Central Retinal Vein Occlusion, Macular Edema, Visual Impairment
Conditions
Keywords
Visual impairment, macular edema, Central retinal vein occlusion, Dexamethasone implant, Ranibizumab
Brief summary
This clinical trial is designed to compare ranibizumab in comparison with Dexamethasone implant® after 6 months of treatment. In the study arm Lucentis will be given monthly in a pro re nata scheme whereas the comparator Dexamethasone implant is given once at Month 0 with sham injections PRN afterwards.
Interventions
DRUGRanibizumab
DRUGDexamethasone implant and sham injections
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients diagnosed with visual impairment due to macular edema following CRVO * Diagnosis of CRVO at maximum 6 months prior to Screening * BCVA using ETDRS charts of 20/40 to 20/400 in the study eye
Exclusion criteria
* Media clarity, pupillary dilation and patient cooperation not sufficient for adequate fundus photographs * Central retinal thickness (CRT) \< 250 µm in the study eye * Prior episode of RVO in the study eye * Active formation of new vessels in the study eye * Anti-VEGF-treatment in the study or the fellow eye 3 months prior to Baseline * IOP ≥ 30mmHg or uncontrolled glaucoma; patients may be re-screened after 1 month if they have undergone glaucoma treatment * Improvement of \> 10 letters on BCVA between Screening and Baseline Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Average BCVA Change From Month 1 Through Month 6 to Baseline | Baseline, month 6 | the average of the changes in BCVA (letters) from baseline to any post-baseline visit, i.e. the mean of six differences to baseline for the six post-baseline visits at month 1 to 6. BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is pproximately 20/20. An increased score indicates improvement in acuity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Baseline, 6 month | BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increased score indicates improvement in acuity. This outcome assessed the number of participants who gained 15, 10 or 5 more letters of visual acuity at month 6 as compared with baseline |
| Time to Achieve a Significant Improvement ≥ 15 Letters | Baseline, month 6 | The time was analyzed by the Kaplan-Maier-Method, adjusting the calculation for dropouts |
| Change Over Time in BCVA | Baseline, month 6 | The analysis was performed by an analysis of covariance (ANCOVA) model with average change in BCVA (letters) from Visit 1 through Visit 6 as dependent variable, and with the factors center, treatment and covariate baseline BCVA as predictors |
| Change Over Time of the Central Retinal Thickness (CRT) | Baseline, month 6 | Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation |
| Mean BCVA Change at Month 6 | Baseline, month 6 | The analysis was performed by an analysis of covariance (ANCOVA) model with average change in BCVA (letters) from Visit 1 through Visit 6 as dependent variable, and with the factors center, treatment and covariate baseline BCVA as predictors |
| Changes in the Quality of Life According to the Short Form (36) Health Survey (SF-36)Questionnaires | Baseline, month 6 | SF-36 summary measures are norm-based scores with mean = 50 and SD = 10. Higher scores indicate better health |
| Changes in the Quality of Life According to Euro Quality of Life (EQ-5D) Questionnaires | Baseline, month 6 | The EQ-5D visual analog scale ranges from 0 to 100, 0 representing the worst and 100 the best imaginable health state. |
| Increase Rate of the Internal Ocular Pressure (IOP ) : Patients With ≥10% Increase in IOP Compared to Baseline | Baseline, month 6 | The proportion of patients with ≥ 10% increase in Internal Ocular Pressure (IOP) compared to baseline at any post-baseline visit. |
| Changes in the Quality of Life According to the National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) Questionnaires | Baseline, month 6 | The VFQ-25 composite and subscale scores range from 0 to 100, a higher score indicating better functioning. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function |
Countries
Germany, Hungary, Poland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab Injections consisted of 0.5 mg/0.05 ml solution to be injected intravitreally | 124 |
| Dexamethasone Intravitreal implant as per commercial label (700 μg Dexamethasone; long acting release (LAR) over 6 months | 119 |
| Total | 243 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 1 | 0 |
| Overall Study | Administrative problems | 1 | 0 |
| Overall Study | Adverse Event | 2 | 28 |
| Overall Study | Consent withdrawn | 4 | 5 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol deviation(s) | 0 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 2 | 13 |
Baseline characteristics
| Characteristic | Ranibizumab | Dexamethasone | Total |
|---|---|---|---|
| Age, Continuous | 65.3 Years STANDARD_DEVIATION 11.4 | 66.9 Years STANDARD_DEVIATION 12.4 | 66.1 Years STANDARD_DEVIATION 11.9 |
| Sex: Female, Male Female | 52 Participants | 46 Participants | 98 Participants |
| Sex: Female, Male Male | 72 Participants | 73 Participants | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 77 / 124 | 99 / 119 |
| serious Total, serious adverse events | 10 / 124 | 16 / 119 |
Outcome results
Primary
Mean Average BCVA Change From Month 1 Through Month 6 to Baseline
the average of the changes in BCVA (letters) from baseline to any post-baseline visit, i.e. the mean of six differences to baseline for the six post-baseline visits at month 1 to 6. BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is pproximately 20/20. An increased score indicates improvement in acuity
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab | Mean Average BCVA Change From Month 1 Through Month 6 to Baseline | 14.6 Letters | Standard Deviation 11.8 |
| Dexamethasone | Mean Average BCVA Change From Month 1 Through Month 6 to Baseline | 4.8 Letters | Standard Deviation 16.2 |
Secondary
Change Over Time in BCVA
The analysis was performed by an analysis of covariance (ANCOVA) model with average change in BCVA (letters) from Visit 1 through Visit 6 as dependent variable, and with the factors center, treatment and covariate baseline BCVA as predictors
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ranibizumab | Change Over Time in BCVA | Month 3 | 14.04 letters |
| Ranibizumab | Change Over Time in BCVA | Month 4 | 12.76 letters |
| Ranibizumab | Change Over Time in BCVA | Month 5 | 13.57 letters |
| Ranibizumab | Change Over Time in BCVA | Month 2 | 12.25 letters |
| Ranibizumab | Change Over Time in BCVA | Month 6 | 14.78 letters |
| Ranibizumab | Change Over Time in BCVA | Month 1 | 9.77 letters |
| Dexamethasone | Change Over Time in BCVA | Month 6 | -3.17 letters |
| Dexamethasone | Change Over Time in BCVA | Month 1 | 9.54 letters |
| Dexamethasone | Change Over Time in BCVA | Month 2 | 11.04 letters |
| Dexamethasone | Change Over Time in BCVA | Month 4 | -1.73 letters |
| Dexamethasone | Change Over Time in BCVA | Month 5 | -2.92 letters |
| Dexamethasone | Change Over Time in BCVA | Month 3 | 4.99 letters |
Secondary
Change Over Time of the Central Retinal Thickness (CRT)
Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab | Change Over Time of the Central Retinal Thickness (CRT) | -376.7 µm | Standard Deviation 274.9 |
| Dexamethasone | Change Over Time of the Central Retinal Thickness (CRT) | -168.7 µm | Standard Deviation 288.3 |
Secondary
Changes in the Quality of Life According to Euro Quality of Life (EQ-5D) Questionnaires
The EQ-5D visual analog scale ranges from 0 to 100, 0 representing the worst and 100 the best imaginable health state.
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Observed participants are only described in this analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab | Changes in the Quality of Life According to Euro Quality of Life (EQ-5D) Questionnaires | 0.1 Units on a scale | Standard Deviation 13.2 |
| Dexamethasone | Changes in the Quality of Life According to Euro Quality of Life (EQ-5D) Questionnaires | 2.0 Units on a scale | Standard Deviation 14.8 |
Secondary
Changes in the Quality of Life According to the National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) Questionnaires
The VFQ-25 composite and subscale scores range from 0 to 100, a higher score indicating better functioning. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab | Changes in the Quality of Life According to the National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) Questionnaires | 6.0 Score on a scale | Standard Deviation 12.1 |
| Dexamethasone | Changes in the Quality of Life According to the National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) Questionnaires | 2.0 Score on a scale | Standard Deviation 10.9 |
Secondary
Changes in the Quality of Life According to the Short Form (36) Health Survey (SF-36)Questionnaires
SF-36 summary measures are norm-based scores with mean = 50 and SD = 10. Higher scores indicate better health
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. observed is only described in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab | Changes in the Quality of Life According to the Short Form (36) Health Survey (SF-36)Questionnaires | SF-36 mental component (n=116,113) | 2.4 Units on a scale | Standard Deviation 8.7 |
| Ranibizumab | Changes in the Quality of Life According to the Short Form (36) Health Survey (SF-36)Questionnaires | SF-36 physical component (n=116,113) | -0.7 Units on a scale | Standard Deviation 6.3 |
| Dexamethasone | Changes in the Quality of Life According to the Short Form (36) Health Survey (SF-36)Questionnaires | SF-36 mental component (n=116,113) | 0.4 Units on a scale | Standard Deviation 9.2 |
| Dexamethasone | Changes in the Quality of Life According to the Short Form (36) Health Survey (SF-36)Questionnaires | SF-36 physical component (n=116,113) | 0.4 Units on a scale | Standard Deviation 6.6 |
Secondary
Increase Rate of the Internal Ocular Pressure (IOP ) : Patients With ≥10% Increase in IOP Compared to Baseline
The proportion of patients with ≥ 10% increase in Internal Ocular Pressure (IOP) compared to baseline at any post-baseline visit.
Time frame: Baseline, month 6
Population: The Safety Set consisted of all patients from the RS who had received at least one application of study treatment and had at least one post-baseline safety assessment. Patients were analyzed according to treatment received. The statement that a patient had no adverse events also constituted a safety assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab | Increase Rate of the Internal Ocular Pressure (IOP ) : Patients With ≥10% Increase in IOP Compared to Baseline | 94 Participants |
| Dexamethasone | Increase Rate of the Internal Ocular Pressure (IOP ) : Patients With ≥10% Increase in IOP Compared to Baseline | 105 Participants |
Secondary
Mean BCVA Change at Month 6
The analysis was performed by an analysis of covariance (ANCOVA) model with average change in BCVA (letters) from Visit 1 through Visit 6 as dependent variable, and with the factors center, treatment and covariate baseline BCVA as predictors
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ranibizumab | Mean BCVA Change at Month 6 | 14.78 Letters |
| Dexamethasone | Mean BCVA Change at Month 6 | -3.17 Letters |
Secondary
Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increased score indicates improvement in acuity. This outcome assessed the number of participants who gained 15, 10 or 5 more letters of visual acuity at month 6 as compared with baseline
Time frame: Baseline, 6 month
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranibizumab | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Loss of ≥10 letters | 4 Participants |
| Ranibizumab | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Loss of ≥15 letters | 1 Participants |
| Ranibizumab | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Gain ≥5 letters | 104 Participants |
| Ranibizumab | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Gain≥15 letters | 73 Participants |
| Ranibizumab | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Loss of ≥5 letters | 5 Participants |
| Ranibizumab | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Gain ≥10 letters | 89 Participants |
| Dexamethasone | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Loss of ≥5 letters | 40 Participants |
| Dexamethasone | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Gain≥15 letters | 22 Participants |
| Dexamethasone | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Loss of ≥15 letters | 31 Participants |
| Dexamethasone | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Loss of ≥10 letters | 35 Participants |
| Dexamethasone | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Gain ≥5 letters | 54 Participants |
| Dexamethasone | Number of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters | Gain ≥10 letters | 38 Participants |
Secondary
Time to Achieve a Significant Improvement ≥ 15 Letters
The time was analyzed by the Kaplan-Maier-Method, adjusting the calculation for dropouts
Time frame: Baseline, month 6
Population: The Full Analysis Set (FAS) consisted of all patients from the Randomized Set (RS) who had received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent-to-treat principle, patients were analyzed according to the treatment assigned
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ranibizumab | Time to Achieve a Significant Improvement ≥ 15 Letters | 62 Time to event (Days) |
| Dexamethasone | Time to Achieve a Significant Improvement ≥ 15 Letters | 98 Time to event (Days) |