Placebo Response Rates in Trials of Licensed Drugs for Irritable Bowel Syndrome With Constipation or Diarrhea: Meta-analysis

doi:10.1016/j.cgh.2021.08.025

Clinical Gastroenterology and Hepatology

Volume 20, Issue 5, May 2022, Pages e923-e944

https://doi.org/10.1016/j.cgh.2021.08.025 Get rights and content

Background & Aims

There are several licensed drugs for irritable bowel syndrome (IBS) that have proven efficacy in randomized controlled trials (RCTs), but placebo response rates are high. We conducted a systematic review and meta-analysis of licensed drugs to estimate magnitude of placebo response rate according to Food and Drug Administration (FDA)-recommended endpoints and to assess how this varies with stringency of the endpoint used to define response.

Methods

We searched MEDLINE, EMBASE CLASSIC and EMBASE, and the Cochrane central register of controlled trials (through January 2021) to identify RCTs comparing licensed drugs with placebo in adult IBS patients. Studies assessed efficacy according to at least one of composite response, abdominal pain response, or stool response. Data were extracted as intention-to-treat analyses, with dropouts assumed to be treatment failures and pooled using a random-effects model.

Results

There were 17 RCTs of licensed drugs versus placebo in IBS with constipation (4603 patients placebo) and 17 trials in IBS with diarrhea (3908 patients placebo). In IBS with constipation, according to FDA criteria, pooled composite, abdominal pain, and stool response rates with placebo over ≥6 of 12 weeks were 18.9%, 34.6%, and 30.1%, respectively. Evaluating response rates over ≥9 of 12 weeks led to placebo response rates of 4.3% for the composite endpoint, 24.5% for abdominal pain, and 7.7% for stool. In IBS with diarrhea, pooled placebo response rates according to FDA criteria were 16.2% for the composite endpoint, 40.2% for abdominal pain, and 16.2% for stool. Increasing the threshold used to define abdominal pain response from ≥30% improvement to ≥40% or ≥50% led to lower placebo response rates of 34.5% and 23.4%.

Conclusions

Future RCTs should adhere to current FDA-recommended endpoints for IBS because these lead to lower placebo response rates. However, consideration should be given to further refining some of these to better differentiate between active drug and placebo.

Section snippets

Search Strategy and Study Selection

We searched the medical literature using MEDLINE (1946–January 2021), EMBASE CLASSIC and EMBASE (1947–January 2021), and the Cochrane central register of controlled trials (Issue 2, January 2021). To identify potentially eligible studies published only in abstract form, we searched conference proceedings (Digestive Disease Week, American College of Gastroenterology, and United European Gastroenterology Week) between 2010 and 2020. We also searched clinicaltrials.gov to obtain data from

Results

We updated our previous systematic reviews and meta-analyses of licensed drugs for IBS-C and IBS-D.6, 7, 8 The search strategy generated 4334 citations, 136 of which appeared to be relevant. Thirty of these fulfilled eligibility criteria (Figure 1). Of these, 15 articles reported on 17 RCTs of licensed drugs versus placebo in IBS-C,15, 16, 17, 18^,²⁰^,²¹^,26, 27, 28, 29, 30, 31, 32, 33, 34 and 15 articles reported on 17 trials in IBS-D.¹⁹^,²²^,²³^,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 The 17

Discussion

We have conducted an up-to-date systematic review and meta-analysis of licensed drugs for IBS-C and IBS-D to estimate magnitude of the placebo response rate according to FDA-recommended endpoints, as well as to assess how this varies with stringency of the endpoint used. In IBS-C, pooled placebo response rates and NNTs were similar for both the composite endpoint and abdominal pain, irrespective of whether trials used strict FDA criteria. In both cases, placebo response rates fell substantially

CRediT Authorship Contributions

Brigida Barberio, MD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Writing – original draft: Lead)

Edoardo Vincenzo Savarino, PhD (Conceptualization: Supporting; Investigation: Supporting; Methodology: Supporting; Supervision: Supporting; Writing – original draft: Supporting)

Christopher J. Black, MBBS (Hons) (Conceptualization: Lead; Data curation: Lead; Formal analysis: Supporting; Investigation: Lead; Methodology: Lead; Writing –

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2023, Clinical Gastroenterology and Hepatology
Pain Catastrophizing and Clinical Outcomes Among Patients Receiving a Novel Cognitive-Behavioral Therapy for Irritable Bowel Syndrome: An Experimental Therapeutics Approach
2023, Behavior Therapy
Irritable bowel syndrome (IBS) is the most common gastrointestinal (GI) condition treated by GI and primary care physicians. Although IBS symptoms (abdominal pain, bowel problems) are generally refractory to medical therapies, consistent research has shown that they improve following cognitive-behavioral therapy (CBT). Notwithstanding empirical support for CBT, there is less research explicating the reasons for why or how it works. Like other pain disorders, the focus on change mechanisms for behavioral pain treatments has focused on pain-specific cognitive-affective processes that modulate pain experience, few of which are more important than pain catastrophizing (PC). The fact that PC changes are seen across treatments of differing theoretical and technical orientation, including CBT, yoga, and physical therapy, suggests that it may be a nonspecific (vs. theory-based) change mechanism akin to therapeutic alliance and treatment expectancy. Therefore, the current study examined change in PC as a concurrent mediator of IBS symptoms severity, global GI symptom improvement, and quality of life among 436 Rome III-diagnosed IBS patients enrolled in a clinical trial undergoing two dosages of CBT versus a nonspecific comparator emphasizing education and support. Results from structural equation modeling parallel process mediation analyses suggest that reduction in PC during treatment are significantly associated with improvement in IBS clinical outcomes through 3-month follow-up. Results from the current study provide evidence that PC may be an important, albeit nonspecific change mechanism, during CBT for IBS. Overall, reducing the emotional unpleasantness of pain through cognitive processes is associated with improved outcomes for IBS.
Response and Adverse Event Rates With Placebo in Gastroparesis: A Systematic Review and Meta-analysis
2023, Clinical Gastroenterology and Hepatology
Citation Excerpt :
The importance of investigating the placebo response and adverse event rates in gastroparesis trials is highlighted by reports of substantial placebo response rates in other gastrointestinal disorders. Among patients with disorders of gut-brain interaction, including FD and IBS, pooled placebo response rates are highly variable, estimated to range between 6% to 73% in FD and between 3% and 83% in IBS.12,14,55 The power of placebo is further underlined by considerable response rates to placebo even among patients with organic gastrointestinal disorders, such as Crohn’s disease and ulcerative colitis.15,16
Multiple drugs have been used to treat gastroparesis symptoms, yet their therapeutic benefits are poorly understood partly due to lack of insight into response and adverse event rates with placebo in randomized controlled trials (RCTs). We evaluated these issues systematically in drug trials for gastroparesis.
We searched the medical literature through August 2, 2022 to identify RCTs comparing active drug with placebo in patients with gastroparesis. We assessed placebo response rates according to at least one of the following endpoints: improvement according to a composite outcome, nausea, vomiting, abdominal pain, bloating, or fullness, as well as total adverse events, and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses with dropouts assumed to be treatment failures. We pooled placebo response and adverse event rates using a random effects model and expressed as proportions with 95% confidence intervals (CIs).
Thirty-five studies were eligible. Among 23 trials reporting a composite endpoint of improvement, the pooled placebo response rate was 29.3% (95% CI, 23.7%–35.2%). Pooled placebo response rates were higher in idiopathic compared with diabetic gastroparesis (34.2% vs 28.1%), among trials that did not use validated symptom questionnaires (31.2% vs 27.4%), and in RCTs of shorter duration (<4 weeks, 32.6% vs ≥9 weeks, 23.2%). Adverse events occurred in 33.8% (95% CI, 26.4%–41.8%) of patients with placebo, in 27 trials, and were less common in idiopathic compared with diabetic gastroparesis (17.9% vs 43.4%), trials of shorter duration (<4 weeks, 33.7% vs ≥9 weeks, 40.7%), and trials with lower randomization ratios of active drug to placebo (1:1, 26.7% vs 3:1, 50.5%).
This meta-analysis assessed placebo response and adverse event rates in gastroparesis. To accurately assess therapeutic gain, future trials should be a minimum of 8 weeks duration, use validated questionnaires, and distinguish gastroparesis subtypes.
Therapeutics, Placebo, and the Importance of Hard Outcomes in Irritable Bowel Syndrome Research
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The Role of the FODMAP Diet in IBS
2024, Nutrients
Control Groups in RCTs Supporting Approval of Drugs for Systemic Rheumatic Diseases, 2012-2022
2023, JAMA Network Open

View all citing articles on Scopus

: Conflicts of interest The authors disclose no conflicts.

^b: Authors share co-senior authorship.

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Electronic Systematic Reviews and Meta-analysesPlacebo Response Rates in Trials of Licensed Drugs for Irritable Bowel Syndrome With Constipation or Diarrhea: Meta-analysis

Background & Aims

Methods

Results

Conclusions

Section snippets

Search Strategy and Study Selection

Results

Discussion

CRediT Authorship Contributions

Lancet

Lancet Gastroenterol Hepatol

Lancet Gastroenterol Hepatol

Gastroenterology

Lancet Gastroenterol Hepatol

J Clin Epidemiol

Lancet

Clin Gastroenterol Hepatol

Gastroenterology

Lancet Gastroenterol Hepatol

Bowel disorders

Gastroenterology

Comparison of the Rome IV criteria with the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care

Gut

Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis

Gut

Relative efficacy of tegaserod in a systematic review and network meta-analysis of licensed therapies for irritable bowel syndrome with constipation

Clin Gastroenterol Hepatol

The placebo effect in irritable bowel syndrome trials: a meta-analysis

Neurogastroenterol Motil

A meta-analysis of the placebo response in complementary and alternative medicine trials of irritable bowel syndrome

Neurogastroenterol Motil

Meta-analysis: factors affecting placebo response rate in irritable bowel syndrome

Aliment Pharmacol Ther

Guidance for industry: irritable bowel syndrome—clinical evaluation of drugs for treatment

Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety

Am J Gastroenterol

Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial

Am J Gastroenterol

Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials

Am J Gastroenterol

Effects of baseline abdominal pain and bloating on response to lubiprostone in patients with irritable bowel syndrome with constipation

Aliment Pharmacol Ther

A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome

Scand J Gastroenterol

Efficacy of tenapanor in treating patients with irritable bowel syndrome with constipation: a 26-week, placebo-controlled phase 3 trial (T3MPO-2)

Am J Gastroenterol

Linaclotide in irritable bowel syndrome with constipation: a phase 3 randomized trial in China and other regions

J Gastroenterol Hepatol

Efficacy and safety of eluxadoline in patients with irritable bowel syndrome with diarrhea who report inadequate symptom control with loperamide: RELIEF phase 4 study

Am J Gastroenterol

Eluxadoline for irritable bowel syndrome with diarrhea

N Engl J Med

Cochrane handbook for systematic reviews of interventions: version 5.1.0

Measuring inconsistency in meta-analyses

BMJ

Electronic Systematic Reviews and Meta-analyses
Placebo Response Rates in Trials of Licensed Drugs for Irritable Bowel Syndrome With Constipation or Diarrhea: Meta-analysis