ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621000624886

Ethics application status

Approved

Date submitted

29/03/2021

Date registered

24/05/2021

Date last updated

16/11/2021

Date data sharing statement initially provided

24/05/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

The brolucizumab anti-vascular endothelial growth factor (anti-VEGF) treatment of Age-Related Macular Degeneration (AMD) Switch Study,

Scientific title

A twelve month, unmasked, prospective study evaluating the effectiveness of the anti-VEGF brolucizumab to increase the interval between treatments, while controlling disease activity, in subjects with neovascular AMD resistant to extension of current anti-VEGF treatment beyond 4 to 8 weeks.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

BRAVAS

Linked study record

Health condition

Health condition(s) or problem(s) studied:

wet age related macular degeneration

Condition category

Condition code

Eye

Diseases / disorders of the eye

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The study treatment will be administered by one of the study doctors (opthalmologists) who are all experienced in administering intravitreal injection procedures.
The study treatment will be provided in pre-filled syringes containing 0.165 ml of brolucizumab at a concentration of 120 mg per mL (19.8 mg in total).
The treating ophthalmologist will inject 6 mg/0.05 ml of brolucizumab into the vitreous cavity.
Eligible participants will be treated with three (loading) doses of 6mg intravitreal brolucizumab at day 0, week 4 and week 8. Thereafter they will be treated according to a treat and extend regimen where the treatment interval will be extended based on the investigators assessment of active disease activity based on predetermined criteria normally used in clinical practice:
• the presence of retinal fluid on optical coherence tomography (SD-OCT) or
• evidence of any new retinal haemorrhage and/or
• a reduction in vision (BCVA) of 5 letters or more (deemed attributable to wAMD) since commencing the study.
A participant’s treatment interval may be extended by two weeks if none of the above criteria are met. If previously extended the treatment interval may be reduced by two, or four, weeks based on the presence of one or more signs of active disease. The minimum interval between treatments will be 4 weeks. The longest interval between treatments will be 12 weeks.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

The proportion of participants with persistent retinal fluid between baseline and 48 weeks after switching to brolucizumab.
The presence of retinal fluid will be determined by Spectral domain optical coherence tomography (SD-OCT).

Timepoint [1]

Baseline and 48 weeks after switching to study intervention.
Study visits will be scheduled every 4 weeks from baseline.
The presence of retinal fluid will be determined by Spectral domain optical coherence tomography (SD-OCT). The presence or absence of retinal fluid will determine the participants treatment interval.
The presence or absence of retinal fluid at baseline and 48 weeks will be used to determine the primary outcome.

Primary outcome [2]

Mean change in Central Retinal Thickness as measured by SD-OCT

Timepoint [2]

Baseline and 48 weeks after study intervention.
Study visits will be scheduled every 4 weeks from baseline.
Central retinal thickness will be measured at each visit: baseline to 48 weeks.
The primary outcome will be the change observed between baseline and:
at 48 weeks .

Secondary outcome [1]

The proportion of participants with treatment intervals extended beyond baseline frequency as recorded in the participants medical records (source documentation).

Timepoint [1]

Baseline and 48 weeks after switching to study intervention.
The participants, recorded, treatment frequency immediately before study treatment initiation and after 48 weeks will be used to assess this outcome

Secondary outcome [2]

The mean change in treatment interval extension over the course of the study.
Based on the treatment intervals recorded in the participants medical records (source documentation)

Timepoint [2]

Baseline and 48 weeks after switching to study intervention

Secondary outcome [3]

The proportion of patients who maintain or improve their BCVA over the course of the study as measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart..
(Defined as no more than a 5 letter loss or more than a 5 letter gain in BCVA, respectively, between baseline and 48 weeks after switching.)

Timepoint [3]

Baseline and 48 weeks post switching to study intervention.
Study visits will be scheduled every 4 weeks from baseline.
The participants BCVA, scored using the ETDRS chart, will be measured at each visit. The BCVA score will be used to determine the participants treatment interval.
The BCVA score at baseline and 48 weeks will be used to derive the outcome measure.

Secondary outcome [4]

Mean change in BCVA score ( measured by ETDRS chart) between baseline and 48 weeks after switching to study intervention.

Timepoint [4]

48 weeks after switching to study intervention.
Study visits will be scheduled every 4 weeks from baseline.
The participants BCVA, scored using the ETDRS chart, will be measured at each scheduled study visit. The BCVA score will be used to determine the participants treatment interval.
The BCVA score at baseline and 48 weeks will be used to derive the outcome measure.

Secondary outcome [5]

Mean change in National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) score between baseline and 48 weeks after switching to study intervention.

Timepoint [5]

Baseline and 48 weeks after switching to study intervention

Secondary outcome [6]

Incidence and severity of all adverse events over the study period as recorded in the participants medical records ( source documents).

Timepoint [6]

Over course of study from baseline to 48 weeks after switching to study intervention.

Secondary outcome [7]

Proportion of participants with resolution of intra-retinal fluid (IRF) based on images from SD-OCT.

Timepoint [7]

Baseline and 48 weeks
Study visits will be scheduled every 4 weeks from baseline.
OCT-SD images will be taken at all scheduled study visits over the course of the study.
Images at baseline and 48 weeks after switching to study intervention will be used to determine the study outcome.

Secondary outcome [8]

Proportion of participants with resolution of sub-retinal fluid (SRF) based on images from SD-OCT.

Timepoint [8]

Secondary outcome [9]

Proportion of participants with resolution of retinal pigment epithelial detachment (PED) based on images from SD-OCT.

Timepoint [9]

Secondary outcome [10]

Proportion of patients who have no evidence of retinal fluid on SD-OCT (stable disease) throughout the study.

Timepoint [10]

Study visits will be scheduled every 4 weeks from baseline.
OCT-SD images will be taken at all scheduled study visits over the course of the study.

Eligibility

Key inclusion criteria

• Ability to provide written informed consent and complete study assessments
• Age 50 years or older
• Confirmed diagnosis of CNV secondary to AMD
• Best corrected visual acuity between 6/6 and 6/60 (85-35 letters), on Early Treatment Diabetic Retinopathy (ETDRS) charts, at baseline
• Currently being treated with regular, approximately 4-8 weekly, intravitreal anti-VEGF injections, for a minimum of six months
• At least one attempt at extending their anti-VEGF treatment regimen beyond the current dosing interval
• SD-OCT evidence of IR, SR, sub RPE fluid or cystoid oedema (but not intra-retinal cysts alone) less than 60 days since last anti-VEGF injection OR who have had a recurrence of IR, SR, sub RPE fluid or cystoid oedema when treatment intervals are extended.

Minimum age

50 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Pregnant or nursing (lactating) women
• Pre or peri-menopausal women not using contraception
• Prior anti-VEGF injection in the study eye within 30 days of baseline
• Prior treatment with photo dynamic therapy (PDT) within 90 days of baseline and more than 6 prior PDT treatments
• Significant sub retinal fibrosis, atrophy or other structural change in the retina that might affect the study outcomes.
• Prior treatment with intravitreal steroid treatment in the study eye within 6 months of baseline
• Intraocular surgery in the study eye within 3 months of baseline ( excepting cataract surgery)
• Prior vitrectomy or other surgical intervention for AMD in the study eye
• Current vitreous haemorrhage or active intraocular inflammation in the study eye
• Uncontrolled glaucoma in the study eye. Intraocular pressure (IOP) greater than 30mmHg on maximal medical therapy.
• History of stroke, acute myocardial infarction and transient ischemic attack within 3 months of study enrolment
• Allergy to fluorescein.
• Known intolerance to brolucizumab or any of its constituents
• Concurrent use of systemic or intravenous anti-VEGF agents
• Use of any medications known to be toxic to the eye (except for those used short term for the treatment of COVID-19 infection)
• Use of any other unstable medical condition that may potentially affect the study outcomes or the participant’s ability to participate in the study.
• Participation in any other clinical trials.

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

None

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

None

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Phase 4

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

The analysis will include descriptive statistics such: the number, mean, standard deviations, median, range and confidence intervals for continuous variables and the frequencies and proportions of categorical variables.
Mean changes in continuous variables will be determined using paired t-tests. The presence of confounding may also be evaluated in regression models by including baseline covariates such as: the patient age, smoking status, disease status, duration of current treatment and study eye baseline visual acuity
Missing outcome measures values will be imputed by the last observation carried forward (LOCF) as the primary approach.
If required, analysis will be conducted on two datasets: Intention to treat (those consented and eligible who received at least 1 injection) and "as per protocol." ( patients who completed the study).
An internal comparison of outcomes, in the fellow and study eyes, of participants who had two eyes eligible at baseline, where the fellow eye treatment (the drug used and the treatment interval) remained unchanged for the duration of the study, will be conducted if feasible

Recruitment

Recruitment status

Withdrawn

Reason for early stopping/withdrawal

Safety concerns

Date of first participant enrolment

Anticipated

31/05/2021

Actual

Date of last participant enrolment

Anticipated

30/11/2021

Actual

Date of last data collection

Anticipated

30/11/2022

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

TAS

Recruitment hospital [1]

Hobart Eye Surgeons - Hobart

Recruitment postcode(s) [1]

7000 - Hobart

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Novartis Pharmaceuticals Australia Pty Limited

Address [1]

54 Waterloo Road,
Macquarie Park, NSW, 2113

Country [1]

Australia

Primary sponsor type

Individual

Name

Clinical Professor Nitin Verma

Address

Hobart Eye Surgeons
182 Argyle Street
Hobart Tasmania 7000

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Bellberry

Ethics committee address [1]

129 Glen Osmond Rd
Eastwood SA 5063

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/04/2021

Approval date [1]

02/06/2021

Ethics approval number [1]

Application No: 2021-03-323

Summary

Brief summary

This is an open label study in patients: previously treated with intravitreal ranibizumab or aflibercept for at least six months; on a 4 to 8 weekly injection regimen with at least one failed attempt to extend their treatment interval; who have persistent retinal fluid at their current treatment interval or have recurrent retinal fluid if the treatment interval is extended.
Eligible participants will switch their study eye treatment to bevacizumab and have three, monthly, loading doses before commencing a treat and extend regimen where the treatment interval will be extended based on the investigators assessment of disease activity and predetermined criteria normally used in clinical practice.
The study will run for 18 months: Six months recruitment with a 12 month treatment period) 
Following enrolment participants will be evaluated monthly.
At each follow up they will have a clinical ophthalmic examination including intra-ocular pressure measurement, assessment of best corrected visual acuity, macular OCT and fundus photography.
A quality of life questionnaire (NEI VQF-25) will be completed at baseline and at study. completion. Fluorescein angiography will be performed when clinically indicated.

Trial website

None

Trial related presentations / publications

None

Public notes

Contacts

Principal investigator

Name

Dr Nitin Verma

Address

Hobart Eye Surgeons
182 Argyle Street
Hobart TAS 7000

Country

Australia

Phone

+61 417873213

Fax

+61 3 6210 6099

[email protected]

Contact person for public queries

Name

Beverley Curry

Address

Hobart Eye Surgeons
182 Argyle Street
Hobart TAS 7000

Country

Australia

Phone

+61 409431402

Fax

+61 3 6210 6099

[email protected]

Contact person for scientific queries

Name

Beverley Curry

Address

Hobart Eye Surgeons
182 Argyle Street
Hobart TAS 7000

Country

Australia

Phone

+61 409431402

Fax

+61 3 6210 6099

[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?

Deidentified data will be provided upon request, this will include age at recruitment and other primary outcome measures

When will data be available (start and end dates)?

Data will be available upon request up to 10 years after study analysis and reports have been published.

Available to whom?

Researchers with an HREC approved study protocol.

Available for what types of analyses?

Any analysis approved by an HREC

How or where can data be obtained?

Data will be made available by emailing the principal investigator ([email protected]) or corresponding author of the published article.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
11202	Study protocol					380863-(Uploaded-29-03-2021-16-04-25)-Study-related document.pdf
11203	Informed consent form					380863-(Uploaded-29-03-2021-16-04-45)-Study-related document.pdf

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.

Trial Review

Documents added manually

Documents added automatically