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

ABSTRACT: 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.

SUBMITTER: Chen J

PROVIDER: S-EPMC7594913 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Chen Jie J Liu Xinghuang X Bai Tao T Hou Xiaohua X

Clinical and translational gastroenterology 20201101 11

<h4>Objectives</h4>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.<h4>Methods</h4>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 reviewer ...[more]

PMID: 33259160

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Project description:BACKGROUND:Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions. MAIN BODY:We use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If non-bleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment. CONCLUSIONS:All-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments.

Dataset Information

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

Publications

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

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