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

Luc Biedermann, Michael Doulberis, Philipp Schreiner, Ole Haagen Nielsen, Frans Olivier The, Stephan Brand, Sabine Burk, Petr Hurz, Pascal Juillerat, Claudia Krieger-Gruebel, Kristin Leu, Gabriel Leventhal, Benjamin Misselwitz, Silvie Scharl, Alain Schoepfer, Frank Seibold, Hans Herfarth, Gerhard Rogler
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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.
一项多中心随机、双盲、安慰剂对照、平行组 IIa 期研究,旨在评估富含花青素的提取物 (ACRE) 对溃疡性结肠炎患者的疗效、安全性和耐受性
背景:在一项开放标签试验研究中,山桑子干能有效改善溃疡性结肠炎(UC)患者的临床、内窥镜和生化指标。目的:在中度严重溃疡性结肠炎的对照临床试验中,研究富含花青素提取物(ACRE)(山桑子的推定活性成分)的疗效:我们进行了一项多中心随机、安慰剂对照、双盲研究(最初计划100名患者;因COVID-19大流行而提前终止)。患者在筛查时均为中重度活动性 UC(梅奥评分 6-12,内镜子评分至少 2),并在基线时进行随机分组(维鲁姆:安慰剂,2:1)。允许继续接受所有针对 UC 的稳定药物治疗。主要终点是第 8 周时的临床反应(梅奥总分至少降低 3 分)。生化指标(粪便钙蛋白)和中央读取的内镜反应是次要终点。研究结果在瑞士六个试验中心筛选出的 48 名患者中,34 人被随机选中。18名 ACRE 患者和 8 名安慰剂患者可在每方案组中进行分析。半数(9/18)ACRE 患者和 3/8 的安慰剂患者在第 8 周时出现了临床反应(CI 0.399-6.963; p=0.278)。77.8%的 ACRE 治疗患者(62.5% 的安慰剂治疗患者)的梅奥评分有所改善。ACRE 治疗组患者的粪便钙蛋白从 1049+/-1139 降至 557+/-756μg/g 粪便,而安慰剂治疗组患者的粪便钙蛋白没有下降(947+/-1039 降至 1040+/-1179; p=0.035)。不良事件很少发生:结论:ACRE疗法在诱导临床反应方面并不明显优于安慰剂。结论:ACRE疗法在诱导临床反应方面并不明显优于安慰剂。此外,治疗结束时钙蛋白明显降低,表明 ACRE 对 UC 具有生化疗效。
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