Efficacy and Safety of Two Different Brolucizumab 6 mg Dosing Regimens in Neovascular Age-related Macular Degeneration
- Conditions
- Age-related Macular Degeneration
- Interventions
- Biological: Brolucizumab
- Registration Number
- NCT04679935
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The purpose of this study was to evaluate the efficacy and safety of two different brolucizumab 6 mg dosing regimens in patients with visual impairment due to age-related macular degeneration (AMD) who have previously received anti-VEGF (vascular endothelial growth factor) treatment.
- Detailed Description
This study was a 52-week randomized, open-label, multi-center, two-arm study for pretreated patients with suboptimal anatomically controlled nAMD. Patients who consented were screened to evaluate eligibility. Eligible patients were randomized in a 1:1 ratio to one of the two treatment arms:
* Brolucizumab 6 mg "loading arm": 1 loading injection every 4 weeks for 3 consecutive injections (baseline, weeks 4 and 8) followed by an injection every 12 weeks.
* Brolucizumab 6 mg "non-loading arm": one initial injection followed by an injection every 12 weeks
There were three periods in this study:
* Screening period: from day -14 to baseline
* Open-label treatment period: from baseline (day 1) to week 48
* Post-treatment follow-up period: from week 48 to week 52
In both study arms, treatment intervals after the initiation phase were either 8 weeks or 12 weeks depending on disease activity status. More frequent injections, i.e., treatment intervals of \< 8 weeks were not allowed after the initiation phase.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 52
- Male or female patients ≥ 50 years of age at screening
- Active choroidal neovascularization (CNV) secondary to AMD that affects the central subfield, including retinal angiomatous proliferation (RAP) with a CNV component, confirmed by presence of active leakage from CNV seen by fluorescein angiography and sequellae of CNV, e.g. pigment epithelial detachment (PED), subretinal or sub-retinal pigment epithelium (sub-RPE) hemorrhage, blocked fluorescence, macular edema (intraretinal fluid (IRF) and/or subretinal fluid (SRF) and/or sub-retinal pigment epithelium (sub-RPE) fluid that affects the central subfield, as seen by spectral domain optical coherence tomography (SD-OCT)) at screening, as confirmed by central reading center (study eye). If active CNV according to the above explained activity criteria is not detectable in screening image data (no IRF and no SRF), presence of residual and/or recurrent fluid (IRF and / or SRF) within the last 6 months before baseline visit is also considered eligible. In this case, historical images must be submitted for analysis by the central reading center.
- Pretreatment with any anti-VEGF drug for a maximum of five years (60 months). Patients should have shown functional and/or anatomical treatment response to the pretreatment(s), prior to participating in this study.
- The treatment initiation phase with the current anti-VEGF must have been completed for at least 6 months with continuous treatment in a ≥ q4w to ≤ q12w injection interval (±2-day window, i.e., 26 to 86 days inclusive) before the baseline visit. At least 4 weeks (minimum 26 days) must have passed between the last anti-VEGF pretreatment and baseline.
- Best-corrected visual acuity (BCVA) score between 83 and 38 letters, inclusive, using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at both screening and baseline visit (study eye)
- Any active intraocular or periocular infection or active intraocular inflammation, at screening or baseline (study eye)
- Uncontrolled glaucoma defined as intraocular pressure (IOP) > 25 mmHg on medication, or according to investigator's judgement, at screening or baseline (study eye)
- Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA <20/200 at screening (except when due to conditions whose surgery may improve VA, e.g. cataract)
- Ocular treatments: treatment with anti-VEGF drugs for > 5 years in the study eye, pretreatment with brolucizumab at any time in the study eye, previous treatment with investigational drugs in the last 6 months, intraocular or periocular steroids at any time, macular laser photocoagulation or photodynamic therapy at any time, peripheral laser photocoagulation within 3 months prior to baseline, intraocular surgery within 3 months prior to baseline, vitreoretinal surgery at any time, aphakia with the absence of posterior capsule (study eye)
- Stroke or myocardial infarction during the 6 month period prior to baseline
- Systemic anti-VEGF therapy during the 3-month period prior to baseline
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Brolucizumab 6 mg non-loading Brolucizumab One initial injection followed by treatment every 12 weeks. Brolucizumab 6 mg loading Brolucizumab 3 x 4-weekly injections followed by treatment every 12 weeks. Brolucizumab 6 mg non-loading Brolucizumab One initial injection followed by treatment every 12 weeks. Brolucizumab 6 mg loading Brolucizumab 3 x 4-weekly injections followed by treatment every 12 weeks.
- Primary Outcome Measures
Name Time Method Week 40 to Week 52: LS Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye Baseline, Week 40 to Week 52 BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts.
Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score between 78 and 23 ETDRS letters (inclusive) at Screening and Baseline in the study eye were included.
Min and max possible scores are 0-100 respectively. A higher score represents better functioning.
- Secondary Outcome Measures
Name Time Method Treatment Intervals Before and During the Study -24 Weeks, Baseline, Week 52 Treatment interval distribution.
Treatment interval during the study, within 24 weeks prior to baseline and interval between the last 2 injections in the study. In the loading arm, data from the loading period was excluded.Distribution of Patients at Every 8 Weeks / Every 12 Weeks Intervals - Frequency of Switches in Treatment Intervals Between Baseline and Week 52 Up to Week 52 Treatment interval distribution
Number of Patients With Prolonged Interval Baseline, Week 52 Treatment interval distribution.
Prolongation was calculated by comparing the mean treatment interval in last 24 weeks prior to first brolucizumab injection (a) with the mean of the average treatment interval during the study (loading phase excluded in the loading arm) and (b) with the last treatment interval during the study. Patients with only 1 injection during the treatment period were calculated as non-responders (no prolon-gation).Proportion of Patients Who Maintained on q12w Regimen. Up to week 52 Treatment interval distribution up to Week 52.
Proportion of patients maintained on q12w treatment frequency in the two brolucizumab groups up to week 52. Patients who discontinued treatment before week 52 were rated as non-responders, i.e., as patients who did not maintain the q12w regimen. In the loading arm, the loading period up to week 12 was not considered in the analysis.Mean Change in Best-corrected Visual Acuity Baseline, Weeks 16 to 28, Week 52 BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts.
Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score between 78 and 23 ETDRS letters (inclusive) at Screening and Baseline in the study eye were included.
Min and max possible scores are 0-100 respectively. A higher score represents better functioning.Number of Patients With Best-corrected Visual Acuity Improvements of >= 5, >= 10 and >= 15 Letters Baseline, up to Week 52 BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts.
Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score between 78 and 23 ETDRS letters (inclusive) at Screening and Baseline in the study eye were included.
Min and max possible scores are 0-100 respectively. A higher score represents better functioning.Number of Patients With Best-corrected Visual Acuity >= 69 Letters Baseline, up to Week 52 BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts.
Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score between 78 and 23 ETDRS letters (inclusive) at Screening and Baseline in the study eye were included.
Min and max possible scores are 0-100 respectively. A higher score represents better functioning.LS Mean Change in Best-corrected Visual Acuity From Baseline at Week 52 Baseline, Week 52 BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts.
Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score between 78 and 23 ETDRS letters (inclusive) at Screening and Baseline in the study eye were included.
Min and max possible scores are 0-100 respectively. A higher score represents better functioning.Change in Central Subfield Thickness From Baseline at Weeks 12, 16, 28 and 52 Baseline, Weeks 12, 16, 28 and 52 Change in central subfield thickness was measured by Spectral domain optical coherence tomography.
Absence of Intraretinal Fluid in the Central Subfield Every 4 weeks from baseline up to Week 52 Change in fluids was measured by Spectral domain optical coherence tomography.
Absence of Subretinal Fluid in the Central Subfield Every 4 weeks from baseline up to Week 52 Change in fluids was measured by Spectral domain optical coherence tomography.
Absence of Sub-retinal Pigment Epithelium Fluid in the Central Subfield Every 4 weeks from baseline up to Week 52 Change in fluids was measured by Spectral domain optical coherence tomography.
Presence of Active Choroidal Neovascularization Leakage At Week 52 Presence of active choroidal neovascularization leakage was measured by Fluorescein angiography.
CNV = choroidal neovascularization; MNV = macular neovascularizationOverview of TEAEs Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of approximately 52 weeks. An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study.
Treatment-emergent AEs are AEs that developed on or after first study treatment administration, or any event previously present that worsened following exposure to the study treatment.Ocular TEAEs in the Study Eye by Primary System Organ Class Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of approximately 52 weeks. An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study.
Treatment-emergent AEs are AEs that developed on or after first study treatment administration, or any event previously present that worsened following exposure to the study treatment.Ocular TEAEs in the Study Eye by Preferred Term (at Least 5% in Any Group) Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of approximately 52 weeks. An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study.
Treatment-emergent AEs are AEs that developed on or after first study treatment administration, or any event previously present that worsened following exposure to the study treatment.Non-ocular TEAEs - Total Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of approximately 52 weeks. An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study.
Treatment-emergent AEs are AEs that developed on or after first study treatment administration, or any event previously present that worsened following exposure to the study treatment.Ocular TEAEs in the Study Eye of Moderate or Severe Intensity Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum timeframe of approximately 52 weeks. An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study.
Treatment-emergent AEs are AEs that developed on or after first study treatment administration, or any event previously present that worsened following exposure to the study treatment.
Trial Locations
- Locations (1)
Novartis Investigative Site
🇨🇭Zuerich, Switzerland