Dietary Interventions in Irritable Bowel Syndrome: Soluble, Insoluble or no Fibre?
Condition: Colonic Diseases, Functional
MeSH terms: Irritable Bowel Syndrome; Colonic Diseases; Colonic Diseases, Functional
Study type: Interventional

Summary: 
      The purpose of this study is to assess the role of dietary fibre in Irritable Bowel Syndrome
      (IBS) treatment, in particular the role of increasing the content of soluble or insoluble
      fibres in the daily diet. The primary objective is to compare soluble (psyllium) and
      insoluble (bran) to placebo, administered over 12 weeks in patients with 'probable' or
      'definite' Irritable Bowel Syndrome. The primary efficacy parameter is the responder rate
      based on weekly assessment of adequate relief of IBS symptoms. Secondary efficacy parameters
      include changes in IBS related symptoms (abdominal pain, bowel habits) and quality of life.
    

Detailed description: 
      INTRODUCTION: In daily practice, both patients and doctors consider dietary factors,
      especially fibre and fluid intake, to play an important role in both the aetiology and the
      persistence of Irritable Bowel Syndrome (IBS) symptoms. The majority of doctors provides
      dietary lifestyle advice, targeted at increasing the fibre content of the daily diet by
      adding insoluble fibre. In addition more than 50% of IBS patients receive pharmacotherapy,
      frequently including bulking agents, in particular soluble fibres such as
      psyllium-supplements. There is, however, limited evidence that fibre therapy may alleviate
      IBS symptoms. In addition, there are indications that insoluble fibres may even worsen IBS
      symptoms. Scientific evidence pertaining to the different effects of soluble and insoluble
      fibres on IBS symptoms is very limited indeed, and methodologically sound RCTs in primary
      care patients are lacking altogether. The latter is important since primary care IBS patients
      differ in many aspects from secondary/tertiary care patients.

      STUDY DESIGN: A double blind parallel-group randomised controlled trial involving IBS
      patients in primary care comparing 12-week intervention of psyllium fibres, bran, and
      placebo. After the intervention, all patients will be followed for an additional 12-week
      period.

      STUDY POPULATION: Patients aged 18-65 years presenting to their General Practitioner (GP)
      with either incident IBS symptoms or with a relapse of pre-existing IBS as well as patients
      with a prior GP diagnosis of IBS and currently experiencing symptoms are eligible for the
      study. Patients will be stratified in two equally large patients groups of (a) 'definite'
      IBS, according to the Rome II diagnostic criteria, and (b) 'probable' IBS, pragmatically
      diagnosed with IBS by their GP. Patients with alarm symptoms (i.e. abnormalities at physical
      examination, fever, weight loss, rectal bleeding), with fibre intolerance, with acute
      abdominal pain, patients with treatment for IBS by a specialist in the prior 48 months,
      patients with an active psychiatric disorder requiring medication and patients unable to fill
      out the questionnaires will be excluded.

      INTERVENTION: Patients will be randomly allocated to a 12-week treatment period with (a) 10
      gram psyllium fibres, (b) 10 gram wheat bran or (c)10 gram identical placebo to be taken in 2
      doses with the meal. In healthy subjects, the median intake is 20 gram fibre per day. When
      focussing on increasing the amount of fibre in the daily diet in IBS treatment, addition of
      10 gram fibre to the diet (bringing the total fibre content of the diet to 30 gram), is
      usually considered adequate. This should be combined with sufficient intake of fluid. All
      study medication will be filled in comparable pots. To prevent constipation, participants
      will be instructed not to change dietary habits, and to take an additional 1 litre of fluids
      daily. Other possible side effects are an unpleasant feeling in de upper gut and rarely
      allergic reactions such as rash, rhinitis and conjunctivitis. Cellulose can possibly bind
      glycosides, salicylates, coumarine derivates en nitrofurantoïne. Participants will be
      instructed to take the fibre at least 2 hours after these medications.

      OUTCOME MEASUREMENTS: In line with previous conclusions on optimal outcome assessment in
      trials on functional GI disease, the primary endpoint is the Adequate Relief question. This
      measure addresses symptom improvement in IBS treatment with a single question (Did you have
      adequate relief of IBS-related abdominal pain or discomfort in the past week?) scored on a
      dichotomous scale. This instrument is a well validated simple outcome assessment for IBS
      treatment. A positive response is defined as more than 2 weeks Adequate Relief per month.
      Secondary outcome measures include IBS symptoms, disease specific quality of life, fibre
      intake, the number of doctor visits, and costs. IBS symptoms will be monitored using the IBS
      symptom severity score (IBS SSS). This is a well- validated IBS symptom score, which
      integrates five aspects of bowel dysfunctioning with the actual intensity of IBS symptoms,
      using visual analogue scales. Disease-specific quality of life will be registrated with the
      Irritable Bowel Syndrome Quality of Life scale (IBS QOL). This instrument includes 30 items
      in nine subscales. It has been validated in different populations. Fibre intake will be
      monitored every 4 weeks using a Food Frequency Questionnaire. Habitual fibre intake can be
      calculated from the questionnaire data. This instrument is a self-administered food frequency
      questionnaire and is validated for ranking subjects according to intake for dietary fibre.
      After the active treatment period of 12 weeks, all patients will be followed up for an
      additional period of 12 weeks to assess the sustainability of the effects of the
      interventions. The primary outcome will be measured on a weekly basis. The secondary
      endpoints will be recorded at 1, 2, 3 and 6 months after start of the intervention, during
      follow-up visits to the general practitioner. All additional consultations, diagnostics
      procedures, medication, and referrals during the intervention period will be recorded in the
      electronic medical file in the practices. Compliance will be checked every visit by the
      weighting of the contents of the trial medications and registration by a patient's diary.

      REQUIRED SAMPLE SIZE: Ninety-five patients are required per treatment arm. Assuming a minimal
      clinically relevant difference in the proportion of responders (i.e. more than 2 weeks of
      Adequate Relief per month) between active and placebo treatment of 20%, a placebo response of
      40%, a treatment effect of 60% is expected. Taking a type II error of 20% and a type I error
      of 5% and allowing 10% of dropouts, totally 285 IBS patients are required. Assuming an
      estimated mean incidence of IBS in primary care, of 8 per 1000 patient years (20 patients per
      practice per year), an expected inclusion rate of 25%, we expect that 60 general
      practitioners, each including 5 patients, will be able to include the required number of
      patients in one year. GPs will be recruited from the Utrecht and Maastricht general
      practitioners research networks. GPs in both networks have a tradition of participating in
      academic research and have ample expertise in participating in clinical trials in primary
      care.

      DATA ANALYSIS: Statistical analysis will be based on the intention-to-treat principle.
      Adequate Relief, IBS Symptom Score and Quality of Life after the 12-week treatment period and
      after the additional 12-week post-treatment period will be compared with the score at
      baseline observation (t=0), using Student T-tests for repeated measurements and variance
      analysis. Stability of the treatment effect in time will be assessed using one-factorial
      ANOVA for repeated measures. The proportion of responders on the Adequate Relief question
      (i.e. > 2 weeks Adequate Relief per months) will be compared using chi-square tests. In case
      of (unexpected) differences in relevant baseline characteristics between the three comparison
      groups multiple regression analyses will be performed.

      ADMINISTRATION: The project will cover 24 months. The first 3 months of the study are
      necessary to prepare the study. The inclusion period lasts 12 months, 6 additional months are
      required to complete the follow-up and to perform the first statistical analyses and to
      prepare the manuscripts. The last 3 months will be used for definitive data analyses and
      finalisation of the reports.
    

Intervention name(s): psyllium fibre (dietary supplement); wheat bran (dietary supplement); rice wheat (placebo)
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Psyllium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Irritable Bowel Syndrome; Diet Therapy; Dietary Fiber; Randomized Controlled Trial; Family Practice