| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diarrhoea in patients with stable ulcerative colitis. |
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| E.1.1.1 | Medical condition in easily understood language |
| Diarrhoea in patients with stable ulcerative colitis . |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033007 |
| E.1.2 | Term | Other ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066557 |
| E.1.2 | Term | Chronic diarrhoea |
| E.1.2 | System Organ Class | 100000004856 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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? |
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| E.2.2 | Secondary objectives of the trial |
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? |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. Stable UC at the time of randomisation, in the clinical opinion of the gastroenterologist1,
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 below2:
a. Whether the patient has experienced any thoughts of harming themselves, or ending their life in the last 7-10 days?
b. Whether the patient currently has any thoughts of harming themselves or ending their life?
c. Whether the patient has any active plans or ideas about harming themselves, or taking their life, in the near future?
10. No recent history of self-reported self-harm (an episode of self-harm within the last 12 months).
11. Willing to be considered for all treatment arms of the trial, and to remain in the treatment arm to which they are assigned.
12. If female must be:
a. post-menopausal (no menses for 12 months without an alternative medical cause), or;
b. surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or;
c. using highly effective contraception (and must agree to continue for 7 days after the last dose of the investigational medicinal product [IMP]). 3
13. Able to complete questionnaires and trial assessments.
14. Able to provide written informed consent.
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| E.4 | Principal 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 to commence seeing a dietitian unless they are randomised to the low FODMAP arm of the trial.
5Cautions to the use of TCAs will not be an exclusion, but these will be recorded at screening and clarified with the patient’s gastroenterologist and the principal investigator (PI) in each centre prior to study entry. These include cardiovascular disease; diabetes; epilepsy; history of psychosis or bipolar disorder; hyperthyroidism; increased intra-ocular pressure; phaeochromocytoma; prostatic hypertrophy (prostate gland enlargement); susceptibility to angle-closure glaucoma; difficulty passing urine.
6 For women of childbearing potential (those not post-menopausal or surgically sterile) a pregnancy test must be performed within 7 days prior to randomisation. Post-menopausal is defined as no menses for 12 months without an alternative medical cause.
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| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase II - 8 weeks
Phase III - 6 months |
|
| E.5.2 | 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? |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Standard first line dietary advice |
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| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 26 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the trial is defined as the date of the last patient’s last data item. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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