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DiPALS: Diaphragm pacing in patients with amyotrophic lateral sclerosis – A randomised controlled trial

McDermott, Christopher J.; Bradburn, Mike J.; Maguire, Chin; Cooper, Cindy L.; Baird, Wendy O.; Baxter, Susan K.; Cohen, Judith; Cantrill, Hannah; Dixon, Simon; Ackroyd, Roger; Baudouin, Simon; Bentley, Andrew; Berrisford, Richard; Bianchi, Stephen; Bourke, Stephen C.; Darlison, Roy; Ealing, John; Elliott, Mark; Fitzgerald, Patrick; Galloway, Simon; Hamdalla, Hisham; Hanemann, C. Oliver; Hughes, Philip; Imam, Ibrahim; Karat, Dayalan; Leek, Roger; Maynard, Nick; Orrell, Richard W.; Sarela, Abeezar; Stradling, John; Talbot, Kevin; Taylor, Lyn; Turner, Martin; Simonds, Anita K.; Williams, Tim; Wedzicha, Wisia; Young, Carolyn; Shaw, Pamela J.

Authors

Christopher J. McDermott

Mike J. Bradburn

Chin Maguire

Cindy L. Cooper

Wendy O. Baird

Susan K. Baxter

Judith Cohen

Hannah Cantrill

Simon Dixon

Roger Ackroyd

Simon Baudouin

Andrew Bentley

Richard Berrisford

Stephen Bianchi

Stephen C. Bourke

Roy Darlison

John Ealing

Mark Elliott

Patrick Fitzgerald

Simon Galloway

Hisham Hamdalla

C. Oliver Hanemann

Philip Hughes

Ibrahim Imam

Dayalan Karat

Roger Leek

Nick Maynard

Richard W. Orrell

Abeezar Sarela

John Stradling

Kevin Talbot

Lyn Taylor

Martin Turner

Anita K. Simonds

Tim Williams

Wisia Wedzicha

Carolyn Young

Pamela J. Shaw



Abstract

Background
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2–3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4® diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure.

Objective
The Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure.

Design
The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy.

Participants
Eligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥ 18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1 : 1 non-deterministic minimisation.

Interventions
Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS.

Main outcome measures
The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost–utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy.

Results
In total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25; p = 0.01).

Conclusions
Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.

Future work
It may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further.

Citation

McDermott, C. J., Bradburn, M. J., Maguire, C., Cooper, C. L., Baird, W. O., Baxter, S. K., …Shaw, P. J. (2016). DiPALS: Diaphragm pacing in patients with amyotrophic lateral sclerosis – A randomised controlled trial. Health Technology Assessment, 20(45), 1-218. https://doi.org/10.3310/hta20450

Journal Article Type Article
Acceptance Date Jan 4, 2016
Publication Date Jun 1, 2016
Deposit Date Nov 14, 2018
Publicly Available Date Nov 14, 2018
Journal Health Technology Assessment
Print ISSN 1366-5278
Electronic ISSN 2046-4924
Publisher NIHR Journals Library
Peer Reviewed Peer Reviewed
Volume 20
Issue 45
Pages 1-218
DOI https://doi.org/10.3310/hta20450
Keywords Health Policy
Public URL https://hull-repository.worktribe.com/output/785063
Publisher URL https://www.journalslibrary.nihr.ac.uk/hta/hta20450/#/full-report
Additional Information Contractual start date: 07-2011; Editorial review begun: 07-2015; Accepted for publication: 01-2016

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Copyright Statement
© Queen’s Printer and Controller of HMSO 2016. This work was produced by McDermottet al.under the terms of acommissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes ofprivate research and study and extracts (or indeed, the full report) may be included in professional journals provided thatsuitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications forcommercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trialsand Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.





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