In a double-blind phase 2 clinical trial, patients with active ulcerative colitis (UC) given doses of 30 or 40 mg apremilast twice daily had greater improvements in inflammation markers and endoscopic and clinical features at 12 weeks than did participants in a placebo group, according to a study published in Clinical Gastroenterology and Hepatology.
New oral therapeutic agents are needed for patients with UC who are unresponsive or intolerant to conventional therapy. This international randomized, multicenter, placebo-controlled trial lasted for a 12-week period was was followed by an active-treatment double-blind extension for 40 weeks (NCT02289417). Participants were adults with active moderate to severe UC (total Mayo score [TMS] ≥6 to ≤11 and Mayo endoscopic score ≥2) for more than 3 months who were intolerant or unresponsive to conventional therapies.
For the initial 12 weeks, participants were randomly assigned to receive twice-daily apremilast 30 mg (n=57), apremilast 40 mg (n=55), or placebo (n=58). Then participants were randomly assigned to twice-daily apremilast 30 or 40 mg for another 40 weeks. Endoscopies and biopsies were performed at baseline in weeks 12 and 52, and fecal and blood samples were collected and analyzed throughout the trial. Clinical remission at week 12 was the primary endpoint, with clinical remission was defined as a TMS of <2 and no individual subscore >1.
Twelve of 55 (21.8%) of patients receiving apremilast 40 mg achieved the primary endpoint compared with 7 of 58 (12.1%) receiving placebo (difference, 7.7%; 95% CI, −6.9 to 22.0; P =.269). Due to the hierarchical stepdown testing procedure to control type 1 error rate at 0.1 for the primary endpoint, the same comparison could not be performed for apremilast 30 mg. However, a nominally higher proportion of participants receiving apremilast 30 mg achieved TMS clinical remission (31.6% [18/57]) compared with placebo (P =.014), and modified Mayo score in remission at week 12 results were consistent for apremilast 30 mg (difference, 24.8%; 95% CI, 7.5-40.1; P =.005).
At week 12, 12 of 53 participants uptitrated from apremilast 30 mg to 40 mg with minimal benefit observed for dose escalation. Therefore, the apremilast 30 mg/40 mg group and the apremilast 30 mg/30 mg group were combined for the week 52 analyses. TMS clinical remission at week 52 was achieved by 40.3% of participants initially randomized to apremilast 30 mg, in 32.7% of those initially randomized to apremilast 40 mg, in 23.1% initially randomized to placebo and switched to apremilast 30 mg at week 12, and in 40.0% initially randomized to placebo and switched to apremilast 40 mg at week 12.
Between-group differences in clinical remission were associated with endoscopic improvement. Both the 30 and 40 mg apremilast groups showed similar improvements from baseline in Mayo score components (rectal bleeding score, stool frequency score, physician’s global assessment). Compared to placebo, both apremilast groups had greater median percentage reductions in fecal calprotectin and C-reactive protein as measured by high-sensitivity blood test through week 12. Headache and nausea were the most frequent apremilast-associated adverse events.
Study investigators conclude, “In this phase 2 study, the primary endpoint was not met; however, apremilast led to numerically greater outcomes in TMS clinical remission, biomarkers, histological and endoscopic response versus placebo over 12 weeks. These improvements were maintained through week 52 at both doses. Safety and tolerability were consistent with previous studies in other indications.”
Disclosure: This clinical trial was supported by Celgene Corporation. Please see the original reference for a full list of authors’ disclosures.
Danese S, Neurath MF, Kopoń A, et al. Effects of apremilast, an oral inhibitor of phosphodiesterase 4, in a randomized trial of patients with active ulcerative colitis [published online January 8, 2020]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.12.032