Trial Outcomes & Findings for A Study of the Efficacy and Safety of Brolucizumab vs. Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema (NCT NCT03481660)

This study was conducted in 79 centers in 23 countries: Belgium (1), Bulgaria (3), Czech Republic (3), Denmark (2), Estonia (2), France (12), Germany (7), Hungary (5), India (5), Republic of Korea (6), Latvia (1), Lebanon (3), Lithuania (2), Malaysia (2), Norway (1), Poland (1), Russia (5), Singapore (2), Slovakia (5), Sweden (1), Switzerland (2), Taiwan (3), Turkey (5).

A Study of the Efficacy and Safety of Brolucizumab vs. Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the period Week 40 through Week 52. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The number of participants maintaining every 12 weeks (q12w) treatment status in the Brolucizumab arm was derived based on Kaplan-Meier estimates time-to-first q8w treatment need. Positive treatment status was defined as intravitreal treatment (IVT) injections per planned dosing regimen \[every 12 weeks (q12w)\].

The number of participants maintaining every 12 weeks (q12w) treatment status in the Brolucizumab arm was derived based on Kaplan-Meier estimates time-to-first q8w treatment need. Positive treatment status was defined as intravitreal treatment (IVT) injections per planned dosing regimen \[every 12 weeks (q12w)\].

Disease activity assessments (DAAs) were performed to identify q8w-need at pre-specified visits (Weeks 32, 36, 48, 60, 72 and every visit from Week 72 through Week 96). Weeks 32 and 36 were the two DAA visits of the initial q12w cycle after the loading phase of the brolucizumab arm. At Week 72 or Week 76 (if DAA/disease stability assessment was missed at Week 72), participants in the brolucizumab were evaluated for an additional 4-week dose regimen extension. The number of participants maintaining every 12 weeks (q12w) treatment status in the Brolucizumab arm was derived based on Kaplan-Meier estimates time-to-first q8w treatment need. Positive treatment status was defined as intravitreal treatment (IVT) injections per planned dosing regimen \[every 12 weeks (q12w)\].

Disease activity assessments (DAAs) were performed to identify q8w-need at pre-specified visits (Weeks 32, 36, 48, 60, 72 and every visit from Week 72 through Week 96). Weeks 32 and 36 were the two DAA visits of the initial q12w cycle after the loading phase of the brolucizumab arm. At Week 72 or Week 76 (if DAA/disease stability assessment was missed at Week 72), participants in the brolucizumab were evaluated for an additional 4-week dose regimen extension. The number of participants maintaining every 12 weeks (q12w) treatment status in the Brolucizumab arm was derived based on Kaplan-Meier estimates time-to-first q8w treatment need. Positive treatment status was defined as intravitreal treatment (IVT) injections per planned dosing regimen \[every 12 weeks (q12w)\].

Disease activity assessments (DAAs) were performed to identify q8w-need at pre-specified visits (Weeks 32, 36, 48, 60, 72 and every visit from Week 72 through Week 96). Weeks 32 and 36 were the two DAA visits of the initial q12w cycle after the loading phase of the brolucizumab arm. At Week 72 or Week 76 (if DAA/disease stability assessment was missed at Week 72), participants in the brolucizumab were evaluated for an additional 4-week dose regimen extension. The number of participants maintaining every 12 weeks (q12w) treatment status in the Brolucizumab arm was derived based on Kaplan-Meier estimates time-to-first q8w treatment need. Positive treatment status was defined as intravitreal treatment (IVT) injections per planned dosing regimen \[every 12 weeks (q12w)\].

Reported categorically for the subjects who completed the study treatment period: every 8 weeks (q8w), Every 12 weeks (q12w), Every 16 weeks (q16w)

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The BCVA score is the number of letters read correctly by the patient, hence an increase in score indicates improvement in acuity. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the periods: Week 4 through Week 52, Week 4 through Week 100. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the periods: Week 20 through Week 52, Week 20 through Week 100, Week 28 through Week 52, Week 28 through Week 100. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. For each participants, this endpoint was defined as the mean change from baseline to the average value over the period Week 88 through Week 100. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 4 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. The overall BCVA score (number of letters read correctly by the patient) was calculated using the BCVA worksheet 0-100 letter score, with higher score indicating improvement in acuity. A positive change from baseline is a favorable outcome. BCVA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The thickness of the retina was measured using Spectral Domain (SD) optical coherence tomography (OCT) equipment (SD-OCT) and reported as a difference, in micrometers. a negative change from baseline indicates a reduction in thickness, whereas a positive change from baseline indicates an increase. An increase in thickness may indicate a progression of the underlying disease. CSFT assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The thickness of the retina was measured using Spectral Domain (SD) optical coherence tomography (OCT) equipment (SD-OCT) and reported as a difference, in micrometers. a negative change from baseline indicates a reduction in thickness, whereas a positive change from baseline indicates an increase. An increase in thickness may indicate a progression of the underlying disease. CSFT assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment. For each participants, this endpoint was derived as the average of the changes from Baseline to Weeks 40, 44, 48, 52. Then the same was derived over the period Week 88 through Week 100, considering the average of the changes from Baseline to Weeks 88, 92, 96, 100. This endpoint was only assessed in the year-2 analysis (Week 100).

The thickness of the retina was measured using Spectral Domain (SD) optical coherence tomography (OCT) equipment (SD-OCT) and reported as a difference, in micrometers. a negative change from baseline indicates a reduction in thickness, whereas a positive change from baseline indicates an increase. An increase in thickness may indicate a progression of the underlying disease. CSFT assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The thickness of the retina was measured using Spectral Domain (SD) optical coherence tomography (OCT) equipment (SD-OCT) and reported as a difference, in micrometers. CSFT assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Presence of Subretinal Fluid (SRF) in the study eye was assessed by spectral domain optical coherence tomography (SD-OCT), angiography, and/or color fundus photography. Subretinal fluid status assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Presence of Intraretinal Fluid (IRF) in the study eye was assessed by spectral domain optical coherence tomography (SD-OCT), angiography, and/or color fundus photography. Intraretinal fluid status assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Presence of Subretinal Fluid (SRF) and/or Intraretinal Fluid (IRF) in the study eye was assessed by spectral domain optical coherence tomography (SD-OCT), angiography, and/or color fundus photography. Fluid status (SRF and/or IRF) assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

Presence of leakage on Fluorescein Angiography as assessed by fluorescein angiography. Leakage on FA assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. DRSS assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. DRSS assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The Diabetic Retinopathy Disease Severity Scale was based on 7-field stereo color fundus photography and measured 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. DRSS assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The Diabetic Retinopathy Disease Severity Scale was based on 7-field stereo color fundus photography and measured 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. DRSS assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The Diabetic Retinopathy Disease Severity Scale was based on 7-field stereo color fundus photography and measured 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative. DRSS assessments after start of alternative diabetic macular edema (DME) treatment in the study eye were censored and replaced by the last value prior to start of this alternative treatment.

The number of participants with ocular and non-ocular adverse events was was assessed by CTCAE and reported categorically: Mild, Moderate, Severe.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

The survey consisted of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. The score of each individual question ranged from 0 (worst) to 100 which indicated the best possible response. The composite score and score of each construct also ranged from 0 to 100 as they were calculated as total scores divided by the number of questions. The higher the values of total scores represented better outcome.

Serum samples were taken approximately 24 hours after the first dose and 24 hours after the treatment at Week 24 to confirm the systemic brolucizumab exposure in patients with visual impairment due to diabetic macular edema.

Integrated ADA Status was categorized: ADA negative or ADA positive with no boost, Induced or Boosted, Missing ADA at pre-dose or no post-dose ADA data. * ADA negative: (a) ADA negative at all time points (pre-dose and post-dose), (b) ADA negative at pre-dose and no titer values above 40 at all other time points, (c) ADA titer of 40 at pre-dose but negative at all other time points. * ADA positive with no boost: ADA positive at pre-dose, post-dose titer values do not increase from pre-dose by more than 3-fold (1 dilution) at any time point. * Induced: ADA negative at pre-dose, post-dose titer value of 120 or more at any time point. * Boosted: ADA positive at pre-dose, post-dose titer values increase from pre-dose by more than 3-fold (1 dilution) at any time point.

Integrated ADA Status - adjusted for pre-existing ADA status was categorized: ADA negative, ADA positive with no boost, Induced, Boosted. * ADA negative: (a) ADA negative at all time points (pre-dose and post-dose), (b) ADA negative at pre-dose and no titer values above 40 at all other time points, (c) ADA titer of 40 at pre-dose but negative at all other time points. * ADA positive with no boost: ADA positive at pre-dose, post-dose titer values do not increase from pre-dose by more than 3-fold (1 dilution) at any time point. * Induced: ADA negative at pre-dose, post-dose titer value of 120 or more at any time point. * Boosted: ADA positive at pre-dose, post-dose titer values increase from pre-dose by more than 3-fold (1 dilution) at any time point.

Pre-existing ADA status and incidence of Adverse Event of Special Interest (AESI) in the study eye was categorized: Negative, Positive.

Integrated ADA status up to Week 100 and incidence of Adverse Event of Special Interest (AESI) in the study eye was categorized: ADA-negative or no boost, Induced or boosted.