The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis

M. Bosman*, S. Elsenbruch, M. Corsetti, J. Tack, M. Simren, B. Winkens, T. Boumans, A. Masclee, D. Keszthelyi

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

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Abstract

Findings Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80.4% [95% CI 66.1-90.6]) of 46 patients in the infliximab-continued group and 25 (54.3% [39.0-69.1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26.1% (95% CI 7.7-44.5; p=0.0076) before adjustment and 27.3% (95% CI 8.0-44.1; p=0.0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3.9% [95% CI -10.3 to 18.1]; p=0.59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66.7%, 95% CI 34.9-90.1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions.Background Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab.Methods We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. Findings Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80.4% [95% CI 66.1-90.6]) of 46 patients in the infliximab-continued group and 25 (54.3% [39.0-69.1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26.1% (95% CI 7.7-44.5; p=0.0076) before adjustment and 27.3% (95% CI 8.0-44.1; p=0.0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3.9% [95% CI & minus;10.3 to 18.1]; p=0.59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66.7%, 95% CI 34.9-90.1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions.Interpretation Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account.Funding Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan.Copyright (c) 2021 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)459-473
Number of pages15
JournalThe Lancet Gastroenterology and Hepatology
Volume6
Issue number6
DOIs
Publication statusPublished - 1 Jun 2021

Keywords

  • IRRITABLE-BOWEL-SYNDROME
  • PLACEBO-CONTROLLED TRIAL
  • CONTROLLED CLINICAL-TRIAL
  • RUN-IN PERIODS
  • DOUBLE-BLIND
  • DIARRHEA-PREDOMINANT
  • ABDOMINAL-PAIN
  • EFFICACY
  • ALOSETRON
  • SYMPTOMS
  • OTILONIUM BROMIDE
  • CIMETROPIUM BROMIDE
  • RECEPTOR ANTAGONIST RAMOSETRON
  • LONG-TERM TREATMENT

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