Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000227291
Ethics application status
Approved
Date submitted
5/02/2018
Date registered
12/02/2018
Date last updated
28/03/2022
Date data sharing statement initially provided
1/10/2019
Date results provided
28/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
An evaluation of the effectiveness of continuous positive airway pressure therapy in participants with obstructive sleep apnoea and angina
Scientific title
A randomised evaluation of the effectiveness of continuous positive airway pressure therapy in participants with obstructive sleep apnoea and angina, and no obstructive coronary artery disease.
Secondary ID [1] 293834 0
None
Universal Trial Number (UTN)
U1111-1208-8950
Trial acronym
NOCAD3 OSA
Linked study record
NOCAD1 - ACTRN12618000149268

Health condition
Health condition(s) or problem(s) studied:
Angina 306460 0
Obstructive Sleep Apnoea 306461 0
Condition category
Condition code
Cardiovascular 305549 305549 0 0
Coronary heart disease
Respiratory 305550 305550 0 0
Sleep apnoea
Cardiovascular 305551 305551 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with angina and no obstructive coronary artery disease from NOCAD1 study will be screened and recruited. Recruited participants will undergo type 2 ambulatory sleep study at participants' residence for the diagnosis of obstructive sleep apnoea.

Participants who have obstructive sleep apnoea and fulfilled the study inclusion/exclusion criteria as outlined for CPAP therapy will be randomly assigned to either "initial CPAP therapy" or "delayed CPAP therapy (no CPAP)" for 6 months, followed by crossover between group's therapy for further 6 months to assess the difference in effects on angina burden and quality of life.

Participants on CPAP therapy will received autoPAP (Philips Respironics, Murrayville, PA) for 1 week, followed by fixed CPAP pressure, set at 90th percentile of autoPAP pressure, as determined by Sleep Physician. Delivery of CPAP device and its accessories by Philips SleepEasy Device Consultant, including education and supports in conjunction with a Sleep Physician. This will take place at the Lyell McEwin Hospital Cardiology Clinical Trial Unit. Data will be available electronically via remote downloading using Encoreanywhere program. Participant's adherence is monitored by accessing device analytics which will be downloaded remotely. Satisfactory adherence towards CPAP therapy will be assessed by Sleep Physician at 1 months, 3 months and 6 months. Minimum amount of usage time should be > 4 hours per night. Participants will be contacted to troubleshoot any difficulties and if any problems arose.

There will be 6 months of no CPAP therapy prior to follow-up outcome assessment after cessation of CPAP therapy.
Intervention code [1] 300222 0
Treatment: Devices
Intervention code [2] 300223 0
Diagnosis / Prognosis
Comparator / control treatment
Active Control - Crossover Study.
A comparative group of participants without obstructive sleep apnoea or did not fulfil the inclusion criteria for CPAP therapy, will serve as a stability of outcomes comparison at 6 months and 12 months.
Control group
Active

Outcomes
Primary outcome [1] 304679 0
Recurrent angina which is defined as one or more episodes of pain per week determined from the Seattle Angina Questionnaire.
Timepoint [1] 304679 0
6 and 12 months after randomisation.
Primary outcome [2] 304680 0
Prevalence of obstructive sleep apnoea in participants with angina and no obstructive coronary artery disease.
The information will be obtained from type 2 ambulatory sleep study.
Timepoint [2] 304680 0
Within 4 weeks after coronary haemodynamics study.
Secondary outcome [1] 342760 0
Hospital admission with recurrent angina.
The information will be obtained from linkage to medical records.
Timepoint [1] 342760 0
Over 12 months after randomisation.
Secondary outcome [2] 342761 0
Cardiovascular death.
The information will be obtained from linkage to medical records.
Timepoint [2] 342761 0
Over 12 months after randomisation.
Secondary outcome [3] 342762 0
Myocardial infarction.
The information will be obtained from linkage to medical records.
Timepoint [3] 342762 0
Over 12 months after randomisation.
Secondary outcome [4] 342763 0
Stroke.
The information will be obtained from linkage to medical records.
Timepoint [4] 342763 0
Over 12 months after randomisation.
Secondary outcome [5] 342764 0
Health Status.
This information obtained from EQ-5D questionnaires which is a standardized instrument for measuring generic health status.
Timepoint [5] 342764 0
6 and 12 months after randomisation.
Secondary outcome [6] 342765 0
Contractile reserve (CR).
CR is measured with strain imaging on low dose dobutamine stress echocardiography (DSE).
Timepoint [6] 342765 0
6 and 12 months after randomisation.
Secondary outcome [7] 342766 0
Augmentation Index (Ax).
Ax is measured with TensioMed arteriography.
Timepoint [7] 342766 0
6 and 12 months after randomisation.
Secondary outcome [8] 342767 0
Aortic pulse wave velocity (PWV).
PWV is measured with TensioMed arteriography.
Timepoint [8] 342767 0
6 and 12 months after randomisation.
Secondary outcome [9] 342768 0
Central retinal vessel calibre (CRVC).
CRVC is obtained with Smartscope® Pro by Optomed will be used. (Non-mydriatic fundus camera)
Timepoint [9] 342768 0
6 and 12 months after randomisation.

Eligibility
Key inclusion criteria
1. Met NOCAD1 study inclusion criteria:
- Clinical diagnosis of angina
- Persistent angina
- Coronary angiography demonstrating normal or no obstructive coronary disease (<50% diameter stenosis)

2. Participants for CPAP therapy with obstructive sleep apnoea diagnosis
- AHI>20
- AHI<20; REM-AHI>45

3. Patients are able and willing to give appropriate informed consent.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Met NOCAD1 study exclusion criteria:
- Admission for an acute coronary syndrome within the preceding month
- Prior coronary artery bypass grafting
- Contra-indications to coronary haemodynamic assessment - patients with permanent pacemaker or de brillator, severe renal or hepatic insu ciency, severe asthma, left ventricular systolic dysfunction (ejection fraction <50%)
- Alternative coronary explanations for the chest pain - obstructive coronary artery disease (Flow limiting coronary stenosis i.e. derived fractional flow reserve (FFR) <0.80), spontaneous coronary spasm (but not catheter related spasm), spontaneous coronary artery dissection
- Other cardiovascular disorders - pulmonary hypertension, pulmonary embolism, hypertrophic cardiomyopathy, or valvular heart disease.
2. Non-English speaking patient
3. Unable to give consent due to cognitive impairment
4. Patient is or may be pregnant
5. Severe comorbidity with severe disability or likelihood of death
6. Significant memory, perceptual or behavioural disorder
7. Neurological deficit preventing self administration of CPAP mask
8. Contra-indication to CPAP use e.g. pneumothorax
9. Severe respiratory disease defined as
- Severe chronic obstructive pulmonary disease (FEV1/FVC<70% and FEV1 <50% predicted)
- Resting SaO2 <90%.
10. Prior use of CPAP treatment of OSA
11. Increased risk of a sleep-related accident and/or excessive daytime sleepiness, defined by any one of the following:
- Driver occupation (eg truck, taxi)
- ‘fall asleep’ accident or ‘near miss’ accident in previous 12 months
- High Epworth Sleepiness Scale score (>15)
12. Severe nocturnal desaturation documented during sleep study as >10% overnight recording time with arterial oxygen saturation of <80%
13. Cheyne-Stokes Respiration (CSResp)

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
N/A
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power Calculation:
The sample size calculations will be performed using R version 3.1.2 2014, The R Foundation for Statistical Computing, with the assistance of a statistician from the University of Adelaide.

The Seattle Angina Questionnaire as an outcome measure was looked at. Journal article Seattle Angina Questionnaire 1995, quoted a change in an SAQ score of 10, as a clinically important difference in scores. A two sample mean test for equality was used with alpha=0.05, power=80%, clinically significant difference of 10% and varying standard deviations. If a standard deviation of 12.5 is chosen then sample size required is 25 per group for a parallel study. A two sample mean crossover design test for equality and a two sample proportion crossover design test for equality were used to calculate the cross-over sample sizes. If a standard deviation of 12.5 is chosen then sample size required is 10 per group for a Cross-over study.

In the sample size calculation for cross over trial, it was found that a sample size of 15-17 patients per group would provide a power of 80% at least to detect the clinically important differences between the control and intervention groups. Adding 10% for loss to follow-up gives N=17-19 per group. So if, in addition to the “CPAP therapy first then No CPAP” group and the “no CPAP therapy first then CPAP therapy” group, the comparative (No CPAP) group should also have a sample size of 17-19 patients.

Data Analysis:
All collected information for the projects outlined above will be entered into an Excel database. The data will be analysed with the help of a statistician from University of Adelaide using the statistical software SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and Stata Statistical Software: Release 14. College Station, TX: StataCorp LP.

Descriptive statistics of the following variables will be presented: age, gender, body mass index, hypertension, dyslipidemia, diabetes mellitus, smoking history, and moderate-to-severe OSA, in addition to outcome and predictor variables. The descriptives will include frequency tables (frequencies and percentages), means (standard deviations) and medians (interquartile ranges) depending on the distribution of the variable. Prevalence of OSA in the NOCAD population will also be presented. Graphs and tables will be used to summarize the data.

Numerical variables in the study like age; HMR Values, etc. will be analysed through simple descriptive statistics in the form of means and standard deviation. Statistical differences will be evaluated using the Student t test for continuous variables, whereas proportions will be compared by applying Chi-square test and relationship between dependent and independent variables will assessed by regression analysis. P value of = 0.05 will be considered significant.

Continuous data will be expressed as mean ± SD. Comparisons of categorical data between groups will be analysed by the Fisher’s exact test or the Chi-square test. Comparisons of continuous variables between groups will be evaluated by the unpaired t-test or the Mann—Whitney test. A multivariate logistic regression analysis was performed to determine independent variables associated with OSA. “The variables used for the analysis were age, gender, body mass index, hypertension, dyslipidemia, diabetes mellitus, smoking history, and moderate-to-severe OSA.” A p < 0.05 was considered to be statistically significant.

To assess the primary hypothesis - the association between angina (SAQ score) and CPAP group (CPAP “Initial”, CPAP “Delayed”, comparative group) - a linear or ordinal logistic regression taking cross-over method into account will be used, giving estimate/odds ratios, 95% confidence intervals and P values.

To assess the secondary hypothesis - the association between non-invasive measurements (CR, PWA ad CRVC) and Quality of life measurements and the predictor: CPAP group - linear regressions will be used if appropriate, taking cross- over method into account. Multivariable linear and ordinal logistic regressions will then be performed using the outcomes above for the predictor CPAP group and potential confounders, using a backwards elimination method. A p< 0.05 is considered to be statistically significant.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Safety concerns
Other reasons/comments
Other reasons
COVID-19 pandemic has affected the CPAP therapy component of the trial.
Date of first participant enrolment
Anticipated
14/02/2018
Actual
14/02/2018
Date of last participant enrolment
Anticipated
Actual
5/11/2020
Date of last data collection
Anticipated
Actual
29/01/2021
Sample size
Target
50
Accrual to date
Final
42
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 9950 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment postcode(s) [1] 18762 0
5112 - Elizabeth Vale

Funding & Sponsors
Funding source category [1] 298448 0
Hospital
Name [1] 298448 0
Cardiology Unit, Lyell McEwin Hospital, Internal Research Fund
Country [1] 298448 0
Australia
Funding source category [2] 298587 0
Commercial sector/Industry
Name [2] 298587 0
Philips-Respironics Inc., a Philips Healthcare company.
Country [2] 298587 0
United States of America
Funding source category [3] 298588 0
Commercial sector/Industry
Name [3] 298588 0
Sleep and Respiratory Care, Philips Australia
Country [3] 298588 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
Department of Medicine
Graduate centre
Level 2, Schulz Building,
The University of Adelaide SA 5005
Country
Australia
Secondary sponsor category [1] 297742 0
None
Name [1] 297742 0
Address [1] 297742 0
Country [1] 297742 0
Other collaborator category [1] 279925 0
Individual
Name [1] 279925 0
Prof Doug McEvoy
Address [1] 279925 0
Adelaide Institute for Sleep Health, Flinders University
C/-Sleep Health Service
Southern Adelaide Local Health Network
Flinders Medical Centre,
Bedford Park SA 5042
Country [1] 279925 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299443 0
TQEH/LMH/MH Human Research Ethics Committee and Northern Adelaide Local Health Network, NALHN Research Governance
Ethics committee address [1] 299443 0
Ethics committee country [1] 299443 0
Australia
Date submitted for ethics approval [1] 299443 0
11/09/2017
Approval date [1] 299443 0
18/12/2017
Ethics approval number [1] 299443 0
HREC/17/TQEH/177

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 2411 2411 0 0
/AnzctrAttachments/374340-EthicsApproval%20Letter%20-%20Q20170901%20Arstall.pdf (Ethics approval)

Contacts
Principal investigator
Name 80418 0
A/Prof Margaret Arstall
Address 80418 0
Cardiology Unit, Lyell McEwin Hospital, Northern Adelaide Local Health Network (NALHN) Haydown Rd, Elizabeth Vale SA 5112
Country 80418 0
Australia
Phone 80418 0
+61 8 81829439
Fax 80418 0
+61 8 82820706
Email 80418 0
[email protected]
Contact person for public queries
Name 80419 0
Sharmalar Rajendran
Address 80419 0
Cardiology Unit, Lyell McEwin Hospital, Northern Adelaide Local Health Network (NALHN) Haydown Rd, Elizabeth Vale SA 5112
Country 80419 0
Australia
Phone 80419 0
+61 8 81829439
Fax 80419 0
+61 8 82820706
Email 80419 0
[email protected]
Contact person for scientific queries
Name 80420 0
Sharmalar Rajendran
Address 80420 0
Cardiology Unit, Lyell McEwin Hospital, Northern Adelaide Local Health Network (NALHN) Haydown Rd, Elizabeth Vale SA 5112
Country 80420 0
Australia
Phone 80420 0
+61 8 81829439
Fax 80420 0
+61 8 82820706
Email 80420 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?
A limited, de-identified set of data available for researchers outside the primary investigators and will be specified in the data sharing plan.
When will data be available (start and end dates)?
No end date determined. Two years after the publication of the primary results of the study. The endpoint of the availability to be specified by the investigators.
Available to whom?
Researchers outside the primary investigators.
Available for what types of analyses?
The type of analyses must be specified in the data sharing agreement between the providing agency and the requesting researchers.
How or where can data be obtained?
Before data are shared, a data-sharing agreement should be established documenting what data are being shared and how the data can be used. The agreement serves two purposes. First, it protects the agency providing the data, ensuring that the data will not be misused. Second, it prevents miscommunication on the part of the provider of the data and the agency receiving the data by making certain that any questions about data use are discussed. The following items should be covered in the data-sharing agreement:

Period of agreement
The intended use of the data
Constraints on the use of the data
Data confidentiality
Data security
Methods of data-sharing


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1053Informed consent form    374340-(Uploaded-14-01-2019-16-02-40)-Study-related document.pdf



Results publications and other study-related documents

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