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Trial registered on ANZCTR


Registration number
ACTRN12616000903482
Ethics application status
Approved
Date submitted
22/04/2016
Date registered
7/07/2016
Date last updated
2/07/2019
Date data sharing statement initially provided
2/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of sleep apnoea (OSA) therapy for the reduction of atrial fibrilliation (AF) burden and morbidity in adults with OSA and AF

Scientific title
The Obstructive Sleep apnoea Intervention in AF (OSI-AF) randomised trial:
Obstructive sleep apnoea treatment to reduce atrial fibrillation burden and morbidity
Secondary ID [1] 288767 0
Nil
Universal Trial Number (UTN)
Trial acronym
OSI-AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation 298018 0
Obstructive Sleep Apnoea 298019 0
Condition category
Condition code
Cardiovascular 298177 298177 0 0
Other cardiovascular diseases
Respiratory 298178 298178 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Obstructive sleep apnoea treatment (CPAP or Mandibular advancement splints (MAS) if unable to tolerate CPAP).
Participants allocated to OSA intervention group will have CPAP education and mask fitting session with an experienced sleep technician to fit the CPAP mask followed by an overnight pressure determination study (with measures of sleep and respiration whilst using CPAP) - this is a standard of care test. In the morning the CPAP machine will be set to the pressure that was shown to abolish obstructive apnoeas and hypopneas as verified by the sleep physician.
Participants will be given instructions on how to use a CPAP machine at home and will be encouraged to use their treatment every night for as long as they are able to tolerate its use during the 2 year treatment period..
Regular follow-up during the study at 3-monthly visits will check compliance with the CPAP. If a participant experiences ongoing problems tolerating the CPAP they will be referred to a dentist who will assess whether they are suitable for treatment with MAS. This is a dental splint worn in the mouth every night during sleep to keep the airway open.

Intervention code [1] 294207 0
Treatment: Devices
Comparator / control treatment
Standard treatment for patients with Atrial Fibrillation as determined by the treating clinician
Control group
Active

Outcomes
Primary outcome [1] 297683 0
Total AF arrhythmia count (cumulative duration of all episodes greater than 30s) quantified using subcutaneous injectable loop recorders (Reveal Linq, Medtronic Inc.) in patients receiving OSA treatment (CPAP or MAS) compared to those receiving no OSA treatment.
Timepoint [1] 297683 0
Continuous monitoring for 2 years
Secondary outcome [1] 321829 0
(ii) cardiovascular outcomes in patients receiving OSA treatment (CPAP or MAS) compared to those receiving no OSA treatment.
Cardiovascular adverse outcomes will be compared in the two treatment groups.
Cardiovascular outcomes will include a composite of cardiac death, MI, stroke, TIA, ACS and any other events deemed as cardiovascular by masked adjudicators.
Timepoint [1] 321829 0
Details of cardiovascular outcomes will be collected from patients and medical records at 3 monthly follow-up visits during the 2 years of follow-up.
Secondary outcome [2] 323191 0
(iii) health related quality of life in patients receiving OSA treatment (CPAP or MAS) compared to those receiving no OSA treatment.
HRQOL will be reported by participants using the EuroQoL (EQ-5D 5L), Short Form 36 questionnaire (SF-36), and UBQ-H and the FOSQ (Functional Outcomes of Sleep Weaver 1996) questionnaires.
Timepoint [2] 323191 0
HRQOL will be collected at baseline, 3-months and then 6 monthly during the 2 years of follow=up
Secondary outcome [3] 323192 0
(iv) Composite of AF related hospitalisations and healthcare utilisation in patients receiving OSA treatment (CPAP or MAS) compared to those receiving no OSA treatment (collected directly from patients or via medical records).
- Hospitalization for AF symptoms (palpitations, dyspnea, chest discomfort, syncope, pre-syncope) or its complications (exacerbation of cardiac failure, acute coronary syndrome, acute cerebral episode),
- scheduled or emergent external cardioversion,
- emergent ambulatory consultation for AF symptoms or related complications,
- anti-arrhythmic (AAM) drug prescription, hospitalization for AAM initiation,
- titration or monitoring, referral for catheter ablation for AF,
- referral for catheter ablation of AV node and pacemaker implantation,
- complications related to systemic anticoagulation therapy.
AF related healthcare utilisation will be formulated and applied by adjudicators blinded to the patient treatment.
Timepoint [3] 323192 0
Details of AF related healthcare utilisation will be collected at 3 monthly follow-up visit during the 2 years of follow-up.
Secondary outcome [4] 323193 0
(v) Cost-effectiveness of OSA treatment, assessed using data linkage to hospital records for: 1) Number of hospital admissions related to AF; 2) Average hospital length of stay and ‘home time’ a patient-centred outcome meaning institutional free time; 3) Quality-adjusted survival.
Total resource use and costs for the intervention and control group will be estimated. Total health outcomes for the intervention and control group will also be estimated.
Timepoint [4] 323193 0
2 years (end of study)
Secondary outcome [5] 323194 0
(vi) serum markers potentially predictive of atrial structural remodelling, pro-arrhythmia and inflammation in patients receiving OSA treatment (CPAP or MAS) compared to those receiving no OSA treatment.
Details of markers to be analysed will be determined prior to database lock and analysis and ANZCTR updated

Timepoint [5] 323194 0
Samples will be collected at baseline, 3-months, 6-months and then annually during the 2 years of follow-up.

Eligibility
Key inclusion criteria
1) Males and females with a history of paroxysmal (at least 2 prior attacks) or persistent AF (<12 months duration [in sinus rhythm at study entry]);
2) Age 18-75;
3) Polysomnography diagnosed OSA of at least moderate severity (AHI >=15);
4) Ability to provide informed consent.

Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Severe OSA related hypoxemia (>10% sleep time with oxygen saturation <80%) and/or awake oxygen saturation less than 92%%
2) Severe respiratory disease (eg Chronic Obstructive Pulmonary Disease or (COPD)
3) Current or prior mechanical treatment for OSA with CPAP or MAS
4) >50% of apnoeas and/or hyponeas associated with Cheyne-Stokes Respiration (CSR) or Central Sleep Apnoea (CSA)
5) Increased risk of sleep-related accident and / or excessive sleepiness defined by any of:
* Severe sleepiness as defined by Epworth Sleepiness Scale (>15)
* Driver occupation (eg taxi, courier or truck driver)
* Sleepiness-related motor vehicle accident, or near accident, within last 12 months prior to enrolment
6) Any relative or absolute contra-indication to CPAP or MAS therapy including chronic cranial injury; recurrent pneumothorax; indication for oral-pharyngeal surgery, edentulous, or loose teeth
7) Any severe other cardiac disease likely to impact ability to comply:


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)
central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be by stratified minimisation at the NMHRC CTC according to source of referral, age, gender, AF type (paroxysmal or persistent <12 months), and OSA severity.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
None
Phase
Phase 3 / Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
A sample size of 200 subjects will offer 95% power at 2P=0.05 to detect a 50% reduction in cumulative AF burden from 2000 hrs total over 2 years to 1000 hr s, SD 1500 hrs. This sample size allows for up to 40% non-compliance by 2 years with adequate OSA treatment (CPAP or MAS), and 10% drop-ins.
Outcome differences will be determined within groups and between groups on an intention-to-treat basis.

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] 5446 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 5447 0
Concord Repatriation Hospital - Concord

Funding & Sponsors
Funding source category [1] 293130 0
Self funded/Unfunded
Name [1] 293130 0
Not yet funded - grant application submitted
Address [1] 293130 0
Not yet funded - grant application submitted
Country [1] 293130 0
Primary sponsor type
University
Name
University of Sydney
Address
c/o NHMRC Clinical Trials Centre, Locked bag 77, Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 291926 0
None
Name [1] 291926 0
Address [1] 291926 0
Country [1] 291926 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294627 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 294627 0
c/- Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 294627 0
Australia
Date submitted for ethics approval [1] 294627 0
11/11/2015
Approval date [1] 294627 0
30/06/2016
Ethics approval number [1] 294627 0

Summary
Brief summary
Atrial fibrillation (AF) is estimated to affect at least 0.25 million adult Australians and is the commonest cardiac arrhythmia world-wide. It accounts for an estimated $1.8 billion in annual direct ($1.25B) and indirect ($0.55B) healthcare costs locally. Annual hospital admissions have risen exponentially over the last 15 years, with costs for AF arrhythmia episodes alone in 2008-9 amounting to $430 million. AF causes a substantial lifetime socio-economic burden, as it causes 7,500 ischaemic strokes in Australia each year. Because the risk of stroke is determined largely by the quantitative burden of arrhythmia, treatments to lower arrhythmia burden are critically important. Obstructive sleep apnoea (OSA) is an independent risk factor for AF and more than triples the risk of stroke in AF, over and above other established risk predictors. Up to 80% of patients with AF have OSA. Current AF treatment strategies are ineffective in >50% of cases overall, particularly among individuals with OSA. Observational studies suggest that treatment of OSA may reduce arrhythmia recurrence, but no large RCTs have directly addressed this question. Reducing the >50% arrhythmia recurrence rate may only be possible when combined with structured OSA treatment. This randomised clinical trial is assessing whether routine OSA treatment in addition to a weight management program reduces AF arrhythmia burden.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64410 0
Prof Tony Keech
Address 64410 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 64410 0
Australia
Phone 64410 0
+ 61 2 9562 5000
Fax 64410 0
Email 64410 0
tony@ctc.usyd.edu.au
Contact person for public queries
Name 64411 0
Ms Rebecca Mister
Address 64411 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 64411 0
Australia
Phone 64411 0
+ 61 2 9562 5000
Fax 64411 0
Email 64411 0
osi-af@ctc.usyd.edu.au
Contact person for scientific queries
Name 64412 0
Prof Tony Keech
Address 64412 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 64412 0
Australia
Phone 64412 0
+ 61 2 9562 5000
Fax 64412 0
Email 64412 0
tony@ctc.usyd.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
Please contact the CTC for the publication and data sharing
What supporting documents are/will be available?
No other documents available
Summary results
No Results