A Multi-Center Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase IIa Study to Evaluate the Efficacy, Safety and Tolerability of an Anthocyanin Rich Extract (ACRE) in Patients with Ulcerative Colitis

Abstract Background In an open label pilot study dried bilberries were effective in inducing clinical, endoscopic and biochemical improvement in ulcerative colitis (UC) patients. Aim was the investigation of efficacy of anthocyanin rich extract (ACRE), the presumptive active ingredient of bilberries, in a controlled clinical trial in moderate-severe UC. Methods We performed a multicenter randomized, placebo-controlled, double-blind study (planned initially for 100 patients; premature termination due to COVID-19 pandemic). Patients had moderate-severe active UC at screening (Mayo-score 6-12, endoscopic sub-score at least 2) and were randomized at baseline (verum: placebo, 2:1). Continuation of all UC-directed stable medical therapy was allowed. Primary endpoint was clinical response at week 8 (reduction of total Mayo-score at least 3 points). Biochemical (fecal calprotectin) and centrally-read endoscopic response were amongst the secondary endpoints. Results Out of 48 patients screened in six Swiss trial centers, 34 were randomized. Eighteen ACRE and eight placebo patients could be analyzed in the Per-Protocol-Set. Half (9/18) of ACRE patients and 3/8 of placebo patients revealed clinical response at week 8 (CI 0.399-6.963; p=0.278). An improvement of the Mayo-score was observed in 77.8% of ACRE treated patients (62.5% of placebo). Fecal calprotectin dropped from 1049+/-1139 to 557+/-756μg/g feces in the ACRE but not in the placebo group (947+/-1039 to 1040+/-1179; p=0.035). Adverse events were rare. Conclusions ACRE therapy was not significantly superior to placebo at inducing a clinical response. However, placebo response was unusual high. Moreover, there was a significant calprotectin decrease at end of treatment, indicative of ACRE biochemical efficacy in UC. Study Highlights What is known Dried bilberries have been reported to ameliorate active ulcerative colitis (UC) in an uncontrolled pilot trial Anthocyanins (flavonoids) are regarded to be the active anti-inflammatory compound of bilberries An anthocyanin rich extract (ACRE) of bilberries was reported to ameliorate colitis in mouse models What is new here In a multi-center randomized, double-blind, placebo controlled, parallel group study in patients with moderate to severe active UC, ACRE did not reach the statistical endpoint of clinical response An unusually high placebo response was observed ACRE induced significant biochemical response with significant decrease in calprotectin levels