Trials In Irritable Bowel Syndrome Research Articles

Revisiting Meta-analyses of Placebo Response in Drug Trials for Irritable Bowel Syndrome: A Call to Disclose Excipients

Revisiting Meta-analyses of Placebo Response in Drug Trials for Irritable Bowel Syndrome: A Call to Disclose Excipients

Using PRECIS-2 in Chinese herbal medicine randomized controlled trials for irritable bowel syndrome: A methodological exploration based on literature

BackgroundThe pragmatism levels of randomized controlled trials (RCTs) mean how similar the interventions delivered in the trial setting match those in the setting where the results will be applied. We aimed to investigate the association between the consistency of pragmatism among the characteristics of RCT design and its effect size of results in Chinese herbal medicine (CHM) for irritable bowel syndrome (IBS). MethodsEight English and Chinese language databases were searched for RCTs on CHM for IBS. Six reviewers independently assessed the pragmatism of trials using the pragmatic-explanatory continuum indicator summary 2 (PRECIS-2) tool. The consistency of pragmatism levels among the characteristics of RCT design was calculated using the coefficient of variation. Linear regression models were adopted to explore influence factors of the pragmatism of RCTs. Results78 RCTs were included. The level of consistency in the pragmatism for RCT's design was significantly correlated with the effect size of the results (binary outcome, r = -0.413; P = 0.005; continuous outcome, r = -0.779, P < 0.001). PRECIS-2 score was higher in trials with individualized interventions than fixed interventions (3.29 [0.32] vs 2.90 [0.32]; Cohen's d relative effect size, 0.52; P < 0.001) and in standard or usual-treatment-controlled trials than placebo-controlled (3.05 [0.37] vs 2.83 [0.28]; Cohen's d relative effect size, 0.32; P = 0.048). ConclusionThe consistency of pragmatism level across the 9 domains of the PRECIS-2 tool in CHM IBS RCTs was positively correlated with the effect size of the results.

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis.

Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome. A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement. Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect. The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect. This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

Inadequate safety reporting in the publications of randomised clinical trials in irritable bowel syndrome: drug versus probiotic interventions.

Randomised controlled clinical trials (RCTs) offer a unique opportunity to obtain controlled efficacy and safety data to support clinical decisions. However, most RCT reporting has a stronger focus on efficacy rather than safety. This study aimed to identify the safety profile of both probiotic and drug interventions in irritable bowel syndrome (IBS). In connection to this paper, an accompanying paper was published in which a meta-analysis was conducted to evaluate the efficacy of probiotic interventions compared to that of drug interventions in IBS. Together, these two studies provide a first assessment regarding the feasibility to determine a burden to benefit ratio for both probiotic and drug interventions in IBS. RCTs including participants (>18 years old) with IBS and comparing probiotic or drugs interventions with control groups were identified by a systematic search of MEDLINE (January 2015 - Jan 2021). Reported safety profiles in drug studies were completer and more detailed as compared with studies on probiotics. Several inconsistencies in safety reporting were identified between and within drug and probiotic studies, such as: didn't report on safety; only reported adverse reactions (ARs) or adverse events (AEs) with a certain severity; didn't report the total number of AEs; didn't split in the control- or experimental arm; didn't specify AEs; and used different thresholds for 'common' AEs. Hence, it is difficult to compare safety data from drug and probiotic RCTs across and between different studies. On the current approaches to safety reporting, we could not establish an unambiguous safety profile for neither probiotic and drug interventions in IBS. These shortcomings hamper a critical comparison of the burden to benefit ratio for IBS intervention.

Low FODMAP diet in irritable bowel syndrome: a review of recent clinical trials and meta-analyses.

The low fermentable oligosaccharides, disaccharides, monosaccharides and polyol (FODMAP) diet is widely used in the dietary management of irritable bowel syndrome (IBS). The aim of this review is to summarize recent evidence regarding the use of the low FODMAP diet in IBS and other gastrointestinal disorders from recent clinical trials and meta-analyses. Several recent systematic reviews and meta-analyses support the use of low FODMAP restriction for global symptoms in IBS in the short term. Uncontrolled follow-up studies show that at least 50% of individuals experience symptom relief following restriction, reintroduction and personalization in the long term. Although evidence from comparative trials in IBS suggests potential benefit of less burdensome approaches (e.g. standard IBS diet and low lactose diet) many studies are insufficiently powered. One established mechanism is colonic gas production that may induce pain signalling measurable in the brain, however altered gastrointestinal epithelial integrity and shifts in microbiome composition and function may also be involved. Quality trials of the low FODMAP diet are emerging and have been transformational in supporting the widespread application to IBS management in some areas (e.g. short-term effectiveness), whereas other areas still require considerable improvements in research evidence (e.g. long-term effectiveness, mechanisms and educational delivery).

Are They Side Effects? Extraintestinal Symptoms Reported During Clinical Trials of Irritable Bowel Syndrome May Be More Severe at Baseline

Many of the reported adverse events in clinical trials of irritable bowel syndrome are extraintestinal symptoms, which typically are assessed by open-ended questions during the trial and not at baseline. This may lead to misattribution of some pre-existing symptoms as side effects to the treatment. The current study analyzed data from a 6-week clinical trial of irritable bowel syndrome. Participants were randomized to receive double-blind peppermint oil, double-blind placebo, or treatment as usual. Extraintestinal symptoms were assessed at baseline and at the end of the study. This analysis included 173 participants (30 received double-blind peppermint oil, 72 received treatment as usual, and 71 received double-blind placebo). At baseline, each group reported approximately 5 extraintestinal symptoms per participant. The number of symptoms per participant decreased to an average of 3 by the end-of-study visit, and this change was statistically significant in all groups (P < .001 for each group). When evaluating individual extraintestinal symptoms, the majority of participants did not report new/worse symptoms. In fact, between the baseline assessment and the final assessment, the average symptom severity decreased significantly in all 3 groups (P < .001). Our study suggests that participants with irritable bowel syndrome often experience extraintestinal symptoms at baseline and that these symptoms generally improve in severity over the course of a clinical trial, regardless of the treatment arm. Systematic assessment of extraintestinal symptoms at the beginning of a clinical trial is necessary to determine more definitively whether these symptoms may be considered an adverse event attributable to a study medication.

The fragility of randomized placebo-controlled trials for irritable bowel syndrome.

The fragility index (FI) represents the number of participants whose status in a trial would have to change from a non-event (not experiencing the primary endpoint) to an event (experiencing the primary endpoint) in order to turn a statistically significant result into a non-significant result. We sought to evaluate the fragility indices of irritable bowel syndrome [IBS-mixed (IBS-M), IBS-constipation (IBS-C), & IBS-diarrhea (IBS-D)] trials. Irritable bowel syndrome trials published in high-impact journals were identified from Medline. Trials had to be in adults, randomized, parallel-armed, with at least one statistically significant binary outcome, and an achieved primary endpoint of therapeutic efficacy. FI and correlation coefficients were calculated, and regression modeling used to identify predictors of a high FI. Twelve trials were analyzed with a median FI of 6 (range: 0-38). Median sample size in all trials was 366 (range: 44-856). Trial publication year (p=0.71), journal impact factor (p=0.52), duration of study (p=0.12), and number need to treat [NNT] (p=0.29) were not predictive of a high FI. While a lower p-value correlated with a higher FI (p=0.039), no correlation was noted between FI and impact factor (R=-0.20, p=0.52), trial publication year (R=0.12, p=0.71), duration of trial (R=-0.46, p=0.13), NNT (R=-0.34, p=0.29), and sample size (R=0.23, p=0.5). The highest FI was in a Ramosetron trial (FI=30) for IBS-D. A median of six participants is needed to nullify results in the included IBS trials suggesting how easily statistical significance based on a threshold p-value may be overturned.

Natural History and Disease Impact of Rome IV Vs Rome III Irritable Bowel Syndrome: A Longitudinal Follow-Up Study

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder diagnosed using the Rome criteria, which have evolved since their original description 30 years ago. Little is known about the effects on the natural history of IBS of moving to the latest iteration, Rome IV, from the previous Rome III criteria. We conducted a 12-month longitudinal follow-up study to examine this. We collected complete demographic, symptom, mood, and psychological health data at baseline from 1097 adults who self-identified as having IBS and met either Rome IV or Rome III criteria. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, treatments commenced, and psychological health. We examined whether subsequent disease behavior in Rome IV- or Rome III-defined IBS differed. At 12 months, 638 (58.2%) of the 1097 participants were followed up successfully. Of these, 452 met Rome IV criteria and 186 met Rome III criteria at baseline. During the 12-month study period, individuals with Rome IV IBS were significantly more likely to have seen a primary care physician (44.7% vs 28.5%; P < .001) or a gastroenterologist (26.3% vs 12.4%; P < .001) for their IBS symptoms, were significantly more likely to have commenced a new treatment (73.0% vs 60.2%; P= .001), and cycled through significantly more treatments (P= .007), for their IBS compared with those with Rome III IBS. At follow-up evaluation, individuals with Rome IV IBS had more severe symptoms, which had a significantly greater impact on activities of daily living, were more likely to report continuous abdominal pain, and a higher proportion showed poor psychological health, compared with those with Rome III IBS (P < .001 for all analyses). The natural history of IBS defined according to Rome IV criteria is more severe than that of Rome III-defined IBS. This has important implications for future treatment trials in IBS.

Overlap of Rome IV Irritable Bowel Syndrome and Functional Dyspepsia and Effect on Natural History: A Longitudinal Follow-Up Study

Disorders of gut-brain interaction, such as irritable bowel syndrome (IBS) and functional dyspepsia (FD), frequently overlap, but the impact of this on the natural history is unknown. We examined this issue in a longitudinal follow-up study conducted in a large cohort of individuals. We collected complete demographic, symptom, mood, and psychological health data from 1374 adults who self-identified as having IBS. We applied the Rome IV criteria to examine what proportion met criteria for IBS and FD, as well as the degree of overlap between them. At 12 months, we collected data regarding IBS symptom severity and impact, consultation behavior, treatments commenced, and psychological health according to degree of overlap between IBS and FD. Overall, 807 individuals met the Rome IV criteria for IBS at baseline and provided complete data. At study entry, overlap of FD occurred in 446 (55.3%) people who met Rome IV criteria for IBS. At 12 months, 451 (55.9%) individuals were successfully followed up. The proportion of individuals consulting their primary care physician (P= .001) or a gastroenterologist (P < .001) because of their IBS was significantly higher in those with overlap of IBS and FD, and the number of new IBS treatments commenced was significantly higher (P= .007). Those with overlap of IBS and FD reported significantly more severe IBS symptoms (P < .001), continuous abdominal pain, and that their IBS symptoms limited normal daily activities ≥50% of the time. Finally, those with overlap were more likely to report abnormal anxiety and depression scores at 12 months compared with those with IBS alone, and to have higher levels of somatization (P < .001 for all analyses). The natural history of people with IBS with overlap FD defined according to Rome IV criteria is more severe than those with IBS alone. This has important implications for future treatment trials in IBS.

Optimising clinical trial design to manage placebo response in randomised controlled trials of irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common gastroenterology referral and is defined by abdominal pain associated with altered bowel habits. In the absence of objective biomarkers, patient perception of symptoms means everything. Evaluating IBS treatment response in practice relies on the physician to ask their patient if they feel better. A simple question, yet one that is greatly influenced by preconceived expectations of treatment outcomes, frequency of care received, and even side-effects of treatment, which can predispose a patient toward perceiving that a treatment is working. 1 Kaptchuk TJ Kelley JM Conboy LA et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ. 2008; 336: 999-1003 Crossref PubMed Scopus (814) Google Scholar , 2 Ballou S Beath A Kaptchuk TJ et al. Factors associated with response to placebo in patients with irritable bowel syndrome and constipation. Clin Gastroenterol Hepatol. 2018; 16: 1738-1744.e1 Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar , 3 Shah E Triantafyllou K Hana AA Pimentel M Adverse events appear to unblind clinical trials in irritable bowel syndrome. Neurogastroenterol Motil. 2014; 26: 482-488 Crossref PubMed Scopus (18) Google Scholar As recently as 10 years ago, the basic question of whether a patient achieved adequate or global relief of symptoms was the most common (and most sensible) endpoint for clinical trials. Yet this endpoint yielded placebo response rates reaching around 40%. Taken even further, active placebo (with informed consent) has even shown promise as an IBS treatment. 4 Kaptchuk TJ Friedlander E Kelley JM et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One. 2010; 5e15591 Crossref PubMed Scopus (532) Google Scholar These realities allude to the challenges in evaluating investigational IBS treatments in randomised, placebo-controlled trials. The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysisMore than a quarter of patients with irritable bowel syndrome had a placebo response in terms of global improvement, with multiple associated moderators. We recommend future trials apply a run-in period of at least 2 weeks and dose once or twice a day to minimise the placebo response rate. Full-Text PDF

The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis

Clinical trials in irritable bowel syndrome are associated with high placebo response rates. We aimed to identify the magnitude of the placebo response and the contributing factors to this occurrence. We did a systematic review and meta-analysis with a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials between April 1, 1959, and April 30, 2020. We included all randomised controlled trials that compared an active pharmacotherapeutic agent with placebo and had a dichotomous outcome of response to therapy (in terms of global improvement or improvement in abdominal pain) in adults (aged ≥18 years) with irritable bowel syndrome. Exclusion criteria were trials reporting on treatment satisfaction as a dichotomous outcome of response to therapy or clinician-reported outcomes and a treatment duration of less than 4 weeks. Our main outcome was identification of the magnitude of the pooled placebo response rate for the following endpoints: global improvement, abdominal pain, and US Food and Drug Administration (FDA) endpoints. We extracted information from published reports and pooled proportions through meta-analysis with random effects. The study was registered with PROSPERO, CRD42020170908. Of the 6863 publications identified, 70 articles describing 73 randomised controlled trials were included in our analysis. The pooled placebo response rate was 27·3% (95% CI 24·3-30·9) using the global improvement endpoint, 34·4% (31·2-37·8) using the abdominal pain endpoint, and 17·9% (15·2-21·0) using the composite FDA endpoint responder definition, all with substantial heterogeneity between the trials. Studies published before 2006, and those done in Europe, with a parallel design, a run-in period of 2 weeks or less, a dose schedule of three times a day or more, or a smaller sample size of the control group were significantly associated with an increased pooled placebo response rate. More than a quarter of patients with irritable bowel syndrome had a placebo response in terms of global improvement, with multiple associated moderators. We recommend future trials apply a run-in period of at least 2 weeks and dose once or twice a day to minimise the placebo response rate. None.

The Design of Clinical Trials in Irritable Bowel Syndrome using Acupuncture and Related Meridian Therapies

Abstract Current allopathic treatments for irritable bowel syndrome (IBS) are of limited efficacy. Complementary therapies, such as acupuncture, moxibustion, massage and cupping, including hijama, are frequently promoted in the lay press as effective alternatives. In addition, a number of clinical trials have been published, especially with regards to acupuncture, which indicate that they do have therapeutic benefits. This review considers the difficulties associated with formulating randomised controlled trials of such therapies and indicates approaches which may allow objective assessments of their effectiveness.

Clinical effects of Lactobacillus strains as probiotics in the treatment of irritable bowel syndrome. Results from the LAPIBSS trial: Future objectives

The objective of this communication is to present and analyze the recent results from the LAPIBSS study in order to improve future clinical trials on the effects of Lactobacillus strains in the treatment of irritable bowel syndrome (IBS). Using a tightly-controlled clinical trial protocol with the highest Jadad score of 5/5, the current trial aimed to demonstrate the efficacy of a 2-strain mixture of Lactobacillus acidophilus (L. acidophilus) to improve IBS symptoms. Eighty patients diagnosed with IBS according to Rome III criteria were recruited to a multicentric, double-blind, in parallel groups, placebo-controlled, randomized clinical trial. Patients were provided with a daily dose of two capsules containing either two probiotic strains (5 x 109 cfu/capsule) or placebo for 8 weeks. The primary endpoint was abdominal pain score assessed with a 100-mm visual analogue scale (VAS). Secondary endpoints included scores of bloating, flatus and rumbling assessed with a 100-mm VAS, a composite score that consisted of the sum of the 4 VAS scores, and the stool frequency and consistency assessed with the Bristol Stool Form Scale. Our study has failed to demonstrate a significant improvement of the primary endpoint of abdominal pain. Significant differences between groups were observed for flatus score at week 4 (P=0.04) and week 8 (P=0.03) and for composite score at week 8 (P=0.04). The consumption of the 2-strain mixture of L. acidophilus over 8 weeks is safe, significantly decreases flatus and composite scores. The significant effect on flatus could result from the species-specific homofermentative properties of L. acidophilus strains. The negative results on abdominal pain and the gained experience are discussed for the future clinical trials in IBS.

475 The Fragility Index of the Randomized Trials for Irritable Bowel Syndrome With Constipation

INTRODUCTION: In the age of frequentist analyses and standardized threshold P-values (&lt;0.05); fragility index (FI), the minimum number of patients that needs to change from “non-responder” to “responder” for the P-value to become &gt;0.05, has been suggested to aid our interpretation of the robustness of the “positive” large randomized control trials (RCTs) (Walsh, M. et al. JCE 2014). This number allows the reader to quickly know the number of patients that the study relies on for its significance, hence a higher index suggests a higher confidence in the results. Based on all available RCTs, we aimed to calculate the FI of medications that are approved by Food and Drug Association (FDA) for (Irritable bowel syndrome with constipation) IBS-C. METHODS: Data from 13 double-blind RCTs on linaclotide, plecanatide, lubiprostone and tegaserod were analyzed. FI was calculated by converting the number of “non-responders” in a dichotomized data to a “responders” to get a P-value &gt; 0.05 by using the Fisher's exact test. We calculated the FI for the FDA endpoint if it was reported, otherwise the dichotomized endpoint evaluating its efficacy was used. A similar calculation was done for diarrhea as the most common side effect in RCTs on IBS-C in each respective study by converting those without diarrhea to those with diarrhea to calculate its FI. RESULTS: All 13 studies had a positive FI except for Johanson et al. studying lubiprostone since the study itself reported a nonsignificant outcome, as well as Novick at al. studying tegaserod (Table 1). The FI for diarrhea was positive for those in linaclotide and 2 studies for plecanatide and tegaserod but not in lubiprostone. The median (mean) FI for efficacy was 27 (28.5), 13 (17.7), 2 (2), and 6 (11) events and the median (mean) FI for diarrhea was 31.5 (29.3), 2 (3), 0 (0), and 8 (5.7) events for linaclotide, plecanatide, lubiprostone and tegaserod respectively. Linear regression showed a significant positive correlation between FI for efficacy and diarrhea with R2 = 0.54 (P = 0.004) (Figure 1). CONCLUSION: Median FI is appropriately positive for RCTs assessing IBS-C on medications currently approved by FDA. We recommend considering the addition of FI, as a simple and useful tool, in future systematic reviews to assist in appropriate and optimal decision making in patient care.

494 The Fragility of Randomized Placebo-Controlled Trials for Irritable Bowel Syndrome Management

INTRODUCTION: Fragility indices (FI) are a novel method to measure the robustness of results in clinical trials. The FI represents the number of participants whose status in a clinical trial would have to change from a non-event (not experiencing the primary endpoint) to an event (experiencing the primary endpoint) to turn a statistically significant result into a non-significant result. The aim of this study was to evaluate the robustness of trials for irritable bowel syndrome (IBS) including IBS-mixed, IBS-constipation, and IBS-diarrhea. METHODS: Trials published in high impact journals comparing the efficacy of therapies for IBS were identified from Medline. Trials had to be in adults, randomized, parallel-armed, with at least one statistically significant (P &lt; 0.05) binary outcome, and a positive result (i.e. primary endpoint met). Only primary endpoints of therapeutic efficacy were considered. Only trials comparing Rifaximin, Eluxadoline, fecal microbiota transplant (FMT), probiotics, Ramosetron, Alosetron, physical activity, Cimetropium and Pinaverium to placebo met the inclusion criteria. FI and correlation coefficients were calculated and regression modeling was also used to identify predictors of a high FI. RESULTS: Thirteen trials meeting the inclusion criteria were analyzed. The impact factor of the journals in which they were published ranged from 3.5-79. The median FI was 6 (range 1-38). The median sample size in all trials was 427 (range: 44-1280). The trial publication year (P = 0.60), journal impact factor (P = 0.16), time point in weeks when the primary outcome was assessed (P = 0.45), duration of the study (P = 0.89), and number needed to treat [NNT] (P = 0.06) were not predictive of a high FI. However, a larger sample size was predictive of a higher FI (P = 0.01). The highest FI was seen in a Ramosetron trial (FI = 38) for IBS-D published in Gastroenterology. No correlation was seen between FI and journal impact factor (R = 0.19, P = 0.55), trial publication year (R = 0.09, P = 0.77), duration of trial (R = -0.45, P = 0.12), time point at which the primary endpoint was assessed (R = -0.12, P = 0.70), NNT (R = -0.34, P = 0.26), and sample size (R = 0.22, P = 0.47) CONCLUSION: Our results suggest that a median of six participants is needed to nullify efficacy outcomes in the included IBS therapy trials. A larger sample size was predictive of a high FI. Some trials used in the formation of evidence-based guidelines are fragile suggesting how easily statistical significance based on a threshold P-value may be overturned.

The Experience Sampling Method—Evaluation of treatment effect of escitalopram in IBS with comorbid panic disorder

BackgroundConfirming treatment response in clinical trials for irritable bowel syndrome (IBS) is challenging, due to the lack of biomarkers and limitations of the currently available symptom assessment tools. The Experience Sampling Method (ESM) might overcome these limitations by collecting digital assessments randomly and repeatedly during daily life. This study evaluated differences in change in abdominal pain between real‐time (ie, ESM) and retrospective (ie, Gastrointestinal Symptom Rating Scale [GSRS] and an end‐of‐day symptom diary) measurements, using data of an RCT on escitalopram vs placebo in patients with IBS and comorbid panic disorder.MethodsTwenty‐nine IBS patients with comorbid panic disorder were included in a 6‐month RCT. The GSRS, diary, and ESM were completed at baseline (t = 0) and after 3 (t = 3) and 6 months (t = 6). Linear mixed models were used.Key resultsExperience Sampling Method analyses revealed a significant interaction between escitalopram and time, and ESM abdominal pain scores were 1.4 points lower in the escitalopram group compared to placebo at t = 6 (on a 1‐to‐7 scale; P = 0.021). When including the interaction with momentary anxiety, the reduction in abdominal pain scores in escitalopram vs placebo was even more pronounced for higher levels of anxiety. Average GSRS‐ and end‐of‐day abdominal pain scores were not significantly different between escitalopram and placebo at t = 3 and 6.Conclusions & InferencesReal‐time ESM has the potential to capture treatment response more sensitively compared to a retrospective end‐of‐day GI symptom diary and the GSRS, by taking into account day‐to‐day symptom variability as well as momentary factors that might moderate treatment effect, such as anxiety.

Clinical Application of Dietary Therapies in Irritable Bowel Syndrome

Diet appears to play a pivotal role in symptom generation in Irritable Bowel Syndrome (IBS). First line dietary therapy for IBS has focused on advice concerning healthy eating and lifestyle management. Research recently has focused on the role of a diet low in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAPs), gluten free (GFD) and wheat free (WFD) diets for the relief of symptoms in IBS. A round table discussion with gastroenterologists and dietitians with a specialist interest in dietary therapies in IBS was held in Sheffield, United Kingdom in May 2017. Existing literature was reviewed. PubMed and EMBASE were searched with the MeSH terms irritable bowel syndrome/diet/diet therapy/gluten/low FODMAP in different combinations to identify relevant articles. A consensus on the application of these dietary therapies into day-to-day practice was developed. Fourteen randomized trials in IBS evaluating the low FODMAP diet (n studies = 9), GFD (n = 4) and WFD (n = 1) were included in this review. The total number of patients recruited from randomized trials reviewed was: n=580 low FODMAP diet (female, n=430), n=203 GFD (female, n=139), n=276 WFD (female, n=215). There was no significant difference in the gender of patients recruited for both the low FODMAP and GFD randomized studies (p=0.12). The response rate in the literature to a low FODMAP diet ranged between 50-76%, and to GFD ranged between 34-71%. Percentage of IBS patients identified as wheat sensitive was reported as 30% in the literature. There are no head-to-head trials to date utilizing the low FODMAP diet, GFD and WFD for dietary treatment of IBS and still a number of concerns for diets, including nutritional inadequacy and alteration of the gut microbiota. The consensus suggests that there is evidence for the use of the low FODMAP diet, GFD and WFD as dietary therapies for IBS; the decision-making process for using each individual therapy should be directed by a detailed history by the dietitian, involving the patient in the process.

364 Power of Placebo: A Meta-Analysis of Trials in Irritable Bowel Syndrome and Ulcerative Colitis

364 Power of Placebo: A Meta-Analysis of Trials in Irritable Bowel Syndrome and Ulcerative Colitis

PTU-187 Sample size calculation in confirmatory trials in irritable bowel syndrome with constipation: experience with linaclotide (constella®): Abstract PTU-187 Table 1

Introduction Sample size (SS) calculation with sufficient power to detect significant and clinically meaningful differences vs placebo is necessary to ensure the validity of confirmatory Phase 3 pivotal trials in irritable bowel syndrome with constipation (IBS-C). Method Using data from a pilot Phase 2b study of linaclotide (Constella®; LIN) in IBS-C (Study 202) and the pivotal Phase 3 LIN trials (Trial 302; Trial 31), we compared 2 statistical assumptions for the Phase 3 SS calculation for the European Medicines Agency (EMA) co-primary endpoints: 1) minimally important clinical differences (MICD) and 2) replication of Phase 2b 290 µg/day results. Protocol design, patient population and endpoints of the trials were also compared. Results There were no relevant differences in protocol design or patient population in the Phase 2b/3 trials. For endpoint assessments, only the range of the pain/discomfort scale differed (Phase 2b: range 1–5; Phase 3: range 0–10). For both EMA endpoints, Phase 2b data showed a higher placebo effect and greater improvement vs placebo compared with Phase 3 data (both not statistically significant; Table 1). The SS for the Phase 3 trials was estimated to have ≥95% global power to detect an MICD of 15% in both endpoints. Based on replication of Phase 2b results, an SS of 134 patients per treatment arm would have been sufficient to achieve ≥95% global power to detect an effect size comparable to Phase 2b. However, this sample size would have only 46% and 67% overall power to detect the actual observed results of Trials 31 and 302, respectively, and even less overall power (13% and 47%, respectively) when the MICD is reduced to 10%. Conclusion In the LIN IBS-C clinical programme, Phase 2b results were not a good predictor of Phase 3 outcome, even without major differences in study design. Caution is needed when calculating SS for Phase 3 IBS-C trials to ensure sufficient power to detect clinically relevant differences vs placebo. Disclosure of interest M. Falques Employee of: Almirall S. A., C. Diaz Employee of: Almirall S. A., D. Vilardell Employee of: Almirall S. A., J. Fortea Employee of: Almirall S. A., J. Johnston Employee of: Ironwood Pharmaceuticals.

PTU-188 Statistical approaches to missing data in trials of irritable bowel syndrome with constipation: experience with linaclotide (constella®): Abstract PTU-188 Table 1

Introduction Missing data may affect validity and interpretation of clinical trials, as different statistical approaches for handling missing data may lead to different conclusions. As patterns of missing data are often unknown until unblinding, study design should be guided by similar trials. Information on handling missing data in trials in irritable bowel syndrome with constipation (IBS-C) is limited. Method This post-hoc analysis compared imputation methods for missing data in 2 pivotal randomised, double-blind, placebo (PBO)-controlled, multicentre Phase 3 clinical trials (Trials 31 and 302) of linaclotide 290 μg once-daily (Constella ® ; LIN) in IBS-C. In both trials, pre-specified European Medicines Agency (EMA)-recommended co-primary endpoints were: 1) 12-week abdominal pain/discomfort responder rate and 2) 12-week IBS degree-of-relief responder rate. These endpoints were analysed using observed cases (OC), last observation carried forward (LOCF), baseline observation carried forward (BOCF), drop-out as non-responder and multiple imputation approaches. Results In Trial 302, the different imputation methods for missing data yielded results consistent with the initial OC approach for both co-primary endpoints (Table 1). Results were similar for Trial 31, with statistically significant treatment differences for all imputation methods for both endpoints ( P 0.0001 for all except for 12-week abdominal pain/discomfort responder: OC, P = 0.0002 and drop-out as non-responder, P = 0.0056). Conclusion All five imputation methods yielded non-biassed results in both LIN Phase 3 IBS-C trials, supporting the robustness of LIN treatment effects on EMA endpoints. The ‘drop-out as non-responder’ approach could be considered to be the most conservative, as using this method the treatment-effect estimates for both co-primary endpoints were lower than those obtained using other methods. Disclosure of interest M. Falques Employee of: Almirall S. A., C. Diaz Employee of: Almirall S. A., D. Vilardell Employee of: Almirall S. A., J. Fortea Employee of: Almirall S. A., J. Johnston Employee of: Ironwood Pharmaceuticals.