DiPALS controlled trial

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.

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