Impact of Clinical Outcome Measures on Placebo Response Rates in Clinical Trials for Chronic Constipation: A Systematic Review and Meta-analysis.

OBJECTIVES: Chronic constipation (CC) is a recurrent functional bowel disorder worldwide. The purpose of this study is to examine its pooled placebo response rate and compare placebo response level in randomized controlled trials (RCTs) with different endpoint assessments. METHODS: PubMed, Cochrane Library, and Embase were electronically searched for therapeutic RCTs of CC with placebo control. Data extraction and assessment of risk of bias were performed independently by 2 reviewers. All the statistical calculation and analysis were performed using R 3.6.0. Our protocol has registered in PROSPERO with registration number: CRD42019121287. RESULTS: There were 46 studies included with 5,992 constipated patients allocated to the placebo arm in total. The pooled placebo response rate was 28.75% (95% confidence interval: 23.83%-33.67%) with significant heterogeneity among trials ((Equation is included in full-text article.)= 93.6%). Treatment efficacy assessed using subjective improvement had a significantly higher placebo response rate than that assessed with improvement in complete (spontaneous) bowel movements or composite improvement (41.40% vs 18.31% or 20.35%, P < 0.001). According to the results of meta-regression, active treatment and endpoint assessment were most likely to lead to the huge heterogeneity among studies. DISCUSSION: Patients with CC have significant response level to placebo. Based on findings in this study, we do not recommend subjective improvement as endpoint while designing therapeutic RCTs for chronic constipated patients.

Management of chronic constipation in patients with diabetes mellitus.

AIM: The aim of this review is to provide an overview of the clinical assessment and evidence-based treatment options for managing diabetes-associated chronic constipation. METHODS: A literature search of published medical reports in English language was performed using the OVID Portal, from PUBMED and the Cochrane Database of Systematic Reviews, from inception to October 2015. A total of 145 abstracts were identified; duplicate publications were removed and 95 relevant full-text articles were retrieved for potential inclusion. RESULTS: Chronic constipation is one of the most common gastrointestinal symptoms in patients with diabetes, and occurs more frequently than in healthy individuals. Treatment goals include improving symptoms and restoring bowel function by accelerating colonic transit and facilitating defecation. Based on guidelines and data from published literature, food and dietary change with exercise and lifestyle change should be the first step in management. For patients recalcitrant to these changes, laxatives should be the next step of treatment. Treatment should begin with bulking agents such as psyllium, bran or methylcellulose followed by osmotic laxatives if response is poor. Lactulose, polyethylene glycol and lactitol are the most frequently prescribed osmotic agents. Lactulose has a prebiotic effect and a carry-over effect (continued laxative effect for at least 6 to 7 days, post cessation of treatment). Stimulants such as bisacodyl, sodium picosulphate and senna are indicated if osmotic laxatives are not effective. Newer agents such as chloride-channel activators and 5-HT4 agonist can be considered for severe or resistant cases. CONCLUSION: The primary aim of intervention in diabetic patients with chronic constipation is to better manage the diabetes along with management of constipation. The physician should explain the rationale for prescribing laxatives and educate patients about the potential drawbacks of long-term use of laxatives. They should contact their physician if short-term use of prescribed laxative fails to provide relief.