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Trial registered on ANZCTR


Registration number
ACTRN12620000837921
Ethics application status
Approved
Date submitted
26/06/2020
Date registered
24/08/2020
Date last updated
24/08/2020
Date data sharing statement initially provided
24/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Characterising ocular blood flow changes with an exercise stimulus using optical coherence tomography angiography (OCT-A).
Scientific title
Characterising ocular blood flow changes with an exercise stimulus using optical coherence tomography angiography (OCT-A) in healthy, normal tension glaucoma and diabetic retinopathy patients.
Secondary ID [1] 301635 0
None
Universal Trial Number (UTN)
U1111-1254-2749
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Normal Tension Glaucoma 318049 0
Diabetic Retinopathy 318050 0
Condition category
Condition code
Eye 316079 316079 0 0
Diseases / disorders of the eye
Cardiovascular 316080 316080 0 0
Normal development and function of the cardiovascular system
Metabolic and Endocrine 316081 316081 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants (healthy controls, patients with normal tension glaucoma and diabetic retinopathy) will perform an isometric handgrip exercise for 3 minutes at 30% of their predetermined force of maximal voluntary contraction. Measurements of biological parameters; Systolic Blood Pressure, Diastolic Blood Pressure, Pulse Rate, and Intraocular Pressure, will be recorded with concurrent OCT-A scans of the macular and optic nerve head regions of one eye.

These measurements will be taken at the following time points:
Baseline 1: 20 minutes before sustained contraction
Baseline 2: 10 minutes before sustained contraction
Intra-Exercise Period: 2 minutes into sustained contraction
Post-Exercise: 10 minutes after the cessation of exercise

Intervention Name: (1) Optical Coherence Tomography Angiography (OCT-A)
* OCT-A is a novel imaging technique which enables rapid, non-invasive, three dimensional imaging of the retinal and choroidal vasculature.
* OCT-A will be performed using the DRI OCT Triton swept source OCT (DRI OCT Triton, TOPCON, Tokyo, Japan).
* Performed by a medical student researcher with prior computer-based and face-to-face OCT-A training.
* Administered four times during the study (two scans at each time point), taking approximately 1 minute for complete examination of one eye at each time point.
* For healthy controls and diabetic retinopathy patients, the dominant eye will be selected, for patients with glaucoma the worse eye (as determined by visual field index) will be selected
* OCT-A images will be evaluated for presence and severity of artefacts using a validated grading system, then processed using a custom approach to determine vessel density (as a surrogate measure for ocular blood flow).
* Any urgent clinical considerations discovered on routine image review are discussed with the treating ophthalmologist.

Intervention Name: (2) Hand Held Dynamometer
* Isometric exercise (handgrip) induces a characteristic rise in systemic blood pressure, heart rate, and sympathetic activity. These parameters are determinants of ocular blood flow.
* The handgrip exercise will be performed using a digital hand dynamometer (Jamar Plus+, Sammons Preston, Rolyon, Bolingbrook, IL) in accordance with the National Health and Nutrition Examination Survey (NHANES) protocol.
* Patients will be taught the correct technique by a medical student researcher.
* Maximal voluntary contraction (MVC) of the forearm will be performed 3 times (3 seconds each) prior to commencement of sustained contraction. Contraction will then be sustained at 30% of the MVC for 3 minutes. All contractions will be performed in a seated position.
Intervention code [1] 317940 0
Diagnosis / Prognosis
Intervention code [2] 317941 0
Early detection / Screening
Comparator / control treatment
A group of healthy volunteers undergoing the same intervention (OCT-A with isometric handgrip exercise) will be the control group.
Control group
Active

Outcomes
Primary outcome [1] 324274 0
To measure the change in peripapillary vessel density (arbitrary units; % difference) induced by isometric exercise using optical coherence tomography angiography (6x6mm scan) in healthy patients, and patients with normal tension glaucoma or diabetic retinopathy.
Timepoint [1] 324274 0
20 minutes prior to exercise, 10 minutes prior to exercise, 2 minutes into exercise (primary timepoint), and 10 minutes post-exercise.
Primary outcome [2] 324275 0
To measure the change in macular vessel density (arbitrary units; % difference) induced by isometric exercise using optical coherence tomography angiography (6x6mm scan) in healthy patients, and patients with normal tension glaucoma or diabetic retinopathy.
Timepoint [2] 324275 0
20 minutes prior to exercise, 10 minutes prior to exercise, 2 minutes into exercise (primary timepoint), and 10 minutes post-exercise.
Secondary outcome [1] 384235 0
To establish the diagnostic accuracy of isometric-exercise OCT-A changes for determining healthy versus glaucomatous or diabetic eyes.
* OCTA changes will be determined by image intensity binarisation using a mean algorithm to give a validated measure of vessel density in arbitrary units
* Images at each timepoint will be co-registered to ensure comparable regions of interest are analysed
* Diagnostic accuracy will be measured using area under a Receiver Operator Characteristic curve, with cutoffs for sensitivity and specificity reported.
Timepoint [1] 384235 0
After image and data analysis.

Eligibility
Key inclusion criteria
Participation will be offered to patients aged between 18-75 years who attend the Port Macquarie Eye Centre (PMEC).

* Healthy controls: patients who attend the clinic for treatment of non-glaucomatous and non-diabetic issues.
* Normal tension glaucoma patients: normal tension glaucoma diagnosed by treating ophthalmologist with a peak IOP <21mmHg.
* Diabetic retinopathy patients: patients with diabetic retinopathy of ICDRSS grade mild or moderate without diabetic macular oedema.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
* Inability to provide informed consent/assent
* Inability to sit at OCT/A
* Hand pathology: chronic hand pain due to any cause, broken skin on the palm or fingers, Rheumatoid Arthritis, hand surgery in the last 3 months
* Ocular pathology: cataracts of nuclear sclerotic grade >2+, refraction spherical equivalent < -3D or > +3D, prior corneal surgery or significant corneal disease, prior glaucoma drainage surgery, cataract surgery within the last 3 months
* Current known pregnancy
* Potentially vasoactive systemic or topical medications: blood pressure treatment particularly beta-blockers, calcium channel blockers, or alpha agonists

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Single group
Other design features
Randomised OCT-A assessment will. be conducted by researchers masked to clinical and enrolment criteria
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Power Calculation:
For the pilot study to detect a 4% difference in PRI pre-vs post isometric exercise amongst healthy controls (assuming a 1.5% standard deviation from comparable studies) with 80% power and a type 1 error rate of 5% would require 9 participants.

Statistical Methods:
* Data will be stored on the secure data management system REDCap.
* Statistical analyses will be performed using SPSS, with significance set at p<0.05.
* Descriptive statistics for continuous variables (mean, standard deviation, median, range) and categorical variables (frequency distributions) will be determined to outline participant characteristics.
* Paired t-tests will be used to compare means of baseline and isometric exercise stimulus peripapillary and macular vessel densities.
* ANOVA and Tukey post-hoc analysis will be used to measure differences in variables between healthy controls, glaucomatous and diabetic eyes.
* Coefficients of variation will be used to measure intra-session reproducibility and repeatability.
* Diagnostic accuracy for determining healthy versus diseased eyes will be established (Sn + Sp) and an optimal cut-off for diagnosis using Euclidean distances. Accuracy will be measured using area under a Receiver Operator Characteristic curve.

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] 16988 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment postcode(s) [1] 30651 0
2444 - Port Macquarie

Funding & Sponsors
Funding source category [1] 306072 0
University
Name [1] 306072 0
University of NSW, Rural Clinical School
Address [1] 306072 0
26 Highfields Circuit
Port Macquarie,
NSW, 2444
Country [1] 306072 0
Australia
Primary sponsor type
University
Name
University of NSW, Rural Clinical School
Address
26 Highfields Circuit
Port Macquarie,
NSW, 2444
Country
Australia
Secondary sponsor category [1] 306533 0
None
Name [1] 306533 0
Address [1] 306533 0
Country [1] 306533 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306294 0
RANZCO Human Research Ethics Committee
Ethics committee address [1] 306294 0
94-98 Chalmers St, Surry Hills, NSW, 2010
Ethics committee country [1] 306294 0
Australia
Date submitted for ethics approval [1] 306294 0
Approval date [1] 306294 0
05/11/2019
Ethics approval number [1] 306294 0
HC No. 104.19

Summary
Brief summary
Glaucoma is a chronic, progressive degeneration of the optic nerve which results in visual loss from the peripheral visual field, creeping towards complete blindness. It is the leading cause of irreversible blindness worldwide and in Australia. There are many sight-saving treatments available, but identifying who is likely to worsen is a critical step to intervening for the right patients.

Problems with the blood flow to the back of the eye have been identified as a significant contributing factor in glaucoma, and may occur early in the pathophysiology of diabetic retinopathy. A new imaging technique called optical coherence tomography angiography (OCT-A) allows rapid, non-invasive imaging of the blood flow of the optic nerve. The blood flow at the back of the eye changes in response to the blood pressure and the pressure inside the eye (IOP). Isometric exercise (a simple handgrip test) is a simple, yet reliable method to increase blood pressure temporarily. This study will help determine if we can detect the changes in blood flow using OCT-A, and whether the changes are different between healthy people and people with glaucoma or diabetes.

In future, this research may help to generate clinical tests to detect glaucoma or diabetes earlier, or pick who will get worse and therefore would benefit from more treatment to prevent vision loss.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103394 0
Dr Hamish Dunn
Address 103394 0
Port Macquarie Eye Centre
35 Ackroyd St,
Port Macquarie, NSW, 2444
Country 103394 0
Australia
Phone 103394 0
+61 2 6584 5554
Fax 103394 0
Email 103394 0
hamish.dunn@sydney.edu.au
Contact person for public queries
Name 103395 0
Dr Hamish Dunn
Address 103395 0
Port Macquarie Eye Centre
35 Ackroyd St,
Port Macquarie, NSW, 2444
Country 103395 0
Australia
Phone 103395 0
+61 2 6584 5554
Fax 103395 0
Email 103395 0
hamish.dunn@sydney.edu.au
Contact person for scientific queries
Name 103396 0
Dr Hamish Dunn
Address 103396 0
Port Macquarie Eye Centre
35 Ackroyd St,
Port Macquarie, NSW, 2444
Country 103396 0
Australia
Phone 103396 0
+61 2 6584 5554
Fax 103396 0
Email 103396 0
hamish.dunn@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual de-identified patient data underlying published results.
When will data be available (start and end dates)?
Beginning 6 months after and ending 3 years after publication of main results.
Available to whom?
Researchers who provide a methodologically sound proposal on a case-by-case basis with approval obtained through the relevant ethics committee.
Available for what types of analyses?
IPD for meta-analyses and other analyses on a case-by-case basis.
How or where can data be obtained?
Application to investigators (contact: hamish.dunn@sydney.edu.au).
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 8348 0
Study protocol
Citation [1] 8348 0
Link [1] 8348 0
Email [1] 8348 0
hamish.dunn@sydney.edu.au
Other [1] 8348 0
Attachment [1] 8348 0
Type [2] 8349 0
Informed consent form
Citation [2] 8349 0
Link [2] 8349 0
Email [2] 8349 0
hamish.dunn@sydney.edu.au
Other [2] 8349 0
Attachment [2] 8349 0
Type [3] 8350 0
Ethical approval
Citation [3] 8350 0
Link [3] 8350 0
Email [3] 8350 0
hamish.dunn@sydney.edu.au
Other [3] 8350 0
Attachment [3] 8350 0
Summary results
No Results