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Trial registered on ANZCTR


Registration number
ACTRN12620000050954
Ethics application status
Approved
Date submitted
13/12/2019
Date registered
22/01/2020
Date last updated
22/01/2020
Date data sharing statement initially provided
22/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Impact of optimized Obstructive Sleep Apnea Therapy in Patients with an Acute Coronary Syndrome: A Pilot Trial
Scientific title
Impact of optimized Obstructive Sleep Apnea Therapy in Patients with an Acute Coronary Syndrome: A Pilot Trial
Secondary ID [1] 300123 0
Nil
Universal Trial Number (UTN)
U1111-1245-1607
Trial acronym
SPACE_TRIAL
Linked study record
Our established prevalence study (SPACE study, No X18-0173 & HREC/18/RPAH/242) will provide the recruitment pathway for this pilot RCT.
Participants completing the prevalence study who meet the criteria will be invited to take part in this pilot trial.

Health condition
Health condition(s) or problem(s) studied:
Coronary Artery Disease 315555 0
Obstructive Sleep Apnea 315556 0
Condition category
Condition code
Cardiovascular 313847 313847 0 0
Coronary heart disease
Respiratory 313848 313848 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study aims to deliver optimized OSA therapy implemented by experienced personnel and the use of current online tools to improve OSA therapy adherence. Furthermore by utilizing robust surrogate cardiovascular measures this study will provide preliminary data of the effect of optimized treatment on vascular health, thereby providing justification for a future study including hard cardiovascular endpoints (ie. myocardial infarction, heart failure, stroke, death). Therefore, this research will inform a prevention trial and provide invaluable information on determining the most appropriate outcome measures, and the effect size of OSA treatment to enable sample size calculations.
This study assess the effects of Positive Airway Pressure (PAP) and Oral Appliance Therapy (OAT) with Usual care on markers of cardiovascular health.
PAP treatment (arm 1): PAP is an electrically powered device using continuous positive airway pressure to treat patients affected by OSA. In this study we will be using the ResMed ‘AirSense 10 AutoSet’ APAP device to treat the degree of OSA. The automatic mode will be used as the primary form of therapy, with the option of switching to fixed pressure at physician discretion where required. Our goal is to achieve a mean adherence of greater than 5 hours per night. Optimized PAP support will be implemented using the following strategies:
PAP implementation by an experience sleep therapist, providing detailed education and support during the initial acclimatization phase (approximately 2 hours), followed by ongoing support (monthly phone calls, approximately 20minutes) and ad hoc face to face visits (approximately 1 hour) as required during the intervention period. AirView (ResMed, Ltd) patient management system: will be used by the sleep therapist and clinicians to monitor and change patients’ device settings in order to optimize therapy. myAir (ResMed Ltd): an online system providing patients with information regarding their progress, enabling patients to better understand their treatment and improve sleep. Patients may receive tailored coaching and tips on how to make therapy more comfortable, congratulatory messages following certain therapy milestones as well as encouragement messages. This system will be provided to patients during their PAP treatment.

OAT treatment (arm 2): A custom-made oral appliance (ResMed, Narval) used in previous clinical trials (mandibular advancement splint (MAS)) will be provided by an experienced dentist. Participants will undergo assessment at the Sydney Dental Hospital by a trained dentist (Dr Oyku Dalci) who will make sure the participants teeth and gums are healthy enough to wear the device. The dentist may also ask for an X-ray of the participants teeth to determine if the device can be worn. Once the dentist confirms eligibility, moulds of the participants teeth will be taken in order to construct the appliance. The device takes approximately two weeks to make. Once the device has been received by the study dentist from the manufacturer, the participant will attend a fitting appointment and the splint will be issued to the participant. The participant may need to visit the study dentist during this period to have progress and any side effects assessed. Once the participant has reached the maximum advancement, they will have one final visit to the study dentist to ensure optimal advancement for treatment of their OSA. Ongoing support will be provided as require in order to optimize usage.
Usual medical care (arm 3): This will represent a control group receiving conventional medical care by their cardiologist and primary care physician. This group will control for effect of time since acute coronary syndrome on markers of cardiovascular function and will not receive an active treatment.

For each of the intervention arms, participants will be expected to use their device daily for 6 months (24 weeks).
Patient support and education for the CPAP group will occur through face-to-face consultations, over-the-phone consultation with the CPAP provider as well as the use of ResMed’s own MyAir App. During the initial consultation with patients the CPAP provider will give a brief overview of Obstructive Sleep Apnea, a detailed explanation of how to use the device, as well as a trial of the mask will be undertaken (approximately 2 hours). ad hoc face to face visits as required will be conducted allow resolution of any CPAP issues, check usage and treatment effectiveness (approximately 1 hour). Patients will also be contacted (via phone) monthly to review usage and treatment effectiveness (approximately 20 min phone call).
Patients in the CPAP group will be signed up to ResMed’s ‘MyAir’ application. Notifications can be messages or alerts sent via email and/or text. They often include video links for more detailed tips on common challenges. MyAir also ensures patients receive praise messages at six set levels as they progress through their therapy. In addition to this patients are given a score out of 100 which describes their previous night’s sleep – included in this score is hours used, mask seal, and apnea events. This is also used as a tool to reinforce good CPAP usage.
The oral appliance therapy (OAT) is worn in the mouth during sleep and is a clinically proven mandibular repositioning device (jaw split) to treat obstructive sleep apnea and snoring. The device works by advancing the lower jaw to maintain an open airway while sleeping. For OAT participants will be provided with an online diary (OATdiary) to log their daily sleep, total time sleeping with the device and fortnightly survey on how they handling their treatment. The trial co-coordinator will have access to this information and will review this information weekly to ensure participants are logging their data thus ensure adherence. Furthermore, patients will receive monthly phone calls to trouble shoot any difficulties as well as encourage device usage.
Intervention code [1] 316349 0
Treatment: Devices
Comparator / control treatment
The comparator will be the Usual care arm: This will represent a control group receiving conventional medical care by their cardiologist and primary care physician. Participants randomized into this group will not be given a device treatment for OSA. Furthermore comparison will also be made between the two different OSA treatments.

Conventional medical care will be any medical care prescribed by the participants cardiologist or primary care physician.
Control group
Active

Outcomes
Primary outcome [1] 322295 0
Optimized positive airway pressure therapy defined as an average nightly therapy usage of >5 hours/night throughout the 6 month intervention using data from AirView
Timepoint [1] 322295 0
Average nightly therapy usage of >5 hours/night from intervention commencement until 6 months post intervention commencement.
Primary outcome [2] 322296 0
Optimized oral appliance therapy defined as an average nightly therapy usage of >5 hours/night throughout the intervention using data from OAT diary.
Timepoint [2] 322296 0
Average nightly therapy usage of >5 hours/night from intervention commencement until 6 months post intervention commencement.
Secondary outcome [1] 377993 0
24 hour ambulatory blood pressure and central blood pressure will be assessed using the automatic Sphygmocor.
Timepoint [1] 377993 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [2] 377994 0
Home sleep testing (polysomnography): composite changes in oxygen desaturation index (ODI), A metric used to define the presence and severity of OSA and to measure rapid eye movement OSA, which has specific association with cardiovascular risk.
Timepoint [2] 377994 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [3] 377997 0
Subjective measure of low and high risk of sleep disordered breathing will be assessed using the Berlin Questionnaire.
Timepoint [3] 377997 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [4] 378000 0
A subjective measure of quality of life will be assessed using the 36-Item short form survey.
Timepoint [4] 378000 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [5] 378001 0
Pulse oximetry: pulse oximetry is a non-invasive method for monitoring a person’s oxygen saturation.
Timepoint [5] 378001 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [6] 378002 0
Inflammation, assessed by composite outcome of of high-sensitivity C-reactive protein (hs-CRP) and Tumour Necrosis Factor Alpha (TNF-a) from venous blood.
Timepoint [6] 378002 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [7] 378004 0
Endothelial function: Assessment of vascular endothelial function by flow-mediated dilatation employs a non-invasive method which involves a brief cuff-mediated arterial occlusion in the arm followed by non-invasive ultrasound scanning of the artery proximal to the site of occlusion.
Timepoint [7] 378004 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [8] 378005 0
Pulse wave velocity: The SphygmoCor XCEL system enables the non-invasive measurement of pulse wave velocity of the blood pressure waveform travelling between two arterial sites.
Timepoint [8] 378005 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [9] 378006 0
Autonomic function: assessing heart rate variability, blood pressure variability, spontaneous baroreflex function. The Human NIBP system accurately determines beat-to-beat blood pressure, enabling assessment of autonomic cardiovascular control such as spontaneous baroreflex function, and blood pressure variability. The human NIBP system operates via a photoplethysmographic cuff (blood pressure cuff with an infrared sensitive photocell), a pressure manometer, an automatic unit for cuff inflation, a 3-lead ECG and a monitor for the digital display of systolic blood pressure, diastolic blood pressure and heart rate. The finger cuff is designed for the adult finger with an automated calibration device attached to the cuff which maintains constant transmural pressure on the finger. Therefore, assessment of autonomic function will be derived from the recorded blood pressure and ECG trace.
Timepoint [9] 378006 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [10] 378008 0
Cardiovascular Risk Factors: Composite outcome of blood lipids (triglycerides, LDL-C, HDL-C) and glycated haemoglobin (HbA1c) quantified by venous sampling. Body mass and height will be measured to determine body mass index using digital scales and measuring tape. Waist circumference will be measured according to standardised methods using a measuring tape.
Timepoint [10] 378008 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [11] 378168 0
Epworth Sleepiness Scale
Timepoint [11] 378168 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [12] 378169 0
A subjective measure of risk of obstructive sleep apnea will be assessed using the STOP-BANG questionnaire.

Timepoint [12] 378169 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [13] 378170 0
functional outcomes sleep questionnaire.
Timepoint [13] 378170 0
Baseline and 6 months post commencement of intervention.
Secondary outcome [14] 378171 0
Seattle angina questionnaire
Timepoint [14] 378171 0
Baseline and 6 months post commencement of intervention.

Eligibility
Key inclusion criteria
• Participants presenting to the established prevalence study (No X18-0173 & HREC/18/RPAH/242) with diagnosed moderate to severe OSA with significant hypoxia, Defined as an Oxygen Desaturation Index (ODI) greater than or equal to 15/hr on home-based polysomnography.
• Completed baseline cardiovascular measurements.
• Clinically suitable for PAP and OAT treatment.
• Willingness to undergo either PAP, OAT or usual care for 6 months.
• Willingness to provide informed consent and willingness to participate and comply with the study requirements.
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Previous OSA treatment.
• Contraindications to PAP (severe nasal obstruction) or OAT (insufficient teeth or dental health issues).
• Women who are lactating or pregnant
• Driving risk, report an accident (or near miss accident) because of sleepiness in the last 6 months
• Need for immediate therapy as assessed by treating sleep physician.
• Patients with a history of psychological illness or conditions such as to interfere with the patients ability to understand the requirements of the study
• Coexisting sleep disorder, shift work, regular use of sedatives or narcotics, pre-existing lung disease (moderate to severe chronic obstructive pulmonary disease) or psychiatric disease; chronic kidney disease (eGFR<60).
• Central sleep apnea >10% of respiratory events being central events, rather than obstructive events

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The allocation sequence for the trial is set up using centralised randomization to maintain allocation concealment.
The allocation sequence was set by our data manager on RedCap and no other person in our trial has access to the allocation sequence.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be done using a online random number generator tool to receive either PAP, OAT or Usual care.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
This is a pilot randomised trial which will enable effect sizes for outcome measures following intervention to be calculated to inform future clinical trials. Therefore, a formal sample size calculation is not possible. We have adopted a sample size of 40 participants per arm. According to an exploration of pilot trial sample sizes values of a pilot trial, a sample size of 35 is theoretically optimal to detect a small effect size while using a conservative approach to estimating standard deviation (using at least 80% upper one-side confidence limit, rather than the estimate itself) to enable sample size calculation for a 90% powered main trial.

Descriptive statistics will be used to present information about therapy acceptance and usage in the sample. Differences between trial arms will be compared using ANOVA. Changes in surrogate cardiovascular measures across the treatment period and between trial arms will be assessed using factorial ANOVA. Calculated effectiveness metrics will be assessed for relationship to changes in outcome variables using correlation and regression analyses.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 15500 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 28855 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 304018 0
Charities/Societies/Foundations
Name [1] 304018 0
Resmed Foundation Clinical Grant
Address [1] 304018 0
7514 Girard Ave, La Jolla, CA 92037, United States
Country [1] 304018 0
United States of America
Primary sponsor type
University
Name
University of Sydney
Address
Administration Building (F23)
Corner of Eastern Avenue and City Road,
The University of Sydney,
Camperdown
NSW
2006
Country
Australia
Secondary sponsor category [1] 304193 0
None
Name [1] 304193 0
Address [1] 304193 0
Country [1] 304193 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304510 0
Human Research Ethics Committee - Sydney Local health District, Royal Prince Alfred Hospital
Ethics committee address [1] 304510 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN
NSW
2050
Ethics committee country [1] 304510 0
Australia
Date submitted for ethics approval [1] 304510 0
12/06/2019
Approval date [1] 304510 0
15/08/2019
Ethics approval number [1] 304510 0

Summary
Brief summary
Obstructive sleep apnoea (OSA) is a surprisingly common disorder and occurs due to upper airway obstruction. OSA is characterised by repetitive periods of obstructed breathing during sleep and is an independent risk factor for coronary artery disease, affecting 40%-60% of cardiac patients. Furthermore, untreated moderate to severe obstructive sleep apnoea (OSA) in patients with established coronary disease is associated with increased cardiovascular morbidity and mortality. Therefore, treating OSA in isolation is key for cardiovascular risk reduction.

The purpose of this trial is to determine whether optimized OSA therapy can be achieved in a cardiovascular population using best-practice compliance enhancement strategies including digital patient engagement tools. Furthermore, we will assess the impact of optimized OSA therapy on surrogate markers of cardiovascular health.

Collectively, we hypothesise, that optimised OSA therapy will be accepted and treatment adherence can be optimised in patients with coronary artery disease and that treatment will improve surrogate markers of cardiovascular health.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97202 0
Prof Peter Cistulli
Address 97202 0
Department of Respiratory and Sleep Medicine
Royal North Shore Hospital
North Foyer Consulting Suites, Ground Floor,
North Shore Private Hospital,
Westbourne Street,
St Leonards NSW 2065
Country 97202 0
Australia
Phone 97202 0
+61 2 9463 2934
Fax 97202 0
Email 97202 0
peter.cistulli@sydney.edu.au
Contact person for public queries
Name 97203 0
Prof Peter Cistulli
Address 97203 0
Department of Respiratory and Sleep Medicine
Royal North Shore Hospital
North Foyer Consulting Suites, Ground Floor,
North Shore Private Hospital,
Westbourne Street,
St Leonards NSW 2065
Country 97203 0
Australia
Phone 97203 0
+61 2 9463 2934
Fax 97203 0
Email 97203 0
peter.cistulli@sydney.edu.au
Contact person for scientific queries
Name 97204 0
Prof Peter Cistulli
Address 97204 0
Department of Respiratory and Sleep Medicine
Royal North Shore Hospital
North Foyer Consulting Suites, Ground Floor,
North Shore Private Hospital,
Westbourne Street,
St Leonards NSW 2065
Country 97204 0
Australia
Phone 97204 0
+61 2 9463 2934
Fax 97204 0
Email 97204 0
peter.cistulli@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results