Management of diarrhoea in ulcerative colitis: multi-arm multi-stage trial of low FODMAP diet, amitriptyline, ondansetron, or loperamide: MODULATE.

INTERVENTION: Trade Name: Amitriptyline Product Name: Amitriptyline Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Amitriptyline hydrochloride CAS Number: 549‐18‐8 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Product Name: Ondansetron Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Ondansetron hydrochloride dihydrate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 4‐ Product Name: Loperamide Pharmaceutical Form: INN or Proposed INN: loperamide hydrochloride Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐ CONDITION: Diarrhoea in patients with stable ulcerative colitis. ; MedDRA version: 20.1 Level: LLT Classification code 10045365 Term: Ulcerative colitis System Organ Class: 100000004856 ; MedDRA version: 20.1 Level: LLT Classification code 10033007 Term: Other ulcerative colitis System Organ Class: 100000004856 ; MedDRA version: 20.1 Level: LLT Classification code 10066557 Term: Chronic diarrhoea System Organ Class: 100000004856 Therapeutic area: Diseases [C] ‐ Digestive System Diseases [C06] SECONDARY OUTCOME: Secondary end point(s): Our secondary objectives are to answer the following questions at both 8 weeks and 6 months:; ; 1. What is the effect of the active treatments, compared with a control of standard first‐line dietary advice, in terms of:; a. Improvement in discomfort from loose stools, via the GSRS‐IBS?; b. Improvement in discomfort from diarrhoea, urgency, and abdominal pain, via the GSRS‐IBS?; c. Markers of disease activity, including escalation of medical therapy, need for surgery, faecal calprotectin, and C‐reactive protein?; d. Mood, via the hospital anxiety and depression scale?; ; • What is the tolerability and safety of the active treatments, compared with a control of standard first‐line dietary advice?; ; • What is the adherence to each of the active treatments, compared with a control of standard first‐line dietary advice? Timepoint(s) of evaluation of this end point: 8 weeks and 6 months PRIMARY OUTCOME: Main Objective: Our primary objectives are to answer the following questions:; ; 1. At phase 2: What is the short‐term effectiveness of a low FODMAP diet, low‐dose amitriptyline, ondansetron, and loperamide, each compared with a control of standard first‐line dietary advice, in terms of improvement in diarrhoea, via the diarrhoea subscale of the gastrointestinal symptom rating scale‐IBS (GSRS‐IBS) at 8 weeks, defined as reporting minor discomfort (score =2) from diarrhoea or less.; ; 2. At phase 3: What is the effectiveness of a maximum of two interventions continued from phase 2 (having shown evidence of short‐term effectiveness) in terms of improved disease‐specific quality of life, via the inflammatory bowel disease questionnaire (IBDQ), at 6 months? Primary end point(s): MODULATE follows a multi‐arm multi‐stage design, with a total of five arms spanning over two phases (phase II and phase III). We therefore have two distinct primary outcome measures that define our phase II and phase III endpoints, at 8 weeks and 6 months, respectively.; ; In phase II, our primary objective is to evaluate the short‐term effectiveness of the four proposed interventions, against a control, with regard to improvement of diarrhoea symptoms. The primary outcome used to measure this is a single item from the gastrointestinal symptom rating scale‐IBS (GSRS‐IBS) questionnaire – question 6, which asks patients how much discomfort has been caused by diarrhoea during the past week, administered at 8 weeks post‐randomisation. Possible responses to the question are scored on a Likert scale 1 to 7. This outcome will be analysed as a binary endpoint using logistic regression, where improvement is defined as those responding with a score of =2 to the diarrhoea question (no discomfort, or minor discomfort).; ; In phase III, our primary objective is to evaluate the effectiveness of a maximum of two interventions, against a control, with regard to improvement of disease‐specific quality of life, at 6 months post randomisation. The primary outcome used to measure this is the Inflammatory Bowel Disease Questionnaire (IBD‐Q), a 32‐item questionnaire measuring inflammatory bowel disease (IBD)‐specific health‐related quality of life. Possible responses to questions in the IBD‐Q are scored on a Likert scale of 1 to 7, giving a total score of between 32 and 224, which will be analysed using linear regression methods. Secondary Objective: Our secondary objectives are to answer the following questions at both 8 weeks and 6 months:; ; 1. What is the effect of the active treatments, compared with a control of standard first‐line dietary advice, in terms of:; ; a. Improvement in discomfort from loose stools, via the GSRS‐IBS?; ; b. Improvement in discomfort from diarrhoea, urgency, and abdominal pain, via the GSRS‐IBS?; ; c. Markers of disease activity, including escalation of medical therapy, need for surgery, faecal calprotectin, and C‐reactive protein?; ; d. Mood, via the hospital anxiety and depression scale?; ; 2. What is the tolerability and safety of the active treatments, compared with a control of standard first‐line dietary advice, including rates of constipation and numbers of patients with a flare of disease activity?; ; 3. What is the adherence to each of the active treatments, compared with a control of standard first‐line dietary advice? Timepoint(s) of evaluation of this end point: Phase II ‐ 8 weeks ; ; Phase III ‐ 6 months INCLUSION CRITERIA: 1. A histological diagnosis of UC in secondary care, including left‐sided colitis or extensive colitis. 2. Age =18 years. 3. At least moderate discomfort from diarrhoea according to the GSRS‐IBS [26] (equating to a score of =4 on the diarrhoea subscale of the GSRS‐IBS) 4. On stable doses of UC‐related medication for =2 months at time of initial screening telephone call. 5. Ongoing diarrhoea for 3 months prior to initial screening telephone call. 6. A CRP =5mg/L (measured as per local practise) within 4 weeks prior to randomisation. 7. FC <250mcg/g [29] within 4 weeks prior to randomisation. 8. Mayo score of =1 at flexible sigmoidoscopy within the past 3 months prior to initial screening telephone call. 9. No evidence of active suicidal ideation at time of initial screening telephone call and prior to randomisation, as determined by the three clinical screening questions below1: a. Whether the patient has experienced any thought