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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] 302687 0
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 319602 0
Condition category
Condition code
Eye 317542 317542 0 0
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] 318966 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325585 0
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] 325585 0
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] 327003 0
Mean change in Central Retinal Thickness as measured by SD-OCT
Timepoint [2] 327003 0
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] 388458 0
The proportion of participants with treatment intervals extended beyond baseline frequency as recorded in the participants medical records (source documentation).
Timepoint [1] 388458 0
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] 388459 0
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] 388459 0
Baseline and 48 weeks after switching to study intervention
Secondary outcome [3] 388460 0
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] 388460 0
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] 388461 0
Mean change in BCVA score ( measured by ETDRS chart) between baseline and 48 weeks after switching to study intervention.
Timepoint [4] 388461 0
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] 393421 0
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] 393421 0
Baseline and 48 weeks after switching to study intervention
Secondary outcome [6] 393422 0
Incidence and severity of all adverse events over the study period as recorded in the participants medical records ( source documents).
Timepoint [6] 393422 0
Over course of study from baseline to 48 weeks after switching to study intervention.
Secondary outcome [7] 394538 0
Proportion of participants with resolution of intra-retinal fluid (IRF) based on images from SD-OCT.
Timepoint [7] 394538 0
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] 394539 0
Proportion of participants with resolution of sub-retinal fluid (SRF) based on images from SD-OCT.
Timepoint [8] 394539 0
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 [9] 394540 0
Proportion of participants with resolution of retinal pigment epithelial detachment (PED) based on images from SD-OCT.
Timepoint [9] 394540 0
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 [10] 394568 0
Proportion of patients who have no evidence of retinal fluid on SD-OCT (stable disease) throughout the study.
Timepoint [10] 394568 0
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?
No
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
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
TAS
Recruitment hospital [1] 17947 0
Hobart Eye Surgeons - Hobart
Recruitment postcode(s) [1] 31811 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 307124 0
Commercial sector/Industry
Name [1] 307124 0
Novartis Pharmaceuticals Australia Pty Limited
Country [1] 307124 0
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] 307700 0
None
Name [1] 307700 0
Address [1] 307700 0
Country [1] 307700 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307236 0
Bellberry
Ethics committee address [1] 307236 0
129 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [1] 307236 0
Australia
Date submitted for ethics approval [1] 307236 0
14/04/2021
Approval date [1] 307236 0
02/06/2021
Ethics approval number [1] 307236 0
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 106510 0
Dr Nitin Verma
Address 106510 0
Hobart Eye Surgeons
182 Argyle Street
Hobart TAS 7000
Country 106510 0
Australia
Phone 106510 0
+61 417873213
Fax 106510 0
+61 3 6210 6099
Email 106510 0
[email protected]
Contact person for public queries
Name 106511 0
Beverley Curry
Address 106511 0
Hobart Eye Surgeons
182 Argyle Street
Hobart TAS 7000
Country 106511 0
Australia
Phone 106511 0
+61 409431402
Fax 106511 0
+61 3 6210 6099
Email 106511 0
[email protected]
Contact person for scientific queries
Name 106512 0
Beverley Curry
Address 106512 0
Hobart Eye Surgeons
182 Argyle Street
Hobart TAS 7000
Country 106512 0
Australia
Phone 106512 0
+61 409431402
Fax 106512 0
+61 3 6210 6099
Email 106512 0
[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.TypeCitationLinkEmailOther DetailsAttachment
11202Study protocol    380863-(Uploaded-29-03-2021-16-04-25)-Study-related document.pdf
11203Informed 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.