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Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care

Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care
Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care
Background: Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear.
Methods: ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care.
Discussion: Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. Trial registration: ISRCTN ISRCTN48075063. Registered on 7th June 2019.
Adult, Amitriptyline/administration & dosage, Double-Blind Method, Humans, Irritable Bowel Syndrome/drug therapy, Multicenter Studies as Topic, Primary Health Care, Quality of Life, Randomized Controlled Trials as Topic, Treatment Outcome
1745-6215
Alderson, Sarah L.
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Wright-Hughes, Alexandra
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Ford, Alexander C.
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Farrin, Amanda
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Hartley, Suzanne
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Fernandez, Catherine
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Taylor, Christopher
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Ow, Pei Loo
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Teasdale, Emma
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Howdon, Daniel
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Guthrie, Elspeth
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Foy, Robbie
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Ridd, Matthew J.
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Bishop, Felicity L.
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Muir, Delia
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Chaddock, Matthew
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Herbert, Amy
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Cooper, Deborah
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Gibbins, Ruth
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Newman, Sonia
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Cook, Heather
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Longo, Roberta
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Everitt, Hazel
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et al.
Alderson, Sarah L.
cc69f2dc-66f3-4552-b6b5-6462969a647f
Wright-Hughes, Alexandra
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Ford, Alexander C.
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Farrin, Amanda
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Hartley, Suzanne
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Fernandez, Catherine
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Taylor, Christopher
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Ow, Pei Loo
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Teasdale, Emma
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Howdon, Daniel
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Guthrie, Elspeth
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Foy, Robbie
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Ridd, Matthew J.
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Bishop, Felicity L.
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Muir, Delia
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Chaddock, Matthew
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Herbert, Amy
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Cooper, Deborah
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Gibbins, Ruth
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Newman, Sonia
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Cook, Heather
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Longo, Roberta
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Everitt, Hazel
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Alderson, Sarah L., Wright-Hughes, Alexandra, Ford, Alexander C., Teasdale, Emma, Gibbins, Ruth, Newman, Sonia and Everitt, Hazel , et al. (2022) Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care. Trials, 23 (1), [552]. (doi:10.1186/s13063-022-06492-6).

Record type: Article

Abstract

Background: Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear.
Methods: ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care.
Discussion: Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. Trial registration: ISRCTN ISRCTN48075063. Registered on 7th June 2019.

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More information

Published date: 8 July 2022
Additional Information: Funding Information: This project is funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA) (grant Ref: 16/162/01; Additional file 3). This report is independent research funded by the NIHR. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: The ATLANTIS trial team includes Maggie Barrett, Gina Bianco, Richard Brindle, Taposhi Nash, and Tom Smith in addition to the named authors. The authors would like to express sincere gratitude to the ATLANTIS PPI panel for their contribution to the study since its inception. The authors would also like to thank our TSC and DMEC members for their oversight throughout the trial: Dr Tim Holt (TSC Chair, University of Oxford), Ms Jill Durnell (PPI representative), Ms Megan Bedford (PPI representative), Prof David Sanders (University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust), Prof Kerry Hood (Cardiff University), Dr Maureen Twiddy (Hull York Medical School), Prof Peter Whorwell (DMEC chair, University of Manchester), Prof Chris Burton (University of Sheffield), Prof Peter Bower (University of Manchester), Miss Natalie Ives (University of Birmingham), and Dr Peter Paine (Salford Royal Foundation Trust). Funding Information: Informed consent will be obtained from participants prior to entry into the trial. The trial was reviewed and received ethical approval from Yorkshire & The Humber Research Ethics Committee on 5 August 2019 (19/YH/0150; Additional file ), the Medicines & Healthcare products Regulatory Agency (EudraCT: 2019–000324-17), the Health Research Authority (IRAS project ID 252282), and local CCGs/R&D departments for each participating site prior to entering patients into the trial. The study is sponsored by the University of Leeds. Publisher Copyright: © 2022, The Author(s).
Keywords: Adult, Amitriptyline/administration & dosage, Double-Blind Method, Humans, Irritable Bowel Syndrome/drug therapy, Multicenter Studies as Topic, Primary Health Care, Quality of Life, Randomized Controlled Trials as Topic, Treatment Outcome

Identifiers

Local EPrints ID: 468658
URI: http://eprints.soton.ac.uk/id/eprint/468658
ISSN: 1745-6215
PURE UUID: 005a094a-5c99-4ea0-80bd-3e5c668becd5
ORCID for Emma Teasdale: ORCID iD orcid.org/0000-0001-9147-193X
ORCID for Felicity L. Bishop: ORCID iD orcid.org/0000-0002-8737-6662
ORCID for Sonia Newman: ORCID iD orcid.org/0009-0007-6827-2861
ORCID for Hazel Everitt: ORCID iD orcid.org/0000-0001-7362-8403

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Date deposited: 19 Aug 2022 16:47
Last modified: 11 Jul 2024 01:54

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Contributors

Author: Sarah L. Alderson
Author: Alexandra Wright-Hughes
Author: Alexander C. Ford
Author: Amanda Farrin
Author: Suzanne Hartley
Author: Catherine Fernandez
Author: Christopher Taylor
Author: Pei Loo Ow
Author: Emma Teasdale ORCID iD
Author: Daniel Howdon
Author: Elspeth Guthrie
Author: Robbie Foy
Author: Matthew J. Ridd
Author: Delia Muir
Author: Matthew Chaddock
Author: Amy Herbert
Author: Deborah Cooper
Author: Ruth Gibbins
Author: Sonia Newman ORCID iD
Author: Heather Cook
Author: Roberta Longo
Author: Hazel Everitt ORCID iD
Corporate Author: et al.

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