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 .).
ANTECEDENTES Y OBJETIVOS: La interleucina-12 y la interleucina-23 son citocinas inflamatorias implicadas en la fisiopatología de la enfermedad de Crohn. Ustekinumab es un anticuerpo monoclonal contra la subunidad p40 de la interleucina-12/23.
MÉTODOS: Se realizó un ensayo doble ciego cruzado de los efectos clínicos de ustekinumab en 104 pacientes con moderada a severa enfermedad de Crohn (población 1). Los pacientes recibieron placebo subcutánea en las semanas 0-3, luego ustekinumab en las semanas 8-11; ustekinumab subcutánea en las semanas 0-3, entonces el placebo en las semanas 8-11; placebo por vía intravenosa en la semana 0, entonces ustekinumab en la semana 8; o ustekinumab intravenosa en la semana 0, entonces el placebo en la semana 8. Además, un ensayo abierto evaluó los efectos de 4 inyecciones subcutáneas semanales o 1 infusión intravenosa de ustekinumab en 27 pacientes que fueron no respondedores primarios o secundarios a infliximab (población 2).
Resultados: En la población 1, tasas de respuesta clínica para los grupos combinados dan ustekinumab y placebo fueron 53% y 30% (P = 0,02), respectivamente en las semanas 4 y 6, y 49% y 40% (P = 0,34), respectivamente, a 8 semanas. En un subgrupo de 49 pacientes que recibieron infliximab anteriormente (ni no respondedores primarios ni secundarios), la respuesta clínica al ustekinumab fue significativamente mayor que el grupo de placebo dado (P <0,05) hasta la semana 8. 2 En la población, las respuestas clínicas en la semana 8 a ustekinumab subcutáneas e intravenosas fueron 43% y 54%, respectivamente. No hubo aumento en el número de eventos adversos serios o adversos en los pacientes que recibieron ustekinumab a través de semana 8 en comparación con placebo.
CONCLUSIONES: El ustekinumab indujeron una respuesta clínica en pacientes con enfermedad moderada a severa de Crohn, especialmente en pacientes previamente dadas infliximab.
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 .).
