assessment Questionnaire-Disability Index (HAQ-DI); Medical Outcomes Survey (MOS) Short Form-36 (SF-36); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and MOS Sleep Scale. Time-to-event data (PtGA and Pain) were collected using an interactive voice response system daily diary (baseline through day 14).
RESULTS: At month 3, tofacitinib 5 and 10 mg BID demonstrated statistically significant improvements versus placebo in PtGA (both p < 0.0001), Pain (both p < 0.0001), HAQ-DI (both p < 0.0001), SF-36 Physical (p < 0.0001) and Mental (p < 0.05 [5 mg BID] and p < 0.0001 [10 mg BID]), Component Summary scores and all domain scores (p < 0.05-p < 0.0001) and FACIT-F (both p < 0.0001). Statistically significant changes from baseline in MOS Sleep Scale were reported for 10 mg BID (p < 0.05). Benefits of tofacitinib treatment were rapid in onset and significant improvements were reported at week 2 for PtGA, Pain and HAQ-DI, and differentiation from baseline was seen as early as 3 days after treatment initiation for interactive voice response system (IVRS) PtGA and IVRS Pain. The numbers needed to treat for patients to report changes greater than or equal to the minimum clinically important difference in PtGA, Pain, HAQ-DI, SF-36 Physical Component Summary score and FACIT-F ranged between 4.0-6.1 (5 mg BID) and 3.2-5.0 (10 mg BID).
CONCLUSION: Tofacitinib monotherapy in DMARD-IR patients resulted in statistically significant and clinically meaningful improvements in multiple PROs versus placebo at month 3, with sustained improvements over 6 months.
TRIAL REGISTRATION: Clinicaltrials.gov registration NCT00814307 , registered 22 December 2008.
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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).
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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.
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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.
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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
This Phase 3 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 as monotherapy 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 the Phase 2 Rheumatoid Arthritis studies.
País»Brazil,Bulgaria,Chile,Colombia,Czech Republic,Dominican Republic,Germany,India,Malaysia,Mexico,Philippines,Poland,Puerto Rico,Russian Federation,Ukraine,United States
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
