BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population).
METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received.
RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-α antagonist failure or the number of prior TNF-α antagonists failed. Safety profiles were similar in both subpopulations.
CONCLUSIONS: Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-α antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.
BACKGROUND: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.
METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150).
RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.
CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).
BACKGROUND & AIMS: There is an increasing need for new treatments for patients with Crohn's disease (CD) in whom previous therapy with tumor necrosis factor (TNF) antagonists has failed. We performed a placebo-controlled, phase 3, double-blind trial to evaluate the efficacy and safety of vedolizumab, an antibody against the integrin α4β7, as induction therapy.
METHODS: Patients with moderately to severely active CD (CD activity index [CDAI] score, 220-400 points) were assigned randomly to groups given vedolizumab (300 mg) or placebo intravenously at weeks 0, 2, and 6. The primary analysis involved 315 patients with previous TNF antagonist failure (ie, an inadequate response to, loss of response to, or intolerance of ≥1 TNF antagonists); we determined the proportion of patients in clinical remission (CDAI, ≤150 points) at week 6. Secondary analyses evaluated outcomes at weeks 6 and 10 in this population and in the overall population (N = 416), which included patients naive to TNF antagonist therapy (n = 101).
RESULTS: Among patients who had experienced previous TNF antagonist failure, 15.2% of those given vedolizumab and 12.1% of those given placebo were in remission at week 6 (P = .433). At week 10, a higher proportion of this population given vedolizumab was in remission (26.6%) than those given placebo (12.1%) (nominal P = .001; relative risk, 2.2; 95% confidence interval, 1.3-3.6). A higher proportion of patients with previous TNF antagonist failure given vedolizumab also had a CDAI-100 response (≥100-point decrease in CDAI score from baseline) at week 6 than those given placebo (39.2% vs 22.3%; nominal P = .001; relative risk, 1.8; 95% confidence interval, 1.2-2.5). Adverse event results were similar among all groups.
CONCLUSIONS: Vedolizumab was not more effective than placebo in inducing clinical remission at week 6 among patients with CD in whom previous treatment with TNF antagonists had failed. The therapeutic benefits of vedolizumab in these patients were detectable at week 10. ClinicalTrials.gov number: NCT01224171.
ANTECEDENTES: La eficacia de Vedolizumab, un anticuerpo de integrina α4β7, en la enfermedad de Crohn es desconocida.
MÉTODOS: En un estudio integrado con los ensayos de inducción y mantenimiento separados, se evaluó la terapia Vedolizumab intravenosa (300 mg) en adultos con enfermedad de Crohn activa. En el ensayo de inducción, 368 pacientes fueron asignados al azar para recibir Vedolizumab o placebo en las semanas 0 y 2 (cohorte 1), y 747 pacientes recibieron Vedolizumab de etiqueta abierta en las semanas 0 y 2 (cohorte 2); estado de la enfermedad se evaluó en la semana 6. En el ensayo de mantenimiento, 461 pacientes que habían tenido una respuesta a Vedolizumab fueron asignados aleatoriamente para recibir placebo o Vedolizumab cada 8 o 4 semanas hasta la semana 52.
RESULTADOS: En la semana 6, un total de 14,5% de los pacientes en la cohorte 1 que recibieron Vedolizumab y el 6,8% que recibieron placebo estaban en remisión clínica (es decir, tenían una puntuación en el índice de la enfermedad de Crohn Actividad [CDAI] de ≤150, con puntuaciones que van de 0 a aproximadamente 600 y las puntuaciones más altas indican una mayor actividad de la enfermedad) (P = 0,02); un total del 31,4% y el 25,7% de los pacientes, respectivamente, tuvieron una respuesta CDAI-100 (disminución ≥100 puntos en el CDAI) (P = 0,23). Entre los pacientes en las cohortes 1 y 2 que tenían una respuesta a la terapia de inducción, 39,0% y 36,4% de los asignados a Vedolizumab cada 8 semanas y cada 4 semanas, respectivamente, estaban en remisión clínica en la semana 52, en comparación con 21,6% asignado a placebo (p <0,001 y P = 0,004 para los dos grupos Vedolizumab, respectivamente, frente a placebo). Los anticuerpos contra Vedolizumab desarrollados en 4,0% de los pacientes. Nasofaringitis ocurrió con más frecuencia, y dolor de cabeza y dolor abdominal con menor frecuencia, en pacientes que reciben Vedolizumab que en los pacientes que recibieron placebo. Vedolizumab, en comparación con el placebo, se asoció con una mayor tasa de eventos adversos graves (24,4% vs. 15,3%), infecciones (44,1% vs. 40,2%) e infecciones graves (5,5% vs. 3,0%).
Conclusiones: Los pacientes tratados con Vedolizumab con enfermedad de Crohn activa eran más propensos que los pacientes que recibieron placebo tener una remisión, pero no una respuesta CDAI-100, en la semana 6; los pacientes con una respuesta a la terapia de inducción que siguió recibiendo Vedolizumab (en lugar de cambiar con el placebo) tenían más probabilidades de estar en remisión en la semana 52. Los eventos adversos fueron más frecuentes con Vedolizumab. (Financiado por Millennium Pharmaceuticals;. 2 GEMINI número ClinicalTrials.gov, NCT00783692).
ANTECEDENTES: En los pacientes con enfermedad de Crohn, la eficacia de ustekinumab, un anticuerpo monoclonal humano contra la interleucina-12 y la interleucina-23, se desconoce.
MÉTODOS: Se evaluó ustekinumab en adultos con moderada a severa enfermedad de Crohn que era resistente al factor de necrosis antitumoral del tratamiento (TNF). Durante la inducción, 526 pacientes fueron asignados al azar para recibir ustekinumab intravenosa (a una dosis de 1, 3, o 6 mg por kilogramo de peso corporal) o placebo en la semana 0. Durante la fase de mantenimiento, 145 pacientes que tenían una respuesta a ustekinumab a las 6 semanas fueron sometidos a una segunda aleatorización para recibir inyecciones subcutáneas de ustekinumab (90 mg) o placebo en las semanas 8 y 16. El punto final primario fue una respuesta clínica a las 6 semanas.
RESULTADOS: La proporción de pacientes que alcanzaron el punto final primario fueron 36,6%, 34,1% y 39,7% para 1, 3 y 6 mg de ustekinumab por kilogramo, respectivamente, en comparación con 23,5% para placebo (p = 0,005 para la comparación con el grupo 6-mg). La tasa de remisión clínica con la dosis de 6 mg no difirió significativamente de la tasa con el placebo a las 6 semanas. La terapia de mantenimiento con ustekinumab, en comparación con el placebo, se tradujo en un aumento significativo de las tasas de remisión clínica (41,7% vs. 27,4%, p = 0,03) y la respuesta (69,4% vs. 42,5%, p <0,001) a las 22 semanas. Las infecciones graves ocurrieron en 7 pacientes (ustekinumab 6 receptora) durante la inducción y 11 pacientes (4 recibir ustekinumab) durante el mantenimiento. El carcinoma de células basales desarrolló en 1 paciente ustekinumab recibir.
Conclusiones: Los pacientes con enfermedad moderada a severa de Crohn que era resistente a los antagonistas del TNF tenido una mayor tasa de respuesta a la inducción con ustekinumab, en comparación con el placebo. Los pacientes con una respuesta inicial a ustekinumab habían aumentado significativamente las tasas de respuesta y remisión con ustekinumab como terapia de mantenimiento. (Financiado por Janssen Investigación y Desarrollo;. CERTIFI número ClinicalTrials.gov, NCT00771667).
Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population).
METHODS:
Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received.
RESULTS:
Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-α antagonist failure or the number of prior TNF-α antagonists failed. Safety profiles were similar in both subpopulations.
CONCLUSIONS:
Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-α antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
