The purpose of this study is to determine the effectiveness and safety, over 6 months, of 5 doses of CP-690,550 for the treatment of adults with active rheumatoid arthritis. Five out of seven subjects will receive CP-690,550. One out of seven will receive adalimumab (Humira®) and one out of seven will only receive inactive substances (placebo.)
OBJETIVO: Comparar la eficacia, seguridad y tolerabilidad de 5 dosis de tofacitinib oral (CP-690, 550) o la monoterapia con adalimumab con placebo para el tratamiento de la artritis reumatoide activa (AR) en pacientes con una respuesta inadecuada a los fármacos antirreumáticos modificadores de la enfermedad.
MÉTODOS: En este 24 semanas, doble ciego, de fase IIb del estudio, los pacientes con AR (n = 384) fueron aleatorizados para recibir placebo, tofacitinib a los 1, 3, 5, 10, o 15 mg por vía oral dos veces al día, o adalimumab en 40 mg inyectaron por vía subcutánea cada 2 semanas (un total de 6 inyecciones) seguido por tofacitinib oral en 5 mg dos veces al día durante 12 semanas. El punto final primario fue la tasa de respuesta de acuerdo con el American College of Rheumatology criterios de mejora de 20% (ACR20) en la semana 12.
Resultados: El tratamiento con tofacitinib a una dosis de ≥ 3 mg dos veces al día dieron como resultado una respuesta rápida con una eficacia significativa en comparación con el placebo, como se indica por el punto final primario (respuesta ACR20 en la semana 12), logrado en 39,2% (3 mg ; P ≤ 0,05), el 59,2% (5 mg, p <0,0001), el 70,5% (10 mg, p <0,0001), y el 71,9% (15 mg, p <0,0001) en el grupo tofacitinib y el 35,9% de los pacientes en el grupo de adalimumab (P = 0,105), en comparación con el 22,0% de los pacientes que recibieron placebo. Las mejoras se mantuvieron en la semana 24, según el ACR20, ACR50, y las tasas de respuesta ACR70, así como las clasificaciones de remisión de acuerdo con la de 3 variables actividad de la enfermedad Puntuación en 28 articulaciones (DAS28) utilizando la proteína C-reactiva y el DAS28 4 variables utilizando la tasa de sedimentación de eritrocitos. Los eventos más comunes emergentes del tratamiento adversos (AEs) en los pacientes en todos los grupos de tratamiento (n = tofacitinib 272) fueron infección del tracto urinario (7,7%), diarrea (4,8%), cefalea (4,8%) y bronquitis (4,8%) .
CONCLUSIÓN: tofacitinib monoterapia en ≥ 3 mg dos veces al día fue eficaz en el tratamiento de los pacientes AR activa con más de 24 semanas y demostró un perfil de seguridad manejable.
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.
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).
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.
The purpose of this study is to determine the effectiveness and safety, over 6 months, of 5 doses of CP-690,550 for the treatment of adults with active rheumatoid arthritis. Five out of seven subjects will receive CP-690,550. One out of seven will receive adalimumab (Humira®) and one out of seven will only receive inactive substances (placebo.)
