Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613001177741
Ethics application status
Approved
Date submitted
22/10/2013
Date registered
28/10/2013
Date last updated
8/06/2022
Date data sharing statement initially provided
5/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating breathing training for lung cancer radiotherapy
Scientific title
Multi-institutional, randomised clinical investigation of the breathing training system: audiovisual biofeedback to improve breathing regularity and reduce medical imaging errors for lung cancer patients undergoing radiotherapy.
Secondary ID [1] 283432 0
Nil known
Universal Trial Number (UTN)
U1111-1149-3840
Trial acronym
Audio-Visual Investigation Advancing Thoracic Radiotherapy (AVIATOR)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lung cancer 290345 0
Condition category
Condition code
Cancer 290740 290740 0 0
Lung - Non small cell
Cancer 290741 290741 0 0
Lung - Small cell
Cancer 290742 290742 0 0
Lung - Mesothelioma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There is a clear link between irregular breathing and errors in medical imaging and radiation treatment. To address the problem of irregular breathing, a respiratory guidance system has been developed by our research group: audiovisual (AV) biofeedback.
AV biofeedback is an interactive, personalised and non-invasive breathing training system designed to assist the patient to breathe regularly. AV biofeedback is comprised of the real-time position management (RPM) system and a visual display (e.g. monitor, tablet computer), none of which are of any risk to the patient. The system is designed to be easily implemented into any treatment or imaging facilities.
The patient views the tablet screen which displays their breathing pattern to them based on the real-time respiratory motion captured by the RPM system.
AV biofeedback will be used during every radiotherapy and imaging session. As for the period and frequency of such sessions, it will vary from site to site and between patients depending on the type of treatment prescribed to them (e.g. 3D-conformal, stereotactic body radiation therapy, or intensity-modulated radiation therapy).
Patients in the intervention arm will undergo a screening procedure that will determine what breathing condition is best used for their treatment: either free breathing or AV biofeedback. This will take the form of a breathing session in which we will record the patient's free breathing and analyse the reproducibility of its amplitude and period. This will then be repeated using AV biofeedback, and which ever breathing condition resulted in the most reproducible breathing signal will be the one to continue to be used throughout the patient's imaging and treatment.
Intervention code [1] 288154 0
Treatment: Devices
Comparator / control treatment
Participants in the control group will take no part in any breathing training, they will simply undergo their conventional treatment with no intervention.
Control group
Active

Outcomes
Primary outcome [1] 290742 0
The primary objective is to test the hypothesis that AV biofeedback will significantly improve breathing regularity for lung cancer patients undergoing imaging and treatment procedures during radiotherapy.
This outcome will be assessed based on a clinically significant reduction of treatment margins calculated using the van Herk method. A clinically significant difference in clinical improvement due to AV biofeedback has been determined to be a margin calculation of less than 5 mm.
Timepoint [1] 290742 0
18 months
Secondary outcome [1] 305145 0
Secondary patient-specific objectives are to evaluate the impact of AV biofeedback by: (1) Quantifying the fraction of patients for whom breathing is more regular with AV biofeedback, (2) Quantifying the variability in breathing motion throughout a course of treatment, (3) Quantify the improvement in image quality with AV biofeedback, (4) Evaluating the patient experience through a perception of care survey, (5) Developing indications and contraindications for the use of AV biofeedback, and (6) Quantifying the differences in image-guided radiotherapy (IGRT) shifts during treatment. (7) Recording toxicity outcomes for up to 12 months after treatment has been completed.
These objectives will be evaluated by: (1) Comparing the numbers of patients recruited in either the AV biofeedback or free breathing arms of the intervention arm. (2) Breathing regularity will be quantified as the root mean square error (RMSE) of respiratory displacement and period. (3) Image quality will be assessed both qualitatively and quantitatively. Quantitative analysis will utilize metrics such as normalized cross correlation-based score (NCCS), and visual assessment-based score (VAS) (4) Patients will be asked to complete the survey after their final treatment. (5) An analysis comparing patient demographics and study outcomes will be performed to determine who AV biofeedback is best suited for. (6) The number and magnitude of couch shifts during treatment will be compared between AV biofeedback and free breathing. (7) Radiation oncologists will complete a toxicity report up to 12 months after treatment has finished.
Timepoint [1] 305145 0
24 months
Secondary outcome [2] 305168 0
Secondary department-specific objectives are to evaluate the impact of AV biofeedback on clinical testing by:
(1) Quantifying any practice changes (e.g. margin reduction),
(2) Quantifying the impact on workflow using the AV biofeedback system through time-motion studies,
(3) Evaluating the operator and clinician confidence in the AV biofeedback system’s reliability and clinical efficacy through a technology-impact survey,
(4) Quantifying the system robustness through hardware and software fault reporting, and
(5) Performing system quality assurance, sharing the results through a web-based upload and provide feedback for QA improvement.

These objectives will be evaluated by:
(1) Margins will compared both qualitatively and quantitatively. Quantitative analysis will be performed by combining random and systematic errors as a result of irregular respiration that occur during treatment.
(2) Times will be recorded during imaging and treatment to determine the additional time required for the use of AV biofeedback.
(3) Clinicians will be asked to complete a survey concerning their confidence in the AV biofeedback system.
(4) Clinicians will report hardware and software issues, whether they be broken equipment or bugs in the software.
(5) Based on point (4) in addition to clinical input to streamline AV biofeedback integration with clinical workflow, the quality assurance process of AV biofeedback will be optimised.
Timepoint [2] 305168 0
24 months

Eligibility
Key inclusion criteria
1) Lung cancer patients (no restrictions to type of radiotherapy being received)
2) >18 years old
3) No gender or ethnic restrictions
4) An ECOG score in the range of 0 to 2
5) Able to give written informed consent and willingness to participate and comply with the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Non-lung cancer patients
2) Pregnant / lactating woman
3) An ECOG score greater than 2

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)
Patients fitting the eligibility criteria will be identified and introduced to this study by their treating physicians who will participate as investigators in this study.
After the patient has agreed to participate in the study; the data manager for that site will contact the University of Sydney Randomisation Group on a toll-free number and enter (1) the site where the patient was recruited (e.g. Royal North Shore Hospital), and (2) the patient's treatment intent (either radical or palliative).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
For the method of randomisation we plan to use minimisation to randomly allocate patients in the trial.

Patients will be randomised in a 2:1 ratio, with 2/3 of the patients being recruited into the AV biofeedback (intervention) arm and 1/3 in the free breathing (control) arm. 2:1 randomisation is appropriate as within the interventional arm there is a screening procedure where only patients whose breathing is more regular with AV biofeedback use this system for their imaging and treatment procedures.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
There are three possible arms the patient may go down in this study, two possible intervention arms and one control arm.
Intervention arm: 2/3 of the patients being recruited into the AV biofeedback (intervention) arm. From here, each patient will undergo a screening procedure in which they will breathe with and without the guidance of AV biofeedback, and the most regular breathing condition (either free breathing or AV biofeedback) will be utilised for the remainder of their imaging and treatment. Those patients who go down the intervention arm, but get screened for free breathing, will not join the control arm, as they have been exposed to AV biofeedback and we want to avoid contaminating the control group; they will form the free breathing intervention arm.
Control arm: 1/3 of patients will go down the free breathing (control) arm, having no experience or exposure to AV biofeedback.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The statistical considerations for this study are largely based on a previous study conducted at Virginia Commonwealth University (VCU) by the chief investigator, Prof Paul Keall, on 24 lung cancer patients. A clinically significant different in clinical improvement due to AV biofeedback has been determined to be a margin calculation of less than 5 mm. Irregular breathing causes larger systematic errors (S) from motion artefacts and variations between the planned and treated anatomy as well as random day to day variations (s) in the treated anatomy. To combine systematic and random errors and estimate the margin contribution due to breathing irregularity we will use the van Herk method: margin = 2.5S + 0.7s. From this calculation, there were 14/24 patients with margins <5 mm with AV biofeedback, while only 5/24 for free breathing in the VCU study.

In this proposed study, we’d like to increase the proportion of patients with reduced margins calculated using the van Herk method. Therefore we have designed an exploratory phase II randomised study examining the potential impact of an AV biofeedback system in regulating breathing in patients receiving radiation therapy for the treatment of lung cancer. Without this system, it is conservatively estimated that approximately 40% of patients experience regular breathing (margin component below 5 mm). Increasing this proportion to 60% using the AV biofeedback system would be clinically worthwhile. Based on Simon’s design, a sample size of 50 patients receiving the AV biofeedback system will have at least 80% power with 95% confidence to rule out a regular rate of 40% in favour of a 60% rate.

To minimise patient selection bias and provide an estimate of regular breathing from a contemporary control, the proposed design will be a randomized phase II with a 50 patients receiving the intervention and 25 standard care. Patients will be randomised in a 2:1 ratio, with 2/3 of the patients being recruited into the AV biofeedback (intervention) arm and 1/3 in the free breathing (control) arm.

Patients will be stratified by treating institution and for treatment intent (palliative vs. radical) to ensure similar balance in the arms across the sites. As the study is not powered for formal comparisons between the groups, estimates of the proportion of patients which do not experience irregular breathing will provide information as to whether further investigation is warranted.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
10/09/2014
Actual
11/04/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
75
Accrual to date
22
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW
Recruitment hospital [1] 2935 0
The Canberra Hospital - Garran
Recruitment hospital [2] 2936 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [3] 2939 0
Westmead Hospital - Westmead
Recruitment hospital [4] 2941 0
Nepean Hospital - Kingswood

Funding & Sponsors
Funding source category [1] 288152 0
Government body
Name [1] 288152 0
NHMRC Development Grant
Country [1] 288152 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Sydney Medical School - Central
The University of Sydney
NSW 2006
Australia
Country
Australia
Secondary sponsor category [1] 286888 0
None
Name [1] 286888 0
Address [1] 286888 0
Country [1] 286888 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290068 0
Hunter New England Ethics Committee
Ethics committee address [1] 290068 0
Ethics committee country [1] 290068 0
Australia
Date submitted for ethics approval [1] 290068 0
Approval date [1] 290068 0
07/10/2013
Ethics approval number [1] 290068 0
12/08/21/4.01

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43778 0
Prof Paul Keall
Address 43778 0
The University of Sydney, ACRF Image X Institute, Suite 201, Biomedical Building - C81, 1 Central Avenue, South Eveleigh, NSW 2015
Country 43778 0
Australia
Phone 43778 0
+61 2 8627 1159
Fax 43778 0
Email 43778 0
[email protected]
Contact person for public queries
Name 43779 0
Youssef Ben Bouchta
Address 43779 0
The University of Sydney, ACRF Image X Institute, Suite 201, Biomedical Building - C81, 1 Central Avenue, South Eveleigh, NSW 2015
Country 43779 0
Australia
Phone 43779 0
+61 2 9114 2199
Fax 43779 0
-
Email 43779 0
[email protected]
Contact person for scientific queries
Name 43780 0
Paul Keall
Address 43780 0
The University of Sydney, ACRF Image X Institute, Suite 201, Biomedical Building - C81, 1 Central Avenue, South Eveleigh, NSW 2015
Country 43780 0
Australia
Phone 43780 0
+61 2 8627 1159
Fax 43780 0
Email 43780 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No provision for this in the protocol or consent


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.