A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients With Crohn's Disease

Clin Gastroenterol Hepatol. 2014 Sep;12(9):1485-93.e2. doi: 10.1016/j.cgh.2014.01.029. Epub 2014 Jan 27.

Abstract

Background & aims: Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through γ-chain-containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn's disease.

Methods: Patients (N = 139; age, ≥18 y) with moderate-to-severe active Crohn's disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn's Disease Activity Index score of ≥70 points [Response-70]). Secondary end points included clinical remission (Crohn's Disease Activity Index score of <150 points) at week 4.

Results: A clinical response was observed in 36% (P = .467), 58% (P = .466), and 46% (P ≥ .999) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P = .417), 24% (P = .776), and 14% (P = .540) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 21% of patients given placebo. The 15-mg dose of tofacitinib reduced levels of C-reactive protein and fecal calprotectin from baseline. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5- or 15-mg doses of tofacitinib.

Conclusions: There were no significant differences in the percentage of patients with moderate-to-severe active Crohn's disease who achieved clinical responses (Response-70) or clinical remission after 4 weeks' administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin levels among patients given the 15-mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov number: NCT00615199.

Keywords: CP-690,550; Crohn’s Disease; Randomized Control Trial; Tofacitinib.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blood Chemical Analysis
  • C-Reactive Protein / analysis
  • Crohn Disease / drug therapy*
  • Feces / chemistry
  • Female
  • Humans
  • Janus Kinases / antagonists & inhibitors*
  • Leukocyte L1 Antigen Complex / analysis
  • Male
  • Middle Aged
  • Piperidines / therapeutic use*
  • Placebos / administration & dosage
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrimidines / therapeutic use*
  • Pyrroles / therapeutic use*
  • Treatment Outcome

Substances

  • Leukocyte L1 Antigen Complex
  • Piperidines
  • Placebos
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • tofacitinib
  • C-Reactive Protein
  • Janus Kinases

Associated data

  • ClinicalTrials.gov/NCT00615199