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Trial registered on ANZCTR


Registration number
ACTRN12614000338662
Ethics application status
Approved
Date submitted
24/03/2014
Date registered
31/03/2014
Date last updated
10/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Multi-level upper airway surgery in patients with moderate to severe obstructive sleep apnoea who have failed medical management.
Scientific title
Multi-level airway surgery in patients with moderate-severe Obstructive Sleep Apnoea (OSA) who have failed medical management to assess change in OSA events and daytime sleepiness.
Secondary ID [1] 284308 0
Nil
Universal Trial Number (UTN)
U1111-1154-8029
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive sleep apnoea 291457 0
Condition category
Condition code
Respiratory 291827 291827 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1:
Participants will undergo multi-level surgery of the upper airway. Surgery will involve a modified uvulopalatopharyngoplasty (UPPP), if patient has tonsils then a bilateral tonsillectomy will be performed as a standard procedure. This is an operation aimed at opening the oropharyngeal and velopharyngeal inlets. Participants will receive Coblation channelling of the tongue (CCT), a method which utilises Coblation (radiofrequency + saline resulting in a localised plasma field) to ablate columns of tissue and this is thought to reduce tongue volume and stiffen the tongue base. The duration of the surgical procedure is approximately 60 minutes with a six week recovery period. This surgical procedure is considered a permanent intervention, however there is the potential for macroglossia to return if there is considerable weight gain.
Arm 2:
Control intervention. Participants will not receive upper airway surgery.
Intervention code [1] 289031 0
Treatment: Surgery
Comparator / control treatment
Standard medical care - including advice about weight loss, avoiding sleeping in the supine position during sleep where relevant and other therapies such as nasal steroids. Participants can consider non surgical approaches used in the management of OSA (retrial of continuous positive airway pressure (CPAP), mandibular advancement splint (MAS) etc.) during the trial but not surgical reconstruction of the upper airway.
Control group
Active

Outcomes
Primary outcome [1] 291745 0
Change in daytime sleepiness as measured by Epworth Sleepiness Scale
Timepoint [1] 291745 0
at baseline and at 1, 3 and 6 months after baseline measurements.
Primary outcome [2] 291746 0
Change in Apnoea-Hypopnoea Index (AHI) as assessed by overnight laboratory-attended sleep study
Timepoint [2] 291746 0
at baseline and at 6 months after baseline measurements
Secondary outcome [1] 307387 0
Change in mean sleep latency as measured by the Multiple Sleep Latency Test (MSLT), and objective laboratory sleepiness assessment.
Timepoint [1] 307387 0
at baseline and at 6 months after baseline measurements.
Secondary outcome [2] 307389 0
Change in sleep measures (arousal index, 3% oxygen desaturation index ODI, lowest oxygen desaturdation, % of time oxygen saturation less than 90%, proportion of complete responders [AHI < 10 at 6 months]) as assessed by polysomnography.
Timepoint [2] 307389 0
at baseline and at 6 months after baseline measurements.
Secondary outcome [3] 307390 0
Change in snoring severity as assessed by bed partner reporting using the Snoring Severity Scale questionnaire (also known as the Snoring Scale Score).
Timepoint [3] 307390 0
at baseline and at 3 and 6 months after baseline measurements.
Secondary outcome [4] 307391 0
Change in daily functioning and quality of life due to sleep disorders as measured by the Functional Outcomes of Sleep Questionnaire (FOSQ).
Timepoint [4] 307391 0
at baseline and at 6 months after baseline measurements
Secondary outcome [5] 307392 0
Change in health-related quality of life as assessed using the European Quality of Life - 5 dimensions questionnaire (EQ-5D-5L).
Timepoint [5] 307392 0
at baseline and at 3 and 6 months after baseline measurements.
Secondary outcome [6] 307393 0
Change in health status produced by surgical intervention measured by the Glasgow Benefit Inventory questionnaire.
Timepoint [6] 307393 0
at 6 months after baseline measurements.
Secondary outcome [7] 307394 0
Measure of indirect costs of the medical intervention from a societal perspective as measured by the Institute for Medical Technology Assessment Productivity Cost Questionnaire (iPCQ).
Timepoint [7] 307394 0
at baseline and at 1 and 6 months after baseline measurements.
Secondary outcome [8] 307395 0
Cardiovascular health as measured by morning, seated office blood pressure.
Timepoint [8] 307395 0
at baseline and at 3 and 6 months after baseline measurements.
Secondary outcome [9] 307396 0
Cardiovascular health as measured by 24 hour ambulatory blood pressure monitoring.
Timepoint [9] 307396 0
at baseline and at 6 months after baseline measurements.
Secondary outcome [10] 307397 0
Change in body measures (BMI, neck circumference, waist circumference, hip circumference) as measured using standard anthropometric measurement techniques.
Timepoint [10] 307397 0
at baseline and at 6 months after baseline measurements.
Secondary outcome [11] 307398 0
Imaging of surgery participants pre- and post-surgical intervention to develop a prediction model for complete responders. Change in airway total airway, tongue fat and tongue volume will be measured by magnetic resonance imaging (MRI) of the upper airway. Participants randomised to Arm 1 only.
Timepoint [11] 307398 0
at baseline and at 6 months after baseline measurements.
Secondary outcome [12] 307399 0
Change in percentage and pattern of airway collapse at the velopharynx and tongue base as assessed by fibreopticpharyngoscopy (nasendoscopy). Participants randomised to Arm 1 only.
Timepoint [12] 307399 0
at baseline and at 6 months after baseline measurements.
Secondary outcome [13] 307400 0
Adherence to other OSA therapies (i.e. continuous positive airway pressure [CPAP] or mandibular advancement splint [MAS] adherence) as measured by CPAP compliance download or device use reporting.
Timepoint [13] 307400 0
at baseline and at 3 and 6 months after baseline measurements.

Eligibility
Key inclusion criteria
- Diagnosis of OSA (defined as Apnoea Hypopnoea Index, AHI, > 15 scored by AASM 2007 alternate criteria).
- At least mild daytime sleepiness defined as ESS (Epworth Sleepiness Scale) > 8. We used this cut point to target those with at least mild daytime sleepiness, but consider that the requirement for the ESS to be > 8 will not adversely affect recruitment.
- Failed CPAP treatment despite persistent, supervised attempts to implement CPAP, or been treated in a tertiary centre sleep lab or by an Australasian Sleep Association accredited sleep service and have not taken up CPAP when prescribed, and failed MAS therapy due to patient refusal, patient found to be unsuitable on dental grounds, patient intolerance, or were never offered MAS as a treatment option.
- CPAP treatment reduces AHI to below 15 events per hour of sleep (N/A for outright refusers of CPAP).
- Aged between 18 and 70 years.
- Body mass index (BMI) less than or equal to 38kg/m2. a) For patients with BMI 35-38: patient will be deemed appropriate provided they are of strong surgical/anatomical suitability, which consists of size 3-4 tonsil, with Friedman tongue 1-2, and dynamic assessment confirming predominant palatine tonsillar collapse
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Prior surgery on palate, tongue, mandible or maxilla. (Previous tonsillectomy is allowed.)
- Nasal obstruction uncontrolled by medication or surgery.
- Clinically significant retrognathia, confirmed by lateral skull x-ray (SNB angle < 72 degrees).
- Moderate to severe COPD (FEV/FVC ratio < 70% and FEV 1 <50%).
- Heart failure (New York Heart classes 2-4).
- Recent history (last 3 months) of a major cardiovascular event i.e. MI, unstable angina, CVA; or major disorder of the pulmonary, renal or nervous systems.
- Chronic narcotic use.
- Major depression i.e. hospitalisation for depression, suicide attempt or symptoms necessitating antidepressant drug dose escalation in the previous 3 months.
- Pregnant or breast feeding.
- Unacceptable anaesthetic or surgical risk (e.g. anticoagulant or antiplatelet medication which cannot be withdrawn).
- History of dysphagia or aspiration.
- Commercial driver.

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)
Once the responsible site-investigator is satisfied that all eligibility criteria have been met the subject will be randomly allocated into one of 2 groups. Allocation will be provided by a central allocation service (site research assistant will email the Pharmacy Department, Repatriation General Hospital, South Australia) to ensure concealment, documentation and integrity.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A minimisation program will be used to balance variables [study site (Repat, RAH, WOLL, MEM, SYD, Perth), gender (M, F), age (<50, greater than or equal to 50), AHI (<50, greater than or equal to 50) and BMI (<28, greater than or equal to 28)], and allocate participants to either the surgical intervention or expected medical 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)
Safety/efficacy
Statistical methods / analysis
Sample Size All calculations assume an overall two sided Type I error rate of 5%. We will sample 102 patients in total. Change in AHI Taking patients from our preliminary study with pre-op ESS>8 and an AHI>20 (n=17) we found the mean difference in AHI pre-post surgery was 33.4 with the SD of the change in AHI 27.3. From these data we calculate 24 patients will be needed in each arm in the present study to detect a >20 change in AHI with 80% power. Change in ESS: The mean (SD) change in ESS from our pilot data (in those who met the ESS/AHI criteria for this trial) was 7.5 (5.0) Thus to detect a change of 3-units in ESS between groups, where change is normally distributed, a total sample of 88 (44/arm) will provide 80% power to demonstrate superiority. When the change is non-normal the asymptotic relative efficiency of the Mann-Whitney U test compared to the t-test is >0.864 for any distribution of change scores under the alternative. Therefore a total sample of 102 gives at least 80% power to detect the same difference in change between groups using this non parametric test.
All analyses will be conducted on an intention to treat basis, and the trial conducted according to CONSORT guidelines. Any missing data will be imputed to replace missing data using multiple imputation. We will use two primary outcomes. The first will be change in AHI. Our pilot data shows a mean AHI of 29 at baseline. The clinical trial inclusion criteria (AHI >15, ESS >8) are likely to lead to a slightly higher mean AHI of around 35-40 in this trial at randomisation. We consider a mean AHI reduction in a cohort of >20 (i.e. more than 50% reduction) to be clinically meaningful and needed to justify cost and potential morbidity of surgery. The proportion of complete responders i.e. those who achieve an AHI < 10 will also be analysed using a chi square test, without a continuity correction.
Our other primary outcome will be change in ESS. Daytime sleepiness is one of the cardinal symptoms adversely affecting quality of life in OSA and the ESS is widely employed in the sleep literature as a measure of OSA treatment effectiveness. It is well validated, simple to perform and reproducible. We have set an a priori superiority margin of 3 in ESS change pre-post intervention between the groups. This is a slightly higher minimum difference than we have used in determining the sample size in RCTs of other OSA treatments as we believe clinicians would consider this change enough to justify the cost and potential morbidity of surgery in a patient with OSA. Change in ESS will be analysed using paired t-test if the data are normally distributed in both groups. In this case the normality and heteroscedasticity of residuals will be examined to validate the model. When the normality assumption is violated the non-parametric Mann-Whitney U test will be used to compare differences between groups.

Recruitment
Recruitment status
Completed
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,SA,WA
Recruitment hospital [1] 2214 0
Repatriation Hospital - Daw Park
Recruitment hospital [2] 2215 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 2216 0
Flinders Private Hospital - Bedford Park
Recruitment hospital [4] 2217 0
Memorial Hospital - North Adelaide
Recruitment hospital [5] 2218 0
Wollongong Hospital - Wollongong
Recruitment hospital [6] 2219 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 2220 0
Figtree Private Hospital - Figtree
Recruitment hospital [8] 6541 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [9] 8651 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 16759 0
2065 - Royal North Shore Hospital
Recruitment postcode(s) [2] 14127 0
2065 - St Leonards
Recruitment postcode(s) [3] 7897 0
2500 - Wollongong
Recruitment postcode(s) [4] 7898 0
2525 - Figtree
Recruitment postcode(s) [5] 7895 0
5000 - Adelaide
Recruitment postcode(s) [6] 7896 0
5006 - North Adelaide
Recruitment postcode(s) [7] 7893 0
5041 - Daw Park
Recruitment postcode(s) [8] 7894 0
5042 - Bedford Park
Recruitment postcode(s) [9] 16758 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 288947 0
Government body
Name [1] 288947 0
National Health and Medical Research Council
Address [1] 288947 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 288947 0
Australia
Funding source category [2] 288948 0
Charities/Societies/Foundations
Name [2] 288948 0
The Repat Foundation
Address [2] 288948 0
The Repat Foundation
Repatriation General Hospital
216 Daws Rd, Daw Park SA 5041
Country [2] 288948 0
Australia
Funding source category [3] 288949 0
University
Name [3] 288949 0
Flinders University
Address [3] 288949 0
Flinders University
Grants and Contracts
GPO Box 2100
Adelaide SA 5001
Country [3] 288949 0
Australia
Primary sponsor type
Individual
Name
Prof. R. Doug McEvoy
Address
Adelaide Institute for Sleep Health
Repatriation General Hospital, C-Block
202-216 Daws Road, Daw Park, SA 5041
Country
Australia
Secondary sponsor category [1] 287629 0
Other
Name [1] 287629 0
Adelaide Institute for Sleep Health
Address [1] 287629 0
Adelaide Institute for Sleep Health
Repatriation General Hospital, C-Block
202-216 Daws Road, Daw Park, SA 5041
Country [1] 287629 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290766 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 290766 0
Southern Adelaide Clinical HREC
The Flats, G5 - Rooms 3 and 4
Flinders Drive
Flinders Medical Centre
Bedford Park SA 5042
Ethics committee country [1] 290766 0
Australia
Date submitted for ethics approval [1] 290766 0
Approval date [1] 290766 0
08/11/2013
Ethics approval number [1] 290766 0
394.13

Summary
Brief summary
Obstructive sleep apnoea (OSA) is characterised by repeated upper airway obstructions during the night. OSA is associated with excessive daytime sleepiness, lower health status and studies suggest obstructed breathing and snoring in sleep are independent risk factors for high blood pressure, heart disease, stroke and mortality. Thus OSA is a serious and costly public health problem that is growing in prevalence because of population increases in both obesity and ageing.
Continuous positive airway pressure (CPAP) therapy is the current treatment of choice for patients with OSA. CPAP is effective in decreasing sleepiness and improves quality of life in patients with OSA. Treatment of OSA with CPAP is cost-effective if worn, but CPAP is poorly tolerated by many patients who find the mask and pressure claustrophobic and uncomfortable. OSA can be effectively treated but poor treatment compliance is a major clinical problem and thus many patients are under treated or not treated at all.
Upper airway surgery for OSA is widely used and reported in observational studies but there are few rigorous and randomized clinical trials to provide and validate these studies. The clinical effectiveness and cost effectiveness of this surgical intervention need to be validated.
This study is a national, multi-centre, randomised, controlled trial with a recruitment target of 102 participants. Participants with OSA who have failed standard OSA treatments will be randomised into two groups: Group 1 will receive reconstructive surgery of the upper airway and Group 2 will receive the standard non-surgical care for OSA. Participants will undergo follow-up for 6 months.
Study participants will be tested for OSA, daytime sleepiness levels, and quality of life improvements before the treatment and at 6 months follow-up. Magnetic resonance imaging of the upper airway will also be used on participants randomised to Group 1, before the surgery and at 6 months, with the aim of developing a prediction model for future patients who will benefit the most from surgery.
The study will be carried out at five sites across Australia to examine the universal effect of this standardised surgical protocol.

AIM: To establish for the first time whether or not upper airway surgery is clinically effective, safe and cost effective for patients with symptomatic OSA who have failed medical management

HYPOTHESIS: Surgery will deliver a better treatment outcome than ongoing medical management of symptomatic OSA as measured by the improvement in Apnoea Hypopnea Index (AHI) and subjective and objective daytime sleepiness in patients who have failed CPAP treatment despite persistent, supervised attempts.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 47134 0
Prof R. Doug McEvoy
Address 47134 0
Flinders University
AISH
GPO Box 2100
ADELAIDE SA 5001
Country 47134 0
Australia
Phone 47134 0
+61 8 7221 8319
Fax 47134 0
+61 8 7221 8360
Email 47134 0
doug.mcevoy@flinders.edu.au
Contact person for public queries
Name 47135 0
Dr Alison Pinczel
Address 47135 0
Flinders University
AISH
GPO Box 2100
ADELAIDE SA 5001
Country 47135 0
Australia
Phone 47135 0
+61 8 7221 8312
Fax 47135 0
+61 8 7221 8360
Email 47135 0
alison.pinczel@flinders.edu.au
Contact person for scientific queries
Name 47136 0
Prof Doug McEvoy
Address 47136 0
Flinders University
AISH
GPO Box 2100
ADELAIDE SA 5001
Country 47136 0
Australia
Phone 47136 0
+61 8 7221 8319
Fax 47136 0
+61 8 7221 8360
Email 47136 0
doug.mcevoy@flinders.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary