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
Conditions
Interventions
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)
Sponsors
University of Leeds
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 74
Exclusion criteria
Exclusion criteria: 1. Inflammatory bowel disease unclassifiable or Crohn’s disease. 2. Ulcerative proctitis. 3. Body mass index=18.5 kg/m2. 4. Previous or planned gastrointestinal IBD-related resectional surgery or previous cholecystectomy. 5. Having received steroids for UC within the last 2 months prior to the initial screening telephone call or at randomisation. 6. Coeliac disease (as confirmed via anti-tissue transglutaminase (tTG) antibodies). 7. A previous diagnosis of colorectal dysplasia or cancer, or no up to date surveillance colonoscopy, as per current British Society of Gastroenterology guidelines [30]. 8. Known allergy to TCAs, ondansetron, or loperamide. 9. Current use of a TCA at the time of the initial screening telephone call or at randomisation. 10. Previous failed treatment with, or regular use of amitriptyline, ondansetron, or loperamide for diarrhoea. 11. Currently on, or have previously tried and failed, a low FODMAP diet under dietitian guidance.4 12. Contraindications5 to the current use of TCAs including patients with any of the following: a. taking monoamine oxidase inhibitors, or receiving them within the last 2 weeks; b. already currently prescribed a TCA for the treatment of depression c. previous myocardial infarction; d. recorded arrhythmias, particularly heart block of any degree, or prolonged Q-T interval on electrocardiogram; e. mania; f. severe liver disease; g. porphyria; h. congestive heart failure; i. coronary artery insufficiency; j. receiving concomitant drugs that prolong the QT interval (e.g. amiodarone, terfenadine, or sotalol). 13. Contraindications to the current use of ondansetron, including: a. concomitant use of apomorphine; b. concomitant use of other drugs that prolong the QT interval. 14. Contraindications to the current use of loperamide, including: a. acute UC; b. acute dysentery, which is characterised by blood in stools and high fever; c. bacterial enterocolitis caused by invasive organisms; d. pseudomembranous colitis associated with the use of broad-spectrum antibiotics. 15. Pregnancy, planned pregnancy during the study, pregnancy within 3 months of study completion, or breastfeeding6. 1 A flexible sigmoidoscopy with Mayo score =1 is only required if there is clinical uncertainty regarding the stability of the patient’s UC and is at the discretion of the treating physician. Rectal bleeding reported by the patient would contribute to the assessment of disease stability and if present should be assessed by flexible sigmoidoscopy. 2Suicidal ideation should be assessed on the screening telephone call. No more than 14 days should elapse between the initial suicidal ideation assessment and study entry/ randomisation. If more than 14 days have elapsed then the suicidal ideation assessment should be repeated. 3Highly effective contraception is defined as one of the following: combined (oestrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; practising true abstinence ( defined as refraining from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject). 4Patients currently waiting to see a dietitian for a low FODMAP diet must agree not
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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?;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?;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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
United Kingdom
Contacts
Public ContactAmy West
Leeds Institute of Clinical Trials Research, University of Leeds
Outcome results
None listed