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Diaphragm Pacing in motor neurone disease/ Amyotrophic Lateral Sclerosis
DOI 10.1186/ISRCTN53817913
ClinicalTrials.gov identifier
EudraCT number
Public title Diaphragm Pacing in motor neurone disease/ Amyotrophic Lateral Sclerosis
Scientific title A randomised controlled trial evaluating NeuRx/4 Diaphragm Pacing (DP) in patients with muscle weakness due to motor neurone disease/ Amyotrophic Lateral Sclerosis
Acronym DiPALS
Serial number at source HTA 09/55/33, DiPALS , Protocol v1
Study hypothesis The proposed study will assess if treatment with DP prolongs life and maintains quality of life when given in addition to current standard care with Non Invasive Ventilation (NIV).
Lay summary Lay summary under review 3
Ethics approval NRES Committee East of England - Cambridge Central, 11/EE/0226 - approval pending as of 13/05/2011
Study design Multicentre randomised controlled trial
Countries of recruitment United Kingdom
Disease/condition/study domain Motor neurone disease
Participants - inclusion criteria 1. Age 18 or older
2. Familial or sporadic MND/ALS diagnosed as laboratory-supported probable, probable, or definite according to the World Federation of Neurology El Escorial criteria
3. Stabilised on Riluzole therapy
4. Respiratory insufficiency as determined by one or more of:
4.1. Forced Vital Capacity (FVC) less than 75% predicted/Sniff Nasal Inspiratory Pressure (SNIP) less than 40 cmH2O
4.2. Supine vital capacity (VC) less than 75% of sitting or standing VC
4.3. Partial pressure of carbon dioxide in the blood (PaCO2) > 6kPa (daytime)
4.4. Significant overnight oxygen (O2) desaturation (>5% of night with Sp02 <90% during overnight oximetery)
5. Bilateral phrenic nerve function clinically acceptable as demonstrated by bilateral diaphragm movement with diaphragm ultrasound or X-ray fluoroscopy
6. Forced Vital Capacity (FVC) > 50% predicted or sniff nasal inspiratory pressure (SNIP) > 30 cmH2O in patients unable to perform FVC (bulbar patients)
Participants - exclusion criteria 1. Prior NIV prescription
2. Pre-existing implanted electrical device such as pacemaker or cardiac defibrillator
3. Underlying cardiac, pulmonary diseases or other disorders that would affect pulmonary tests independently of MND/ALS or would increase the risk of general anaesthesia
4. Current pregnancy or breastfeeding
5. Significant decision making incapacity preventing informed consent by the subject due to a major mental disorder such as major depression or schizophrenia or dementia
6. Marked obesity affecting surgical access to diaphragm or significant scoliosis/ chest wall deformity
7. The involvement in any respiratory trial that can influence the safety or outcome measures of this study within three months of the planned implantation of the device or during the year of follow up
8. Pre-existing diaphragm abnormality such as a hiatus hernia or paraoesophageal hernia of abdominal contents ascending into the thoracic cavity
Anticipated start date 04/07/2011
Anticipated end date 02/02/2015
Status of trial Ongoing
Patient information material Not available in web format, please contact C.Maguire@sheffield.ac.uk for a patient information sheet
Target number of participants 108
Interventions 54 participants to be recruited to each of the 2 arms.

Arm 1 = Standard care alone (NIV), Arm 2 = Standard care (NIV) plus DP

NIV arm patients will attend clinic for initiation of NIV with a possible overnight stay. Baseline NIV settings, NIV prescription given, type of interface, humidification and type of machine will be recorded. The patient will take home a Patient Diary and be asked to record the amount of NIV used.

In the DP arm participants will be admitted to hospital for insertion of the DP device. A pre-operative safety check will occur either during the admission or in the week leading up to surgery. During the implantation procedure, incisions of 0.5 to 1 inch long will be made in the abdomen. More than one incision will be made so instruments can be passed through the abdominal wall as per standard laparoscopic procedure. The surgeon will identify the best location to place the electrodes within the diaphragm. A probe will be used to temporarily place an electrode on the surface of the diaphragm and to stimulate the diaphragm muscle at several locations to find the best location. Two electrodes will then be placed in each side of the diaphragm muscle. The lead wires from these electrodes will travel under the skin to the abdominal wall. The wires will be trimmed so that the ends sticking out of the skin are only 2 - 6 inches in length. An X-ray will be taken following the surgery to check the position of the wires and to make sure no air has travelled above the diaphragm and into the chest. If the damage to the nerve supply to the diaphragm is too great it is possible that the diaphragm will not be able to be stimulated with the electrodes and diaphragm pacing system. The scan/x-ray of the diaphragm performed during screening are an attempt to assess whether the diaphragm is stimulatable. However it is only possible to know for sure during the operation. If during the operation it is clear that the diaphragm is not stimulatable then the operation will be stopped and the device will not be inserted.

Evaluation of the electrodes and system will be performed prior to discharge from hospital. A system check of the wires will be completed. Electrode evaluation will be performed by adjusting individual stimulus parameters (pulse amplitude, width, and frequency) using the clinical station so that a comfortable level of stimulation can be identified for the diaphragm conditioning sessions. The patient will be given a daily target for the number and length of diaphragm pacing sessions. This will be recorded by the study team member in the patient diary.

Training of the participant and their caregiver will take place prior to discharge. This will include instruction in the care and use of the stimulator and data collection in the patient diary. Verbal and written instruction will be provided in a patient/caregiver instruction manual. Following surgery a one week follow up appointment will be booked for participants in the treatment arm before they leave the hospital.

Participants (in both arms) will return at 2, 3, 6, 9 and 12 months post randomisation for data collection which includes quality of life outcome measures. An option of home visits or collecting data over the phone will also be available should the participant wish. Survival data will be collected until the completion of the study. A final survival check will be performed on all participants following the last follow up visit for the last participant recruited.

A sub sample of 12 participants from the DP group will be selected for the qualitative interviews. These will take place 1 and 6 months post implantation and participants will be given the choice of coming into clinic or a home visit for the interview. All interviews will be transcribed and analysed by the qualitative researcher. All other data will be stored in a central database and will be accessed by trial research staff through username and password. Health economics model will be drawn up and used to analyse quality of life and cost data by an experienced health economist.
Primary outcome measure(s) The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND/ amyotrophic lateral sclerosis (ALS) with respiratory muscle weakness.
Secondary outcome measure(s) To evaluate the effect of DP on:

Efficacy endpoints
1. Quality adjusted life years (QALYs) as calculated by combining EQ-5D and mortality data
2. Quality of life: sleep apnoea quality of life index (SAQLI), and SF-36
3. Quality of life of the main carer of the patient (Caregiver Burden Inventory)

For each efficacy endpoint, the treatment effect will be assessed by analysing the difference between groups over the 12-month follow-up period, and the difference at 12 months.

Safety endpoints
Safety (adverse events) and tolerability (patient withdrawal from treatment)
Sources of funding 1. National Institute of Health Research (NIHR) - HTA (UK) (09/55/33)
2. Motor Neurone Disease Association (MNDA) (UK)
Trial website
Publications 1. 2012 protocol in http://www.ncbi.nlm.nih.gov/pubmed/22897892
Contact name Dr  Christopher  McDermott
  Address Sheffield Institute for Translational Neuroscience
University of Sheffield
385a Glossop Rd
  City/town Sheffield
  Zip/Postcode S10 2HQ
  Country United Kingdom
Sponsor Sheffield Teaching Hospitals NHS Foundation Trust (UK)
  Address STH Research Department
1st Floor
11 Broomfield Rd
  City/town Sheffield
  Zip/Postcode S10 2SE
  Country United Kingdom
Date applied 11/05/2011
Last edited 06/02/2013
Date ISRCTN assigned 31/05/2011
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