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

• ClinicalTrials.gov Identifier: NCT05136222
• Recruitment Status: Recruiting
• First Posted: November 29, 2021
• Last Update Posted: June 23, 2022
• Sponsor: University of Melbourne
• Collaborators: 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
• Information provided by (Responsible Party): University of Melbourne

Tracking Information

• First Submitted Date: October 21, 2021
• First Posted Date: November 29, 2021
• Last Update Posted Date: June 23, 2022
• Actual Study Start Date: December 15, 2021
• Estimated Primary Completion Date: February 28, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 25, 2021)

Adherence with NIV [ Time Frame: Change during the acclimatization period (~3 weeks) and during the NIV treatment period (~7-8 weeks) (approx. 10 weeks total per participant). ]

Defined as using NIV > 4 hours/day during the NIV treatment period.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 19, 2022)

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

Original Secondary Outcome Measures (submitted: November 25, 2021)

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

Current Other Pre-specified Outcome Measures (submitted: June 19, 2022)

Arterial Blood Gas (ABG) (during polysomnography) [ Time Frame: RCT: During the baseline (following the acclimatisation period) and during the follow-up assessment. Cohort: Not Collected. ]

Arterial Blood Gas

Original Other Pre-specified Outcome Measures (submitted: November 25, 2021)

Arterial blood gas (during polysomnography) [ Time Frame: RCT: During the baseline (following the acclimatisation period) and during the follow-up assessment. Cohort: Not Collected. ]

ABG

Descriptive Information

• Brief Title: Polysomnographic Titration of Non-invasive Ventilation in Motor Neurone Disease
• Official Title: A Multi-centre Randomised Controlled Trial of Polysomnographic Titration of Non-invasive Ventilation in Motor Neurone Disease (PSG4NIVinMND; 3, Three Letter Acronyms [3TLA])
• Brief Summary: A two-arm, individual participant randomised controlled, assessor-blinded trial in 7 MND care centres across Australia will be undertaken.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomised controlled trial with 12 month cohort follow-up

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

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.

Primary Purpose: Treatment

• Condition: Motor Neuron Disease / Amyotrophic Lateral Sclerosis

Intervention

• Other: Intervention polysomnography
  Please refer to 'Arms: Intervention' section.
• Other: Sham polysomnography
  Please refer to 'Arms: Control' section.

Study Arms

• Experimental: Intervention

  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.

  Intervention: Other: Intervention polysomnography
• Placebo Comparator: Control
  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.
  Intervention: Other: Sham polysomnography

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 25, 2021): 244
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 28, 2028
• Estimated Primary Completion Date: February 28, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: David Berlowitz, PhD; +613 9496 3871; david.berlowitz@austin.org.au

• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT05136222
• Other Study ID Numbers: CT20020
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Dataset in de-identified form will be shared on request to corresponding author.
• Time Frame: 5 years from study completion.

Access Criteria

Subject to optional consent, where participants give permission for data to be used for the purpose of:

1. The ethically approved research project only.
2. This ethically approved research project and any closely related future research projects.
3. This ethically approved research project and any future research projects that may or may not be related to this project.

• Current Responsible Party: University of Melbourne
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Melbourne
• Original Study Sponsor: Same as current

Collaborators

• 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

Investigators

• Study Chair: Abbey Sawyer, PhD; University of Melbourne

• PRS Account: University of Melbourne
• Verification Date: June 2022