ReviewPrimary Endpoints for Irritable Bowel Syndrome Trials: A Review of Performance of Endpoints
Section snippets
Psychometric Validation Standards
Although psychometric validation is considered “an on-going process of conducting various studies to confirm various hypotheses regarding the internal structure of the construct and its relationships with other variables,”5 validation of a symptom-based measure generally requires evidence for a basic set of properties. In particular, it must be demonstrated that the instrument addresses all symptoms that are indicative of the disorder and importance to patients (content validity); is adequately
Recommendations of Rome III Committee on Selection of Endpoints
After appraising the wide range of endpoints proposed or used in the published literature, the general recommendations included in the Rome III guideline3 were summarized as follows: “Adequate relief and satisfactory relief are the current standards for primary outcome assessment in treatment trials in FGIDs. Alternative outcome measures such as integrative symptom questionnaires are also acceptable. All of these measures require additional validation.”
The Rome III Committee further commented
Objective of the Review
This review appraises the relative merits and level of validation of the 3 endpoints recommended by the Rome III Committee as primary endpoints in treatment trials of IBS, adequate and satisfactory relief and the IBS-SS.
Description
The adequate relief endpoint incorporates 2 unique features; it lets the patient integrate all relevant symptoms and normalizes the assessment to the patient’s own reference system of improvement (ie, adequate is relative to the patient’s own reference system). Both of these features are considered crucial in the case of evaluating treatment responses in IBS, because patients with IBS have multiple symptoms, and the relative contribution of each symptom, including the most bothersome symptom to
Irritable Bowel Syndrome Severity Scale
The Rome III guidance document considers the IBS-SS25 to be the only IBS symptom severity scale available to assess responsiveness for clinical trials. Its validation and responsiveness to treatment were based on studies of usual medical care or hypnotherapy rather than drug therapeutic studies. Given this endorsement by Rome III, it is important to understand the content, validation, and characteristics of the IBS-SS total score as a trial endpoint.
Comparison of Performance of Satisfactory Relief and an Integrated Symptom Questionnaire
Whitehead et al2 have reported that the endpoint of satisfactory relief, when used by IBS patients receiving usual medical care without a placebo control group, is confounded by baseline symptom severity and does not accurately reflect symptom improvement. They compared a binary satisfactory relief measure to the IBS-SS, which assessed symptom severity as mild, moderate, or severe, in 350 patients (81% female; average age, 50 years). This study was performed in a health maintenance organization
Conclusion
There is a need for greater validation of all IBS endpoints. Trials are required to characterize the responsiveness of the IBS-SS to drug therapy. This analysis suggests that although further validations of binary endpoints are desirable, the adequate relief endpoint is currently supported by psychometric data based on published studies and is easily understood by IBS patients.35 Those trials have demonstrated the responsiveness of the measure to a variety of orally administered medications in
References (35)
Drugs targeting functional bowel disorders: lessons from drug trials
Curr Opin Pharmacol
(2002)- et al.
Design of treatment trials for functional gastrointestinal disorders
Gastroenterology
(2006) - et al.
Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial
Lancet
(2000) - et al.
Symptom complaints and healthcare seeking behavior in subjects with bowel dysfunction
Gastroenterology
(1984) - et al.
National Cooperative Crohn’s Disease Study: study design and conduct of the study
Gastroenterology
(1979) - et al.
A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales
Pain
(1994) - et al.
Measurement of pain: patient preference does not confound pain measurement
Pain
(1981) - et al.
Effect of alosetron on bowel urgency and global symptoms in women with severe, diarrhea-predominant irritable bowel syndrome: analysis of two controlled trials
Clin Gastroenterol Hepatol
(2004) - et al.
Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome
Am J Gastroenterol
(2001) - et al.
Reports of “satisfactory relief” by IBS patients receiving usual medical care are confounded by baseline symptom severity and do not accurately reflect symptom improvement
Am J Gastroenterol
(2006)
Guidance for industry: patient-reported outcome measures—use in medical product development to support labeling claims
Principles of test theories
Personal view: adequate relief as a primary endpoint in irritable bowel syndrome
Aliment Pharm Ther
A double-blind, placebo-controlled study of the efficacy and safety of non-prescription ranitidine 75 mg in the prevention of meal-induced heartburn
Aliment Pharmacol Ther
Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist
Aliment Pharmacol Ther
A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome
Arch Intern Med
A dose-ranging, placebo-controlled, randomized trial of alosetron in patients with functional dyspepsia
Aliment Pharmacol Ther
Cited by (80)
Efficacy of whole system ayurveda protocol in irritable bowel syndrome – A Randomized controlled clinical trial
2023, Journal of Ayurveda and Integrative MedicineCitation Excerpt :It is responsive, reproducible, it measures the outcome in the same direction as other measures. ROME III has encouraged use of IBS-AR in clinical trials [30]. Assessments were done at baseline, 15th, 30th, 45th and 60th day of the intervention with the help of various assessment parameters.
Skills or Pills: Randomized Trial Comparing Hypnotherapy to Medical Treatment in Children With Functional Nausea
2022, Clinical Gastroenterology and HepatologyCitation Excerpt :In accordance with previous studies, this trial reports high adequate relief rates in the HT group (81% at the 6-month follow-up evaluation and 70% after the 12-month follow-up evaluation).31 Adequate relief refers to children’s and parents’ own reference and judgment of symptom improvement and reflects the experience of being nauseous, independently of symptom severity.43 Therefore, we believe that adequate relief can be even more valuable in evaluating treatment response than predefined definitions for treatment success.44
Patients’ perceptions on non‐specific effects of acupuncture: Qualitative comparison between responders and non‐responders
2022, Integrative Medicine ResearchDefining Optimal Care for Functional Gut Disorders - Multi-Disciplinary Versus Standard Care: A Randomized Controlled Trial Protocol
2019, Contemporary Clinical TrialsDesign of treatment trials for functional gastrointestinal disorders
2016, GastroenterologyCitation Excerpt :Binary end points are easy to administer and straightforward to interpret.46,47 Previous systematic reviews and the Rome III guidance supported the use of binary end points as a standard for IBS and FGID clinical trials.46–48 However, the FDA currently discourages the use of these binary end points in clinical registration trials, based on concerns about the possibility that a clinical response with a binary end point may depend on baseline severity, may not detect MCIDs, and may lack capacity to track key illness domains or discriminate between clinical disease subgroups.
Efficacy of a Chinese Herbal Medicine in Providing Adequate Relief of Constipation-predominant Irritable Bowel Syndrome: A Randomized Controlled Trial
2015, Clinical Gastroenterology and Hepatology
Drs Camilleri (RO1 DK54681, K24 DK02638), Drossman (R24 DK067674), Mayer (P50 DK64539, R24 AT002681, R01 DK58173, R01 DK48351), and Talley (UO1 DK 65713) receive grants for studies in the field of functional gastrointestinal disorders from the National Institutes of Health. The authors received support from RTI, a not-for-profit research institute, for travel to a face-to-face meeting. Dr Camilleri receives current research support for single center pharmacodynamic studies from GlaxoSmithKline, Johnson and Johnson, and Bristol-Myers Squibb and serves as a consultant for Astellas, Dynogen, GlaxoSmithKline, Novartis, Theravance, and Zeria. Dr Drossman receives research support from Novartis Pharmaceuticals, Microbia, and Procter & Gamble pharmaceuticals and is a consultant for Novartis, Procter & Gamble, Microbia, Astellas, and Tioga. Dr Fehnel is a consultant for Microbia, Novartis, and Tioga. Dr Mangel is a consultant for Tioga, Vela, Bristol-Myers Squibb, Astellas, GlaxoSmithKline, Trine, Napo, Microbia, Novartis, Boehringer Ingelheim, Pharmos, and Theravance. Dr Mayer receives research support for single center pharmacodynamic studies from Avera, GlaxoSmithKline, Johnson & Johnson, Lilly, and Novartis and serves as a consultant for GlaxoSmithKline, Novartis, Avera, Allergan, AstraZeneca, and Sanofi. Dr Talley is a consultant for AstraZeneca, Axcan, Chugai, EBMed, Giaconda, GlaxoSmithKline, Kosan, KV Pharmaceuticals, Medscape, ProEd Communication, Renovis, Inc, Solvay, Strategic Consultants International, Takeda Pharmaceuticals, Inc, TAP Pharmaceutical Products, Inc, Therapeutic Gastrointestinal Group, Theravance, Yamanouchi and receives research support from Merck KGaA, Novartis, TAP Pharmaceuticals, Axcan, Boehringer-Ingelheim, and Forest.