Christopher J McDermott1, Mike J Bradburn2, Chin Maguire2, Cindy L Cooper2, Wendy O Baird3, Susan K Baxter3, Judith Cohen2, Hannah Cantrill2, Simon Dixon4, Roger Ackroyd5, Simon Baudouin6, Andrew Bentley7, Richard Berrisford8, Stephen Bianchi9, Stephen C Bourke10, Roy Darlison11, John Ealing12, Mark Elliott13, Patrick Fitzgerald3, Simon Galloway7, Hisham Hamdalla12, C Oliver Hanemann14, Philip Hughes15, Ibrahim Imam16, Dayalan Karat17, Roger Leek18, Nick Maynard19, Richard W Orrell20, Abeezar Sarela13, John Stradling19, Kevin Talbot19, Lyn Taylor21, Martin Turner19, Anita K Simonds22, Tim Williams17, Wisia Wedzicha20, Carolyn Young23, Pamela J Shaw1. 1. Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK. 2. Sheffield Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK. 3. School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK. 4. Health Economics and Decision Science, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK. 5. Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield, UK. 6. Royal Victoria Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust and the University of Newcastle, Newcastle upon Tyne, UK. 7. University Hospital of South Manchester NHS Foundation Trust, Manchester, UK. 8. Plymouth Hospitals NHS Trust, Derriford Hospital, Plymouth, UK. 9. Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK. 10. North Tyneside General Hospital, Northumbria Healthcare NHS Foundation Trust and Newcastle University, North Shields, UK. 11. Independent patient and public involvement representative, UK. 12. Salford Royal Hospitals NHS Foundation Trust, Salford, UK. 13. Leeds Teaching Hospitals NHS Trust, St James' University Hospital, Leeds, UK. 14. Plymouth University, Plymouth, UK. 15. Plymouth Hospitals NHS Trust Peninsula Medical and Dental Schools, Plymouth, UK. 16. South Devon Healthcare NHS Foundation Trust, Devon, UK. 17. Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. 18. Motor Neurone Disease Association, Birmingham, UK. 19. Oxford University Hospitals NHS Trust, Oxford, UK. 20. The National Heart and Lung Institute, Imperial College London, London, UK. 21. PAREXEL International Corporation, Sheffield, UK. 22. National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, UK. 23. Walton Centre for Neurology & Neurosurgery NHS Foundation Trust, Liverpool, UK.
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 riluzolefor 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) plusDP 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 toNIV 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. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53817913. FUNDING: 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.
RCT Entities:
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. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53817913. FUNDING: 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: Stephen J Walters; Richard M Jacques; Inês Bonacho Dos Anjos Henriques-Cadby; Jane Candlish; Nikki Totton; Mica Teo Shu Xian Journal: Trials Date: 2019-09-13 Impact factor: 2.279