ANZCTR - Registration

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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

20/06/2022

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]

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

Diabetic Retinopathy

Condition category

Condition code

Eye

Diseases / disorders of the eye

Cardiovascular

Normal development and function of the cardiovascular system

Metabolic and Endocrine

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]

Diagnosis / Prognosis

Intervention code [2]

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]

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]

20 minutes prior to exercise, 10 minutes prior to exercise, 2 minutes into exercise (primary timepoint), and 10 minutes post-exercise.

Primary outcome [2]

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]

20 minutes prior to exercise, 10 minutes prior to exercise, 2 minutes into exercise (primary timepoint), and 10 minutes post-exercise.

Secondary outcome [1]

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]

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

Sex

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

Recruiting

Date of first participant enrolment

Anticipated

28/08/2020

Actual

31/08/2020

Date of last participant enrolment

Anticipated

1/12/2023

Actual

Date of last data collection

Anticipated

1/12/2023

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Port Macquarie Base Hospital - Port Macquarie

Recruitment postcode(s) [1]

2444 - Port Macquarie

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of NSW, Rural Clinical School

Address [1]

26 Highfields Circuit
Port Macquarie,
NSW, 2444

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

RANZCO Human Research Ethics Committee

Ethics committee address [1]

94-98 Chalmers St, Surry Hills, NSW, 2010

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

05/11/2019

Ethics approval number [1]

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

Dr Hamish Dunn

Address

Port Macquarie Eye Centre
35 Ackroyd St,
Port Macquarie, NSW, 2444

Country

Australia

Phone

+61 2 6584 5554

Fax

hamish.dunn@sydney.edu.au

Contact person for public queries

Name

Hamish Dunn

Address

Port Macquarie Eye Centre
35 Ackroyd St,
Port Macquarie, NSW, 2444

Country

Australia

Phone

+61 2 6584 5554

Fax

hamish.dunn@sydney.edu.au

Contact person for scientific queries

Name

Hamish Dunn

Address

Port Macquarie Eye Centre
35 Ackroyd St,
Port Macquarie, NSW, 2444

Country

Australia

Phone

+61 2 6584 5554

Fax

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?

Doc. No.	Type	Email
8348	Study protocol	hamish.dunn@sydney.edu.au
8349	Informed consent form	hamish.dunn@sydney.edu.au
8350	Ethical approval	hamish.dunn@sydney.edu.au

Results publications and other study-related documents

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