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Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2).
Chey, WD, Lembo, AJ, Yang, Y, Rosenbaum, DP
The American journal of gastroenterology. 2021;(6):1294-1303
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INTRODUCTION Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the long-term efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). METHODS In this randomized double-blind study (ClinicalTrials.gov identifier: NCT02686138), patients with IBS-C received tenapanor 50 mg b.i.d. or placebo b.i.d. for 26 weeks. The primary endpoint was the proportion of patients who had a reduction of ≥30.0% in average weekly worst abdominal pain and an increase of ≥1 weekly complete spontaneous bowel movement from baseline, both in the same week, for ≥6 of the first 12 treatment weeks (6/12-week combined responder). RESULTS Of the 620 randomized patients with IBS-C, 593 (95.6%) were included in the intention-to-treat analysis set (tenapanor: n = 293; placebo: n = 300) and 481 patients (77.6%) completed the 26-week treatment period. In the intention-to-treat analysis set (mean age: 45.4 years; 82.1% women), a significantly greater proportion of patients treated with tenapanor were 6/12-week combined responders than those treated with placebo (36.5% vs 23.7%; P < 0.001). Abdominal symptoms and global symptoms of IBS were significantly improved with tenapanor compared with placebo. Diarrhea, the most common adverse event, was typically transient and mild to moderate in severity. Diarrhea led to study drug discontinuation for 19 (6.5%) and 2 patients (0.7%) receiving tenapanor and placebo, respectively. DISCUSSION Tenapanor 50 mg b.i.d. improved IBS-C symptoms over 26 weeks and was generally well tolerated, offering a potential new long-term treatment option for patients with IBS-C (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B797).
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Effect of Three Diets (Low-FODMAP, Gluten-free and Balanced) on Irritable Bowel Syndrome Symptoms and Health-Related Quality of Life.
Paduano, D, Cingolani, A, Tanda, E, Usai, P
Nutrients. 2019;(7)
Abstract
Several studies have reported some efficacy of diets low in fermentable carbohydrates (Fermentable Oligo-, Di-, Monosaccharides and Polyols (FODMAPs)) in Irritable Bowel Syndrome (IBS). There is no evidence of its superiority compared to gluten-free and balanced diets in improving IBS patients' quality of life (QoL). The aim of this study is to assess whether different diets can improve QoL in IBS. Forty-two patients with IBS, according to Rome IV criteria, were enrolled. Low-FODMAP, gluten-free and balanced diets were proposed to each patient in the same succession. Each diet was followed for 4 weeks. The Bristol Stool Scale, the Visual Analogue Scale (VAS) for bloating and abdominal pain, and the SF12 questionnaire for health-related quality of life were applied at the beginning and at the end of each diet. Twenty-eight of the forty-two patients completed all the three diets. All the three diets reduced symptom severity (p < 0.01), bloating (p < 0.01) and abdominal pain (p < 0.01), and improved quality of life (p < 0.05); 3% of patients expressed a preference for the low-FODMAP diet, 11% for the gluten-free and 86% for the balanced diet (p < 0.01). The balanced diet improves QoL and VAS pain, provides an adequate quantity of FODMAPs and is more appreciated by patients. For these reasons, the balanced diet could be recommended to patients with irritable bowel syndrome.
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Assessment of the effectiveness and safety of ethosuximide in the treatment of abdominal pain related to irritable bowel syndrome - IBSET: protocol of a randomised, parallel, controlled, double-blind and multicentre trial.
Kerckhove, N, Scanzi, J, Pereira, B, Ardid, D, Dapoigny, M
BMJ open. 2017;(7):e015380
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is characterised by the association of abdominal chronic pain with bowel habit disorders in the absence of identifiable organic disease. This is the first reason for consultation in gastroenterology, with an estimated prevalence of 10%-15% in industrialised countries. Although this is a benign gastrointestinal disease, its chronicity profoundly impacts the patient's quality of life and causes considerable health spending. Actual medical treatments are poorly efficient on IBS-related abdominal pain, making it a major public health concern. The mechanisms causing IBS symptoms are unknown. Recent studies have shown the involvement of T-type channel in abdominal pain. We aim to evaluate the therapeutic potential of ethosuximide, a T-type channel blocker, on the abdominal pain of patients presenting an IBS. METHODS AND ANALYSIS The IBSET trial is a randomised, controlled, parallel, double-blind and multicentre study. It is the first clinical trial evaluating the efficacy and safety of ethosuximide on abdominal pain related to IBS. Adults with IBS that report significant abdominal pain (≥4/10) at least for 3 months will be included. 290 patients will be randomly assigned to receive either ethosuximide or placebo over 12 weeks after 1 week of run-in period. The primary endpoint is the rate of responders (pain reduction ≥30% and Subject Global Assessment of Relief score ≥4). The intensity of abdominal pain will be assessed by an 11-point Numerical Rating Scale before and after 12 weeks of treatment and the score of the Subject Global Assessment of Relief scale at the end of treatment. The secondary endpoints are the safety of ethosuximide, the intensity and features of IBS and quality of life. ETHICS AND DISSEMINATION The study was approved by an independent medical ethics committee (CPP Sud-Est VI, Clermont-Ferrand, France). The results will be published in a peer-review journal and presented at international congresses. TRIAL REGISTRATION NUMBER NCT02973542; Pre-results.
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Randomised controlled trial of mesalazine in IBS.
Barbara, G, Cremon, C, Annese, V, Basilisco, G, Bazzoli, F, Bellini, M, Benedetti, A, Benini, L, Bossa, F, Buldrini, P, et al
Gut. 2016;(1):82-90
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OBJECTIVE Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. DESIGN We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. RESULTS A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. CONCLUSIONS Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. TRIAL REGISTRATION NUMBER ClincialTrials.gov number, NCT00626288.
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Irritable bowel syndrome symptom severity improves equally with probiotic and placebo.
Lyra, A, Hillilä, M, Huttunen, T, Männikkö, S, Taalikka, M, Tennilä, J, Tarpila, A, Lahtinen, S, Ouwehand, AC, Veijola, L
World journal of gastroenterology. 2016;(48):10631-10642
Abstract
AIM: To determine the effects of Lactobacillus acidophilus NCFM on irritable bowel syndrome (IBS) symptoms and quality of life (QoL). METHODS In this randomized triple-blind trial, adult IBS volunteers who were recruited according to Rome III criteria received 109 or 1010 colony-forming units of NCFM or placebo daily for 12 wk. IBS Symptom Severity Score (IBS-SSS), which constituted the primary outcome, and secondary outcomes, including individual IBS symptoms, IBS-related QoL questionnaire, anxiety and depression, defecation frequency, and stool consistency, were assessed at baseline at the end of the 8-wk run-in period, after 4 and 12 wk of intervention, and after a 4-wk washout. RESULTS A total of 340 of 391 randomized volunteers completed the trial. IBS-SSS improved over 12 wk of treatment in all treatment groups, decreasing by a mean ± SD of 44.0 ± 80.2, 50.8 ± 82.4, and 48.3 ± 72.2 in the placebo, active low-dose, and active high-dose groups, respectively. Similarly, secondary outcomes did not differ between treatment groups. However, in a post hoc analysis of volunteers with moderate to severe abdominal pain at baseline (VAS > 35/100), the treatment significantly reduced the sensation of abdominal pain. Pain scores fell by 20.8 ± 22.8, 29.4 ± 17.9, and 31.2 ± 21.9 in the placebo, active low-dose, and active high-dose groups, respectively (P value for placebo vs combined active doses = 0.0460). CONCLUSION NCFM alleviates moderate to severe abdominal pain, consistent with earlier observations of this strain mitigating visceral pain through increased analgesic receptor expression.
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Probiotic treatment of irritable bowel syndrome in children.
Martens, U, Enck, P, Zieseniss, E
German medical science : GMS e-journal. 2010;:Doc07
Abstract
UNLABELLED Treatment of functional bowel disorders of irritable bowel-type (IBS) in children remains a difficult task because of a lack of drugs with low adverse event profile. We here report the results of a treatment study in 203 children (66 boys and 137 girls) age 4 to 18 years (mean: 10.5+/-4.5 years) with typical IBS symptoms with abdominal pain and either predominant diarrhea (n=50), constipation (n=56), alternating stool frequency (n=28) or unspecific pain (n=69). The average duration of symptoms prior to therapy was 175 days. Most (95%) patients up to age 11 were treated with a daily dose of 10 drops of Symbioflor 2 (SF2) (SymbioPharm, Herborn) (cells and autolysate of 1.5-4.5x10(7) CFU of bacteria of Escherichia coli type), in the elder children 77% received this dosage, while the remaining received a higher dose up to 30 drops/day. Treatment lasted 43 days on average. RESULTS All patients tolerated the treatment well and without adverse events. The key IBS symptoms (abdominal pain, stool frequency) as well as the other symptoms (bloating, mucous and blood in stool, need for straining at stools, urge to defecate) improved significantly during treatment. Global assessment of therapy by parents and doctors was altogether positive. In summary these data confirm efficacy and tolerability of this probiotic compound in children and adolescents and supplement published data of probiotic IBS therapy in adults.
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Intrarectal lidocaine is an effective treatment for abdominal pain associated with diarrhea-predominant irritable bowel syndrome.
Verne, GN, Sen, A, Price, DD
The journal of pain. 2005;(8):493-6
Abstract
UNLABELLED Irritable bowel syndrome (IBS) is one of the most common disorders seen by gastroenterologists. Visceral hypersensitivity is now well recognized as a clinical marker for the disease. Intrarectal lidocaine has been previously shown to decrease pain report from rectal distension in patients with IBS without any significant serum lidocaine levels. We conducted a prospective, double-blind, crossover trial on 10 patients with IBS to evaluate the effects of 300 mg intrarectal lidocaine jelly on abdominal pain. Ten Caucasian premenopausal women who met the Rome II criteria for diarrhea-predominant IBS were recruited into the study. All of the patients that participated had intermittent left lower quadrant pain and diarrhea. Each patient participated in 2 sessions in which saline jelly (placebo) and lidocaine jelly was administered on a double-blind, crossover basis. Patients participated in these sessions at a time when their ongoing pain was at least 3 on a 0 to 10 visual analogue scale. In comparison to placebo saline jelly, lidocaine jelly significantly decreased abdominal pain (P < .02) for at least 4 hours. None of the patients experienced any side effects. Intrarectal lidocaine may be a potentially useful treatment for chronic abdominal pain in IBS. PERSPECTIVE The possible presence of abnormal sodium channels in the rectal and or colonic visceral afferents of patients with IBS might serve as a clue as to the effectiveness of rectal lidocaine. The dose of lidocaine used in this study may be of sufficient strength to normalize aberrant sodium channels that may be present in the colon of patients with IBS without affecting normal sodium channels of either IBS or control subjects.
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Symptomatic efficacy of beidellitic montmorillonite in irritable bowel syndrome: a randomized, controlled trial.
Ducrotte, P, Dapoigny, M, Bonaz, B, Siproudhis, L
Alimentary pharmacology & therapeutics. 2005;(4):435-44
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BACKGROUND Beidellitic montmorillonite is a purified clay containing a double aluminium and magnesium silicate. AIM: To assess the efficacy and the safety of beidellitic montmorillonite (3 g, t.d. for 8 weeks) in patients with irritable bowel syndrome (IBS). METHODS A multicentre, double-blind, placebo-controlled, randomized study with parallel groups, was performed in IBS patients selected according to ROME I criteria. Patients were included after a 1-week washout period to confirm that abdominal pain and/or discomfort was rated at least 2 on a 0-4 graded Likert scale. Patients were then randomized and stratified according to their predominant bowel habit profile into three groups. The use of rescue medication was allowed: polyethylene glycol 4000 (10-20 g/day) as a laxative agent in case of stool absence for three consecutive days, phloroglucinol (80 to a maximum of 320 mg/day) as a spasmolytic agent for no more than 8 days. The main end-point was the improvement of abdominal pain and/or discomfort by at least 1 point on the Likert scale. RESULTS A total of 524 patients constituted the overall intent-to-treat population (ITT), 263 were assessed in the beidellitic montmorillonite group, i.e. 93 diarrhoea-predominant IBS (D-IBS), 83 constipation-predominant IBS (C-IBS), 87 alternating constipation/diarrhoea-IBS (A-IBS); 261 in the placebo group, i.e. 81 D-IBS, 92 C-IBS and 88 A-IBS. Initial analysis in the ITT population demonstrated a higher rate of success with beidellitic montmorillonite (51.7%) when compared with the placebo group (45.2%); however, the difference was not statistically significant. Improvement was significant in C-IBS both in ITT (beidellitic montmorillonite group = 49.4%, placebo group = 31.5%, P < 0.016) and per protocol populations (59.4% vs. 37.8%) (P < 0.01). The time to improvement of abdominal pain and/or discomfort (log Rank test) was also significantly in favour of beidellitic montmorillonite, (P < 0.04). The average number of stools per day was not different from baseline, either in all patients or in C-IBS patients. Spasmolytic and laxative agent intakes were not different between the two groups. Subjective evaluation by patients of treatment efficacy and visual analogue scale test of treatment efficacy by investigators were significantly better in the beidellitic montmorillonite group (P < 0.05). Tolerance of beidellitic montmorillonite was considered optimal without any significant adverse event. CONCLUSIONS Although pain or discomfort was not significantly improved in the entire IBS population treated with beidellitic montmorillonite in comparison with placebo, this study demonstrates that beidellitic montmorillonite is efficient for C-IBS patients (P < 0.016). This effect of beidellitic montmorillonite on pain cannot be explained by changes in bowel habits. The efficacy of this well-tolerated therapy warrants further confirmatory therapeutic trials in C-IBS patients.
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Sexual and physical abuse are not associated with rectal hypersensitivity in patients with irritable bowel syndrome.
Ringel, Y, Whitehead, WE, Toner, BB, Diamant, NE, Hu, Y, Jia, H, Bangdiwala, SI, Drossman, DA
Gut. 2004;(6):838-42
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BACKGROUND Patients with irritable bowel syndrome (IBS) have reduced pain thresholds for rectal distension. In addition, the prevalence of sexual/physical abuse in referred IBS patients is high and is associated with greater pain reporting, poorer health status, and poorer outcome. This lead to a hypothesis that abuse history may sensitise patients to report pain at a lower threshold. AIM: To compare rectal pain thresholds in women with IBS who had a history of severe abuse to IBS women with no history of abuse. METHODS We studied 74 IBS patients with a history of severe physical and/or sexual abuse and 85 patients with no history of abuse. Abuse history was assessed by a previously validated self-report abuse screening questionnaire. Rectal sensory thresholds were assessed using an electronic barostat and determined by the ascending method of limit (AML) and by the tracking technique. RESULTS IBS patients with a history of severe abuse had significantly higher rectal pain thresholds, as measured by AML (F (1, 111) = 6.06; p = 0.015) and the tracking technique (F (1, 109) = 5.21; p = 0.024). Patients with a history of severe abuse also reported a significantly higher threshold for urgency to defecate (F (1, 113) = 11.23; p =.001). CONCLUSION Severe sexual/physical abuse is associated with higher urge and pain thresholds for rectal distension in IBS patients. This suggests that the greater pain reporting and poorer health status in IBS patients with abuse history are not related to increased rectal pain sensitivity. Further studies are needed to determine the causes of these findings.