Clinical Trials Register

Summary
EudraCT Number:	2019-000324-17
Sponsor's Protocol Code Number:	GA18/118305
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-11-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2019-000324-17

A.3

Full title of the trial

Amitriptyline at Low-dose and Titrated for Irritable Bowel Syndrome as Second-line Treatment (The ATLANTIS study): A Double-blind Placebo-controlled Trial

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Amitriptyline at Low-dose and Titrated for Irritable Bowel Syndrome as Second-line Treatment (The ATLANTIS study): A Double-blind Placebo-controlled Trial

A.3.2

Name or abbreviated title of the trial where available

The ATLANTIS study v1.0

A.4.1

Sponsor's protocol code number

GA18/118305

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Leeds
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	NIHR - Health Technology Assessment (HTA) Programme
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leeds Institute of Clinical Trials Research, University of Leeds
B.5.2	Functional name of contact point	Dr Heather Cook
B.5.3	Address:
B.5.3.1	Street Address	CTRU, University of Leeds
B.5.3.2	Town/ city	Leeds
B.5.3.3	Post code	LS2 9JT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0113 343 3914
B.5.6	E-mail	Atlantis@leeds.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Amitriptyline HCl 10mg Teva film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Nederland BV
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Amitriptyline HCl 10mg Teva film-coated tablets
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Amitriptyline hydrochloride
D.3.9.1	CAS number	549-18-8
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Irritable Bowel Syndrome (IBS)

E.1.1.1

Medical condition in easily understood language

Irritable Bowel Syndrome (IBS)

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

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

E.1.3

Condition being studied is a rare disease

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?

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

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.

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.

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.

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be measured at 6 months post randomisation

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.

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

The end of the trial is defined as the date of the last patient’s last data item.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1