title: DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis - a randomised controlled trial.
abstract: 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.
  
  
  
  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.
  
  
  
  The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy.
  
  
  
  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.
  
  
  
  Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS.
  
  
  
  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.
  
  
  
  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).
  
  
  
  Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.
  
  
  
  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.
  
  
  
  Current Controlled Trials ISRCTN53817913.
  
  
  
  This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McDermott
authors.affiliation: Sheffield Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Bradburn
authors.affiliation: Sheffield Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Chin
authors.initials: C
authors.lastname: Maguire
authors.affiliation: Sheffield Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Cooper
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Wendy O
authors.initials: WO
authors.lastname: Baird
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Baxter
authors.affiliation: Sheffield Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Cohen
authors.affiliation: Sheffield Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Cantrill
authors.affiliation: Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Dixon
authors.affiliation: Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield, UK.
authors.forename: Roger
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authors.lastname: Ackroyd
authors.affiliation: Royal Victoria Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust and the University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Baudouin
authors.affiliation: University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bentley
authors.affiliation: Plymouth Hospitals NHS Trust, Derriford Hospital, Plymouth, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Berrisford
authors.affiliation: Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: North Tyneside General Hospital, Northumbria Healthcare NHS Foundation Trust and Newcastle University, North Shields, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bourke
authors.affiliation: Independent patient and public involvement representative, UK.
authors.forename: Roy
authors.initials: R
authors.lastname: Darlison
authors.affiliation: Salford Royal Hospitals NHS Foundation Trust, Salford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Ealing
authors.affiliation: Leeds Teaching Hospitals NHS Trust, St James' University Hospital, Leeds, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Elliott
authors.affiliation: School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fitzgerald
authors.affiliation: University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Galloway
authors.affiliation: Salford Royal Hospitals NHS Foundation Trust, Salford, UK.
authors.forename: Hisham
authors.initials: H
authors.lastname: Hamdalla
authors.affiliation: Plymouth University, Plymouth, UK.
authors.forename: C Oliver
authors.initials: CO
authors.lastname: Hanemann
authors.affiliation: Plymouth Hospitals NHS Trust Peninsula Medical and Dental Schools, Plymouth, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Hughes
authors.affiliation: South Devon Healthcare NHS Foundation Trust, Devon, UK.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Imam
authors.affiliation: Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Dayalan
authors.initials: D
authors.lastname: Karat
authors.affiliation: Motor Neurone Disease Association, Birmingham, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Leek
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Maynard
authors.affiliation: The National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Orrell
authors.affiliation: Leeds Teaching Hospitals NHS Trust, St James' University Hospital, Leeds, UK.
authors.forename: Abeezar
authors.initials: A
authors.lastname: Sarela
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Stradling
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.affiliation: PAREXEL International Corporation, Sheffield, UK.
authors.forename: Lyn
authors.initials: L
authors.lastname: Taylor
authors.affiliation: Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
authors.affiliation: National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Simonds
authors.affiliation: Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Williams
authors.affiliation: The National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Wisia
authors.initials: W
authors.lastname: Wedzicha
authors.affiliation: Walton Centre for Neurology & Neurosurgery NHS Foundation Trust, Liverpool, UK.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Young
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications*; D003362:Cost-Benefit Analysis; D003964:Diaphragm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D063087:Noninvasive Ventilation / Q000379:methods*; D011788:Quality of Life; D012131:Respiratory Insufficiency / Q000209:etiology* / Q000628:therapy*