1. Patients with active ulcerative colitis who failed prior treatment achieved significantly greater remission of disease and mucosal healing compared to those treated with placebo.
2. Remission of ulcerative colitis symptoms over 1 year was significantly greater for patients who initially responded to tofacitinib and continued therapy compared to patients who responded and then were treated with a placebo.
Evidence Rating: 1 (Excellent)
Study Rundown: Ulcerative colitis is an inflammatory condition of the colon. The condition is difficult to treat despite an array of therapies available. Janus kinase (JAK) receptors are involved in many intracellular immune pathways associated with inflammatory bowel disease, therefore JAK inhibitors may prove useful in treatment of ulcerative colitis. Prior phase 2 trials indicated tofacitinib, a JAK inhibitor, can induce remission of ulcerative colitis. In three phase 3 trials, tofacitinib was further evaluated as an induction and maintenance treatment for patients with ulcerative colitis.
The studies randomized patients with moderate to severe active ulcerative colitis into treatment and placebo groups. In the first 2 studies (OCTAVE 1 and 2), patients received 10 mg of tofacitinib twice a day or a placebo for 8 weeks. At 8 weeks, treated patients were significantly more likely to have achieved remission and gastrointestinal mucosal healing than those treated with placebo. For the third trial (OCTAVE Sustain), patients who responded to tofacitinib were randomized to receive 5 mg tofacitinib, 10 mg tofacitinib, or a placebo twice a day. At 1 year, patients receiving either treatment dose were significantly more likely than those treated with placebo to still be in remission and have mucosal healing.
Click to read the study, published today in NEJM
Relevant Reading: Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550)
In-Depth [randomized controlled trial]: This work describes the results of three separate, multinational, randomized controlled trials carried out from 2012 to 2016. All trials included adult patients with a confirmed diagnosis of ulcerative colitis defined as moderate to severe as assessed by the Mayo score, which included pre- and post-treatment endoscopy. All patients included had to have failed prior treatment for ulcerative colitis, and were generally not allowed to be on other ulcerative colitis treatments during the trial. The first two trials (OCTAVE 1 and 2) randomly assigned patients to treatment groups of 10 mg tofacitinib twice a day (n = 476 and 439, respectively) or a placebo (n = 122 and 112, respectively) for 8 weeks. Key endpoints were remission and mucosal healing at 8 weeks, both assessed by Mayo scores. At 8 weeks, patients in OCTAVE 1 and 2 trials treated with tofacitinib experienced remission significantly more than those in the placebo groups (OCATVE 1 – 18.5% vs 8.2%, p = 0.007; OCTAVE 2 – 16.6% vs 3.6%, p < 0.001). Mucosal healing was also more common in the treatment groups compared to the placebo groups (31.3% vs 15.6%, p < 0.001; 28.4% vs 11.6%, p < 0.001; respectively).
In the OCTAVE Sustain trail, patients who responded to tofacitinib were randomized to receive maintenance therapy over 52 weeks with 5 mg tofacitinib (n = 198), 10 mg tofacitinib (n = 197), or placebo (n=198) twice a day. Their study endpoints were also remission and mucosal healing. At 52 weeks, patients in either the 5 mg or 10 mg tofacitinib groups were more likely to be in remission (34.3% and 40.6%, respectively) than those treated with placebo (11.1%, p < 0.001 for both comparisons with placebo group). Mucosal healing was also more common in the treated groups (37.4% and 45.7%, respectively) compared to the placebo group (13.1%, p < 0.001 for both comparisons with placebo group). In the OCTAVE Sustain trial, adverse events occurred in the 5 mg, 10 mg, and placebo groups at rates of 72.2%, 79.6%, and 75.3%, respectively. The most frequent adverse events, besides worsening ulcerative colitis, were nasopharyngitis, arthralgia, and headache.
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