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Alimentary Pharmacology and Therapeutics

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

A. C. Ford* & P. Moayyedi

*Department of Academic Medicine, SUMMARY St. James’s University Hospital, Leeds, UK. Gastroenterology Division, McMaster Background University, Health Sciences Center, Irritable bowel syndrome (IBS) is a functional disorder of the gastrointesti- Hamilton, ON, Canada. nal tract with a significant placebo response.

Aim Correspondence to: Dr A. C. Ford, Department of To conduct a systematic review and meta-analysis examining the magnitude Academic Medicine, Room 7.22, of placebo response rate in treatment trials for IBS. Clinical Sciences Building, St. James’s University Hospital, Beckett Street, Methods Leeds, LS9 7TF, UK. MEDLINE, EMBASE and the Cochrane central register of controlled trials E-mail: [email protected] were searched to identify randomized controlled trials (RCTs) comparing pharmacological therapies with placebo in adult IBS patients. Studies Publication data reported either global assessment of IBS symptom cure or improvement or Submitted 18 March 2010 abdominal pain cure or improvement. Data were extracted as intention-to- First decision 7 April 2010 Resubmitted 9 April 2010 treat analyses with drop-outs assumed to be treatment failures and pooled Accepted 9 April 2010 using a random-effects model. Proportion of placebo patients experiencing Epub Accepted Article 16 April 2010 symptom improvement or resolution was reported with a 95% confidence interval (CI). Effect of trial characteristics on magnitude of placebo As part of AP&T’s peer-review process, response was examined. a technical check of this meta-analysis was performed by Dr. P. Collins. Results In all, 73 RCTs were eligible, including 8364 patients with IBS allocated to placebo. Pooled placebo response rate across all RCTs was 37.5% (95% CI 34.4–40.6%). Rates were higher in European RCTs, RCTs that used physi- cian-reported outcomes and RCTs using shorter duration of therapy.

Conclusions Placebo response rates across RCTs of pharmacological therapies in IBS were high. Future research should identify patient characteristics predicting placebo response.

Aliment Pharmacol Ther 2010; 32: 144–158

144 ª 2010 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2010.04328.x Meta-analysis: placebo response rate in the irritable bowel syndrome

INTRODUCTION MATERIALS AND METHODS Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder consisting of abdominal Search strategy and trial selection pain in association with a disturbance in bowel habit.1 Studies were identified through a search developed to The condition follows a chronic relapsing and remitting inform an updated monograph on the management of course.2, 3 Sufferers represent a significant burden to the IBS for the American College of Gastroenterology.16 A health service for reasons of consumption of medical search of the medical literature was conducted using resources, such as consultations in primary and second- MEDLINE (1950 to January 2010), EMBASE (1980 to ary care,3–6 investigations,7 drugs8 and unnecessary surgi- January 2010) and the Cochrane central register of con- cal procedures.9 trolled trials (2009). Randomized controlled trials exam- Despite evidence from recent meta-analyses demon- ining the effect of pharmacological therapies in adult strating that some pharmaceutical agents, including anti- patients (over the age of 16 years) with IBS were eligible spasmodic drugs, peppermint oil, and for inclusion (Box 1). The first period of cross-over drugs acting on the 5-hydroxytryptamine (5-HT) recep- RCTs was also eligible for inclusion. In the case of all tor are of benefit for the treatment of IBS in the short- RCTs, the control arm was required to receive placebo. term,10–12 there is no medical intervention proven to Duration of therapy had to be at least 7 days. The diag- alter the long-term natural history of the condition and nosis of IBS could be based on either a physician’s opin- there is no agreement on a gold-standard for the treat- ion or symptom-based diagnostic criteria, supplemented ment of IBS. by the results of investigations to exclude organic disease, As a result, whenever a new pharmaceutical agent is where trials deemed this necessary. Trials had to report developed for IBS, it is compared with placebo in a either a global assessment of IBS symptom cure or randomized controlled trial (RCT). There is no struc- improvement or abdominal pain cure or improvement, tural abnormality that can be corrected by successful after completion of therapy, preferably as reported by therapy and response to treatment is therefore assessed the patient, but if this was not recorded, then as docu- by improvement in symptoms. This is a subjective out- mented by the investigator or via questionnaire data. come and, in an effort to standardize research, the Where RCTs included patients with other functional GI Rome foundation has made recommendations as to disorders or did not report these types of dichotomous how best to assess response to therapy in treatment data, but were otherwise eligible for inclusion in the trials conducted in IBS and the other functional GI disorders.13 Evidence from the systematic review literature sug- Box 1 | Eligibility criteria gests that a significant proportion of patients assigned to Randomized controlled trials placebo will respond to therapy, even in RCTs of thera- Adults (participants aged > 16 years) pies for organic GI conditions such as inflammatory Diagnosis of irritable bowel syndrome based on either a bowel disease or peptic ulcer, where mucosal or ulcer clinician’s opinion, or meeting specific diagnostic criteria*, 14, 15 healing are the outcomes of interest. In functional supplemented by negative investigations where trials GI disorders, where trial endpoints are likely to be less deemed this necessary tangible than this, the placebo response rate may be even Compared pharmacological therapies with placebo higher. However, despite the fact that there have been Minimum duration of therapy 7 days numerous published RCTs of pharmacological therapies Global assessment of irritable bowel syndrome symptoms or in IBS, this issue has not been well studied. This is abdominal pain following therapyà important, as high placebo response rates will statistically reduce the possibility of seeing a positive impact of active * Manning, Kruis score, Rome I, II, or III. therapy and RCTs should be designed to minimize pla- Antispasmodics, peppermint oil, antidepressants, 5-HT3 cebo response. We have therefore conducted a systematic antagonists, 5-HT4 and mixed 5-HT3 antagonists ⁄ 5-HT agonists. review and meta-analysis to assess the magnitude of the 4 placebo response rate in treatment trials of IBS and have à Preferably patient-reported, but if this was not available, then as assessed by a physician or questionnaire data. examined trial characteristics and features of design that may influence this.

Aliment Pharmacol Ther 2010; 32: 144–158 145 ª 2010 Blackwell Publishing Ltd A. C. Ford and P. Moayyedi systematic review, we attempted to contact the original included assessing placebo response rate according to investigators to obtain further information. various trial characteristics (see below). Placebo-controlled trials in irritable bowel syndrome were identified with the terms irritable bowel syndrome Data extraction and functional diseases, colon [both as medical subject All data were extracted independently by two reviewers heading (MeSH) and free text terms] and IBS, spastic on to a Microsoft Excel spreadsheet (XP professional edi- colon, irritable colon and functional adj5 bowel (as free tion; Microsoft Corp, Redmond, WA, USA) as dichoto- text terms). These were combined using the set operator mous outcomes (global IBS symptoms absent or AND with studies identified with the terms: parasym- improved, or abdominal pain absent or improved in the patholytics, , , muscarinic antago- placebo arms of the included RCTs) (Box 2). In addition, nists, butylscopolammonium bromide, psychotropic the following clinical data were extracted for each trial: drugs, antidepressive agents, antidepressive agents (tricy- year of publication, geographical location, setting (pri- clic), , , , , mary, secondary, or tertiary care), number of centres, cri- dothiepin, , , selective teria used to define IBS, IBS subtype according to re-uptake inhibitors, paroxetine, sertraline, fluoxetine, predominant stool pattern reported by the patient (diar- citalopram, venlafaxine, serotonin antagonists, serotonin rhoea-predominant, constipation-predominant or alter- agonists, , receptors (serotonin, 5-HT3) and nating bowel habit), dosing schedule of the placebo, receptors (serotonin, 5-HT4) (both as MeSH terms and duration of therapy, proportion of trial patients receiving free text terms), and the following free text terms: placebo, active pharmacological therapy used, primary spasmolytics, spasmolytic agents, antispasmodics, mebe- outcome measure used to define symptom improvement verine, , , , or cure following therapy (patient- vs. physician-reported , hyoscine butyl bromide, butyl- and global IBS symptoms vs. abdominal pain or discom- scopolamine, peppermint oil, colpermin, 5-HT3, 5-HT4, fort), whether the method used to generate the randomi- , , ramosetron, and zation schedule was stated, whether the method of . concealment of allocation was stated and overall trial There were no language restrictions and abstracts of quality (assessed using the Jadad scale, Box 3).17 Data the papers identified by the initial search were evaluated were extracted as intention-to-treat analyses, with all by the lead reviewer for appropriateness to the study drop-outs assumed to be treatment failures, wherever question and all potentially relevant papers were trial reporting allowed this. obtained and evaluated in detail. Foreign language papers were translated where necessary. Abstract books of con- Data synthesis and statistical analysis ference proceedings between 2001 and 2009 were hand- Data were pooled using a random-effects model, to give searched to identify potentially eligible RCTs published a more conservative estimate of the magnitude of the only in abstract form. We also contacted pharmaceutical placebo response rate, allowing for any heterogeneity companies and searched the Food and Drug Administra- between trials.18 Outcomes were expressed as the pooled tion Agency (FDA) website to obtain data from unpub- proportion of patients assigned to placebo with global lished RCTs. The bibliographies of all identified relevant IBS symptoms or abdominal pain absent or improved trials were used to perform a recursive search of the lit- erature. Articles were independently assessed by two reviewers using pre-designed eligibility forms, according to the prospectively defined eligibility criteria. Any Box 2 | Data extraction methodology disagreement between investigators was resolved by consensus. Outcome of interest: improvement in or absence of global irritable bowel syndrome symptoms preferable; if not reported, then improvement in or absence of abdominal pain. Outcome assessment Reporting of outcomes: patient-reported preferable; if not The primary outcome assessed was the magnitude of the available, then investigator-reported. placebo response rate, in terms of improvement in, or Time of assessment: upon completion of therapy. resolution of, global IBS symptoms or abdominal pain, in all RCTs of pharmacological therapies conducted in Denominator used: true intention-to-treat analysis; if not available, then all evaluable patients. IBS after cessation of therapy. Secondary outcomes

146 Aliment Pharmacol Ther 2010; 32: 144–158 ª 2010 Blackwell Publishing Ltd Meta-analysis: placebo response rate in the irritable bowel syndrome

present individual patients within each treatment arm. Box 3 | Jadad score calculation The technique is therefore vulnerable to giving spurious Item Score results due to the ecological fallacy.20 Was the study described as randomized? 1 STATSDIRECT version 2.4.4 (StatsDirect Ltd, Sale, Was the method used to generate the sequence 1 Cheshire, UK) was used to generate Forest plots of the of randomization described and appropriate pooled proportions of patients assigned to placebo with (random numbers, computer-generated, etc)? global IBS symptoms or abdominal pain absent or Was the study described as double-blind? 1 improved after completion of therapy, with 95% confi- Was the method of double-blinding described 1 dence intervals. Pooled placebo response rates were com- and appropriate (identical placebo, active pared between the pre-defined subgroups using the placebo, dummy, etc)? Cochran Q statistic to assess for any heterogeneity Was there a description of withdrawals and 1 between placebo response rates for the different sub- drop-outs? group analyses we conducted and, because of multiple Deduct one point if method used to generate )1 analyses, a P value of <0.01 was considered statistically sequence of randomization described, but significant. inappropriate (allocated alternately or according to date of birth or hospital number). RESULTS ) Deduct one point if study described as 1 The search strategy generated 3383 citations of which double-blind, but method of blinding inappropriate. 177 appeared to be relevant to the systematic review and were retrieved for further assessment (Figure 1). Of these 177 RCTs, 104 were excluded for various reasons leaving 73 eligible trials,21–92 containing 8364 individuals with after completion of therapy, with a 95% confidence inter- IBS who were randomized to receive placebo. Five val (CI). of these RCTs were published in abstract form The results of individual RCTs can be diverse and this only73–75, 82, 83 and data from two placebo-controlled tri- inconsistency within a single meta-analysis can be quan- als of tegaserod in IBS (B307 and B351) were published tified with a statistical test of heterogeneity to assess in a single document on the FDA website.84 We whether the variation across trials is caused by true contacted original investigators in seven of the studies to heterogeneity or chance. This quantity is termed I2 and clarify data or obtain supplementary informa- its value ranges from 0% to 100%, with 0% representing tion.42, 49, 72, 82, 83, 85, 87 Agreement between reviewers no observed heterogeneity and larger values indicating for assessment of trial eligibility was good (kappa statis- increasing heterogeneity. A value below 50% was chosen tic = 0.90). Characteristics of individual RCTs, including to represent low levels of heterogeneity.19 the magnitude of the placebo response in each trial, are Subgroup analyses were conducted according to year provided in Table 1. of publication, geographical location, trial setting, single vs. multi-centre trials, criteria used to define IBS, pre- Placebo response rate in all trials dominant stool pattern reported by the patient, dosing The pooled placebo response rate in the 73 RCTs we schedule of the placebo, duration of therapy, proportion identified was 37.5% (95% CI 34.4% to 40.6%), with of trial patients receiving placebo, active pharmacological considerable heterogeneity between trials (I2 = 86.2%, therapy used, primary outcome measure used to define P < 0.001). The placebo response rate in individual symptom improvement or cure following therapy RCTs varied from 0% in two trials21, 23 to 91.7%57 (patient vs. physician-reported and global IBS symptoms (Figure 2). vs. abdominal pain or discomfort), whether method of randomization or concealment of allocation was reported Placebo response rate according to year of publication, and trial quality according to the Jadad scale. We did trial location, setting and number of centres not perform meta-regression in this systematic review Trials were divided into those published before 1999 and and meta-analysis, but rather subgroup analyses accord- those published in 1999 or later, as accepted endpoints ing to individual trial characteristics because the former for evaluating the success of therapy in IBS treatment tri- technique evaluates the average of patient characteristics als changed around this point in time. There was, how- within each trial, and these summary data may misre- ever, no significant difference in placebo response rates

Aliment Pharmacol Ther 2010; 32: 144–158 147 ª 2010 Blackwell Publishing Ltd A. C. Ford and P. Moayyedi

Citations identified in literature Placebo response rate according to diagnostic criteria search (n = 3383) used to define IBS and predominant stool pattern reported by the patient A clinical diagnosis (usually according to a physician’s

Excluded (title and abstract revealed assessment) of IBS was the most frequent criterion used not appropriate) (n = 3206) to define the presence of the condition21–25, 27–32, 34, 36– 41, 45, 48, 50, 51, 53–57, 89 and pooled placebo response rate was the highest in trials that used this definition at 42.0% (Table 2), compared with the Rome I or II criteria Studies retrieved for evaluation (n = 177) (36.0% and 34.4% respectively). However, the difference Excluded (n = 104) because: between these rates was not statistically significant • No placebo arm = 30 • Outcome of interest not (Cochran Q = 1.3, P = 0.25 and Cochran Q = 2.15, reported = 25 • Data not extractable = 17 P = 0.14 respectively). There were few trials that reported • Cross-over study with no the predominant stool pattern reported by the patient, extractable data = 10 • Duplicate publication = 10 but some trials recruited diarrhoea- or constipation-pre- • Not the intervention of dominant patients exclusively,32, 44, 52, 64, 67, 70, 71, 73– interest = 3 78, 80, 82–84, 86–91 • Included patients with allowing us to examine the effect of this organic GI disease = 2 • Not randomised = 2 patient characteristic on pooled placebo response rates. • Treatment duration less than No statistically significant difference, in terms of pooled 7 days = 1 • Included treated IBS patients placebo response rate, between RCTs recruiting constipa- in remission prior to trial commencement = 1 tion-predominant or diarrhoea-predominant IBS • Adverse events data only = 1 patients, was detected (Cochran Q = 0.6, P = 0.45) • Patients did not have IBS = 1 • Study terminated prematurely (Table 2). Randomised controlled trials = 1 eligible for inclusion (n = 73) Placebo response rate according to criteria and symptom data used to define response Figure 1 | Flow diagram of assessment of trials identified There were only four RCTs that used a physician- in the systematic review. reported outcome to define response to ther- apy34, 36, 37, 56 and the pooled placebo response rate was significantly higher in these trials compared with those between these two time periods (Cochran Q = 0.60, that used a patient-reported outcome (53.0% vs. 37.4%, P = 0.44) (Table 2). A majority of RCTs were conducted Cochran Q = 7.8, P = 0.005) (Table 2). In terms of in Europe,21, 22, 24, 26–31, 34–37, 39–41, 46, 48, 49, 51, 53–56, 58, symptom data used to define response, majority of stud- 61, 81, 85, 87–91 and the pooled placebo response rate was ies used improvement or relief of global IBS symptoms, the highest in these trials at 42.7% (Table 2). This rate although 13 used improvement or relief of abdominal was significantly higher than that in RCTs conducted in pain or discomfort.25, 32, 44, 45, 54, 59, 61–63, 69, 71, 72, 87 Asia (25.0%, Cochran Q = 8.8, P = 0.003),23, 25, 50, 67, 70, There was no significant difference in pooled placebo 80 the Middle-East (23.0%, Cochran Q = 9.4, P = response rate according to the symptom data used to 0.002),44, 52, 66, 69 and North America (33.0%, Cochran define response (Cochran Q = 0.6, P = 0.43) (Table 2). Q = 7.3, P = 0.007).38, 42, 45, 47, 59, 60, 62–65, 68, 71, 75, 78, 86, 92 However, the number of Asian and Middle Eastern Placebo response rate according to dosing schedule, studies was low (n = 6 and n = 4 respectively) and the duration of therapy and proportion of trial patients differences observed among Asian, Middle-Eastern and assigned to placebo North American RCTs were not statistically significant The most common dosing schedule used in eligible (Table 2). When the effect of trial setting and number of RCTs was three times daily24, 27–33, 35–37, 39– centres was examined, pooled placebo response rate was 41, 54, 56, 58, 69, 73–75, 87–90 and pooled placebo response very similar in RCTs based in secondary and tertiary rate was the highest in these trials at 43.0%, compared care, and in single and multi-centre trials, with no statis- with RCTs that used a once or twice daily schedule tically significant difference detected (Cochran Q = 0.08, (32.2% and 36.0% respectively) (Table 2), but again, P = 0.78 for both analyses) (Table 2). these differences did not reach formal statistical

148 Aliment Pharmacol Ther 2010; 32: 144–158 ª 2010 Blackwell Publishing Ltd lmn hrao hr21;3:144–158 ª 32: 2010; Ther Pharmacol Aliment

00BakelPbihn Ltd Publishing Blackwell 2010 Table 1 | Characteristics of included trials

Geographical Number of Criteria used Active Duration of Dosing Sample Placebo response Jadad Trial location centres to define IBS* treatment therapy schedule size rate (%) score Heefner et al.45 North America Multiple Clinical Desimipramine 8 weeks o.d. 44 10 ⁄ 22 (45.5) 4 Myren et al.51 Europe Multiple Clinical Trimipramine 4 weeks o.d. 61 21 ⁄ 31 (67.7) 2 Nigam et al.23 Asia Single Clinical Amitriptyline 12 weeks o.d. 42 0 ⁄ 21 (0) 3 Boerner et al.48 Europe Single Clinical Doxepin 8 weeks o.d. 83 22 ⁄41 (53.7) 4 Bergmann et al.53 Europe Single Clinical Trimipramine 12 weeks o.d. 35 2 ⁄ 16 (12.5) 2 Vij et al.50 Asia Single Clinical Doxepin 6 weeks o.d. 50 5 ⁄ 25 (20.0) 5 Drossman et al.42 North America Multiple Rome I Desipramine 12 weeks o.d. 172 21 ⁄ 57 (36.8) 5 Kuiken et al.46 Europe Single Rome I 6 weeks o.d. 40 9 ⁄ 21 (42.9) 5 47

Tabas et al. North America Single Rome I Paroxetine 12 weeks o.d. 90 10 ⁄ 46 (21.7) 5 M

44 e

Vahedi et al. Middle East Single Rome II Fluoxetine 12 weeks o.d. 44 3 ⁄ 22 (13.6) 5 t a -

49 a

Tack et al. Europe Single Rome II Citalopram 6 weeks o.d. 23 1 ⁄ 12 (8.3) 4 n a

43 l Talley et al. Australasia Multiple Rome II Citalopram and 12 weeks o.d. 33 11 ⁄ 16 (68.8) 5 y s i

imipramine s :

52 p

Vahedi et al. Middle East Single Rome II Amitriptyline 8 weeks o.d. 54 11 ⁄ 27 (40.7) 5 l a c

66 e

Abdul-Baki et al. Middle East Single Rome II Imipramine 12 weeks Titrated 107 12 ⁄ 48 (25.0) 5 b 65 o

Masand et al. North America Multiple Rome II Paroxetine 12 weeks o.d. 72 6 ⁄ 36 (16.7) 4 r e

68 s Ladabaum et al. North America Multiple Rome II Citalopram 8 weeks o.d. 54 15 ⁄ 27 (55.6) 5 p o

39 n Levy et al. Europe Single Clinical Pinaverium 2 weeks t.d.s. 50 7 ⁄ 25 (28.0) 3 s e

32 r Moshal and Herron Africa Single Clinical Trimebutine 4 weeks t.d.s. 20 6 ⁄ 10 (60.0) 4 a t 36 e

Piai and Mazzacca Europe Single Clinical Prifinium 3 weeks t.d.s. 18 3 ⁄ 9 (33.3) 4 i n

21 t Ritchie and Truelove Europe Single Clinical Hyoscine 12 weeks q.d.s. 24 0 ⁄ 12 (0) 4 h e 40 i

D’Arienzo and D’Agostino Europe Single Clinical Octilonium 4 weeks t.d.s. 28 10 ⁄ 14 (71.4) 3 r r i 37 t Fielding Europe Single Clinical Trimebutine 24 weeks t.d.s. 60 17 ⁄ 30 (56.7) 3 a b l Delmont 56 Europe Single Clinical Pinaverium 4 weeks t.d.s. 60 17 ⁄ 30 (56.7) 4 e b

38 o Page and Dirnberger North America Multiple Clinical 2 weeks q.d.s. 97 16 ⁄ 49 (32.7) 4 w e

54 l

Baldi et al. Europe Single Clinical Otilonium 4 weeks t.d.s. 30 8 ⁄ 15 (53.3) 4 s y

31 n

Ghidini et al. Europe Single Clinical and 8 weeks t.d.s. 60 20 ⁄ 30 (66.7) 3 d r

trimebutine o m 149 e A 150 .

Table 1 | (Continued) C . F

Geographical Number of Criteria used Active Duration of Dosing Sample Placebo response Jadad o r Trial location centres to define IBS* treatment therapy schedule size rate (%) score d a

22 n Kruis et al. Europe Single Clinical 16 weeks q.d.s. 80 12 ⁄40 (30.0) 4 d P

41 .

Virat and Hueber Europe Single Clinical Pinaverium 1 week t.d.s. 78 13 ⁄ 39 (33.3) 2 M

28 o

Centonze et al. Europe Single Clinical Cimetropium 24 weeks t.d.s. 48 5 ⁄ 24 (20.8) 4 a y

34 y

Gilvarry et al. Europe Single Clinical Pirenzipine 4 weeks b.d. 24 6 ⁄ 12 (50.0) 4 e d Passaretti et al.30 Europe Single Clinical Cimetropium 4 weeks t.d.s. 40 8 ⁄ 20 (40.0) 4 i Dobrilla et al.29 Europe Single Clinical Cimetropium 12 weeks t.d.s. 70 24 ⁄ 35 (68.6) 4 Schafer and Ewe27 Europe Single Clinical Hyoscine 4 weeks t.d.s. 360 114 ⁄ 178 (64.0) 3 Castiglione et al.55 Europe Single Clinical Otilonium 4 weeks Not stated 60 10 ⁄ 30 (33.3) 2 Pulpeiro et al.57 South America Single Clinical Propinox 4 weeks Not stated 75 33 ⁄ 36 (91.7) 3 Glende et al.33 Multiple Multiple Rome I Otilonium 15 weeks t.d.s. 317 36 ⁄ 160 (22.5) 3 Mitchell et al.35 Europe Multiple Rome II Alverine 12 weeks t.d.s. 107 23 ⁄ 54 (42.6) 5 Lech et al.24 Europe Single Clinical Peppermint oil 4 weeks t.d.s. 47 6 ⁄ 24 (25.0) 3 Liu et al.25 Asia Single Clinical Peppermint oil 4 weeks q.d.s. 110 21 ⁄ 55 (38.2) 4 Capanni et al.58 Europe Single Rome II Peppermint oil 12 weeks t.d.s. 178 31 ⁄ 87 (35.6) 5 Cappello et al.26 Europe Single Rome II Peppermint oil 8 weeks b.d. 57 10 ⁄ 29 (34.5) 5 Merat et al.69 Middle East Single Rome II Peppermint oil 8 weeks t.d.s. 90 6 ⁄ 45 (13.3) 5 Camilleri et al.59 North America Multiple Rome I Alosetron 12 weeks b.d. 370 26 ⁄ 80 (32.5) 4 Bardhan et al.61 Europe Multiple Rome I Alosetron 12 weeks b.d. 462 60 ⁄ 117 (51.3) 4 Camilleri et al.62 North America Multiple Rome I Alosetron 12 weeks b.d. 647 94 ⁄ 323 (29.1) 5

lmn hrao hr21;3:144–158 32: 2010; Ther Pharmacol Aliment Camilleri et al.63 North America Multiple Rome I Alosetron 12 weeks b.d. 626 82 ⁄ 317 (25.9) 5 Lembo et al.60 North America Multiple Rome II Alosetron 12 weeks b.d. 801 113 ⁄ 269 (42.0) 4 72

ª Chey et al. Multiple Multiple Rome I Alosetron 48 weeks b.d. 714 166 ⁄ 363 (45.7) 4 00BakelPbihn Ltd Publishing Blackwell 2010 Chang et al.71 North America Single Rome I Alosetron 12 weeks b.d. 662 51 ⁄ 128 (39.8) 4 Krause et al.64 North America Multiple Rome II Alosetron 12 weeks b.d. 705 54 ⁄ 176 (30.7) 5 Bradette et al.73 Not stated Not stated Romeà Cilansetron 24 weeks t.d.s. 792 179 ⁄ 397 (45.1) 3 Miner et al.75 North America Not stated Romeà Cilansetron 12 weeks t.d.s. 692 97 ⁄ 348 (27.9) 3 Francisconi et al.74 Not stated Not stated Romeà Cilansetron 12 weeks t.d.s. 745 116 ⁄ 368 (31.5) 3 lmn hrao hr21;3:144–158 ª 32: 2010; Ther Pharmacol Aliment 00BakelPbihn Ltd Publishing Blackwell 2010

Table 1 | (Continued)

Geographical Number of Criteria used Active Duration of Dosing Sample Placebo response Jadad Trial location centres to define IBS* treatment therapy schedule size rate (%) score Matsueda et al.67 Asia Multiple Rome II Ramosetron 12 weeks o.d. 539 71 ⁄ 269 (26.4) 4 Matsueda et al.70 Asia Multiple Rome II Ramosetron 12 weeks o.d. 418 28 ⁄ 109 (25.7) 4 Hamling et al.82 Not stated Multiple Rome I Tegaserod 20 weeks b.d. 123 9 ⁄ 38 (23.7) 3 Langaker et al.83 Not stated Multiple Rome I Tegaserod 12 weeks b.d. 547 28 ⁄ 113 (24.8) 3 Muller-Lissner et al.76 Multiple Multiple Rome I Tegaserod 12 weeks b.d. 881 99 ⁄ 288 (34.4) 4 Novick et al.78 North America Multiple Rome I Tegaserod 12 weeks b.d. 1519 292 ⁄ 752 (38.8) 5 79 Kellow et al. Multiple Multiple Rome II Tegaserod 12 weeks b.d. 520 140 ⁄ 261 (53.6) 5 M

81 e t

Nyhlin et al. Europe Multiple Rome II Tegaserod 12 weeks b.d. 647 90 ⁄ 320 (28.1) 5 a -

77 a Tack et al. Multiple Multiple Rome II Tegaserod 4 weeks b.d. 2660 209 ⁄ 525 (39.8) 5 n a l

80 y

Harish et al. Asia Single Rome II Tegaserod 12 weeks b.d. 40 10 ⁄ 20 (50.0) 5 s i s Chey et al.92 North America Multiple Rome II Tegaserod 4 weeks b.d. 661 128 ⁄ 332 (38.6) 5 : p l 84 a

B307 Multiple Multiple Rome I Tegaserod 12 weeks b.d. 845 105 ⁄ 285 (36.8) 4 c e

84 b B351 Multiple Multiple Rome I Tegaserod 12 weeks b.d. 799 59 ⁄ 267 (22.1) 4 o r

86 e

Camilleri et al. North America Single Rome II Renzapride 2 weeks o.d. 48 2 ⁄ 12 (16.7) 4 s p

87 o

George et al. Europe Multiple Rome II Renzapride 12 weeks o.d. 510 36 ⁄ 125 (28.8) 4 n s Spiller et al.85 Europe Multiple Rome II Renzapride 8 weeks o.d. 168 23 ⁄ 42 (54.8) 5 e r a

89 t

Van Outryve et al. Europe Single Clinical Cisapride 12 weeks t.d.s. 69 11 ⁄ 33 (33.3) 4 e i Schutze et al.88 Europe Multiple Rome I Cisapride 12 weeks t.d.s. 96 34 ⁄ 48 (70.8) 4 n t 91 h Farup et al. Europe Multiple Rome I Cisapride 12 weeks t.d.s. 70 20 ⁄ 37 (54.1) 4 e i r

90 r

Ziegenhagen and Kruis Europe Multiple Rome I Cisapride 12 weeks t.d.s. 82 20 ⁄ 42 (47.6) 4 i t a b l * Irritable bowel syndrome. e b

o.d. once daily; b.d., twice daily; t.d.s., three times daily; q.d.s., four times daily. o w e

à Iteration of Rome criteria not specified. l s y n d r o m 151 e A. C. Ford and P. Moayyedi

L'Abbe plot (symbol size represents sample size) Cochran Q = 3.1, P = 0.08 for both 5-HT3 antagonists 100 and 5-HT4 agonists) (Table 2). There was also a trend for the response rate to be higher in RCTs that used

80 mixed 5-HT3 antagonists ⁄ 5-HT4 agonists compared with those that used peppermint oil, but again this difference 60 did not reach statistical significance (Cochran Q = 3.2, P = 0.07) (Table 2). 40 Placebo response rate according to reporting of

Experimental percent 20 method used to generate the randomization schedule or to conceal allocation 0 0 20 40 60 80 100 A majority of RCTs did not report either of these fea- Control percent tures of their design. Pooled placebo response rate was slightly lower in trials that stated the method used to Figure 2 | L’Abbe plot of placebo response rates generate the randomization schedule, but this difference (The lower line represents equality between experimen- was not statistically significant (Cochran Q = 1.4, tal treatment and control, with circles above this line P = 0.24) (Table 2). The pooled placebo response rate representing trials where experimental treatment was was almost identical when RCTs were subgrouped superior to control). according to whether or not the method used to conceal treatment allocation was reported. significance (Cochran Q = 4.7, P = 0.03 and Cochran Q = 3.2, P = 0.07 respectively). Duration of therapy var- Placebo response rate according to trial quality ied from 1 week to 48 weeks. Pooled placebo response Most RCTs scored 4 or more on the Jadad scale. When rate was the highest in trials using 1–4 weeks of therapy pooled placebo response rates according to trial quality at 46.0%,24, 25, 27, 30, 32, 34, 36, 38–41, 51, 54–57, 77, 86, 92 were assessed, these were the highest in those with a which was significantly higher than in RCTs that used score of 3 (40.0%), but the response rate was not signifi- more than 8 weeks of therapy (34.0%, Cochran Q = 8.5, cantly lower in studies with a score of 4 (37.8%, Cochran P = 0.004),21–23, 28, 29, 33, 35, 37, 42–44, 47, 53, 58–67, 70–76, 78– Q = 0.15, P = 0.70) or 5 (36.0%, Cochran Q = 0.51, 84, 87–91, but not in trials using 5–8 weeks of therapy P = 0.47). (39.8%, Cochran Q = 0.8, P = 0.37) (Table 2).26, 31, 45, 46, 48–50, 52, 68, 69, 85 A majority of trials assigned DISCUSSION patients to active therapy or placebo in a 1:1 ratio, and The present systematic review and meta-analysis of pla- pooled placebo response rate was higher in these RCTs cebo-controlled randomized trials conducted in IBS compared with trials where fewer patients received patients has demonstrated a pooled placebo response rate placebo than active therapy,42, 59–61, 64, 70, 71, 76, 77, 82–87 of 37.5%. The rate was significantly higher in European although this difference was not statistically significant RCTs compared with those conducted in Asia, the (Cochran Q = 2.3, P = 0.13) (Table 2). Middle-East or North America, in trials with a treatment duration of 1–4 weeks compared with those that used Placebo response rate according to active 8 weeks or more of therapy, and in RCTs that used a pharmacological therapy used physician-reported outcome to define response to ther- Antispasmodic drugs were the active pharmacological apy compared with those that used a patient-reported agent used in the greatest number of trials.21, 22, 27–41, 54–57 endpoint, although in the latter case, there were only Pooled placebo response rates were the highest in RCTs four studies that used a physician-reported outcome that that used antispasmodics or mixed 5-HT3 antagonists ⁄ provided data for the analysis. 5-HT4 agonists (45.0% for both). Whilst there was a Pooled placebo response rates were generally higher in trend for the observed response rate to be higher in RCTs using clinical criteria to define the presence of IBS, RCTs that used antispasmodics compared with those compared with those that used the Rome I or II criteria, using peppermint oil, 5-HT3 antagonists or 5-HT4 agon- trials that used a three times daily dosing schedule, trials ists, these differences were not statistically significant that assigned patients to placebo or active therapy in a

(Cochran Q = 4.5, P = 0.03 for peppermint oil and 1:1 ratio, trials of antispasmodics and mixed 5-HT3

152 Aliment Pharmacol Ther 2010; 32: 144–158 ª 2010 Blackwell Publishing Ltd Meta-analysis: placebo response rate in the irritable bowel syndrome

Table 2 | Effect of trial characteristics on magnitude of the placebo response

Number of Number of patients Pooled placebo 95% confidence P value trials receiving placebo response rate (%) interval I2 (%) for I2 All trials 73 8364 37.5 34.4–40.6 86.2 <0.001 Year of publication Before 1999 33 1700 39.0 33.0–46.0 86.5 <0.001 1999 or later 40 6706 36.1 32.7–39.5 86.2 <0.001 Trial location Asia 6 499 25.0 16.0–36.0 80.5 <0.001 Europe 33 1622 42.7 36.6–48.8 82.7 <0.001 Middle-East 4 142 23.0 13.0–35.0 61.5 0.05 North America 16 2974 33.0 30.0–37.0 73.8 <0.001 Trial setting Secondary care 21 663 39.0 31.0–48.0 79.2 <0.001 Tertiary care 20 673 37.0 26.2–48.4 88.6 <0.001 Number of centres Single 37 1301 36.9 30.1–44.0 85.2 <0.001 Multi 33 5950 38.0 34.0–41.0 86.8 <0.001 Criteria used to define IBS* Clinical 28 906 42.0 33.0–51.0 85.9 <0.001 Rome I 19 3482 36.0 31.0–41.0 86.6 <0.001 Rome II 23 2863 34.4 29.8–39.2 82.6 <0.001 Predominant stool pattern Constipation 16 2617 36.0 31.0–42.0 82.7 <0.001 Diarrhoea 8 1822 33.0 28.0–39.0 83.0 <0.001 Criteria used to define response Patient-reported 66 8122 37.4 34.2–40.6 87.0 <0.001 Physician-reported 4 81 53.0 42.0–63.0 0 0.64 Symptom data used to define response Abdominal pain 13 1622 35.0 29.0–42.0 83.8 <0.001 Global symptoms 54 6175 38.0 35.0–42.0 87.4 <0.001 Dosing schedule o.d. 20 977 32.2 25.2–39.7 81.1 <0.001 b.d. 21 5015 36.0 32.0–40.0 85.8 <0.001 t.d.s. 25 2102 43.0 37.0–50.0 87.2 <0.001 Duration of therapy 1–4 weeks 19 1446 46.0 39.0–54.0 83.8 <0.001 5–8 weeks 11 321 39.8 28.7–51.4 78.3 <0.001 >8 weeks 43 6597 34.0 31.0–37.0 86.8 <0.001 Proportion of trial patients assigned to placebo Approximately 50% 57 5733 38.7 34.7–42.7 87.7 <0.001

Aliment Pharmacol Ther 2010; 32: 144–158 153 ª 2010 Blackwell Publishing Ltd A. C. Ford and P. Moayyedi

Table 2 | (Continued)

Number of Number of patients Pooled placebo 95% confidence P value trials receiving placebo response rate (%) interval I2 (%) for I2 Significantly less than 50% 16 2631 34.0 30.0–39.0 79.0 <0.001 Active pharmacological therapy Antidepressant 16 468 32.0 22.4–42.5 82.4 <0.001 Antispasmodic 21 852 45.0 35.0–55.0 87.9 <0.001 Peppermint oil 5 240 30.0 21.0–40.0 62.1 0.03

5-HT3 antagonist 13 3264 35.0 30.0–40.0 87.6 <0.001

5-HT4 11 3201 35.0 30.0–40.0 88.3 <0.001

Mixed 5-HT3 7 339 45.0 31.0–58.0 83.2 <0.001 antagonists ⁄ 5-HT4 agonists Generation of randomization schedule Stated 27 3811 35.0 31.0–40.0 83.0 <0.001 Not stated or unclear 46 4553 38.8 34.5–43.3 87.8 <0.001 Concealment of allocation Stated 7 895 37.0 29.0–45.0 74.2 <0.001 Not stated or unclear 66 7469 37.5 34.2–40.9 87.0 <0.001 Score on Jadad scale 3 14 1782 40.0 30.0–50.0 93.9 <0.001 4 32 2894 37.8 33.3–42.5 81.7 <0.001 5 23 3572 36.0 31.0–40.0 81.9 <0.001

* Irritable bowel syndrome. o.d. once daily; b.d. twice daily; t.d.s. three times daily.

antagonists ⁄ 5-HT4 agonists and trials of lower quality random effects model to provide a more conservative according to the Jadad scale, but none of these differ- estimate of the pooled placebo response rate, meaning ences reached formal statistical significance. Specific fea- that the magnitude of this effect is unlikely to have been tures of RCT design such as trial setting, number of overestimated. Weaknesses of the study include the fact involved centres, predominant stool pattern of recruited that there was statistically significant heterogeneity when patients, as well as whether or not investigators reported trial data were pooled, which was not explained by any the method used to generate the randomization schedule of our subgroup analyses, and the fact that without and to conceal treatment allocation appeared to have lit- access to individual patient data, it is difficult to draw tle effect on pooled placebo response rates in our analy- any conclusions about specific patient characteristics that ses, nor did the year of publication of the trial. may have contributed to the findings of our study. Strengths of the present study include the search strat- A previously published systematic review and meta- egy, which was exhaustive and the fact that we contacted analysis has examined this issue.93 The authors identified original investigators to obtain supplementary data in 45 placebo-controlled trials, containing 3352 individuals some cases, to maximize the number of identified RCTs with IBS who were randomized to receive placebo. They providing data for these analyses. We assessed the reported a placebo response rate of 40% when data for impact of individual trial characteristics on pooled all eligible trials were pooled. The response rate was sig- placebo response rates in subgroup analyses. We also nificantly lower in studies that used the Rome criteria to performed an intention-to-treat analysis, where all drop- define the presence of IBS, but there were no other fea- outs were assumed to be treatment failures and used a tures of the studies identified that they examined,

154 Aliment Pharmacol Ther 2010; 32: 144–158 ª 2010 Blackwell Publishing Ltd Meta-analysis: placebo response rate in the irritable bowel syndrome including trial duration, score on the Jadad scale and our analyses, these had no statistically significant effect type of active pharmacological therapy, which predicted on the magnitude of the placebo response. placebo response rate. There are several limitations of The number of IBS patients achieving response or this study. First, there has been a considerable amount remission of their symptoms with placebo in this study of data published in the 5 years since this meta-analysis appears to be somewhere between one in two and one in was conducted. Secondly, the authors included RCTs of three. This information is important for the conduct of therapies for IBS that are not accepted as conventional future RCTs in the condition, as it may be helpful in treatments for the condition, such as activated charcoal, informing power calculations on which to base trial loxiglumide and naloxone. Thirdly, they included cross- recruitment. Recent trials of renzapride and citalopram over studies in which data extraction according to initial in IBS both failed to demonstrate any significant benefit treatment allocation was not possible. Finally, they of these drugs,68, 95 partly because of the high response missed eligible studies that were published and available rates observed in the placebo arms of the trials, which at the time their meta-analysis was conducted. The pres- meant that the studies were underpowered to detect a ent study therefore provides new and important infor- statistically significant difference, and in the case of ren- mation about the magnitude of the placebo response zapride, led the pharmaceutical company that had devel- rate in IBS, as well as examining a larger number of trial oped the drug to abandon further investment in its characteristics and features of design that may influence clinical development.96 Trials that use a longer duration this. of treatment and use given once or twice The finding that placebo response rates were signifi- daily might be expected to reduce the placebo response cantly higher in RCTs conducted in European popula- rate and may have a better ability to demonstrate the tions is novel. Possible explanations for this are benefit of active therapy. speculative, but it may be that there are cultural differ- In conclusion, our systematic review and meta-analy- ences that influence the magnitude of the placebo effect. sis has demonstrated a pooled placebo response rate in The fact that trials with a duration of therapy of between all available RCTs of pharmacological therapies in IBS of 1 and 4 weeks reported a significantly larger placebo 37.5%. Future research should concentrate on identifying effect than trials using more than 8 weeks is interesting patient characteristics that predict such a response to and suggests that any observed benefit of placebo in the treatment, perhaps using trial data at the individual treatment of IBS may ameliorate over time. The trend patient level. towards a higher placebo response rate seen with an increase in dosing schedule is a phenomenon that has ACKNOWLEDGEMENTS also been described when data from healing rates in duo- Declaration of personal interests: Alexander C Ford: None denal ulcer trials were examined.14 There is evidence declared. Paul Moayyedi: Chair at McMaster University from the systematic review literature that RCTs that do partly funded by an unrestricted donation by AstraZeneca, not report the method used to generate the randomiza- and has received consultant’s and speaker’s bureau fees tion schedule and to conceal allocation tend to overesti- from AstraZeneca, AxCan Pharma, Nycomed and mate the efficacy of the active therapy.94 It could Johnson and Johnson. Declaration of funding interests: therefore be expected that placebo response rates would We are grateful to the American College of Gastroenter- be lower in trials that did not report these features of ology for funding a series of systematic reviews on the their design and it is therefore interesting to note that in management of irritable bowel syndrome.

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