Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001995268
Ethics application status
Approved
Date submitted
6/12/2018
Date registered
12/12/2018
Date last updated
13/04/2023
Date data sharing statement initially provided
12/12/2018
Date results information initially provided
9/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Targeted Therapy for Sleep Apnoea: A Novel Personalised Approach
Scientific title
Targeted Therapy to Treat Sleep Apnoea: A Novel Personalised Approach Using Mandibular Advancement Split Therapy Plus Combination Therapy in Incomplete Responders
Secondary ID [1] 296788 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive sleep apnoea 310685 0
Condition category
Condition code
Respiratory 309385 309385 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are multiple arms in this project.
In arm 1: up to 130 participants who are recommended mandibular advancement splint (MAS) therapy by their treating physician will be studied. Following a diagnostic sleep study, participants will complete a detailed physiological sleep study to define the key phenotypic causes of sleep apnoea according to critical closing pressure (Pcrit), Arousal threshold, Loop gain, Muscle responsiveness (PALM) scale phenotypic characterisation using simplified novel methodology and gold standard methodology described previously (Eckert et al, Am J Resp Crit Care Med, 2013, Terrill et al, Eur Resp J, 2015, Eckert Sleep Med Rev, 2018). Participants will be fitted with an Oventus custom-made MAS by the study dentist and treatment efficacy (apnoea/hypopnoea index [AHI]) will be assessed via overnight polysomnography. Each phenotypic trait will be compared between responders and non-responders. We will also use our recently developed novel predictive algorithm (Dutta et al, Annals of ATS, 2021) to predict treatment outcomes.

Arm 2: aims to investigate the therapeutic efficacy (reduction in AHI) of mechanism-based targeted therapy (including combination therapy) to treat obstructive sleep apnoea (OSA) in incomplete responders (residual AHI> 10 events/h sleep) to MAS therapy alone.
Specifically, incomplete responders (quantified during an in-laboratory treatment efficacy study) will return for one or more repeat sleep studies with targeted combination therapy based on Pcrit, Arousal threshold, Loop gain, Muscle responsiveness (PALM) scale phenotypic characterisation completed in arm 1 until the AHI is reduced to <10events/h sleep.
Interventions include:
1) Expiratory positive airway pressure (EPAP) valves (8h sleep study) + positional therapy
2) O2 (4L/min via the nose, mouth or oronasally, 8h sleep study)
3) Zolpidem (10mg if <65y or 5mg if >65y, single dose, just prior to 8h sleep study, oral tablet)
4) Atomoxetine 80mg combined with oxybutynin 5mg (single doses), just prior to 8h sleep study, oral tablets
5) Continuous positive airway pressure (CPAP, titrated to eliminate respiratory events [2-20cmH2O], 8h sleep study)
All participants in this arm will receive an EPAP valve + positional therapy (unless baseline Pcrit is <-3cmH2O in which case an EPAP valve alone will be delivered). In addition, interventions 2 to 4 will be added for those with unstable respiratory control (intervention 2), low arousal threshold (intervention 3), poor muscle responsiveness (intervention 4) one at a time based on PALM scale categorisation (if two or more traits are severely impaired the order of the interventions will be randomised). CPAP+MAS will be combined as a final option only if the other targeted interventions do not reduce the AHI to <10 events/h.
Interventions will be delivered by the study investigators in-laboratory to ensure adherence for these acute, single night studies. For those who continue to use an EPAP valve after the study, comfort and tolerance will be assessed via telephone call and home sleep study 1 month after completion of the lab visits.

Arm 3: in up to 40 participants who complete arm 1, a 1 to 1.5h MRI study will be performed by an investigator and a radiographer with and without MAS to provide mechanistic insight into how the MAS device works to change airway size and motion and assess the impact of route of breathing.
Intervention code [1] 313107 0
Treatment: Devices
Intervention code [2] 313108 0
Treatment: Drugs
Comparator / control treatment
Participants will act as their own controls (baseline and mandibular advancement splint only sleep studies as comparators to the targeted therapy study).
Control group
Active

Outcomes
Primary outcome [1] 308361 0
OSA severity as measured by the AHI ( number of apnoeas and hypopnoeas per hour of sleep) quantified from overnight polysomnography (Arms 1 and 2).
Timepoint [1] 308361 0
Overnight sleep study
Secondary outcome [1] 354728 0
Sleep efficiency quantified from overnight polysomnography (Arms 1 and 2).
Timepoint [1] 354728 0
Overnight sleep study
Secondary outcome [2] 354729 0
Oxygen desaturation quantified from overnight polysomnography (Arms 1 and 2).
Timepoint [2] 354729 0
Overnight sleep study
Secondary outcome [3] 354730 0
Arousal Index quantified from overnight polysomnography (Arms 1 and 2).
Timepoint [3] 354730 0
Overnight sleep study
Secondary outcome [4] 354832 0
Upper airway dimensions and genioglossus motion with and without MAS and during oral versus nasal breathing during MRI (Arm 3)
Timepoint [4] 354832 0
MRI scan visit

Eligibility
Key inclusion criteria
• Adult men and women with OSA aged between 18 and 80 years who are otherwise healthy.
• Have been recommended MAS by their sleep physician for treatment of their OSA and have had an incomplete therapeutic response (residual AHI>10 events/h sleep)
• Are able to undergo an MRI scan, and do not have any dental implants, crowns or bridges (up to n=40 only for imaging sub-study)
• Participants who are willing and able to give written informed consent and willingness to participate and comply with the study procedures
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• People with contraindications to MRI, which include the presence of a pacemaker, metal shards (e.g. from shrapnel or association with meta work) or other metal implants in the body, in particular dental crowns, implants or bridges (n=40 subset only)
• Contraindications to MAS treatment (periodontal disease or dental caries, less than 10 teeth per dental arch, exaggerated gag reflex)
• Patients taking medications known to affect sleep or pharyngeal muscle activity.
• Patients with previous side effects or known allergy to zolpidem
• People with intellectual or mental impairment or any condition that may interfere with their ability to consent for themselves
• Patients with a previous history of addiction to alcohol or drugs
• Women lactating, pregnant or of childbearing potential who are not willing to avoid becoming pregnant during the study
• Patients with any other medical condition which may interfere in the evaluation of the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Where participants are identified to have major impairment in 2 phenotypic non-anatomcial traits (i.e. high loop gain + low arousal threshold or poor muscle responsiveness) according to PALM scale categorisation, the order of the first targeted intervention (O2 or zolpidem) will be randomised using computerised sequence generation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Targeted treatment will be tailored to the individual using PALM scale categorisation.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
13/12/2018
Actual
13/12/2018
Date of last participant enrolment
Anticipated
30/06/2021
Actual
30/06/2021
Date of last data collection
Anticipated
31/03/2022
Actual
6/09/2022
Sample size
Target
65
Accrual to date
Final
109
Recruitment in Australia
Recruitment state(s)
NSW,SA
Recruitment hospital [1] 18700 0
Prince of Wales Private Hospital - Randwick
Recruitment hospital [2] 18701 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 33138 0
5042 - Flinders University
Recruitment postcode(s) [2] 33139 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 301368 0
Government body
Name [1] 301368 0
Australain Government, Department of Industry, Innovation and Science: Cooperative Research Centre Project Grant: ‘Targeted therapy for sleep apnoea: A novel personalised approach (Lead Industry Partner: Oventus Medical)
Country [1] 301368 0
Australia
Primary sponsor type
Other Collaborative groups
Name
NeuRA
Address
139 Barker Street,
Randwick, NSW, 2034
Country
Australia
Secondary sponsor category [1] 301034 0
None
Name [1] 301034 0
Address [1] 301034 0
Country [1] 301034 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302104 0
South Eastern Sydney Local Health District
Ethics committee address [1] 302104 0
Prince of Wales Hospital
G71 East Wing
Edmund Blacket Building
RANDWICK NSW 2031
Ethics committee country [1] 302104 0
Australia
Date submitted for ethics approval [1] 302104 0
02/03/2018
Approval date [1] 302104 0
08/05/2018
Ethics approval number [1] 302104 0
18/047 (HREC/18/POWH/124)

Summary
Brief summary
This project is part of a large program of work involving targeted therapy for obstructive sleep apnoea (OSA) using a novel mandibular advancement split (MAS) in up to 130 participants. The specific goal of arm 2 of this project is to investigate the therapeutic efficacy of mechanism-based targeted therapy (including combination therapy) to treat OSA in people who have an incomplete response to MAS therapy alone (residual apnoea/hypopnoea index [AHI]> 10 events/h sleep). Specifically, we will use sophisticated phenotyping techniques to deliver targeted combination therapy (including oxygen therapy and pharmacotherapy). Accordingly, our goal is to find an individualized treatment solution for all patients. Our goal is to publish the findings from the various study arms including the targeted therapy component throughout the study.
Trial website
Trial related presentations / publications
Dutta R, Tong BK, Eckert DJ. Development of a physiological-based model that uses standard polysomnography and clinical data to predict oral appliance treatment outcomes in obstructive sleep apnea. J Clin Sleep Med 2022 Mar 1;18(3):861-870.
doi: 10.5664/jcsm.9742.
Public notes

Contacts
Principal investigator
Name 89126 0
Prof Danny Eckert
Address 89126 0
NeuRA
139 Barker Street
Randwick, NSW 2031
Country 89126 0
Australia
Phone 89126 0
+61 2 9399 1814
Fax 89126 0
Email 89126 0
[email protected]
Contact person for public queries
Name 89127 0
Ms Carolin Tran (NeuRA sleep lab manager)
Address 89127 0
NeuRA
139 Barker Street
Randwick, NSW 2031
Country 89127 0
Australia
Phone 89127 0
+61 2 9399 1886
Fax 89127 0
Email 89127 0
[email protected]
Contact person for scientific queries
Name 89128 0
Prof Danny Eckert
Address 89128 0
NeuRA
139 Barker Street
Randwick, NSW 2031
Country 89128 0
Australia
Phone 89128 0
+61 2 9399 1814
Fax 89128 0
Email 89128 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual participant data for the key study outcomes will be provided in the publications.
When will data be available (start and end dates)?
After the study is complete and the findings are published. No end date.
Available to whom?
Everyone with access to the journal publication.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Individual, de identified participant data will be available via the journal publication.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
662Ethical approval    376517-(Uploaded-06-12-2018-17-56-55)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Dutta R, Tong BK, Eckert DJ. Development of a phys... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseDevelopment of a physiological-based model that uses standard polysomnography and clinical data to predict oral appliance treatment outcomes in obstructive sleep apnea.2022https://dx.doi.org/10.5664/jcsm.9742
EmbaseStepwise Add-On and Endotype-informed Targeted Combination Therapy to Treat Obstructive Sleep Apnea A Proof-of-Concept Study.2023https://dx.doi.org/10.1513/AnnalsATS.202210-892OC
N.B. These documents automatically identified may not have been verified by the study sponsor.