Polysomnographic Titration of Non-invasive Ventilation in Motor Neurone Disease

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

Detailed Description
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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.

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

Conditions
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Motor Neuron Disease / Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Other: Intervention polysomnography
* Other: Sham polysomnography


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised controlled trial with 12 month cohort follow-up
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>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. | Other: Intervention polysomnography<br>* Please refer to 'Arms: Intervention' section.<br>|
| Placebo Comparator: Control<br>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. | Other: Sham polysomnography<br>* Please refer to 'Arms: Control' section.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adherence with NIV | Defined as using NIV > 4 hours/day during the NIV treatment period. | Change during the acclimatization period ( 3 weeks) and during the NIV treatment period ( 7-8 weeks) (approx. 10 weeks total per participant). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intolerance of NIV | Defined as cessation of NIV during the NIV treatment period and/or < 4 hours. | Change during the acclimatization period (  3 weeks) and during the NIV treatment period ( 7-8 weeks) (approx. 10 weeks total per participant). | 
| Respiratory function | Forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC] | 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. | 
| Maximal inspiratory/expiratory pressure | 'MIPs/MEPs'. | 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. | 
| Sniff nasal pressure | 'SNIP'. | 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. | 
| Arousal index (during polysomnography) | 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. | 
| Asynchrony index (during polysomnography) | Defined as the number of asynchrony events per hour of sleep. | During the baseline (following the  3 week acclimatisation period) and during the follow-up assessment (  week 3 + 7). Cohort: Not Collected. | 
| Oxygen indices (during polysomnography) | 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. | 
| Total sleep time (during polysomnography) | Total amount of time asleep in minutes. | During the baseline (following the  3 week acclimatisation period) and during the follow-up assessment (  week 3 + 7). Cohort: Not Collected. | 
| % rapid eye movement (REM) sleep (during polysomnography) | 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. | 
| % slow wave sleep (SWS) (during polysomnography) | Percentage of 'deep sleep'. | During the baseline (following the  3 week acclimatisation period) and during the follow-up assessment (  week 3 + 7). Cohort: Not Collected. | 
| Asynchrony sub-indices (during polysomnography) | Ineffective efforts, double-trigger etc. | During the baseline (following the  3 week acclimatisation period) and during the follow-up assessment (  week 3 + 7). Cohort: Not Collected. | 
| Dyspnoea Amyotrophic Lateral Sclerosis (DALS-15) | A measure of breathlessness in people with ALS/MND. | During the baseline ( week 0) and during the follow-up assessment (  week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement. | 
| Health-related quality of life - Severe Respiratory Insufficient Questionnaire (SRI) | A measure of health-related quality of life. | During the baseline ( week 0) and during the follow-up assessment (  week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement. | 
| Health-related quality of life - Assessment of Quality of Life (8-Dimension-AQoL) | A measure of health-related quality of life. | During the baseline ( week 0) and during the follow-up assessment (  week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement. | 
| Health-related quality of life - Calgary Sleep Apnoea Quality of Life Index (SAQLI) | A measure of health-related quality of life. | During the baseline ( week 0) and during the follow-up assessment (  week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement. | 
| Functional rating - Amyotrophic Lateral Sclerosis Functional Rating Scale (Revised) (ALSFRS) | 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. | 
| Sleep quality - Pittsburgh Sleep Quality Index (PSQI) | A measure of sleep quality. | RCT: During the baseline and during the follow-up assessment. Cohort: At 3, 6 and 12 months following RCT commencement. | 
| Daytime somnolence - Epworth Sleepiness Scale (ESS) | A measure of daytime sleepiness. | During the baseline ( week 0) and during the follow-up assessment (  week 3 + 7). Cohort: At 3, 6 and 12 months following RCT commencement. | 
| Daytime somnolence - Karolinska Sleepiness Scales (KSS) | 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. | 
| Carer burden - Caregiver Burden Scale (CBS) | 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. | 
| Cost effectiveness of the intervention | Economic evaluation using MBS/PBS data. | Throughout the trial period (approx. 5 years) (retrospective analysis). | 
| Usual clinical care practices | Multidisciplinary clinician surveys at each recruitment site. | At trial commencement and trial end. | 
| Usual care and the barriers and enablers to undertaking the intervention | Multidisciplinary clinician focus groups at each recruitment site. | At trial commencement (start of RCT) and trial end (end of RCT; approx. 4 to 5 years). | 
| Experience of receiving the intervention and the barriers and enablers to the PSG and NIV usage | Participant semi-structured interviews. | At trial end (end of RCT; approx. 4 to 5 years) | 
| Experience of the person they are caring for receiving the intervention and the barriers and enablers to the PSG and NIV usage | Caregiver semi-structured interviews. | At trial end (end of RCT; approx. 4 to 5 years). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-invasive ventilation, Polysomnography, Sleep study, Amyotrophic lateral sclerosis, Chronic respiratory failure