Study to Assess the Efficacy and Safety of Brolucizumab 6mg Compared to Aflibercept 2 mg in a Treat-to-control Regimen (TALON)

Novartis Pharmaceuticals734 enrolled

Overview

This was a 64-week randomized, double-masked, multi-center, active-controlled, two-arm study in patients with neovascular age related macular degeneration (nAMD) who have not previously received anti- vascular endothelial growth factor (VEGF) treatment.

At the baseline Visit, subjects who met the eligibility criteria were randomized in a 1:1 ratio to receive either: -Brolucizumab 6 mg: 3 × 4-week injections and one 8-week injection, followed by Treat-to- Control treatment from Week 16 up to Week 60/62 -Aflibercept 2 mg: 3 × 4-week injections and one 8-week injection, followed by Treat-to-Control treatment from Week 16 up to Week 60/62. For all subjects, the last potential study treatment was at the Week 60 visit (or at the Week 62 visit for subjects whose actual treatment interval would require a treatment at Week 62). The initiation phase starts on Day 1 and ends on Week 16. Treat to Control regimen starts on Week 16 until end of treatment (Week 60/62). In both treatment arms, treatment intervals after the initiation phase were either 8 weeks, 12 weeks, or 16 weeks. Per the original protocol, if it was determined that a patient required more frequent injections than q8w, he/she would be moved to a q4w treatment interval. However, this option was removed per Protocol amendment 02, after which, dosing intervals shorter than q8w were not permitted.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

734

Conditions

Age-related Macular Degeneration

Interventions

Brolucizumab 6 mgBIOLOGICAL

Intra-vitreal injection

Aflibercept 2 mgBIOLOGICAL

Intra-vitreal injection

Eligibility

Sex: ALLMin age: 50 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Signed informed consent must be obtained prior to participation in the study * Male or female patients ≥ 50 years of age at screening who are treatment naive * 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 (study eye) * Presence of intraretinal fluid (IRF) or subretinal fluid (SRF) that affects the central subfield, as seen by Spectral Domain Optical Coherence Tomography (SD-OCT) (study eye) * 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) Exclusion Criteria: * Ocular conditions/disorders at screening or baseline which could, in the opinion of the investigator, prevent response to study treatment or may confound interpretation of study results, compromise visual acuity or require planned medical or surgical intervention during the first 12-month study period, structural damage of the fovea, atrophy or fibrosis at the center of the fovea (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 judgment, at screening or baseline (study eye) * Ocular treatments: previous treatment with any anti-vascular endothelial growth factor (VEGF) drugs or investigational drugs, intraocular or periocular steroids, macular laser photocoagulation, photodynamic therapy, vitreoretinal surgery, intraocular surgery (study eye) * Stroke or myocardial infarction during the 6-month period prior to baseline * Systemic anti-VEGF therapy at any time.

Locations (118)

Outcomes

Primary Outcomes

Distribution of the Last Interval With no Disease Activity up to Week 32 - Study Eye

No disease activity is defined as no change in visual acuity and no change in other signs of the disease (e.g. Intraretinal Fluid (IRF), Subretinal Fluid (SRF), hemorrhage, leakage, etc.). Treatment interval distribution. Number (%) of subjects at 12/8/4-weeks intervals up to Week 32 for the study eye. If the study treatment is discontinued before Week 16, then the treatment interval is 4 weeks; otherwise. the last interval with no disease activity is used (if there was disease activity, the last interval is shortened by 4 weeks, down to a minimum of 4 weeks). If the duration of the last interval falls within the following ranges of (4-week, 8-week) or (8-week, 12-week) or ≥12-week then the floor value of these ranges was used.

Time frame: Up to Week 32

Average Change From Baseline at Week 28 and Week 32 in Best-corrected Visual Acuity (BCVA) - Study Eye

BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. Least squares mean estimate - for weeks 28 and 32 combined.

Time frame: Baseline, Week 28 and Week 32

Secondary Outcomes

Distribution of the Last Interval With no Disease Activity up to Week 64 - Study Eye

No disease activity is defined as no change in visual acuity and no change in other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.). Treatment interval distribution. The number of subjects at 16/12/8/4-weeks intervals as the last interval with no disease activity. If the study treatment is discontinued before Week 16, then the treatment interval is 4 weeks; otherwise. the last interval with no disease activity is used (if there was disease activity, the last interval is shortened by 4 weeks, down to a minimum of 4 weeks). If the duration of the last interval falls within the following ranges of (4-week, 8-week) or (8-week, 12-week) or (12-weeks, 16-weeks) or ≥16-week then the floor value of these ranges was used.

Time frame: Up to Week 64

Data from ClinicalTrials.gov

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Novartis Investigative Site

Phoenix, Arizona, United States

Novartis Investigative Site

Huntington Beach, California, United States

Novartis Investigative Site

Loma Linda, California, United States

Novartis Investigative Site

Riverside, California, United States

Novartis Investigative Site

Santa Ana, California, United States

Novartis Investigative Site

Fort Lauderdale, Florida, United States

Novartis Investigative Site

Fort Myers, Florida, United States

Novartis Investigative Site

Orlando, Florida, United States

Novartis Investigative Site

Pinellas Park, Florida, United States

Novartis Investigative Site

Winter Haven, Florida, United States

...and 108 more locations

Distribution of the Maximal Intervals With no Disease Activity up to Week 64 - Study Eye

No disease activity is defined as no change in visual acuity and no change in other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.). Maximal interval distribution. Number of subjects at 16/12/8/4-weeks intervals as the last interval with no disease activity. If the study treatment is discontinued before Week 16 included, then the treatment interval is 4 weeks; otherwise, the last interval with no disease activity is used (if there was disease activity, the last interval is shortened by 4 weeks, down to a minimum of 4 weeks). If the duration of the maximal interval falls within the following ranges of \[4-weeks, 8-weeks) or \[8-weeks, 12-weeks) or \[12-weeks, 16-weeks\] or ≥16-weeks then the floor value of these ranges is used.

Time frame: Up to Week 64

Number of Participants With no Disease Activity - Study Eye

Disease activity assessment as determined by visual acuity and assessment of other signs of the disease (e.g. IRF, SRF, hemorrhage, leakage, etc.).

Time frame: Weeks 14 and 16

Time From Last Loading Injection to First Visit With No Disease Activity (Weeks) - 75th Percentile - Study Eye

Intraretinal fluid (IRF) and subretinal fluid (SRF) were assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) (study eye). Please note that this endpoint can be impacted by the optional disease activity assessment visits and the flexible dosing regimen, in addition to the randomized treatment. Hence, the observed treatment effect may be confounded by the study design artifacts.

Time frame: Up to Week 64

Time-to-first Dry Retina - Time to the First Visit With no Intraretinal Fluid (IRF) or Subretinal Fluid (SRF) - Study Eye

Intraretinal fluid (IRF) and subretinal fluid (SRF) were assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) (study eye).

Time frame: Up to Week 64

Average Change From Baseline at Week 60 and Week 64 in Best-corrected Visual Acuity (BCVA) - Study Eye

Time frame: Baseline, Week 60 and Week 64

Number of Participants With Best-corrected Visual Acuity Improvements of ≥ 15 Letters in BCVA From Baseline or Reached BCVA ≥ 84 Letters up to Week 32/64 Per Treatment Arm - Study Eye

Time frame: Baseline, Week 32, and Week 64

Number of Participants With Best-corrected Visual Acuity ≥ 69 Letters - Study Eye

Time frame: Week 32 and Week 64

Average Change From Baseline in Central Subfield Thickness (CSFT) - Study Eye

CSFT was measured by Spectral Domain Optical Coherence Tomography

Time frame: Baseline, Weeks 28 and 32 and at Weeks 60 and 64

Number of Participants With Presence of Intraretinal Fluid and/or Subretinal Fluid in the Central Subfield - Study Eye

Intraretinal Fluid and/or Subretinal Fluid status was measured by Spectral Domain Optical Coherence Tomography (SD-OCT).

Time frame: At Weeks 28, 32, 60 and 64

Number of Participants With Presence of Sub-Retinal Pigment Epithelium Fluid in the Central Subfield - Study Eye

Sub-Retinal Pigment Epithelium fluid status was measured by Spectral Domain Optical Coherence Tomography (SD-OCT).

Time frame: At Weeks 28, 32, 60 and 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Composite Scores - Study Eye

The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. Each subscale score has a range of 0 to 100 inclusive and will be calculated from the re-scaled raw data. A composite score is derived based on the average of the 11 subscales.

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - General Vision - Study Eye

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Ocular Pain - Study Eye

Time frame: Baseline, Week 32, and Week 64

Change From Baseline n Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Near Activities - Study Eye

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Distance Activities - Study Eye

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Social Functioning - Study Eye

The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. Each subscale score has a range of 0 to 100 inclusive and will be calculated from the re-scaled raw data. A composite score is derived based on the average of the 11 subscales.

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Mental Health - Study Eye

The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. Each subscale score has a range of 0 to 100 inclusive and will be calculated from the re-scaled raw data. A composite score is derived based on the average of the 11 subscales.

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Role Difficulties - Study Eye

The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. Each subscale score has a range of 0 to 100 inclusive and will be calculated from the re-scaled raw data. A composite score is derived based on the average of the 11 subscales.

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Dependency - Study Eye

The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning or outcome. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. Each subscale score has a range of 0 to 100 inclusive and will be calculated from the re-scaled raw data. A composite score is derived based on the average of the 11 subscales.

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Driving - Study Eye

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Color Vision - Study Eye

Time frame: Baseline, Week 32, and Week 64

Change From Baseline in Visual Function Questionnnaire-25 (VFQ-25) - Subscale Score - Peripheral Vision - Study Eye

Time frame: Baseline, Week 32, and Week 64

Number of Participants With Treatment Emergent Ocular Adverse Events (Greater Than or Equal to 1% in Any Treatment Arm) by Preferred Term for the Study Eye

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.

Time frame: Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 483 days, approx. 69 weeks, 1.3 years.

Number of Participants With Treatment Emergent Non-ocular Adverse Events (Greater Than or Equal to 2% in Any Treatment Arm) - Summary Table

Time frame: Adverse events are reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 483 days, approx. 69 weeks, 1.3 years.