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Ranibizumab

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ranibizumab with Grid\&Direct short pulse laser photocoagulation

Ranibizumab is a biologic and known anti-VEGF (vascular endothelial growth factor) medication approved for treatment of ME (Macular Edema) due to RVO (Retinal Vein occlusion)

0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL, with or without laser treatment

Grid\&Direct short pulse laser photocoagulation is a kind of laser treatment to retina within vascular arcades and used to suppress macular edema

Grid&Direct short pulse laser photocoagulation

Novartis Pharmaceuticals

This is a Phase IV, randomized, open-label, active-controlled, 2-arm, multicenter study. The primary objective was assessed by the difference in the mean number of ranibizumab injections applied up to Month 11 between the 2 treatment arms. Patients were randomized in a 1:1 ratio to 1 of the 2 treatment arms; i.e. Arm 1 ranibizumab monotherapy, Arm 2 ranibizumab with Grid\&Direct short pulse laser photocoagulation combination therapy. There were 3 periods in this study: Screening Period (visit 1), Treatment Period (visit 2 to Visit 13) and Follow-up Period (visit 14). In addition to screening and Baseline (visit 2), there were monthly visits from Month 1 to Month 12. This study included male and female patients (≥20 years old) diagnosed with visual impairment due to ME secondary to BRVO.

Phase IV, randomized, open-label, active-controlled, 2-arm, multicenter study

Study to Show a Superior Benefit in Terms of Reduction of Ranibizumab Injections in Patients Receiving Ranibizumab Plus Laser Photocoagulation Combination Therapy Without Loss of Efficacy and Safety

A 12-month, Phase IV, Open-label, Randomized, Active Controlled, 2-arm, Multicenter Study Assessing the Efficacy and Safety of Intravitreal Ranibizumab Combined With Grid&Direct Short Pulse Laser Photocoagulation Versus a PRN Ranibizumab Monotherapy in Japanese Patients With Macular Edema Secondary to Branch Retinal Vein Occlusion (BRVO)

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Number of ranibizumab treatments from Day 1 to Month 11 using full analysis set (observed) based on a stratified Cochran-Mantel-Haenszel (CMH) test. Stratification was done based on categories of baseline decimal VA (\<0.3, or =\>0.3). Difference of mean number of injections, 95% confidence interval (CI) of difference and one-sided p-value of the CMH test was reported. Analysis was conducted within the FAS with observed data.

Stratification was based on baseline visual acuity on logMAR scale (\<0.52, \>=0.52). Test was one-sided.

Summary of BCVA (letters) absolute value and change from Baseline at Month 12 in the study eye - full analysis set (LOCF) was based on an analysis of variance (ANOVA) model with treatment group, and stratification factors. Stratification was done based on categories of baseline decimal VA (\<0.3, or =\>0.3). The analyses was conducted within the FAS using the LOCF approach

Stratification was based on baseline visual acuity on logMAR scale (\<0.52, \>=0.52). Test was one-sided.

Summary of BCVA (logMAR) absolute value and change from Baseline at Month 12 in the study eye - full analysis set (LOCF) was based on an analysis of variance (ANOVA) model with treatment group, and stratification factors. Stratification was based on baseline visual acuity (\< 0.52, \>= 0.52). The analyses was conducted within the FAS using the LOCF approach

Endpoints related to the number and proportion of patients with BCVA letter gain or loss from Baseline (Day1) was analyzed via stratified CMH test with stratification factors as described in primary model. The mean (SD) average (per patient) BCVA (logMAR) change from Baseline through Month 12

Summary of BCVA (logMAR) mean average change from Baseline from Month 1 through Month 12 in the study eye

The mean change in investigator-assessed CSFT from Month 1 through Month 12 was compared to Baseline (Day1) by the treatment arms. The analyses at each visit was based on an analysis of variance (ANOVA) model as analogous to BCVA. The analyses was conducted within the FAS using the Last-Observation-Carried-Forward (LOCF) approach

All cause mortality (deaths) was collected from First Patient First Visit (FPFV) to Last Patient Last Visit (LPLV) up to a maximum of 12 months

0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL

Ranibizumab 0.5 mg

0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL with the laser treatment.

Ranibizumab 0.5 mg+ Laser

Total

0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL with the laser treatment

Ranibizumab 0.5 mg and Laser

Age, Continuous

<65 years

>=65 years

Age, Customized

Sex: Female, Male

Asian

Race/Ethnicity, Customized

Study Director

Ranibizumab 0.5 mg Laser

Randomized Set, i.e.; all randomized patients.

Difference in Mean Number of Ranibizumab Injections

baseline

month 12

change from baseline to month 12

The Full Analysis Set (FAS) consisted of all randomized patients who received at least one administration of ranibizumab injection.

The Mean Change in Best Corrected Visual Acuity (BCVA) Using Decimal Chart and Early Treatment Diabetic Retinopathy Study (ETDRS) Compared to Baseline

month12

The Mean Change in BCVA From Month 1 Through Month 12 Compared to Baseline (Day 1) by the Treatment Arms

Month 6 - BCVA improvement of >=1

month 6 - BCVA improvement of >=5

month 6 - BCVA improvement of >=10

Month 6 - BCVA improvement of >=15

Month 6 - BCVA improvement of >=30

month 6 Score >=73

month 6 Score >=80

month 6 Score >=85

month 6 loss of <15

Month 12 - BCVA improvement of >=1

Month 12 - BCVA improvement of >=5

Month 12 - BCVA improvement of >=10

Month 12 - BCVA improvement of >=15

Month 12 - BCVA improvement of >=30

month 12 Score >=73

month 12 Score >=80

month 12 Score >=85

month 12 Loss of <15

Full Analysis Set (FAS) consisted of all randomized patients who received at least one administration of ranibizumab injection

BCVA (Letters) Number and Proportion of Patients With a BCVA Improvement vs. Baseline, Loss Less Than 15 Letters, or Attainment of Greater Than or Equal to 85 Letters at Month 6 and at Month 12 in the Study Eye

change in baseline from month 12

The Mean Change in Change in Central Subfield Foveal Thickness (CSFT) From Month 1 Through Month 12 Compared to Baseline (Day1) by the Treatment Arms

Overall Study

Nervous System Diseases

Vision, Low

As of Month 6 ranibizumab 0.5 mg PRN intravitreal injection

Sham injection

Provided efficacy and safety data on intravitreal injections of ranibizumab 0.5 mg in patients with visual impairment due to macular edema secondary to BRVO

Ranibizumab Intravitreal Injections Versus Sham Control in Patients With Branch Retinal Vein Occlusion (BRVO)

A Randomized Double-masked, Phase III Study Assessing Ranibizumab Intravitreal Injections Versus Sham Control in Patients With Visual Impairment Due to Macular Edema (ME) Secondary to Branch Retinal Vein Occlusion (BRVO) [Blossom]

Best Corrected Visual Acuity (BCVA) was assessed in a sitting position using ETDRS-like visual acuity testing charts at an initial testing distance of 4 meters. Mean Visual Acuity was averaged over all monthly assessments from month 1 to month 6 and compared to Baseline.

Best Corrected Visual Acuity (BCVA) was assessed in a sitting position using ETDRS-like visual acuity testing charts at an initial testing distance of 4 meters. Mean Visual Acuity was averaged over all monthly assessments from month 1 to month 12 and compared to Baseline

Best Corrected Visual Acuity (BCVA) was assessed in a sitting position using ETDRS-like visual acuity testing charts at an initial testing distance of 4 meters

Visual acuity (VA) was assessed at every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. This outcome measure describes for each post-baseline month whether or not a patient lost less than 15 letters of VA as compared with baseline.

OCT (optical coherence tomography) was used to assess CSFT (Central Sub-Field Thickness) representing the average retinal thickness of the circular area within 1 mm diameter around the foveal center

Fluorescein leakage area was assessed using Fluorescein angiography (FA) in conjunction with 7-field color fundus photography (CF) at Screening, Month 3, Month 6 and End of Study visit for both eyes

The VFQ-25 consists of 25 vision related questions across 11 vision related subscales, including general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision and peripheral vision, and a general health rating. Items are converted to a 0-100 scale on each subscale and for the composite score where higher scores represents better functioning.

The Safety Set consisted of all patients who received at least one application of study treatment and had at least one post-Baseline safety assessment. Patients were analyzed according to the treatment received. The statement that a patient had no AEs also constituted a safety assessment.

Sham With Ranibizumab 0.5 mg

sham + ranibizumab 0.5 mg PRN as of Month 6 (hereafter referred to as sham group up to Month 6 and sham with ranibizumab or sham without ranibizumab after Month 6)

Sham Without Ranibizumab 0.5 mg

Sham Injection

One patient was randomized to the ranibizumab group but received no study treatment during the study period and discontinued the study after Visit 2. Therefore, excluded from the Safety set

The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment group they had been assigned to at randomization. Mean value interpolation and last observation carried forward (MV-LOCF)

Average Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 1 Through Month 6

Average Change of Best Corrected Visual Acuity (BCVA) in Patients From Baseline to Month 1 Through Month 12

Month 1

Month 2

Month 3

Month 4

Month 5

Month 6

Month 7

Month 8

Month 9

Month 10

Month 11

Month 12

Best Corrected Visual Acuity (BCVA) Change Over Time

Month 1 Gain of >=5 letters

Month 1 Gain of >=10 letters

Month 1 Gain of >=15 letters

Month 1 Gain of >=30 letters

Month 2 Gain of >=5 letters

Month 2 Gain of >=10 letters

Month 2 Gain of >=15 letters

Month 2 Gain of >=30 letters

Month 3 Gain of >=5 letters

Month 3 Gain of >=10 letters

Month 3 Gain of >=15 letters

Month 3 Gain of >=30 letters

Month 4 Gain of >=5 letters

Month 4 Gain of >=10 letters

Month 4 Gain of >=15 letters

Month 4 Gain of >=30 letters

Month 5 Gain of >=5 letters

Month 5 Gain of >=10 letters

Month 5 Gain of >=15 letters

Month 5 Gain of >=30 letters

Month 6 Gain of >=5 letters

Month 6 Gain of >=10 letters

Month 6 Gain of >=15 letters

Month 6 Gain of >=30 letters

Month 7 Gain of >=5 letters

Month 7 Gain of >=10 letters

Month 7 Gain of >=15 letters

Month 7 Gain of >=30 letters

Month 8 Gain of >=5 letters

Month 8 Gain of >=150 letters

Month 8 Gain of >=15 letters

Month 8 Gain of >=30 letters

Month 9 Gain of >=5 letters

Month 9 Gain of >=10 letters

Month 9 Gain of >=15 letters

Month 9 Gain of >=30 letters

Month 10 Gain of >=5 letters

Month 10 Gain of >=10 letters

Month 10 Gain of >=15 letters

Month 10 Gain of >=30 letters

Month 11 Gain of >=5 letters

Month 11 Gain of >=10 letters

Month 11 Gain of >=15 letters

Month 11 Gain of >=30 letters

Month 12 Gain of >=5 letters

Month 12 Gain of >=10 letters

Month 12 Gain of >=15 letters

Month 12 Gain of >=30 letters

Number of Participants With a Best Corrected Visual Acuity (BCVA) Improvement of ≥5, ≥10, ≥15, and ≥30 Letters Over Time

Month 1, Loss of < 15 letters

Month 2, Loss of < 15 letters

Month 3, Loss of < 15 letters

Month 4, Loss of < 15 letters

Month 5, Loss of < 15 letters

Month 6, Loss of < 15 letters

Month 7, Loss of < 15 letters

Month 8, Loss of < 15 letters

Month 9, Loss of < 15 letters

Month 10, Loss of < 15 letters

Month 11, Loss of < 15 letters

Month 12, Loss of < 15 letters

Number of Participants With Best Corrected Visual Acuity (BCVA)Loss of 15 Letters in the Study Eye

Change in Central-Sub-Field- Thickness (CSFT) Over Time

Change in Total Area of Fluorescein Leakage (Center Subfield) From Baseline Over Time

Change in Total Area of Fluorescein Leakage (Inner Subfield) From Baseline Over Time

Change in Total Area of Fluorescein Leakage (Outer Subfield) From Baseline Over Time

Change from Baseline at M3 (n=187,91)

Change from Baseline at M6 (n=185,88)

Change from Baseline at M12 (n=176,88)

The Full Analysis Set (FAS) consisted of all patients to whom study treatment had been assigned. Following the intent-to-treat principle, patients were analyzed according to the treatment group they had been assigned to at randomization. n=the number of patients with a value for both baseline and the specific post-baseline visit.

Change From Baseline in NEI-VFQ-25 Composite and Subscale Scores at Month 3, Month 6 and Month 12

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Show a Superior Benefit in Terms of Reduction of Ranibizumab Injections in Patients Receiving Ranibizumab Plus Laser Photocoagulation Combination Therapy Without Loss of Efficacy and Safety	NCT02953938	Macular Edema S...	Ranibizumab Grid&Direct sho...	20 Years -	Novartis
Ranibizumab Intravitreal Injections Versus Sham Control in Patients With Branch Retinal Vein Occlusion (BRVO)	NCT01976338	Macular Edema S...	Ranibizumab 0.5... Sham injection	18 Years -	Novartis
Ranibizumab Intravitreal Injections Versus Sham Control in Patients With Branch Retinal Vein Occlusion (BRVO)	NCT01976338	Macular Edema S...	Ranibizumab 0.5... Sham injection	18 Years -	Novartis
Study to Show a Superior Benefit in Terms of Reduction of Ranibizumab Injections in Patients Receiving Ranibizumab Plus Laser Photocoagulation Combination Therapy Without Loss of Efficacy and Safety	NCT02953938	Macular Edema S...	Ranibizumab Grid&Direct sho...	20 Years -	Novartis
Ranibizumab Intravitreal Injections Versus Sham Control in Patients With Branch Retinal Vein Occlusion (BRVO)	NCT01976338	Macular Edema S...	Ranibizumab 0.5... Sham injection	18 Years -	Novartis
Study to Show a Superior Benefit in Terms of Reduction of Ranibizumab Injections in Patients Receiving Ranibizumab Plus Laser Photocoagulation Combination Therapy Without Loss of Efficacy and Safety	NCT02953938	Macular Edema S...	Ranibizumab Grid&Direct sho...	20 Years -	Novartis

Spots Global Cancer Trial Database for branch retinal vein occlusion