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

ABSTRACT: ONO-2952 is a novel and selective inhibitor of translocator protein 18 kDa that reduces stress-induced defecation and visceral hyperalgesia in rat models.To evaluate the efficacy and safety of ONO-2952 in females with irritable bowel syndrome with diarrhoea in an exploratory proof-of-concept study.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.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.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).

SUBMITTER: Whitehead WE

PROVIDER: S-EPMC5157770 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

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

Alimentary pharmacology & therapeutics 20161107 1

<h4>Background</h4>ONO-2952 is a novel and selective inhibitor of translocator protein 18 kDa that reduces stress-induced defecation and visceral hyperalgesia in rat models.<h4>Aim</h4>To evaluate the efficacy and safety of ONO-2952 in females with irritable bowel syndrome with diarrhoea in an exploratory proof-of-concept study.<h4>Methods</h4>A randomised, double-blind, placebo-controlled study was conducted at 49 US centres. Two hundred subjects with irritable bowel syndrome with diarrhoea (Ro ...[more]

PMID: 27910150

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Project description:AimTo study whether selected bacterial 16S ribosomal RNA (rRNA) gene phylotypes are capable of distinguishing irritable bowel syndrome (IBS).MethodsThe faecal microbiota of twenty volunteers with IBS, subdivided into eight diarrhoea-predominant (IBS-D), eight constipation-predominant (IBS-C) and four mixed symptom-subtype (IBS-M) IBS patients, and fifteen control subjects, were analysed at three time-points with a set of fourteen quantitative real-time polymerase chain reaction assays. All assays targeted 16S rRNA gene phylotypes putatively associated with IBS, based on 16S rRNA gene library sequence analysis. The target phylotypes were affiliated with Actinobacteria, Bacteroidetes and Firmicutes. Eight of the target phylotypes had less than 95% similarity to cultured bacterial species according to their 16S rRNA gene sequence. The data analyses were made with repeated-measures ANCOVA-type modelling of the data and principle component analysis (PCA) with linear mixed-effects models applied to the principal component scores.ResultsBacterial phylotypes Clostridium cocleatum 88%, Clostridium thermosuccinogenes 85%, Coprobacillus catenaformis 91%, Ruminococcus bromii-like, Ruminococcus torques 91%, and R. torques 93% were detected from all samples analysed. A multivariate analysis of the relative quantities of all 14 bacterial 16S rRNA gene phylotypes suggested that the intestinal microbiota of the IBS-D patients differed from other sample groups. The PCA on the first principal component (PC1), explaining 30.36% of the observed variation in the IBS-D patient group, was significantly altered from all other sample groups (IBS-D vs control, P = 0.01; IBS-D vs IBS-M, P = 0.00; IBS-D vs IBS-C, P = 0.05). Significant differences were also observed in the levels of distinct phylotypes using relative values in proportion to the total amount of bacteria. A phylotype with 85% similarity to C. thermosuccinogenes was quantified in significantly different quantities among the IBS-D and control subjects (-4.08 +/- 0.90 vs -3.33 +/- 1.16, P = 0.04) and IBS-D and IBS-M subjects (-4.08 +/- 0.90 vs -3.08 +/- 1.38, P = 0.05). Furthermore, a phylotype with 94% similarity to R. torques was more prevalent in IBS-D patients' intestinal microbiota than in that of control subjects (-2.43 +/- 1.49 vs -4.02 +/- 1.63, P = 0.01). A phylotype with 93% similarity to R. torques was associated with control samples when compared with IBS-M (-2.41 +/- 0.53 vs -2.92 +/- 0.56, P = 0.00). Additionally, a R. bromii-like phylotype was associated with IBS-C patients in comparison to control subjects (-1.61 +/- 1.83 vs -3.69 +/- 2.42, P = 0.01). All of the above mentioned phylotype specific alterations were independent of the effect of time.ConclusionSignificant phylotype level alterations in the intestinal microbiotas of IBS patients were observed, further emphasizing the possible contribution of the gastrointestinal microbiota in IBS.

Project description:BACKGROUND: Increased concentrations of 5-hydroxytryptamine (5-HT) can be detected in the systemic circulation after a meal and may be involved in the physiological control of gastrointestinal motility. Abnormalities of 5-HT release after a meal might explain some of the postprandial symptoms associated with the irritable bowel syndrome (IBS). AIM: To investigate the effect of a standard meal on plasma 5-HT and urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations in patients with diarrhoea predominant IBS and in healthy volunteers. METHODS: After an overnight fast, six volunteers and five patients with IBS were given a carbohydrate-rich meal. Blood and urine samples were taken before and for four hours after the meal. Platelet-poor plasma 5-HT and urinary 5-HIAA were analysed by reversed phase high performance liquid chromatography with fluorometric detection. 5-HIAA was expressed as a ratio with urinary creatinine concentration, which was measured by spectrophotometry. RESULTS: During the four hour postprandial period, 5-HT concentrations were significantly higher in patients with IBS than in healthy volunteers at 0.5 hours (p < 0.05), 2 hours (p < 0.05) and 2.5 hours (p < 0.05). 5-HT was not detected in the plasma in the fasting state in patients or volunteers. Median peak 5-HT in patients with IBS (359 (198-796) nmol/l) was significantly greater than volunteers (83 (7-190)) (p < 0.05). "Area under the curve" for 5-HT detection was greater for patients with IBS (317 (138-771)) than for healthy volunteers (51 (4-129); p < 0.05). The duration of the 5-HT peak was significantly longer in patients with IBS (3 (1-3) hours) than in the healthy volunteers (1 (1-1) hours; p < 0.01). Postprandial urinary median 5-HIAA values in controls (5.6 (5.5-5.8) mumol/mmol creatinine) and patients with IBS (3.0 (2.5-6.8) mumol/mmol creatinine) were not significantly different from preprandial values (controls: 5.9 (5.5-6.6) mumol/mmol creatinine; patients with IBS: (6.2 (2.4-9.3) mumol/mmol creatinine). CONCLUSION: These findings indicate that there may be a difference in the way that 5-HT is released in patients with diarrhoea predominant IBS, and could suggest a possible role for 5-HT in the postprandial symptoms of these patients.

Project description:BackgroundIrritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D.MethodsThis trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of "responders" in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron.DiscussionThe TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron's mechanisms of action we hope to better identify patients with IBS-D who are likely to respond.Trial registrationISRCTN, ISRCTN17508514 , Registered on 2 October 2017.

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

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

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