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A Study of Faricimab (RO6867461) in Participants With Center-Involving Diabetic Macular Edema (BOULEVARD)

Primary Purpose

Diabetic Macular Edema

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Faricimab

Ranibizumab

About this trial

This is an interventional treatment trial for Diabetic Macular Edema

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Macular edema associated with diabetic retinopathy
Decreased visual acuity attributable primarily to DME
Diagnosis of diabetes mellitus

Exclusion Criteria:

High risk proliferative diabetic retinopathy
Cataract surgery within 3 months of Baseline, or any other previous intraocular surgery
Uncontrolled glaucoma
Current or history of ocular disease in the study eye other than DME
Major illness or major surgical procedure within 1 month prior to Day 1
Uncontrolled blood pressure
Glycosylated hemoglobin (HbA1c) greater than (>) 12 percent (%) at screening
Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin within 4 months prior to Day 1

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Arm A: 0.3 mg Ranibizumab

Arm B: 1.5 mg Faricimab

Arm C: 6 mg Faricimab

Arm Description

Participants will receive 0.3 milligrams (mg) ranibizumab every fourth week up to Week 20, for a total of 6 administrations, followed by an observational period up to Week 36. If a participant meets pre-specified criteria the participant will receive a single dose of 0.3 mg ranibizumab and exit the study.

Participants will receive 1.5 mg faricimab every fourth week up to Week 20, for a total of 6 administrations, followed by an observational period up to Week 36. If a participant meets pre-specified criteria the participant will receive a single dose of 0.3 mg ranibizumab and exit the study.

Participants will receive 6 mg faricimab every fourth week up to Week 20, for a total of 6 administrations, followed by an observational period up to Week 36. If a participant meets pre-specified criteria the participant will receive a single dose of 0.3 mg ranibizumab and exit the study.

Outcomes

Primary Outcome Measures

Mean Change From Baseline in BCVA Letter Score at Week 24, in Treatment-Naive Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The primary analysis used a Linear Mixed Effects Model for Repeated Measurements. Missing values were not imputed; it was assumed that the data were missing at random.

Secondary Outcome Measures

Mean Change From Baseline in BCVA Letter Score at Week 24, in Previously Treated Participants

Mean Change From Baseline in BCVA Letter Score at Week 24, in All Participants

Mean Percentage of Participants Who Gained ≥15 ETDRS Letters From Baseline BCVA Score at Week 24, in Treatment-Naive Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants Who Gained ≥15 ETDRS Letters From Baseline BCVA Score at Week 24, in Previously Treated Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants Who Gained ≥15 ETDRS Letters From Baseline BCVA Score at Week 24, in All Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants With BCVA ≥69 Letters (20/40 or Better) at Week 24, in Treatment-Naive Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants With BCVA ≥69 Letters (20/40 or Better) at Week 24, in Previously Treated Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants With BCVA ≥69 Letters (20/40 or Better) at Week 24, in All Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants With BCVA ≥84 Letters (20/20 or Better) at Week 24, in Treatment-Naive Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants With BCVA ≥84 Letters (20/20 or Better) at Week 24, in Previously Treated Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Percentage of Participants With BCVA ≥84 Letters (20/20 or Better) at Week 24, in All Participants

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Mean Change From Baseline in Foveal Center Point Thickness at Week 24, in Treatment-Naive Participants

Foveal center point thickness (FCPT) is defined as the thickness from the inner limiting membrane to the retinal pigment epithelial at the horizontal slice closest to the center of the fovea. Foveal center point thickness was measured using spectral domain optical coherence tomography (SD-OCT).

Mean Change From Baseline in Foveal Center Point Thickness at Week 24, in Previously Treated Participants

Mean Change From Baseline in Foveal Center Point Thickness at Week 24, in All Participants

Mean Change From Baseline in Central Subfield Thickness at Week 24, in Treatment-Naive Participants

Central subfield thickness (CST) is defined as the mean thickness from the inner limiting membrane to the retinal pigment epithelial over the 1 millimetre (mm) central subfield. Central subfield thickness was measured using SD-OCT.

Mean Change From Baseline in Central Subfield Thickness at Week 24, in Previously Treated Participants

Mean Change From Baseline in Central Subfield Thickness at Week 24, in All Participants

Percentage of Participants With Presence of Subretinal Fluid in the Study Eye at Week 24, in Treatment-Naive Participants

Subretinal fluid is defined as the presence of fluid between the retina and the retinal pigment epithelium. Resolution of subretinal fluid was measured using SD-OCT.

Percentage of Participants With Presence of Subretinal Fluid in the Study Eye at Week 24, in Previously Treated Participants

Subretinal fluid is defined as the presence of fluid between the retina and the retinal pigment epithelium. Resolution of subretinal fluid was measured using SD-OCT.

Percentage of Participants With Presence of Intraretinal Fluid in the Study Eye at Week 24, in Treatment-Naive Participants

Intraretinal fluid is described as the presence of fluid within the retina. Resolution of intraretinal fluid was measured by SD-OCT.

Percentage of Participants With Presence of Intraretinal Fluid in the Study Eye at Week 24, in Previously Treated Participants

Intraretinal fluid is described as the presence of fluid within the retina. Resolution of intraretinal fluid was measured by SD-OCT.

Number of Participants With Presence or Absence of Leakage at the Macula at Week 24, in Treatment-Naive Participants

Leakage at the macula describes the leakage of fluorescein at the macula region as measured by fundus fluorescein angiography (FFA).

Number of Participants With Presence or Absence of Leakage at the Macula at Week 24, in Previously Treated Participants

Leakage at the macula describes the leakage of fluorescein at the macula region as measured by fundus fluorescein angiography (FFA).

Mean Change From Baseline in the Size of the Foveal Avascular Zone at Week 24, in All Participants

The size of the foveal avascular zone was to be measured by fundus fluorescein angiography (FFA).

Mean Plasma Concentrations of Ranibizumab (Arm A) or Faricimab (Arms B and C) Over Time, in All Participants

Plasma concentrations of ranibizumab were measured by an appropriate assay only from samples of participants randomized to Arm A: 0.3 mg Ranibizumab. Plasma concentrations of faricimab were measured by a specific validated enzyme-linked immunoabsorbent assay (ELISA) only from samples of participants randomized to Arm B: 1.5 mg Faricimab and Arm C: 6 mg Faricimab. Baseline was defined as the last non-missing predose assessment. The lower limit of quantification (LLOQ) for the ranibizumab and faricimab assays were 0.015 nanograms per millilitre (ng/mL) and 0.800 ng/mL, respectively. Values below the limit of quantification were imputed as LLOQ divided by 2.

Baseline and Change From Baseline in Free Vascular Endothelial Growth Factor (VEGF) Plasma Levels Over Time, in Treatment-Naive Participants

The concentration of free VEGF was determined in plasma samples using an enzyme-linked immunosorbent assay (ELISA) method. The lower limit of quantification (LLOQ) of the assay was 15.6 picograms per millilitre (pg/mL). Plasma free VEGF concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Baseline and Change From Baseline in Free Vascular Endothelial Growth Factor (VEGF) Plasma Levels Over Time, in Previously Treated Participants

Baseline and Change From Baseline in Total Angiopoietin-2 (Ang-2) Plasma Levels Over Time, in Treatment-Naive Participants

Total Ang-2 concentrations were determined in plasma samples using an appropriate assay method. The lower limit of quantification (LLOQ) of the assay was 0.09 nanograms per millilitre (ng/mL). Plasma total Ang-2 concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Baseline and Change From Baseline in Free Angiopoietin-2 (Ang-2) Plasma Levels Over Time, in Treatment-Naive Participants

Free Ang-2 concentrations were determined in plasma samples using an appropriate assay method. The lower limit of quantification (LLOQ) of the assay was 0.9 nanograms per millilitre (ng/mL). Plasma free Ang-2 concentrations below the limit of quantification were imputed as LLOQ divided by 2.

Baseline and Change From Baseline in Total Angiopoietin-2 (Ang-2) Plasma Levels Over Time, in Previously Treated Participants

Baseline and Change From Baseline in Free Angiopoietin-2 (Ang-2) Plasma Levels Over Time, in Previously Treated Participants

Safety Summary of the Number of Participants With at Least One Adverse Event During the Treatment Period (up to Week 24), in All Participants

This safety summary reports the number and percentage of participants who experienced at least one adverse event (AE) within 28 days of the end of the treatment period (i.e., up to Week 24). AEs are categorized as any AEs, ocular AEs occurring in the study eye or fellow eye, systemic AEs, serious AEs, AEs related to treatment with study drug, AEs leading to discontinuation of treatment with study drug, and AEs with fatal outcome. Multiple occurrences of the same AE in one individual were counted only once.

Safety Summary of the Number of Participants With at Least One Adverse Event During the Post-Treatment Observation Period, in All Participants

This safety summary reports the number and percentage of participants who experienced at least one adverse event (AE) during the post-treatment observation period (i.e., from Week 24 up to Week 36). AEs are categorized as any AEs, ocular AEs occurring in the study eye or fellow eye, systemic AEs, serious AEs, AEs related to treatment with study drug, AEs leading to discontinuation of treatment with study drug, and AEs with fatal outcome. Multiple occurrences of the same AE in one individual were counted only once.

Number of Participants With at Least One Ocular Adverse Event in the Study Eye or the Fellow Eye During the Treatment Period by Highest Intensity, in All Participants

The investigator assessed adverse event severity according to the following grading scale: Mild = Discomfort noticed, but no disruption of normal daily activity; Moderate = Discomfort sufficient to reduce or affect normal daily activity; Severe = Incapacitating with inability to work or to perform normal daily activity. Only the most severe intensity was counted for multiple occurrences of the same adverse event per participant at the preferred term level. Severity and seriousness are not synonymous; regardless of severity, some adverse events may have also met seriousness criteria.

Number of Participants With at Least One Systemic Adverse Event During the Treatment Period by Highest Intensity, in All Participants

Number of Participants With Abnormal Systolic Blood Pressure Over Time, in All Participants

Abnormal systolic blood pressure (supine) was defined as any value outside of the standard reference range, from <70 (low) to >180 (high) millimetres of mercury (mmHg) or a change from baseline of greater than 30 mmHg (decrease or increase). Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Number of Participants With Abnormal Diastolic Blood Pressure Over Time, in All Participants

Abnormal diastolic blood pressure (supine) was defined as any value outside of the standard reference range, from <40 (low) to >110 (high) millimetres of mercury (mmHg) or a change from baseline of greater than 20 mmHg (decrease or increase). Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Number of Participants With an Abnormal Heart Rate Over Time, in All Participants

Abnormal heart rate (supine) was defined as any value outside of the standard reference range, from <40 (low) to >100 (high) beats per minute. Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Number of Participants With Abnormal Body Temperature Over Time, in All Participants

Abnormal body temperature (supine) was defined as any value outside of the standard reference range, from <36.5 (low) to >37.5 (high) degrees Celsius. Baseline was defined as the last non-missing predose assessment. Not every abnormal vital sign qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy.

Mean Heart Rate at Baseline and Week 24, as Measured by Electrocardiogram in All Participants

Triplicate 12-lead electrocardiogram (ECG), i.e., three useful ECGs without artifacts, were performed on all evaluable participants. To minimize variability, it was important that participants be in a resting position for at least 10 minutes prior to the ECG evaluation. Body position was to be consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation, mobile phones) were to be minimized before and during ECG recording. Triplicate ECGs were to be obtained within a 5-minute interval. The predefined standard reference range for heart rate measured by ECG was 40 (low) to 100 (high) beats per minute.

Mean PR, RR, QT, QRS, QTcB, and QTcF Intervals at Baseline and Week 24, as Measured by Electrocardiogram in All Participants

Triplicate 12-lead electrocardiogram (ECG), i.e., three useful ECGs without artifacts, were performed on all evaluable participants. To minimize variability, it was important that participants be in a resting position for at least 10 minutes prior to the ECG evaluation. Body position was to be consistently maintained for each ECG evaluation to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation, mobile phones) were to be minimized before and during ECG recording. Triplicate ECGs were to be obtained within a 5-minute interval. Baseline was defined as the last non-missing predose assessment. The predefined standard reference ranges for the intervals measured by ECG were defined as follows (ranges are from low to high, in milliseconds [msec]): PR: 120-200 msec; RR: 600-1500 msec; QT: 200-500 msec; QRS: 40-120 msec.

Number of Participants With Marked Laboratory Abnormalities in Hematology Tests, in All Participants

Clinical laboratory tests for hematology parameters were performed and any marked abnormal values (High or Low) were based on Roche's predefined standard reference ranges. Marked laboratory abnormalities are presented according to COG3007 abnormality criteria: Single, Not Last = abnormality detected at a single assessment, but not at the last assessment; Last or Replicated = abnormality detected at the last assessment or replicated at one or more assessments. Not every laboratory abnormality qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. Abs. = absolute count; Ery. = erythrocyte; Hemo. = hemoglobin

Number of Participants With Marked Laboratory Abnormalities in Blood Chemistry Tests, in All Participants

Clinical laboratory tests for blood chemistry parameters were performed and any marked abnormal values (High or Low) were based on Roche's predefined standard reference ranges. Marked laboratory abnormalities are presented according to COG3007 abnormality criteria: Single, Not Last = abnormality detected at a single assessment, but not at the last assessment; Last or Replicated = abnormality detected at the last assessment or replicated at one or more assessments. Not every laboratory abnormality qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. SGOT/AST = serum glutamic oxaloacetic transaminase / aspartate aminotransferase

Number of Participants With Marked Laboratory Abnormalities in Coagulation Tests, in All Participants

Clinical laboratory tests for coagulation parameters were performed and any marked abnormal values (High or Low) were based on Roche's predefined standard reference ranges. Marked laboratory abnormalities are presented according to COG3007 abnormality criteria: Single, Not Last = abnormality detected at a single assessment, but not at the last assessment; Last or Replicated = abnormality detected at the last assessment or replicated at one or more assessments. Not every laboratory abnormality qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a change in concomitant therapy. aPTT = activated partial thromboplastin time; INR = International Normalized Ratio (prothrombin time)

Number of Participants Who Tested Negative or Positive for Anti-Drug Antibodies Against Faricimab Over Time

The number and percentage of participants who tested negative or positive for plasma anti-drug antibodies (ADA) to faricimab at baseline and at the study visits was tabulated, except for those who were randomized to treatment with ranibizumab in Arm A.

Full Information

NCT ID

NCT02699450

First Posted

March 1, 2016

Last Updated

August 31, 2020

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT02699450

Brief Title

A Study of Faricimab (RO6867461) in Participants With Center-Involving Diabetic Macular Edema

Acronym

BOULEVARD

Official Title

A Multiple-Center, Multiple-Dose, Randomized, Active Comparator-Controlled, Double-Masked, Parallel Group, 36-Week Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of RO6867461 Administered Intravitreally in Patients With Diabetic Macular Edema

Study Type

Interventional

2. Study Status

Record Verification Date

August 2020

Overall Recruitment Status

Completed

Study Start Date

April 27, 2016 (Actual)

Primary Completion Date

September 15, 2017 (Actual)

Study Completion Date

December 14, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This is a multiple-center, multiple-dose, randomized, active comparator-controlled, double-masked, three parallel group, 36-week study in participants with center-involving diabetic macular edema (DME). Only one eye will be selected as the study eye. Where both eyes meet all eligibility criteria, the eye with the worse best corrected visual acuity (BCVA) will be defined as the study eye. The study will consist of a treatment period (20 weeks) and an observational period (up to 16 weeks). Treatment naive participants will be randomized in a 1:1:1 ratio to one of the Arms A, B and C, respectively. Participants previously treated with intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) will be randomized in a 1:1 ratio to Arms A and C.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetic Macular Edema

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

229 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A: 0.3 mg Ranibizumab

Arm Type

Active Comparator

Arm Description

Arm Title

Arm B: 1.5 mg Faricimab

Arm Type

Experimental

Arm Description

Arm Title

Arm C: 6 mg Faricimab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Faricimab

Other Intervention Name(s)

RO6867461, RG7716

Intervention Description

Faricimab will be administered by IVT injection in the study eye.

Intervention Type

Drug

Intervention Name(s)

Ranibizumab

Other Intervention Name(s)

Lucentis

Intervention Description

Ranibizumab will be administered by IVT injection in the study eye.

Primary Outcome Measure Information:

Title

Mean Change From Baseline in BCVA Letter Score at Week 24, in Treatment-Naive Participants

Description

Time Frame

Baseline, Week 24

Secondary Outcome Measure Information:

Title

Mean Change From Baseline in BCVA Letter Score at Week 24, in Previously Treated Participants

Description

Time Frame

Baseline, Week 24

Title

Mean Change From Baseline in BCVA Letter Score at Week 24, in All Participants

Description

Time Frame

Baseline, Week 24

Title

Mean Percentage of Participants Who Gained ≥15 ETDRS Letters From Baseline BCVA Score at Week 24, in Treatment-Naive Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Baseline, Week 24

Title

Mean Percentage of Participants Who Gained ≥15 ETDRS Letters From Baseline BCVA Score at Week 24, in Previously Treated Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Baseline up to Week 24

Title

Mean Percentage of Participants Who Gained ≥15 ETDRS Letters From Baseline BCVA Score at Week 24, in All Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Baseline up to Week 24

Title

Mean Percentage of Participants With BCVA ≥69 Letters (20/40 or Better) at Week 24, in Treatment-Naive Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Week 24

Title

Mean Percentage of Participants With BCVA ≥69 Letters (20/40 or Better) at Week 24, in Previously Treated Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Week 24

Title

Mean Percentage of Participants With BCVA ≥69 Letters (20/40 or Better) at Week 24, in All Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Week 24

Title

Mean Percentage of Participants With BCVA ≥84 Letters (20/20 or Better) at Week 24, in Treatment-Naive Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Week 24

Title

Mean Percentage of Participants With BCVA ≥84 Letters (20/20 or Better) at Week 24, in Previously Treated Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Week 24

Title

Mean Percentage of Participants With BCVA ≥84 Letters (20/20 or Better) at Week 24, in All Participants

Description

Best corrected visual acuity (BCVA) at a starting test distance of 4 meters was measured using a set of three Precision VisionTM or Lighthouse distance acuity charts (modified ETDRS Charts 1, 2, and R) prior to dilating eyes by a trained and certified visual acuity examiner masked to study drug arm assignment. The BCVA examiner was masked to study eye and treatment assignment and only performed the refraction and BCVA assessment, but was not allowed to perform any other tasks involving direct care. The BCVA examiner was also masked to the BCVA letter scores of a participant's previous visits and could only know the participant's refraction data from previous visits. The BCVA letter score ranges from 0 to 100 (best score attainable), and a gain in BCVA letter score from baseline indicates an improvement in visual acuity. The outcome measure was analyzed using a Generalized Estimating Equations Model. Missing values were not imputed; it was assumed that the data were missing at random.

Time Frame

Week 24

Title

Mean Change From Baseline in Foveal Center Point Thickness at Week 24, in Treatment-Naive Participants

Description

Time Frame

Baseline, Week 24

Title

Mean Change From Baseline in Foveal Center Point Thickness at Week 24, in Previously Treated Participants

Description

Time Frame

Baseline, Week 24

Title

Mean Change From Baseline in Foveal Center Point Thickness at Week 24, in All Participants

Description

Time Frame

Baseline, Week 24

Title

Mean Change From Baseline in Central Subfield Thickness at Week 24, in Treatment-Naive Participants

Description

Time Frame

Baseline, Week 24

Title

Mean Change From Baseline in Central Subfield Thickness at Week 24, in Previously Treated Participants

Description

Time Frame

Baseline, Week 24

Title

Mean Change From Baseline in Central Subfield Thickness at Week 24, in All Participants

Description

Time Frame

Baseline, Week 24

Title

Percentage of Participants With Presence of Subretinal Fluid in the Study Eye at Week 24, in Treatment-Naive Participants

Description

Subretinal fluid is defined as the presence of fluid between the retina and the retinal pigment epithelium. Resolution of subretinal fluid was measured using SD-OCT.

Time Frame

Week 24

Title

Percentage of Participants With Presence of Subretinal Fluid in the Study Eye at Week 24, in Previously Treated Participants

Description

Subretinal fluid is defined as the presence of fluid between the retina and the retinal pigment epithelium. Resolution of subretinal fluid was measured using SD-OCT.

Time Frame

Week 24

Title

Percentage of Participants With Presence of Intraretinal Fluid in the Study Eye at Week 24, in Treatment-Naive Participants

Description

Intraretinal fluid is described as the presence of fluid within the retina. Resolution of intraretinal fluid was measured by SD-OCT.

Time Frame

Week 24

Title

Percentage of Participants With Presence of Intraretinal Fluid in the Study Eye at Week 24, in Previously Treated Participants

Description

Intraretinal fluid is described as the presence of fluid within the retina. Resolution of intraretinal fluid was measured by SD-OCT.

Time Frame

Week 24

Title

Number of Participants With Presence or Absence of Leakage at the Macula at Week 24, in Treatment-Naive Participants

Description

Leakage at the macula describes the leakage of fluorescein at the macula region as measured by fundus fluorescein angiography (FFA).

Time Frame

Week 24

Title

Number of Participants With Presence or Absence of Leakage at the Macula at Week 24, in Previously Treated Participants

Description

Leakage at the macula describes the leakage of fluorescein at the macula region as measured by fundus fluorescein angiography (FFA).

Time Frame

Week 24

Title

Mean Change From Baseline in the Size of the Foveal Avascular Zone at Week 24, in All Participants

Description

The size of the foveal avascular zone was to be measured by fundus fluorescein angiography (FFA).

Time Frame

Baseline, Week 24

Title

Mean Plasma Concentrations of Ranibizumab (Arm A) or Faricimab (Arms B and C) Over Time, in All Participants

Description

Time Frame

Predose at Baseline and Weeks 1, 4, 12, 20, 24, 26, 28, 32, and 36

Title

Baseline and Change From Baseline in Free Vascular Endothelial Growth Factor (VEGF) Plasma Levels Over Time, in Treatment-Naive Participants

Description

Time Frame