Polysomnographic Titration of Non-invasive Ventilation in Motor Neurone Disease (3TLA)

A Multi-centre Randomised Controlled Trial of Polysomnographic Titration of Non-invasive Ventilation in Motor Neurone Disease (PSG4NIVinMND; 3, Three Letter Acronyms [3TLA])

Austin Hospital, Melbourne Australia, Institute for Breathing and Sleep, Australia, Royal Prince Alfred Hospital, Sydney, Australia, Macquarie University, Australia, Macquarie Health, Western Sydney Local Health District, Flinders Medical Centre, Sir Charles Gairdner Hospital, The Prince Charles Hospital, Monash University, Motor Neurone Disease Australia, FightMND, Australian Motor Neurone Disease Registry, Calvary Bethlehem, Perron Institute for Neurological and Translational Science

A two-arm, individual participant randomised controlled, assessor-blinded trial in 7 MND care centres across Australia will be undertaken.

Non-invasive ventilation (NIV) is a treatment that uses positive pressure delivered via a face mask or mouthpiece to assist a person to breathe. It can be used as a long-term treatment for people whose breathing is failing - usually due to chronic conditions that produce weakness of the respiratory muscles such as motor neurone disease / amyotrophic lateral sclerosis [MND/ALS]chronic obstructive pulmonary disease). Most people with MND/ALS use NIV at night initially. Even though NIV may improve survival and function, many are unable to use it for more than 4 hours per day (which is considered a threshold amount of use in order to gain a benefit) and many others are unable to tolerate it at all. Our team has recently provided evidence that specific and individualised titration of NIV leads to better outcomes in people with MND. This previous trial determined that the use of a sleep study (also called 'polysomnography') can improve the way people are initially set up with NIV. This study will replicate and extend the single site study in a large, multi-centre randomised controlled trial (RCT) across multiple sites This multi-centre RCT will also include a 12-month follow-up period to evaluate longer-term outcomes.

Non-invasive ventilation, Polysomnography, Sleep study, Amyotrophic lateral sclerosis, Chronic respiratory failure

The attending sleep scientist will refer to a database that reveals (statistician-generated) participant's treatment allocation. The sleep scientist will not reveal the treatment allocation to the Clinical team, Research team or the participant. Centralised allocation concealment will be ensured through the Adept/REDCap trial database.

This trial of PSG-assisted commencement of non-invasive ventilation (NIV) in motor neurone disease (MND) follows the methodology of our previous single-site study (Hannan et al 2019 ERJ), with the addition of an open label cohort that extends until (the earlier of) 12 months or death. After empirical NIV set-up and an acclimatisation period (3 weeks), participants will undergo single night in-laboratory polysomnography (PSG). The PSG will be performed and supervised by a sleep scientist. In the intervention group, the "intervention" PSG results will be used to adjust/titrate NIV settings to optimize ventilation and improve synchrony between the patient and the NIV device. Participants will be asked to continue to use NIV as prescribed for the subsequent 7 week intervention period.

The participants allocated to the control group will also be asked to attend a single night in-laboratory PSG. The NIV settings will not be adjusted throughout the PSG ("sham" PSG). Participants in the control group will retain their original settings after the sham PSG, and will be asked to continue to use NIV in this manner for the subsequent 7 week intervention period.

Change during the acclimatization period (~3 weeks) and during the NIV treatment period (~7-8 weeks) (approx. 10 weeks total per participant).

Change during the acclimatization period (~ 3 weeks) and during the NIV treatment period (~7-8 weeks) (approx. 10 weeks total per participant).

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement as able.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement as able.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement as able.

Defined as the number of electroencephalogram (EEG) arousals observed per hour of total sleep time (TST).

During the baseline (following the ~3 week acclimatisation period) and during the follow-up assessment (~ week 3 + 7). Cohort: Not Collected.

During the baseline (following the ~3 week acclimatisation period) and during the follow-up assessment (~ week 3 + 7). Cohort: Not Collected.

Multiple measures to summarise oxygenation as one single outcome including oxygen desaturation index (defined as the total number of oxygen desaturation episodes [= 4%] per hour of total), sleep time, nadir SpO2, and time with SpO2 < 90%, area under the curve and others.

During the baseline (following the ~3 week acclimatisation period) and during the follow-up assessment (~ week 3 + 7). Cohort: Not Collected.

During the baseline (following the ~3 week acclimatisation period) and during the follow-up assessment (~ week 3 + 7). Cohort: Not Collected.

Percentage of sleep characterised by eye movement, relaxation of the body, faster. respiration, and increased brain activity

During the baseline (following the ~3 week acclimatisation period) and during the follow-up assessment (~ week 3 + 7). Cohort: Not Collected.

During the baseline (following the ~3 week acclimatisation period) and during the follow-up assessment (~ week 3 + 7). Cohort: Not Collected.

During the baseline (following the ~3 week acclimatisation period) and during the follow-up assessment (~ week 3 + 7). Cohort: Not Collected.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

A clinical measure of functional rating in people with ALS/MND. Minimum score: 0, maximum score: 40. The higher the score the more function is retained.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

RCT: During the baseline and during the follow-up assessment. Cohort: At 3, 6 and 12 months following RCT commencement.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

The KSS is rating of the current daytime sleepiness state using a 9-point scale (1 = very alert to 9 = very sleepy, fighting sleep).

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

A measure of caregiver burden. Rated ona scale from 0 (never) to 4 (nearly always), with higher scores indicating greater carer burden.

During the baseline (~week 0) and during the follow-up assessment (~ week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement.

Experience of the person they are caring for receiving the intervention and the barriers and enablers to the PSG and NIV usage

RCT: During the baseline (following the acclimatisation period) and during the follow-up assessment. Cohort: Not Collected.

Inclusion Criteria: Age >18 years Clinical indication to commence long term NIV Confirmed clinical diagnosis of underlying condition Exclusion Criteria: Medically unstable Hypoventilation attributable to medications with sedative/respiratory depressant side- effects Use of NIV for more than 1 month in the previous 3 months Inability to provide informed consent Previous intolerance of NIV

Subject to optional consent, where participants give permission for data to be used for the purpose of: The ethically approved research project only. This ethically approved research project and any closely related future research projects. This ethically approved research project and any future research projects that may or may not be related to this project.