Meiyun Ke

Design of treatment trials for functional gastrointestinal disorders.

This article summarizes recent progress and regulatory guidance on design of trials to assess the efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo-controlled, parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively, a sham procedure and control intervention with similar expectation of benefit, but lacking the treatment principle, are recommended. Investigators should be aware of, and attempt to minimize, expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location before initiation and results should be published regardless of outcome.This document summarizes recent progress and regulatory guidance on design of trials to assess efficacy of new therapies for functional gastrointestinal disorders (FGIDs). The double-masked, placebo controlled parallel-group design remains the accepted standard for evaluating treatment efficacy. A control group is essential, and a detailed description of the randomization process and concealed allocation method must be included in the study report. The control will most often be placebo, but for therapeutic procedures and for behavioral treatment trials, respectively a sham procedure and control intervention with similar expectation of benefit but lacking the treatment principle are recommended. Investigators should be aware of and attempt to minimize expectancy effects (placebo, nocebo, precebo). The primary analysis should be based on the proportion of patients in each treatment arm who satisfy a treatment responder definition, or a prespecified clinically meaningful change in a patient-reported outcome measure. Data analysis should use the intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include secondary outcome measures to support or explain the primary outcome and an analysis of harms data. Trials should be registered in a public location prior to initiation, and results should be published regardless of outcome.

Gastro-oesophageal reflux disease in Asia

Gastro‐oesophageal reflux disease (GORD) occurs more frequently in Europe and North America than in Asia but its prevalence is now increasing in many Asian countries. Many reasons have been given for the lower prevalence of GORD in Asia. Low dietary fat and genetically determined factors, such as body mass index and maximal acid output, may be important. Other dietary factors appear to be less relevant. Increased intake of carbonated drinks or aggravating medicines may influence the increasing rates of GORD in some Asian countries but no strong evidence links other factors, such as the age of the population, smoking or alcohol consumption, to GORD. The management of GORD in Asia is similar to that in Europe and North America but the lower incidence of severe oesophagitis in Asia may alter the approach slightly. Also, because Asians tend to develop stomach cancer at an earlier age, endoscopy is used routinely at an earlier stage of investigation. Gastro‐oesophageal reflux disease is essentially a motility disorder, so short‐term management of the disease can usually be achieved using prokinetic agents (or histamine (H2)‐receptor antagonists). More severe and recurrent GORD may require proton pump inhibitors (PPI) or a combination of prokinetic agents and PPI. The choice of long‐term treatment may be influenced by the relative costs of prokinetic agents and PPI.

Asian consensus on irritable bowel syndrome.

Background and Aims:  Many of the ideas on irritable bowel syndrome (IBS) are derived from studies conducted in Western societies. Their relevance to Asian societies has not been critically examined. Our objectives were to bring to attention important data from Asian studies, articulate the experience and views of our Asian experts, and provide a relevant guide on this poorly understood condition for doctors and scientists working in Asia.

Asian Consensus Report on Functional Dyspepsia

Background/Aims Environmental factors such as food, lifestyle and prevalence of Helicobacter pylori infection are widely different in Asian countries compared to the West, and physiological functions and genetic factors of Asians may also be different from those of Westerners. Establishing an Asian consensus for functional dyspepsia is crucial in order to attract attention to such data from Asian countries, to articulate the experience and views of Asian experts, and to provide a relevant guide on management of functional dyspepsia for primary care physicians working in Asia. Methods Consensus team members were selected from Asian experts and consensus development was carried out using a modified Delphi method. Consensus teams collected published papers on functional dyspepsia especially from Asia and developed candidate consensus statements based on the generated clinical questions. At the first face-to-face meeting, each statement was reviewed and e-mail voting was done twice. At the second face-to-face meeting, final voting on each statement was done using keypad voting system. A grade of evidence and a strength of recommendation were applied to each statement according to the method of the GRADE Working Group. Results Twenty-nine consensus statements were finalized, including 7 for definition and diagnosis, 5 for epidemiology, 9 for pathophysiology and 8 for management. Algorithms for diagnosis and management of functional dyspepsia were added. Conclusions This consensus developed by Asian experts shows distinctive features of functional dyspepsia in Asia and will provide a guide to the diagnosis and management of functional dyspepsia for Asian primary care physicians.

Asian consensus report on functional dyspepsia

Background and Aim:  Environmental factors such as food, lifestyle and prevalence of Helicobacter pylori infection are widely different in Asian countries compared with the West, and physiological functions and genetic factors of Asians may also be different from those of Westerners. Establishing an Asian consensus for functional dyspepsia is crucial in order to attract attention to such data from Asian countries, to articulate the experience and views of Asian experts, and to provide a relevant guide on management of functional dyspepsia for primary care physicians working in Asia.

Primary Care Management of Chronic Constipation in Asia: The ANMA Chronic Constipation Tool

Chronic constipation (CC) may impact on quality of life. There is substantial patient dissatisfaction; possible reasons are failure to recognize underlying constipation, inappropriate dietary advice and inadequate treatment. The aim of these practical guidelines intended for primary care physicians, and which are based on Asian perspectives, is to provide an approach to CC that is relevant to the existing health-care infrastructure. Physicians should not rely on infrequent bowel movements to diagnose CC as many patients have one or more bowel movement a day. More commonly, patients present with hard stool, straining, incomplete feeling, bloating and other dyspeptic symptoms. Physicians should consider CC in these situations and when patients are found to use laxative containing supplements. In the absence of alarm features physicians may start with a 2-4 week therapeutic trial of available pharmacological agents including osmotic, stimulant and enterokinetic agents. Where safe to do so, physicians should consider regular (as opposed to on demand dosing), combination treatment and continuous treatment for at least 4 weeks. If patients do not achieve satisfactory response, they should be referred to tertiary centers for physiological evaluation of colonic transit and pelvic floor function. Surgical referral is a last resort, which should be considered only after a thorough physiological and psychological evaluation.

Effect of Prucalopride in the Treatment of Chronic Constipation in Asian and Non-Asian Women: A Pooled Analysis of 4 Randomized, Placebo-controlled Studies.

Background/Aims To compare the efficacy and safety of prucalopride, a novel selective high-affinity 5-hydroxytryptamine type 4 receptor agonist, versus placebo, in Asian and non-Asian women with chronic constipation (CC). Methods Data of patients with CC, receiving once-daily prucalopride 2-mg or placebo for 12-weeks, were pooled from 4 double-blind, randomized, phase-III trials (NCT00488137, NCT00483886, NCT00485940 and NCT01116206). The efficacy endpoints were: average of ≥ 3 spontaneous complete bowel movements (SCBMs)/week; average increases of ≥ 1 SCBMs/week; and change from baseline in each CC-associated symptom scores (bloating, abdominal pain, hard stool and straining). Results Overall, 1,596 women (Asian [26.6%], non-Asian [73.4%]) were included in this analysis. Significantly more patients in the prucalopride group versus placebo experienced an average of ≥ 3 SCBMs/week in Asian (34% vs. 11%, P < 0.001) and non-Asian (24.6% vs. 10.6%, P < 0.001) subgroups. The number of patients reporting an increase of ≥ 1 SCBMs/week from baseline was significantly higher in the prucalopride group versus placebo among both Asian (57.4% vs. 28.3%, P < 0.001) and non-Asian (45.3% vs. 24.0%, P < 0.001) subgroups. The difference between the subgroups was not statistically significant. Prucalopride significantly reduced the symptom scores for bloating, hard stool, and straining in both subgroups. Conclusions Prucalopride 2-mg once-daily treatment over 12-weeks was more efficacious than placebo in promoting SCBMs and improvement of CC-associated symptoms in Asian and non-Asian women, and was found to be safe and well-tolerated. There were numeric differences between Asian and non-Asian patients on efficacy and treatment emergent adverse events, which may be partially due to the overlap with functional gastrointestinal disorders in non-Asian patients.

Pathophysiological and psychosocial study in patients with functional vomiting.

Background/Aims To explore clinical patterns, predisposing factors, psychosocial aspects and the possible pathogenesis in Functional Vomiting (FV) patients. Methods Ten healthy subjects and 19 FV patients participated in this study. Gastrointestinal symptoms and psychological state were evaluated by questionnaires, including Zung self-rating anxiety and depression scale and Eysenck personality questionnaire. Cutaneous electrogastrography, perfusion nutrition load test and intragastric pressure were performed in patients. Perfusion nutrition load test and intragastric pressure were also performed in healthy subjects. Results FV involved young female predominantly (4 male, 15 female; age 25.8 ± 8.4 years). Postprandial vomiting soon after meal without self-induced maneuver was the most common pattern of FV. Prevalence for overlaps between FV and functional dyspepsia was high (84.2%). Emotional changes and stress contributed to the development of FV. Prevalence of abnormal psychological status and personality in patients with FV was high (83.3% and 47.1%). Patients with FV had significant postprandial gastric dysrhythmia, impaired gastric accommodation and enhanced gastric sensitivity. There were significant correlations between clinical presentations, gastric function and psychological states. Conclusions Patients with FV had abnormal psychological status, gastric dysmotility and hypersensitivity, which indicated that both of peripheral and central abnormalities could contribute to the pathogenesis of FV.

Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea

Background/Aims Physical and/or emotional stresses are important factors in the exacerbation of symptoms in irritable bowel syndrome (IBS). Several lines of evidence support that a major impact of stress on the gastrointestinal tract occurs via the enteric nervous system. We aimed to evaluate histological changes in the submucosal plexus (SMP) and myenteric plexus (MP) of the distal ileum in concert with the intestinal motor function in a rat model of IBS with diarrhea. Methods The rat model was induced by heterotypic chronic and acute stress (CAS). The intestinal transit was measured by administering powdered carbon by gastric gavage. Double immunohistochemical fluorescence staining with whole-mount preparations of SMP and MP of enteric nervous system was used to assess changes in expression of choline acetyltransferase, vasoactive intestinal peptide, or nitric oxide synthase in relation to the pan neuronal marker, anti-Hu. Results The intestinal transit ratio increased significantly from control values of 50.8% to 60.6% in the CAS group. The numbers of enteric ganglia and neurons in the SMP were increased in the CAS group. The proportions of choline acetyltransferase- and vasoactive intestinal peptide-immunoreactive neurons in the SMP were increased (82.1 ± 4.3% vs. 76.0 ± 5.0%, P = 0.021; 40.5 ± 5.9% vs 28.9 ± 3.7%, P = 0.001), while nitric oxide synthase-immunoreactive neurons in the MP were decreased compared with controls (23.3 ± 4.5% vs 32.4 ± 4.5%, P = 0.002). Conclusions These morphological changes in enteric neurons to CAS might contribute to the dysfunction in motility and secretion in IBS with diarrhea.

Response of Esophagus to High and Low Temperatures in Patients With Achalasia

Background/Aims Achalasia patients would feel exacerbated dysphagia, chest pain and regurgitation when they drink cold beverages or eat cold food. But these symptoms would relieve when they drink hot water. Reasons are unknown. Methods Twelve achalasia patients (mean age, 34 ± 10 years; F:M, 3:9) who never had any invasive therapies were chosen from Peking Union Medical College Hospital. They were asked to fill in the questionnaire on eating habits including food temperature and related symptoms and to receive high-resolution manometry examination. The exam was done in 2 separated days, at swallowing room temperature (25℃) then hot (50℃) water, and at room temperature (25℃) then cold (2℃) water, respectively. Parameters associated with esophageal motility were analyzed. Results Most patients (9/12) reported discomfort when they ate cold food. All patients reported no additional discomfort when they ate hot food. Drinking hot water was effective in 5/8 patients who ever tried to relieve chest pain attacks. On manometry, cold water increased lower esophageal sphincter (LES) resting pressure (P = 0.003), and prolonged the duration of esophageal body contraction (P = 0.002). Hot water decreased LES resting pressure and residue pressure during swallow (P = 0.008 and P = 0.002), increased LES relaxation rate (P = 0.029) and shortened the duration of esophageal body contraction (P = 0.003). Conclusions Cold water could increase LES resting pressure, prolong the contraction duration of esophageal body, and exacerbate achalasia symptoms. Hot water could reduce LES resting pressure, assist LES relaxation, shorten the contraction duration of esophageal body and relieve symptoms. Thus achalasia patients are recommended to eat hot and warm food and avoid cold food.