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Trial registered on ANZCTR


Registration number
ACTRN12621000305820
Ethics application status
Approved
Date submitted
25/11/2020
Date registered
18/03/2021
Date last updated
8/09/2022
Date data sharing statement initially provided
18/03/2021
Date results information initially provided
8/09/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Brolucizumab Treatment For Pigment Epithelial Detachment In Treatment-Resistant Neovascular Age Related Macular Degeneration
Scientific title
Brolucizumab Treatment For Pigment Epithelial Detachment In Treatment-Resistant Neovascular Age Related Macular Degeneration
Secondary ID [1] 302866 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Age related macular degeneration 319867 0
Condition category
Condition code
Eye 317805 317805 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravitreal injection of brolucizumab 6.0mg will be administered by an ophthalmologist.
All eligible subjects will initially receive 3 monthly loading doses of 6.0mg of intravitreal brolucizumab injection. Following these loading doses, a disease activity assessment will be performed at week 16.
Disease Activity Criteria at Week 16:
• Decrease in BCVA of greater than or equal to 5 letters compared with Baseline
• Decrease in BCVA of greater than or equal to 3 letters and CSFT increase greater than 75µm compared with Week 12
• Decrease in BCVA of greater than or equal 5 letters due to neovascular AMD disease activity compared with Week 12
• New or worse intraretinal cysts (IRC) /intraretinal fluid (IRF) compared with Week 12

If a subject meet any of the above disease criteria at week 16, the subject will be assigned to receive injections every 8 weeks (q8w) thereafter, up to study exit (Week 16, 24, 32, 40 and 48).
If a subject does not meet any of the above disease activity criteria, the subject will be injected every 12 weeks (q12w) up to study exit (week 20, 32 and 44).
Patients will be given individual timetable for their scheduled appointments.
Intervention code [1] 319157 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325828 0
Mean change in pigment epithelial detachment (PED) height at weeks 24 and 52 compared to the baseline as seen on Spectral domain optical coherence tomography (SD-OCT).
Timepoint [1] 325828 0
Baseline, 24 and 52 weeks
Primary outcome [2] 326127 0
Proportion of patients with resolution of pigment epithelial detachment as seen on SD-OCT
Timepoint [2] 326127 0
Baseline, 24 weeks and 52 weeks
Secondary outcome [1] 389248 0
Proportion of patients who have no fluid on SD-OCT
Timepoint [1] 389248 0
Baseline, 12, 24 and 52 weeks
Secondary outcome [2] 390206 0
Mean structural changes of pigment epithelial detachment (PED) on OCT-Angiography.
Timepoint [2] 390206 0
At Week 12, 24 compared to baseline.
Secondary outcome [3] 390207 0
Mean change in visual acuity at weeks 12, 24 and 52 compared to the baseline as measured on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.
Timepoint [3] 390207 0
Baseline, week 12, 24 and 52
Secondary outcome [4] 390208 0
Proportion of patients who gain 5 letters as seen on the ETDRS chart.
Timepoint [4] 390208 0
Baseline, weeks 12, 24 and 52.
Secondary outcome [5] 390209 0
Mean change in central foveal thickness measured by SD-OCT compared to baseline.
Timepoint [5] 390209 0
Baseline, weeks 12, 24 and 52
Secondary outcome [6] 390210 0
Proportion of patients with development of macular atrophy as seen on SD-OCT.
Timepoint [6] 390210 0
baseline and week 52
Secondary outcome [7] 390211 0
The change of retinal function measured by Macular Integrity Assessment (MAIA) compared to the baseline.
Timepoint [7] 390211 0
Baseline, weeks 24 and 52
Secondary outcome [8] 390212 0
Mean change in National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) score between baseline and
weeks 24 and 52.
Timepoint [8] 390212 0
Baseline, weeks 24 and 52.
Secondary outcome [9] 390213 0
Incidence and severity of adverse events over study period.
Common Side Effects (1 to less than 10 in 100 participants receiving brolucizumab may have); decreased sharpness of vision when assessing visual acuity, clouding of the lens, bloodshot eye, small particles or spots drifting across the field of vision or eye pain upon asking the patient of symptoms, bleeding in the retina, detachment or tear of one of the layers at the back of the eye, inflammation of tissues lining the inside of the eye, inflammation or scratching of the surface of the eye, allergic reactions assessed through clinical examination, increase in the pressure within the eye assessed using applanation tonometry.
Uncommon Side Effects (1 to less than 10 in 1000 participants receiving brolucizumab may have); redness of the eye , increased tear production , a feeling of having something in the eye, blindness, blockage of an artery in the eye, inflammation of the inside of the eye, detachment of one of the layers in the back of the eye ,swelling in the front of the eye, eye inflammation, bleeding in the eye all assessed through clinical examination.
Timepoint [9] 390213 0
Over course of study from baseline to 52 weeks post commencement.
Secondary outcome [10] 392096 0
with best corrected visual acuity (BCVA) better than 20/40
Timepoint [10] 392096 0
Baseline, weeks 12, 24 and 52.
Secondary outcome [11] 392097 0
Mean change in central foveal volume measured by SD-OCT compared to baseline.
Timepoint [11] 392097 0
Baseline, weeks 12, 24 and 52.
Secondary outcome [12] 392997 0
Proportion of patients who gain 10 letters as seen on the ETDRS chart.
Timepoint [12] 392997 0
Baseline, weeks 12, 24 and 52
Secondary outcome [13] 392998 0
Proportion of patients who gain 15 letters as seen on the ETDRS chart.
Timepoint [13] 392998 0
Baseline, weeks 12, 24 and 52

Eligibility
Key inclusion criteria
Subjects must give written informed consent before any study related procedures are performed
Subjects must be 50 years of age or older at baseline
Pigment epithelial detachment (PED) secondary to neovascular macular degeneration (AMD). PED is defined as a discrete or localised dome-shaped or irregular elevation of the retinal pigment epithelium (RPE) on SD-OCT that was optically empty (i.e. serous) with a focus of neovascularisation at the edge or that was comprised of heterogeneous tissue of mixed reflectivity or layering within the sub-PED compartment.
Previously treated neovascular age-related macular degeneration, “treatment resistance” is defined as eyes with persistent active/exudation despite at least 4 previous ranibizumab and/or aflibercept treatments in the 6 months prior to baseline, not including loading dose, with a minimal interval of 8 weeks between the last anti-vascular endothelial growth factor (anti-VEGF) injection and the baseline injection
Best corrected baseline visual acuity between 20-78 letters on ETDRS chart (Snellen equivalent 6/12 to 6/120) in the study eye.
Active choroidal neovascularisation (CNV) lesions secondary to AMD that affect the central subfield (excluding retinal angiomatous proliferation [RAP] and polypoidal vasculopathy [PCV]) in the study eye, confirmed by the angiography and Principal Investigator.
Total area of CNV must comprise >50% of the total lesion area in the study eye.
Intra and or subretinal fluid affecting the central subfield of the study eye.
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any active intraocular or periocular infection or active intraocular inflammation (eg, infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis) in either eye at Baseline
Central subfield of the study eye affected by fibrosis or geographic atrophy assessed by colour fundus photography autofluorescence.
Total area of fibrosis greater than or equal to 50% of the total lesion in the study eye
Subretinal blood affecting the central subfield and/or greater than or equal to 50% of the lesion of the study eye
Subject has received any investigational treatment for neovascular AMD (other than vitamin supplements) in the study eye at any time
Eyes diagnosed with Retinal Angiomatous Proliferation or Polypoidal Choroidal Vasculopathy lesion
Any history or evidence of a concurrent intraocular condition in the study eye, including retinal diseases other than neovascular AMD, that, in the judgment of the Investigator, could either require medical or surgical intervention during the course of the study to prevent or treat visual loss that might result from that condition or that limits the potential to gain visual acuity upon treatment with the investigational product
Retinal pigment epithelium (RPE) rip/tear in the study eye at Baseline
Current vitreous haemorrhage or history of vitreous haemorrhage in the study eye within 4 weeks prior to Baseline
History or evidence of the following in the study eye:
Previous photodynamic therapy (PDT)
Intraocular or refractive surgery within the 90-day period prior to Baseline
Previous penetrating keratoplasty or vitrectomy
Previous panretinal photocoagulation
Previous submacular surgery, other surgical intervention or laser treatment for AMD
Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg on medication or according to Investigator’s judgment at Baseline
Aphakia and/or absence of the posterior capsule in the study eye at Screening or Baseline
Intra- or periocular use of corticosteroids in the study eye during the 6-month period prior to Baseline
Use of topical ocular corticosteroids in the study eye for 60 or more consecutive days within the 90-day period prior to Baseline
Use of systemic corticosteroids for 30 or more consecutive days within the 90 days prior to Baseline, with the exception of low stable doses of corticosteroids (defined as less than or equal to 10 mg prednisolone or equivalent dose used for 90 days or more). Inhaled, nasal or dermal steroids are also permitted
Previous therapeutic radiation near the region of the study eye
History of a medical condition (disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding) that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product
History of hypersensitivity to any component of the test article, control article, or clinically relevant sensitivity to fluorescein dye (or indocyanine green), as assessed by the Investigator
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until termination of gestation, confirmed by a positive hCG pregnancy test and women of child-bearing potential, defined as all women less than 1 year postmenopausal or less than 6 weeks since sterilization at Baseline, unless they are using effective methods of contraception during dosing of study treatment. Effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before Baseline. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to Baseline). For female subjects in the study, the vasectomized male partner should be the sole partner for that subject
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
Placement of an intrauterine device (IUD) or intrauterine system (IUS)
Participation in an investigational drug, biologic, or device study within 30 days or the duration of 5 half-lives of the investigational product (whichever is longer) prior to Baseline Note: observational clinical studies solely involving over-the-counter vitamins, supplements, or diets are not exclusionary
Systemic anti-vascular endothelial growth factor (VEGF) therapy within the 90-day period prior to Baseline
Stroke or myocardial infarction in the 90-day period prior to Baseline
Uncontrolled blood pressure defined as a systolic value greater than or equal to 160 mmHg or diastolic value greater than or equal to 100 mmHg at Screening

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 4
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/04/2021
Actual
21/04/2021
Date of last participant enrolment
Anticipated
Actual
18/06/2021
Date of last data collection
Anticipated
Actual
3/06/2022
Sample size
Target
55
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 18096 0
Sydney Retina Clinic & Day Surgery - Sydney
Recruitment postcode(s) [1] 32085 0
2000 - Sydney

Funding & Sponsors
Funding source category [1] 307283 0
Commercial sector/Industry
Name [1] 307283 0
Novartis
Country [1] 307283 0
Australia
Primary sponsor type
Other
Name
Sydney Retina Clinic & Day Surgery
Address
13/187 Macquarie Street, Sydney NSW 2000
Country
Australia
Secondary sponsor category [1] 307926 0
None
Name [1] 307926 0
Address [1] 307926 0
Country [1] 307926 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307381 0
Bellberry PTY LTD
Ethics committee address [1] 307381 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 307381 0
Australia
Date submitted for ethics approval [1] 307381 0
31/12/2020
Approval date [1] 307381 0
15/03/2021
Ethics approval number [1] 307381 0
2020-10-1016

Summary
Brief summary
This is a prospective, open-labelled study in patients with pigment epithelial detachment (PED) secondary to neovascular macular degeneration. All subjects will receive 6.0mg of intravitreal brolucizumab every 4 weeks between baseline and week 8 (3 loading doses), and subsequently receive 6.0mg of intravitreal brolucizumab every 8 or 12 weeks for the remainder of the study period (weeks 52).
Fifty five subjects who meet the inclusion/exclusion criteria will be recruited from Sydney Retina Clinic and followed up for 52 weeks. All assessments and treatments will be performed at Sydney Retina Clinic. All eligible subjects will initially receive 3 monthly loading doses of 6.0mg of intravitreal brolucizumab injection. Following these loading doses, a disease activity assessment will be performed at week 16.
Disease Activity Criteria at Week 16:
• Decrease in BCVA of greater than or equal to 5 letters compared with Baseline
• Decrease in BCVA of greater than or equal to 3 letters and CSFT increase greater than 75µm compared with Week 12
• Decrease in BCVA of greater than or equal 5 letters due to neovascular AMD disease activity compared with Week 12
• New or worse intraretinal cysts (IRC) /intraretinal fluid (IRF) compared with Week 12

If a subject meet any of the above disease criteria at week 16, the subject will be assigned to receive injections every 8 weeks (q8w) thereafter, up to study exit (Week 16, 24, 32, 40 and 48).
If a subject does not meet any of the above disease activity criteria, the subject will be injected every 12 weeks (q12w) up to study exit (week 20, 32 and 44).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107030 0
A/Prof Andrew Chang
Address 107030 0
Sydney Retina, 13/187 Macquarie Street, Sydney NSW 2000
Country 107030 0
Australia
Phone 107030 0
+61 292213755
Fax 107030 0
Email 107030 0
achang@sydneyretina.com.au
Contact person for public queries
Name 107031 0
Dr Thomas Hong
Address 107031 0
Sydney Retina, 13/187 Macquarie Street, Sydney NSW 2000
Country 107031 0
Australia
Phone 107031 0
+61 292213755
Fax 107031 0
Email 107031 0
thomas.hong@acurio.com.au
Contact person for scientific queries
Name 107032 0
Dr Thomas Hong
Address 107032 0
Sydney Retina. 13/187 Macquarie Street, Sydney NSW 2000
Country 107032 0
Australia
Phone 107032 0
+61 292213755
Fax 107032 0
Email 107032 0
thomas.hong@acurio.com.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?
Deidentified data will be provided upon request, this may include date of birth and other primary outcome measures.
When will data be available (start and end dates)?
Data will be available upon request after study analysis and reports have been published, this will be available for 14 years.
Available to whom?
Clinicians.
Available for what types of analyses?
All types.
How or where can data be obtained?
Data will be made available by emailing the principal investigator/corresponding author of the article. achang@sydneyretina.com.au


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
9862Study protocol    380993-(Uploaded-17-03-2021-10-26-21)-Study-related document.docx
9863Informed consent form    380993-(Uploaded-17-03-2021-10-26-48)-Study-related document.docx



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.