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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| mono therapy | Active Comparator | ranibizumab alone |
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| combination therapy | Experimental | ranibizumab with Grid&Direct short pulse laser photocoagulation |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ranibizumab | Biological | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in Mean Number of Ranibizumab Injections | 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. | Month 1 through Month 12 |
| Measure | Description | Time Frame |
|---|---|---|
| The Mean Change in Best Corrected Visual Acuity (BCVA) Using Decimal Chart and Early Treatment Diabetic Retinopathy Study (ETDRS) Compared to Baseline | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Nagakute | Aichi-ken | 480-1195 | Japan | ||
| Novartis Investigative Site |
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
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Below is the participant flow of Randomized patients
73 patients were screened and 59 were randomized on a 1:1 ratio to the ranibizumab group (29 patients) and ranibizumab with laser group (30 patients). Of the randomized patients, 56 (94.9%) completed the study and 11 months of treatment. 3 (5.1%) discontinued both study and study treatment: 2 (3.4%) withdrew consent and 1 (1.7%) had adverse event
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| ID | Title | Description |
|---|---|---|
| FG000 | Ranibizumab 0.5 mg | 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL |
| FG001 | Ranibizumab 0.5 mg and Laser | 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL with the laser treatment |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 21, 2018 | Nov 11, 2019 |
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Phase IV, randomized, open-label, active-controlled, 2-arm, multicenter study
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| Grid&Direct short pulse laser photocoagulation | Radiation | Grid&Direct short pulse laser photocoagulation is a kind of laser treatment to retina within vascular arcades and used to suppress macular edema |
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| Month 1 through Month 12 (for ETDRS: Month 6 and Month 12) |
| The Mean Change in BCVA From Month 1 Through Month 12 Compared to Baseline (Day 1) by the Treatment Arms | 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 | Month 1 through Month 12 |
| 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 | 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 | Month 6 and 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 | 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 | Month 1 through Month 12 |
| Fukuoka |
| Fukuoka |
| 812-8582 |
| Japan |
| Novartis Investigative Site | Kita-gun | Kagawa-ken | 761-0793 | Japan |
| Novartis Investigative Site | Tsu | Mie-ken | 514-8507 | Japan |
| Novartis Investigative Site | Matsumoto | Nagano | 390-8621 | Japan |
| Novartis Investigative Site | Mitaka | Tokyo | 181-8611 | Japan |
| Novartis Investigative Site | Hokkaido | 078-8510 | Japan |
| COMPLETED | Completed Study Prior to 12 Months |
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| NOT COMPLETED |
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Randomized Set
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| ID | Title | Description |
|---|---|---|
| BG000 | Ranibizumab 0.5 mg | 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL |
| BG001 | Ranibizumab 0.5 mg and Laser | 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL with the laser treatment |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Age, Customized | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Difference in Mean Number of Ranibizumab Injections | 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. | Randomized Set, i.e.; all randomized patients. | Posted | Mean | Standard Deviation | number of injections | Month 1 through Month 12 |
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| Secondary | The Mean Change in Best Corrected Visual Acuity (BCVA) Using Decimal Chart and Early Treatment Diabetic Retinopathy Study (ETDRS) Compared to Baseline | 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. | The Full Analysis Set (FAS) consisted of all randomized patients who received at least one administration of ranibizumab injection. | Posted | Mean | Standard Deviation | letters read correctly | Month 1 through Month 12 (for ETDRS: Month 6 and Month 12) |
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| Secondary | The Mean Change in BCVA From Month 1 Through Month 12 Compared to Baseline (Day 1) by the Treatment Arms | 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 | FAS | Posted | Mean | Standard Deviation | logMAR | Month 1 through Month 12 |
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| Secondary | 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 | 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 | Full Analysis Set (FAS) consisted of all randomized patients who received at least one administration of ranibizumab injection | Posted | Count of Participants | Participants | Month 6 and Month 12 |
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| Secondary | 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 | 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 | Full Analysis Set (FAS) | Posted | Mean | Standard Deviation | mm | Month 1 through Month 12 |
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AEs and SAEs were collected for the maximum duration of treatment and follow up for a participant per protocol for approximately 12 months.
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
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ranibizumab 0.5 mg | 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL | 0 | 29 | 1 | 29 | 16 | 29 |
| EG001 | Ranibizumab 0.5 mg+ Laser | 0.5 mg ranibizumab applied one + PRN as intravitreal injection of 0.05 mL with the laser treatment. | 0 | 30 | 2 | 30 | 15 | 30 |
| EG002 | Total | Total | 0 | 59 | 3 | 59 | 31 | 59 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bowen's disease | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (21.1) | Systematic Assessment |
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| Putamen haemorrhage | Nervous system disorders | MedDRA (21.1) | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | MedDRA (21.1) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Tinnitus | Ear and labyrinth disorders | MedDRA (21.1) | Systematic Assessment |
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| Conjunctival haemorrhage | Eye disorders | MedDRA (21.1) | Systematic Assessment |
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| Corneal erosion | Eye disorders | MedDRA (21.1) | Systematic Assessment |
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| Dry eye | Eye disorders | MedDRA (21.1) | Systematic Assessment |
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| Keratitis | Eye disorders | MedDRA (21.1) | Systematic Assessment |
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| Macular fibrosis | Eye disorders | MedDRA (21.1) | Systematic Assessment |
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| Photopsia | Eye disorders | MedDRA (21.1) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (21.1) | Systematic Assessment |
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| Feeling abnormal | General disorders | MedDRA (21.1) | Systematic Assessment |
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| Hepatic function abnormal | Hepatobiliary disorders | MedDRA (21.1) | Systematic Assessment |
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| Seasonal allergy | Immune system disorders | MedDRA (21.1) | Systematic Assessment |
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| Influenza | Infections and infestations | MedDRA (21.1) | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA (21.1) | Systematic Assessment |
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| Periodontitis | Infections and infestations | MedDRA (21.1) | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA (21.1) | Systematic Assessment |
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| Foot fracture | Injury, poisoning and procedural complications | MedDRA (21.1) | Systematic Assessment |
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| Tooth fracture | Injury, poisoning and procedural complications | MedDRA (21.1) | Systematic Assessment |
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| Intraocular pressure increased | Investigations | MedDRA (21.1) | Systematic Assessment |
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| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA (21.1) | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (21.1) | Systematic Assessment |
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| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (21.1) | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (21.1) | Systematic Assessment |
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| Dysarthria | Nervous system disorders | MedDRA (21.1) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (21.1) | Systematic Assessment |
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| Hemiplegia | Nervous system disorders | MedDRA (21.1) | Systematic Assessment |
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| Migraine | Nervous system disorders | MedDRA (21.1) | Systematic Assessment |
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| Atrophic vulvovaginitis | Reproductive system and breast disorders | MedDRA (21.1) | Systematic Assessment |
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| Dry skin | Skin and subcutaneous tissue disorders | MedDRA (21.1) | Systematic Assessment |
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| Erythema | Skin and subcutaneous tissue disorders | MedDRA (21.1) | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA (21.1) | Systematic Assessment |
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The terms and conditions of Novartis' agreement with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publications of the pooled data (i.e., data from all sites) in the clinical trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | +1 (862) 778-8300 | novartis.email@novartis.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 30, 2019 | Nov 11, 2019 | SAP_001.pdf |
| ID | Term |
|---|---|
| D008269 | Macular Edema |
| D012170 | Retinal Vein Occlusion |
| ID | Term |
|---|---|
| D008268 | Macular Degeneration |
| D012162 | Retinal Degeneration |
| D012164 | Retinal Diseases |
| D005128 | Eye Diseases |
| D020246 | Venous Thrombosis |
| D013927 | Thrombosis |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000069579 | Ranibizumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
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| >=65 years |
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| Male |
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| Participants |
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