Randomised clinical trial: exploratory phase 2 study of ONO-2952 in diarrhoea-predominant irritable bowel syndrome

W E Whitehead, K Duffy, J Sharpe, T Nabata, M Bruce, W E Whitehead, K Duffy, J Sharpe, T Nabata, M Bruce

Abstract

Background: ONO-2952 is a novel and selective inhibitor of translocator protein 18 kDa that reduces stress-induced defecation and visceral hyperalgesia in rat models.

Aim: To evaluate the efficacy and safety of ONO-2952 in females with irritable bowel syndrome with diarrhoea in an exploratory proof-of-concept study.

Methods: A randomised, double-blind, placebo-controlled study was conducted at 49 US centres. Two hundred subjects with irritable bowel syndrome with diarrhoea (Rome III criteria) were randomised to ONO-2952 20 mg, or 60 mg, or placebo. Subjects recorded irritable bowel syndrome symptoms daily during a 2-week baseline period, the 4-week treatment period and for 4 weeks post-treatment. The co-primary endpoints were change from baseline to week 4 in abdominal pain, stool consistency and stool frequency.

Results: Improvements in irritable bowel syndrome symptoms were seen with ONO-2952 over placebo in per-protocol analyses for all three co-primary endpoints, but these did not reach statistical significance at the 5% level. The largest improvement was seen with ONO-2952 60 mg. ONO-2952 was well tolerated with a safety profile similar to that of placebo. Most adverse events were mild or moderate in severity and not treatment related.

Conclusion: ONO-2952 showed evidence of clinical efficacy in reducing irritable bowel syndrome-related symptoms in female subjects with irritable bowel syndrome with diarrhoea, and further evaluation is, therefore, warranted to assess its potential as a treatment for irritable bowel syndrome with diarrhoea (NCT01844180).

© 2016 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
(a) Study design and (b) subject disposition. *Based on actual treatment received. **Pharmacokinetic concentrations on day 29 that were below the limit of quantification and so were consistent with noncompliance with the study protocol. FAS, full analysis set; IBS, irritable bowel syndrome; PPS, per‐protocol set; q.d., once daily; SAF, safety analysis set.
Figure 2
Figure 2
Least‐squares mean (95% CI) change from baseline in weekly scores for (a) worst abdominal pain experienced in the past 24 h, (b) number of days per week with ≥1 stool of BSS type 6 or 7, and (C) weekly number of stools (per‐protocol set). *P < .05; #P < 0.10 vs. placebo; $P < 0.10 vs. placebo over weeks 1–4 (repeated measures analysis). BSS, Bristol Stool Score; CI, confidence interval.
Figure 3
Figure 3
Responder analysis for (a) daily responders, (b) weekly responders and (c) daily responders according to differing thresholds for abdominal pain (on‐treatment period, per‐protocol set).

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