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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05606991




Registration number
NCT05606991
Ethics application status
Date submitted
12/07/2022
Date registered
7/11/2022
Date last updated
18/04/2024

Titles & IDs
Public title
The Effect of OSA on Brain Waste Clearance
Scientific title
The Impact of 2 Weeks CPAP Withdrawal on Brain Waste Clearance in Adults With Severe Obstructive Sleep Apnoea - A Randomised Controlled Crossover Trial
Secondary ID [1] 0 0
BrainOSA-0522
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnea 0 0
Dementia 0 0
Cognitive Impairment 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Sleep apnoea
Neurological 0 0 0 0
Dementias
Neurological 0 0 0 0
Alzheimer's disease
Mental Health 0 0 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - CPAP Withdrawal

No intervention: CPAP on - Participants will continue with their usual continuous positive airway pressure (CPAP) therapy as advised by their treating physician.

Experimental: CPAP off - Participants will be weaned off their usual continuous positive airway pressure (CPAP) therapy and enter a 2-week period of non-treatment.


Other interventions: CPAP Withdrawal
Complete withdrawal of continuous positive airway pressure (CPAP) therapy for a 2-week period.
Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Changes in sleep-wake amplitudes (peak-trough) of blood levels of Aß
Timepoint [1] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [1] 0 0
Changes in NREM slow wave parietal cortex activity
Timepoint [1] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [2] 0 0
Changes in brain tissue oxygenation during sleep
Timepoint [2] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [3] 0 0
Changes in brain blood volume during sleep
Timepoint [3] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [4] 0 0
Changes in arterial stiffness indices during sleep
Timepoint [4] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [5] 0 0
Changes in central aortic blood pressure during sleep
Timepoint [5] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [6] 0 0
Changes in pulse wave velocity (PWV)
Timepoint [6] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [7] 0 0
Changes in sympathetic and parasympathetic activity during wake and sleep periods
Timepoint [7] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [8] 0 0
Changes in sleep-wake amplitudes (peak-trough) of blood levels of p-tau-180
Timepoint [8] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [9] 0 0
Changes in sleep-wake amplitudes (peak-trough) of blood levels of p-tau-217
Timepoint [9] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [10] 0 0
Changes in sleep-wake amplitudes (peak-trough) of blood levels of glial fibrillary acidic protein (GFAP)
Timepoint [10] 0 0
Pre- and 2 weeks post-intervention
Secondary outcome [11] 0 0
Changes in sleep-wake amplitudes (peak-trough) of blood levels of neurofilament light chain (NfL)
Timepoint [11] 0 0
Pre- and 2 weeks post-intervention

Eligibility
Key inclusion criteria
* Community dwelling adults aged 35-65 years.
* Polysomnography-confirmed severe OSA with apnea hypopnea index (AHI) = 30/hour, with Non-Rapid Eye Movement (NREM) AHI = 15/hour.
* Established CPAP use for treatment of OSA with compliance of > 3 months, with = 5 hours use per night for > 5 nights per week.
* Willing to withdraw from CPAP use for 14 nights.
* Able to give informed verbal and written consent.
* Fluent in spoken, and comprehension of English.
Minimum age
35 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
* Commercial drivers (e.g.: drivers of heavy vehicles, public passenger vehicles, or vehicles requiring dangerous goods driver license).
* History of severe cardiovascular disease (e.g.: stroke, myocardial infarction, atrial fibrillation).
* Presence of cognitive impairment and/or established diagnosis of dementia.
* Regular use of medications which affect sleep (e.g.: benzodiazepines, opioids, stimulants, sedating antihistamines).
* Regular 24-hour shift workers, presence of jetlag, or history of trans-meridian travel (crossing 2 or more time zones) in the past 2 weeks.
* Advice against withdrawal of CPAP treatment, as determined by the participant's treating physician or study physician.
* Vulnerable to driving impairment without CPAP therapy/upon withdrawal of CPAP therapy, as assessed by: (a) positive response(s) to screening questions in the modified ASTN-Motor Vehicle Accident Questionnaire, reporting driving accidents and/or impairments prior to established CPAP therapy; AND/OR (b) the participant's treating physician.
* Prior history of severe COVID-19 infection involving significant neurological symptoms (e.g.: reduced level of consciousness, delirium, encephalopathy) - warranting hospitalization.
* Current COVID-19 infection and/or experience of ongoing symptoms/sequelae following a recent COVID-19 infection.
* Not up to date with the COVID-19 vaccination schedule - as per the current Australian Technical Advisory Group on Immunization (ATAGI) definition for individuals aged 16 years and over - at the time of writing this Protocol, defined as having:

1. Received 2 primary doses of any Therapeutic Goods Administration (TGA)-approved or TGA-recognized COVID-19 vaccine at least 14 days apart (except for the Janssen COVID-19 vaccine, where only 1 primary dose is required); PLUS
2. A booster dose of a TGA-approved COVID-19 vaccine (Pfizer, Moderna or AstraZeneca) at a recommended interval of 3-6 months after the receipt of 2nd primary dose; OR
3. For severely immunocompromised individuals: received 3 primary doses of any TGA-approved or TGA-recognized COVID-19 vaccine, with dose 3 administered within 6 months of receiving dose 2.
* Other medical conditions deemed by study physicians to warrant exclusion.

Study design
Purpose of the study
Other
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
18/07/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2024
Actual
Sample size
Target
38
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Woolcock Institute of Medical Research - Glebe
Recruitment postcode(s) [1] 0 0
2095 - Glebe

Funding & Sponsors
Primary sponsor type
Other
Name
Woolcock Institute of Medical Research
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
National Health and Medical Research Council, Australia
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Recent ground-breaking research has shown that clearance of toxic neuro-metabolites from the brain including the proteins ß-Amyloid (Aß) and tau that form dementia causing plaques and tangles is markedly impaired when sleep is disturbed. This suggests that dementia risk may be increased in people with sleep disorders such as obstructive sleep apnea (OSA). Longitudinal studies have linked OSA with a 70-85% increased risk for mild cognitive impairment and dementia.

Despite this strong link, little is known about the OSA-specific mechanistic underpinnings. It is not fully understood as to how sleep disturbance in OSA inhibit brain glymphatic clearance. However, it is known that OSA inhibits slow wave sleep, profoundly activates sympathetic activity, and elevates blood pressure - particularly during sleep. These disturbances have, in turn, been shown to independently inhibit glymphatic function. Previous studies have attempted to sample human cerebrospinal fluid (CSF) involved in glymphatic clearance for dementia biomarkers during sleep. However, these studies were severely limited by the need for invasive CSF sampling. To address this problem, a set of newly available, highly sensitive blood based SIMOA assays will be used to study glymphatic function in people treated for severe OSA who undergo CPAP withdrawal. Furthermore, novel methods will be utilized to capture changes in slow wave sleep, blood pressure and brain blood flow together with sleep-wake changes in blood levels of excreted neuro-metabolites to define the pathophysiological mechanisms that inhibit brain cleaning in OSA.
Trial website
https://clinicaltrials.gov/study/NCT05606991
Trial related presentations / publications
Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb 22;363(6429):880-884. doi: 10.1126/science.aav2546. Epub 2019 Jan 24.
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. doi: 10.1126/science.1180962. Epub 2009 Sep 24.
Bubu OM, Andrade AG, Umasabor-Bubu OQ, Hogan MM, Turner AD, de Leon MJ, Ogedegbe G, Ayappa I, Jean-Louis G G, Jackson ML, Varga AW, Osorio RS. Obstructive sleep apnea, cognition and Alzheimer's disease: A systematic review integrating three decades of multidisciplinary research. Sleep Med Rev. 2020 Apr;50:101250. doi: 10.1016/j.smrv.2019.101250. Epub 2019 Dec 12.
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012 Aug 15;4(147):147ra111. doi: 10.1126/scitranslmed.3003748.
Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224.
Bucks RS, Olaithe M, Rosenzweig I, Morrell MJ. Reviewing the relationship between OSA and cognition: Where do we go from here? Respirology. 2017 Oct;22(7):1253-1261. doi: 10.1111/resp.13140. Epub 2017 Aug 4.
Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis. JAMA Neurol. 2017 Oct 1;74(10):1237-1245. doi: 10.1001/jamaneurol.2017.2180. Erratum In: JAMA Neurol. 2018 Jan 1;75(1):133. doi: 10.1001/jamaneurol.2017.3677.
Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, Ancoli-Israel S, Stone KL. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA. 2011 Aug 10;306(6):613-9. doi: 10.1001/jama.2011.1115.
Ju YS, Zangrilli MA, Finn MB, Fagan AM, Holtzman DM. Obstructive sleep apnea treatment, slow wave activity, and amyloid-beta. Ann Neurol. 2019 Feb;85(2):291-295. doi: 10.1002/ana.25408. Epub 2019 Jan 17.
Public notes

Contacts
Principal investigator
Name 0 0
Keith Wong, MBBS FRACP
Address 0 0
Woolcock Institute of Medical Research
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05606991