E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Irritable Bowel Syndrome (IBS) |
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E.1.1.1 | Medical condition in easily understood language |
Irritable Bowel Syndrome (IBS) |
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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 | PT |
E.1.2 | Classification code | 10023003 |
E.1.2 | Term | Irritable bowel syndrome |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10023003 |
E.1.2 | Term | Irritable bowel syndrome |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
Does 6 months of amitriptyline treatment improve IBS symptoms compared with placebo?
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E.2.2 | Secondary objectives of the trial |
1. What is the effect of amitriptyline, compared with placebo, on global symptoms of IBS at 3 and 12 months?
2. What is the effect of amitriptyline, compared with placebo, on relief of IBS symptoms at 3, 6, and 12 months?
3. What is the effect of amitriptyline, compared with placebo, on anxiety at 3, 6, and 12 months?
4. What is the effect of amitriptyline, compared with placebo, on depression at 3, 6, and 12 months?
5. What is the effect of amitriptyline, compared with placebo on patient reported relief of IBS symptoms, measured weekly?
6. What is the effect of amitriptyline, compared with placebo, on self-reported health care use at 3, 6, and 12 months?
7. What is the effect of amitriptyline, compared with placebo, on health-related quality of life at 3, 6, and 12 months?
8. What is the effect of amitriptyline, compared with placebo, on ability to work and participate in other activities at 3, 6, and 12 months?
9. What is the effect of amitriptyline, compared with placeb |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A nested qualitative study will explore participants’ and GPs’ experiences of treatments and participating in the ATLANTIS trial. We will aim to interview approximately 30 GPs after the participant recruitment period. Through the main study informed consent procedures, all participants will be asked for consent to be invited to take part in interviews. A sub-sample of participants will subsequently be invited to take part in two semi-structured 1-hour telephone interviews. Approximately 20 participants will be interviewed from each arm of the trial. The majority of the interviews will be conducted at approximately 6 and 12 months post-randomisation. |
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E.3 | Principal inclusion criteria |
1. A diagnosis of IBS (of any subtype of stool pattern [diarrhoea, constipation, mixed]) in their primary care record, and fulfilling the Rome IV criteria;
2. Age ≥18 years;
3. Ongoing symptoms, defined as an IBS severity scoring system (IBS-SSS) score of ≥75 at screening, despite having tried dietary changes and first-line therapies as defined by NICE (antispasmodics [e.g. mebeverine], fibre supplements [e.g. fybogel], or anti-diarrhoeals[e.g. loperamide]), assessed at screening via patient self-report;
4. A normal haemoglobin, total white cell count (WCC), and platelets within the last 6 months prior to screening;
5. A normal CRP within the last 6 months prior to screening;
6. Exclusion of coeliac disease, via anti-tTG antibodies, as per NICE guidance;
7. No evidence of active suicidal ideation, as determined by three clinical screening questions below, and no recent history of self-harm (an episode of self-harm within the last 12 months prior to screening).
(i) Whether the patient has experienced any thoughts of harming themselves, or ending their life in the last 7-10 days?
(ii) Whether the patient currently has any thoughts of harming themselves or ending their life?
(iii) Whether the patient has any active plans or ideas about harming themselves, or taking their life, in the near future?
8. If female, must be: a. postmenopausal (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 (must agree to be continued for 7 days after the last dose of the investigational medicinal product).
9. Able to complete questionnaires and trial assessments;
10. Able to provide written informed consent.
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E.4 | Principal exclusion criteria |
1. Aged >60 years and with no GP review in the 12 months prior to screening;
2. Meeting locally adapted NICE 2-week referral criteria for suspected lower gastrointestinal cancer;
3. A known documented diagnosis of inflammatory bowel disease or coeliac disease;
4. A previous diagnosis of colorectal cancer;
5. Patients currently participating in or who have been involved in any other CTIMP trial in the previous 3 months prior to screening;
6. Pregnant or breastfeeding;
7. Planning to become pregnant within the next 18 months;
8. Current use of a TCA, or use of a TCA within the last 2 weeks prior to randomisation, for another indication;
9. Allergy to TCAs;
10. Other contraindications to the use of TCAs, including patients with any of the following: • taking monoamine oxidase inhibitors (MAOIs), or receiving them within the last 2 weeks; • already prescribed a TCA for the treatment of depression; • previous myocardial infarction; • recorded arrhythmias, particularly heart block of any degree, prolonged Q-T interval on ECG; • mania; • severe liver disease; • porphyria; • congestive heart failure; • coronary artery insufficiency; • receiving concomitant drugs that prolong the QT interval (e.g. amiodarone, terfenadine, or sotalol).
Other cautions to the use of TCAs will not be an exclusion, but these will be recorded at screening and clarified with the patient’s GP and the lead GP in each hub prior to study entry.
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E.5 End points |
E.5.1 | Primary end point(s) |
What is the effect of amitriptyline, compared with placebo, on patient-reported global symptoms of IBS at 6 months?
The IBS-SSS is widely used in trials of medical therapies in IBS. It is a 5-item self-administered questionnaire measuring presence, severity, and frequency of abdominal pain, presence and severity of abdominal distension/tightness, satisfaction with bowel habit, and degree to which IBS symptoms are affecting, or interfering with, the person’s life in general. The maximum score is 500 points: <75 points indicates symptoms that are felt to be in remission, with normal bowel function; 75-174 points indicates mild IBS symptoms; 175-299 points moderate IBS; and 300-500 points severe IBS. PPI input felt that 6 months of blinded treatment was probably the maximum reasonable initial commitment from a patient perspective. Hence the primary outcome measure will be collected at this time point. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be measured at 6 months post randomisation |
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E.5.2 | Secondary end point(s) |
The IBS-SSS will also be measured at 3 and 12 months as a secondary endpoint.
Subjective Global Assessment (SGA) of relief of IBS symptoms is frequently used in treatment trials in IBS to identify responders to therapy. Participants rate their relief from IBS symptoms on a scale of 1 to 5 ranging from "completely relieved" to "worse". Scores are dichotomised so that those scoring from 1-3 are considered responders and those 4-5 non-responders. This measure will be assesses at 3, 6 and 12 months.
Relief of IBS symptoms will be measured via a binary response to the question: “Have you had adequate relief of your IBS symptoms?” asked electronically, or via a paper based diary. Participants will be sent a weekly text reminder from CTRU to complete the assessment. This will be recorded weekly.
HADS is a well-validated, commonly used, self-report instrument for detecting anxiety and depression in people with medical illnesses. It consists of a total of seven items measuring anxiety, and seven measuring depression, scored from 0 to 3, with a total score of 21 for each. Higher scores indicate more severe anxiety or depression. These measures (HADS-A and HADS-D scores) will be assessed at 3, 6 and 12 months.
Acceptability of treatment will be measured by participant self-report, as well as the decision to continue trial medication beyond 6 months. Participants will be asked “On balance do you find this medication acceptable to take and would you want to keep taking it”. This will be assessed at 6 months.
Adherence to therapy will be measured by the research nurse during the planned phone calls at 3 weeks, 3 months, 6 months, 9 months, and 12 months. Participants will be asked “Since you were last asked, which of the options best describes how often you have taken at least one tablet of the trial medication daily?” A. Every day or nearly everyday B. Half of the days or more than half of the days C. Less than half of the days D. None or nearly none of the days
AEs to amitriptyline or placebo will be collected via a validated self-completed questionnaire, the Antidepressant Side effect Checklist (ASEC), which consists of 21 potential AEs rated on a scale of 0 (absent) to 3 (severe), and also asks the individual whether they deemed the AE to be treatment-related. This has been shown to demonstrate good agreement with a psychiatrist’s rating of the occurrence of treatment-related AEs with antidepressants. All reported AEs will be assessed with respect to seriousness, relationship to trial medication (suspected or not suspected), and expectedness (expected or unexpected). This will be assessed at 3, 6 and 12 months.
Health care use, use of other medications for IBS, and need for referral to secondary care will be self-reported by the participant via a resource use questionnaire, using a 3-month recall period (6-month recall period at 12 months). This will collect data concerning all resource use and medications in the community, and in primary and secondary care. Private costs and days off work related to IBS will also be collected. This will be assessed at 3, 6 and 12 months.
The EQ-5D-3L is the most frequently used measure for generating quality adjusted life years. It has been demonstrated to be appropriate in patients with IBS. This will be assessed at 3, 6 and 12 months.
WASAS measures the effect of chronic diseases on people's ability to work and manage at home, and participate in social or private leisure activities and relationships. The WASAS has been shown to be sensitive to change in IBS trials. It has five aspects scored from 0 (not affected) to 8 (severely affected), with a total possible score of 40. This will be assessed at 3, 6 and 12 months.
The PHQ-12 comprises 12 somatic symptoms from the PHQ, each symptom scored from 0 ("not bothered at all") to 2 ("bothered a lot"). Somatoform behaviour is a measure of mood and psychological health, and it is common in people with IBS.” This will be assessed at 6 months.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be measured at 3 months, 6 months and 12 months.
Endpoint 5 will be measured weekly up to 6 months
Endpoint 11 and 12 will be also be measured at 9 and 12 months for participants remaining on treatment. |
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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) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 75 |
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 | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 31 |