DiPALS controlled trial
A randomised controlled trial evaluating NeuRx/4 Diaphragm Pacing in patients with respiratory muscle weakness due to Motor Neurone Disease.
The context
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) is a new technique which may offer additional or alternative benefits to patients with ALS, in respiratory failure.
We aimed to establish the safety and efficacy of diaphragm pacing with the NeuRx/4 DP system in patients with respiratory muscle weakness due to ALS.
What we did and what we found
We undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK.
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) who had been stabilised on riluzole for 30 days, were 18 years or older and were in respiratory failure.
The primary outcome was overall survival. A number of secondary clinical outcomes were measured to assess participant quality of life.
74 participants were randomised into the trial (and analysed): 37 participants to NIV plus pacing and 37 to standard care before the DMEC advised initially suspension of recruitment (December 2013), and subsequently discontinuation of pacing in all patients (June 2014), on safety grounds.
Follow up assessments continued until the planned end of the study in December 2014.
The median survival (inter-quartile range) was 22·5 (11·8; upper quartile not reached) months in the NIV arm; and was 11·0 (6·7 to 17·0) months in the NIV plus pacing arm, with an adjusted hazard ratio of 2·27 (95% CI 1·22 to 4·25; p=0·01).
Impact
This is the first randomised controlled trial of non-invasive ventilation alone versus non-invasive ventilation plus pacing.
Addition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS.
Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.
Both the funder and sponsor agreed that given the substantial cost of the device and the apparent reduction in life years in the pacing arm the planned health economic analyses were unnecessary.
To date, we have fed back results to research participants on the trial and the MND community via the MND Association.
In addition to this, the Chief Investigator has attended several conferences to disseminate the findings of the research to MND Neurologists and Respiratory Clinicians both in the UK and worldwide.
Future plans
DPS should not be used as routine treatment in ALS patients experiencing respiratory insufficiency as it is associated with poor survival.
Results of the trial have been published in Lancet Neurology, Health Technology Assessment and actively disseminated at conferences.
NICE guidance IPG593 (Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by motor neurone disease) have incorporated our findings.
Work is ongoing in ScHARR to review further impact of the Trial based on international use of DPS for MND.
Project staff
| Name | Site | Telephone Number | |
|---|---|---|---|
| Dr Christopher McDermott Chief Investigator |
Sheffield Institute for Translational Neuroscience (SITraN) | +44 (0)114 2222261 | c.j.mcdermott@sheffield.ac.uk |
| Dr Cindy Cooper Director, CTRU |
ScHARR | +44 (0)114 2220743 | c.l.cooper@sheffield.ac.uk |
| Chin Maguire Study Manager |
ScHARR | +44 (0)114 2220717 | c.maguire@sheffield.ac.uk |
| Amanda Loban Data Manager |
ScHARR | +44 (0)114 2220685 | a.loban@sheffield.ac.uk |
| Mike Bradburn Statistician |
ScHARR | +44 (0)114 2220706 | m.bradburn@sheffield.ac.uk |
| Simon Dixon Health Economist |
ScHARR | +44 (0)114 2220724 | s.dixon@sheffield.ac.uk |
| Heather Dakin Trial Support Officer |
ScHARR | +44 (0)114 2226385 |
h.dakin@sheffield.ac.uk |
| Wendy Baird Qualitative Methodology |
ScHARR | +44 (0)114 2220819 |
Sites
| Site Study Members | City | Hospital | Role |
|---|---|---|---|
| Christopher McDermott | Sheffield | Royal Hallamshire Hospital | Chief Investigator / Consultant Neurologist |
| Pamela Shaw | Sheffield | Royal Hallamshire Hospital | Principal Investigator |
| Stephen Bianchi | Sheffield | Royal Hallamshire Hospital | Respiratory Consultant |
| Roger Ackroyd | Sheffield | Northern General Hospital | Surgeon |
| Andrew Bentley | Manchester | University Hospital of South Manchester | Principal Investigator/ Respiratory Consultant |
| John Ealing | Manchester | Salford Royal Hospital Foundation Trust | Consultant Neurologist |
| Simon Galloway | Manchester | University Hospital of South Manchester | Surgeon |
| Katie McCalman | Manchester | University Hospital of South Manchester | Research Nurse |
| Kevin Talbot | Oxford | John Radcliffe Hospital | Principal Investigator / Consultant Neurologist |
| John Stradling | Oxford | John Radcliffe Hospital | Respiratory Consultant |
| Nick Maynard | Oxford | John Radcliffe Hospital | Surgeon |
| Rachel Marsden | Oxford | John Radcliffe Hospital | Research Nurse |
| Tim Williams | Newcastle | Royal Victoria Infirmary | Principal Investigator / Consultant Neurologist |
| Simon Baudouin | Newcastle | Royal Victoria Infirmary | Respiratory Consultant |
| Dayalan Karat | Newcastle | Royal Victoria Infirmary | Surgeon |
| Steve Dodds | Newcastle | Royal Victoria Infirmary | Research Nurse |
| Philip Hughes | Plymouth | Derriford Hospital | Principal Investigator/ Respiratory Consultant |
| Oliver Hanemann | Plymouth | Derriford Hospital | Neurology Consultant |
| Richard Berresford | Plymouth | Derriford Hospital | Surgeon |
| Mary Jo Trimmer | Plymouth | Derriford Hospital | Research Nurse |
| Mark Elliott | Leeds | St James University Hospital | Principal Investigator |
| Agam Jung | Leeds | St James University Hospital | Consultant Neurologist |
| Abezar Sarela | Leeds | St James University Hospital | Surgeon |
| Clair Favager | Leeds | St James University Hospital | Research Nurse |
| Craig Armstrong | Leeds | St James University Hospital | Research Nurse |
| Richard Orrell | London | Royal Free Hospital | Principal Investigator |
| Christine Mickelson | London | Royal Free Hospital | Consultant Respiratory Therapist |
| Zak Rahman | London | Royal Free Hospital | Surgeon |
| Mark Baker | London | Royal Free Hospital | Research Nurse |