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Meta-Analysis: Factors Affecting Placebo Response Rate in Irritable Bowel Syndrome. Alexander Ford, Paul Moayyedi

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Meta-Analysis: Factors Affecting Placebo Response Rate in Irritable Bowel Syndrome. Alexander Ford, Paul Moayyedi Meta-analysis: Factors Affecting Placebo Response Rate in Irritable Bowel Syndrome. Alexander Ford, Paul Moayyedi To cite this version: Alexander Ford, Paul Moayyedi. Meta-analysis: Factors Affecting Placebo Response Rate in Irri- table Bowel Syndrome.. Alimentary Pharmacology and Therapeutics, Wiley, 2010, 32 (2), pp.144. 10.1111/j.1365-2036.2010.04328.x. hal-00552561 HAL Id: hal-00552561 https://hal.archives-ouvertes.fr/hal-00552561 Submitted on 6 Jan 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Alimentary Pharmacology & Therapeutic Meta-analysis: Factors Affecting Placebo Response Rate in Irritable Bowel Syndrome. ForJournal: Alimentary Peer Pharmacology Review & Therapeutics Manuscript ID: APT-0225-2010.R1 Manuscript Type: Meta-analysis Date Submitted by the 09-Apr-2010 Author: Complete List of Authors: Ford, Alexander; St James's University Hospital, Department of Academic Medicine Moayyedi, Paul; McMaster University, Gastroenterology Division Functional GI diseases < Disease-based, Irritable bowel syndrome Keywords: < Disease-based, Large intestine < Organ-based, Clinical pharmacology < Topics, Meta-analyses < Topics Page 1 of 53 Alimentary Pharmacology & Therapeutic Ford et al. 1 of 51 1 2 3 TITLE PAGE 4 5 6 7 8 Title: Meta-analysis: Factors Affecting Placebo Response Rate in Irritable Bowel 9 10 11 Syndrome. 12 13 14 15 Short running head: Placebo Response Rate in IBS. 16 17 18 19 20 Authors: AlexanderFor C Ford 1,Peer Paul Moayyedi Review2. 21 22 23 24 1 25 Department of Academic Medicine, St. James’s University Hospital, Leeds, UK. 26 27 2Gastroenterology Division, McMaster University, Health Sciences Center, Hamilton, 28 29 Ontario, Canada. 30 31 32 33 34 Abbreviations: 5-HT 5-hydroxytryptamine 35 36 37 b.i.d. twice daily 38 39 CI confidence interval 40 41 GI gastrointestinal 42 43 44 IBS irritable bowel syndrome 45 46 MeSH medical subject headings 47 48 o.d. once daily 49 50 51 q.i.d. four times daily 52 53 RCT randomised controlled trial 54 55 t.i.d. three times daily 56 57 58 59 60 Alimentary Pharmacology & Therapeutic Page 2 of 53 Ford et al. 2 of 51 1 2 3 Correspondence: Dr. Alex Ford 4 5 6 Department of Academic Medicine 7 8 Room 7.22 9 10 11 Clinical Sciences Building 12 13 St. James’s University Hospital 14 15 Beckett Street 16 17 18 Leeds 19 20 ForLS9 7TF Peer Review 21 22 United Kingdom 23 24 25 Email: [email protected] 26 27 Telephone: +44 28 29 Facsimile: +44 30 31 32 33 34 Keywords: Irritable bowel syndrome 35 36 37 Meta-analysis 38 39 Randomised controlled trials 40 41 Placebo 42 43 44 45 46 47 48 Word count: 3936 49 50 51 52 53 54 55 56 57 58 59 60 Page 3 of 53 Alimentary Pharmacology & Therapeutic Ford et al. 3 of 51 1 2 3 SUMMARY 4 5 6 Background: Irritable bowel syndrome (IBS) is a functional disorder of the 7 8 gastrointestinal tract. Magnitude of placebo response rate in treatment trials for IBS, 9 10 11 and what factors may influence this, is important. 12 13 Aims: To conduct a systematic review and meta-analysis examining this. 14 15 Methods: MEDLINE, EMBASE, and the Cochrane central register of controlled 16 17 18 trials were searched to identify randomised controlled trials (RCTs) comparing 19 20 pharmacological therapiesFor with Peer placebo in adultReview IBS patients. Studies reported either 21 22 global assessment of IBS symptom cure or improvement, or abdominal pain cure or 23 24 25 improvement. Data were extracted as intention-to-treat analyses with drop-outs 26 27 assumed to be treatment failures, and pooled using a random effects model. 28 29 Proportion of placebo patients experiencing symptom improvement or resolution was 30 31 32 reported, with a 95% confidence interval (CI). Effect of trial characteristics on 33 34 magnitude of placebo response was examined. 35 36 37 Results: 73 RCTs were eligible, including 8364 patients with IBS allocated to 38 39 placebo. Pooled placebo response rate across all RCTs was 37.5% (95% CI 34.4%- 40 41 40.6%). Rates were higher in European RCTs, RCTs that used physician-reported 42 43 44 outcomes, and RCTs using shorter duration of therapy. 45 46 Conclusions: Placebo response rates across RCTs of pharmacological therapies in 47 48 IBS were high. Future research should identify patient characteristics predicting 49 50 51 placebo response. 52 53 54 55 56 57 58 59 60 Alimentary Pharmacology & Therapeutic Page 4 of 53 Ford et al. 4 of 51 1 2 3 INTRODUCTION 4 5 6 7 8 Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) 9 10 11 disorder consisting of abdominal pain in association with a disturbance in bowel habit. 12 1 2, 3 13 The condition follows a chronic relapsing and remitting course. Sufferers 14 15 represent a significant burden to the health service due to the consumption of medical 16 17 3-6 7 18 resources, such as consultations in primary and secondary care, investigations, 19 20 drugs, 8 and unnecessaryFor surgical Peer procedures. Review 9 21 22 Despite evidence from recent meta-analyses demonstrating that some 23 24 25 pharmaceutical agents, including antispasmodic drugs, peppermint oil, antidepressants, 26 27 and drugs acting on the 5-hydroxytryptamine (5-HT) receptor are of benefit for the 28 29 treatment of IBS in the short-term, 10-12 there is no medical intervention proven to alter 30 31 32 the long-term natural history of the condition, and there is no agreement on a gold- 33 34 standard for the treatment of IBS. 35 36 37 As a result, whenever a new pharmaceutical agent is developed for IBS it is 38 39 compared with placebo in a randomised controlled trial (RCT). There is no structural 40 41 abnormality that can be corrected by successful therapy and response to treatment is 42 43 44 therefore assessed by improvement in symptoms. This is a subjective outcome and, in 45 46 an effort to standardise research, the Rome foundation has made recommendations as 47 48 to how best to assess response to therapy in treatment trials conducted in IBS and the 49 50 13 51 other functional GI disorders. 52 53 Evidence from the systematic review literature suggests that a significant 54 55 proportion of patients assigned to placebo will respond to therapy, even in RCTs of 56 57 58 therapies for organic GI conditions such as inflammatory bowel disease or peptic 59 60 ulcer, where mucosal or ulcer healing are the outcomes of interest. 14, 15 In functional Page 5 of 53 Alimentary Pharmacology & Therapeutic Ford et al. 5 of 51 1 2 3 GI disorders, where trial endpoints are likely to be less tangible than this, the placebo 4 5 6 response rate may be even higher. However, despite the fact that there have been 7 8 numerous published RCTs of pharmacological therapies in IBS this issue has not been 9 10 11 well studied. This is important, as high placebo response rates will statistically reduce 12 13 the possibility of seeing a positive impact of active therapy, and RCTs should be 14 15 designed to minimise placebo response. We have therefore conducted a systematic 16 17 18 review and meta-analysis in order to assess the magnitude of the placebo response rate 19 20 in treatment trials Forof IBS, and Peer have examined Review trial characteristics and features of 21 22 design that may influence this. 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Alimentary Pharmacology & Therapeutic Page 6 of 53 Ford et al. 6 of 51 1 2 3 MATERIALS AND METHODS 4 5 6 7 8 Search Strategy and Trial Selection 9 10 11 Studies were identified through a search developed to inform an updated 12 13 monograph on the management of IBS for the American College of Gastroenterology. 14 15 16 A search of the medical literature was conducted using MEDLINE (1950 to January 16 17 18 2010), EMBASE (1980 to January 2010), and the Cochrane central register of 19 20 controlled trials (2009).For Randomised Peer controlled Review trials examining the effect of 21 22 pharmacological therapies in adult patients (over the age of 16 years) with IBS were 23 24 25 eligible for inclusion (Box 1). The first period of cross-over RCTs were also eligible 26 27 for inclusion. In the case of all RCTs the control arm were required to receive placebo. 28 29 Duration of therapy had to be at least 7 days. The diagnosis of IBS could be based on 30 31 32 either a physician’s opinion or symptom-based diagnostic criteria, supplemented by 33 34 the results of investigations to exclude organic disease, where trials deemed this 35 36 37 necessary.Trials had to report either a global assessment of IBS symptom cure or 38 39 improvement, or abdominal pain cure or improvement, after completion of therapy, 40 41 preferably as reported by the patient, but if this was not recorded then as documented 42 43 44 by the investigator or via questionnaire data.
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