Choroidal Neovascularization, Diabetic Retinopathy, Glaucoma, Neovascular, Macular Edema
Conditions
Brief summary
The pupose of this study is to evaluate the safety and the efficacy of ranibizumab in rare VEGF driven ocular diseases.
Interventions
DRUGranibizumab
One injection of Ranibizumab 0.5 mg and retreatment according to disease activity and/or visual impairment on an as needed regimen (PRN)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Active choroidal neovascularization (CNV) * Active macular edema (ME) * Rubeosis iridis/neovascular glaucoma. * Proliferative diabetic retinopathy requiring vitrectomy.
Exclusion criteria
* wet Age-related macular degeneration * pathologic myopia * pseudoxanthoma elasticum * diabetic macular edema * retinal vein occlusion * \< 18 years of age * History of hypersensitivity to ranibizumab * Use of any systemic anti-angiogenic drugs 3 months before inclusion * Women of child-bearing potential and Pregnant or nursing (lactating) women. * Active or suspected ocular infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | 24 months | Frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs) for ocular and non-ocular events. Due to early termination, only descriptive analysis was conducted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Best Corrected Visual Acuity (BCVA) for Patients With Choroidal Neovascularization (CNV) and Macular Edema (ME) | 3 months, 12 months | BCVA change for diseases affecting the macular area either through CNV or ME. BCVA is tested using the ETDRS (Early Treatment Diabetic Retinopathy Study), the Snellen or Monoyer scales. The three scales are designed to measure visual acuity. ETDRS score is expressed in letter, Snellen and Monoyer score in fraction. BCVA assessment is presented in ETDRS after conversion if collected in Snellen or Monoyer. (Monoyer converted to Snellen = 2 x (Monoyer fraction) and Snellen converted to approximate ETDRS letters = 1x log(Snellen fraction). ETDRS letter score was transformed in logMAR unit for statistical analysis (- LogMAR = -(ETDRS-85)/50). The worse ETDRS letter score is 0 (logMAR 2.3) and the best ETDRS letter score is 100 (logMAR -0.3). |
| Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 3 month, 12 month | The extent of iris neovascularization was assessed by iris photography and graded using the Teich and Walsh grading system. This grading system measures the number of quadrant at iris pupillary zone or iris ciliary zone where iris neovascularization (NV) is observed. Grade 0 = No iris vascularization, Grade 1= Less than 2 quadrants of NV at iris pupillary zone, Grade 2 = More than 2 quadrants of NV at iris pupillary zone, Grade 3 =Grade 2 + less than 3 quadrants of NV at iris ciliary zone and/or ectropion uveae; Grade 4 =More than 3 quadrants of NV at iris ciliary zone and/or ectropion uveae) |
| Proportion of Patient With Vitreous Cavity Hemorrhage Occurrence for Patient With Proliferative Retinopathy | 3 months, 12 month | Occurrence of postoperative vitreous cavity hemorrhage |
| Proportion of Patients With Angiographic Leakage | 3 months, 12 month | Angiography was taken via fluorescein angiography. Any increases of angiographic leakage was counted between baseline and month 3. Also any decreases of angiographic leakage was counted between baseline and 3 month. |
| Ranibizumab Injection | 3 months, 12 month | Number of ranibizumab injections needed by decreased visual acuity and/or increasing retinal thickness in 3 months of observation period |
| Mean Change From Baseline in Change in Central Retinal Thickness for Patients With CNV (Choroidal Neovascularization) and ME (Macular Edema) | 3 months, 12 month | CRT in micrometers assessed by Optical Tomography (OCT) at each single study visit. A reduction is thickness indicates an improvement is the lesion area |
Countries
France
Participant flow
Recruitment details
open-label, single arm study evaluating the safety of 0.5 mg ranibizumab. Patients received individualized ranibizumab intravitreal injections based on evidence of disease activity. The study was early terminated due to low recruitment that hampered to address the primary endpoint of the study
Participants by arm
| Arm | Count |
|---|---|
| CNV (Choroidal Neovascularization) All patients received 0.5 mg ranibizumab IVT injection | 93 |
| ME (Macular Edema) All patients received 0.5 mg ranibizumab IVT injection | 84 |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) All patients received 0.5 mg ranibizumab IVT injection | 56 |
| PDR/V (Proliferative Diabetic Retinopathy requiring Vitrectomy). All patients received 0.5 mg ranibizumab IVT injection | 34 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 7 | 1 |
| Overall Study | Early termination | 87 | 60 | 43 | 28 |
| Overall Study | Lost to Follow-up | 3 | 5 | 4 | 2 |
| Overall Study | Protocol deviation | 1 | 2 | 1 | 1 |
| Overall Study | Subject's no longer requires study drug | 0 | 0 | 0 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 1 | 13 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 4 | 2 | 2 |
Baseline characteristics
| Characteristic | CNV (Choroidal Neovascularization) | ME (Macular Edema) | RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | PDR/V | Total |
|---|---|---|---|---|---|
| Age, Continuous | 49.7 Years STANDARD_DEVIATION 16.85 | 64.5 Years STANDARD_DEVIATION 13.99 | 70.9 Years STANDARD_DEVIATION 13.02 | 56.5 Years STANDARD_DEVIATION 9.86 | 59.7 Years STANDARD_DEVIATION 16.62 |
| Sex: Female, Male Female | 48 Participants | 35 Participants | 26 Participants | 17 Participants | 126 Participants |
| Sex: Female, Male Male | 45 Participants | 49 Participants | 30 Participants | 17 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 93 | 0 / 84 | 7 / 58 | 1 / 35 |
| other Total, other adverse events | 46 / 93 | 66 / 84 | 40 / 58 | 21 / 35 |
| serious Total, serious adverse events | 11 / 93 | 15 / 84 | 31 / 58 | 14 / 35 |
Outcome results
Primary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs) for ocular and non-ocular events. Due to early termination, only descriptive analysis was conducted.
Time frame: 24 months
Population: Safety population: all patients who received at least one application of study treatment and had at least one post-baseline safety assessment. The statement that a patient had no adverse events also constituted a safety assessment. All safety evaluations were carried out on the safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CNV (Choroidal Neovascularization) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Non- serious adverse events | 2 Participants |
| CNV (Choroidal Neovascularization) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Death | 1 Participants |
| CNV (Choroidal Neovascularization) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serious adverse events | 11 Participants |
| ME (Macular Edema) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Non- serious adverse events | 21 Participants |
| ME (Macular Edema) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Death | 0 Participants |
| ME (Macular Edema) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serious adverse events | 15 Participants |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serious adverse events | 31 Participants |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Non- serious adverse events | 1 Participants |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Death | 7 Participants |
| PDR/V | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Non- serious adverse events | 0 Participants |
| PDR/V | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Death | 1 Participants |
| PDR/V | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serious adverse events | 14 Participants |
Secondary
Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma
The extent of iris neovascularization was assessed by iris photography and graded using the Teich and Walsh grading system. This grading system measures the number of quadrant at iris pupillary zone or iris ciliary zone where iris neovascularization (NV) is observed. Grade 0 = No iris vascularization, Grade 1= Less than 2 quadrants of NV at iris pupillary zone, Grade 2 = More than 2 quadrants of NV at iris pupillary zone, Grade 3 =Grade 2 + less than 3 quadrants of NV at iris ciliary zone and/or ectropion uveae; Grade 4 =More than 3 quadrants of NV at iris ciliary zone and/or ectropion uveae)
Time frame: 3 month, 12 month
Population: Intent-to-treat population (ITT): all patients who received at least one application of study treatment and had at least one post-baseline efficacy assessment. The ITT population was the main analysis set for efficacy evaluations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 3 Month,Grade 0 | 12 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 3 Month, Grade 1 | 6 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 3 Month, Grade 2 | 8 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 3 Month, Grade 3 | 3 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 3 Month, Grade 4 | 2 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 12 Month, Grade 0 | 11 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 12 Month, Grade 1 | 4 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 12 Month, Grade 2 | 2 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 12 Month, Grade 3 | 4 Teich and Walsh grading |
| CNV (Choroidal Neovascularization) | Average Change of Neovascularization Extension for Patients With Neovascular Glaucoma | 12 Month, Grade 4 | 4 Teich and Walsh grading |
Secondary
Change From Baseline Best Corrected Visual Acuity (BCVA) for Patients With Choroidal Neovascularization (CNV) and Macular Edema (ME)
BCVA change for diseases affecting the macular area either through CNV or ME. BCVA is tested using the ETDRS (Early Treatment Diabetic Retinopathy Study), the Snellen or Monoyer scales. The three scales are designed to measure visual acuity. ETDRS score is expressed in letter, Snellen and Monoyer score in fraction. BCVA assessment is presented in ETDRS after conversion if collected in Snellen or Monoyer. (Monoyer converted to Snellen = 2 x (Monoyer fraction) and Snellen converted to approximate ETDRS letters = 1x log(Snellen fraction). ETDRS letter score was transformed in logMAR unit for statistical analysis (- LogMAR = -(ETDRS-85)/50). The worse ETDRS letter score is 0 (logMAR 2.3) and the best ETDRS letter score is 100 (logMAR -0.3).
Time frame: 3 months, 12 months
Population: Intent-to-treat population (ITT): all patients who received at least one application of study treatment and had at least one post-baseline efficacy assessment. The ITT population was the main analysis set for efficacy evaluations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNV (Choroidal Neovascularization) | Change From Baseline Best Corrected Visual Acuity (BCVA) for Patients With Choroidal Neovascularization (CNV) and Macular Edema (ME) | 3 Month | 7.3 Letters | Standard Deviation 14.47 |
| CNV (Choroidal Neovascularization) | Change From Baseline Best Corrected Visual Acuity (BCVA) for Patients With Choroidal Neovascularization (CNV) and Macular Edema (ME) | 12 Month | 5.7 Letters | Standard Deviation 12.08 |
| ME (Macular Edema) | Change From Baseline Best Corrected Visual Acuity (BCVA) for Patients With Choroidal Neovascularization (CNV) and Macular Edema (ME) | 3 Month | 4.5 Letters | Standard Deviation 11.61 |
| ME (Macular Edema) | Change From Baseline Best Corrected Visual Acuity (BCVA) for Patients With Choroidal Neovascularization (CNV) and Macular Edema (ME) | 12 Month | 5.2 Letters | Standard Deviation 16.46 |
Secondary
Mean Change From Baseline in Change in Central Retinal Thickness for Patients With CNV (Choroidal Neovascularization) and ME (Macular Edema)
CRT in micrometers assessed by Optical Tomography (OCT) at each single study visit. A reduction is thickness indicates an improvement is the lesion area
Time frame: 3 months, 12 month
Population: Intent-to-treat population (ITT): all patients who received at least one application of study treatment and had at least one post-baseline efficacy assessment. The ITT population was the main analysis set for efficacy evaluations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNV (Choroidal Neovascularization) | Mean Change From Baseline in Change in Central Retinal Thickness for Patients With CNV (Choroidal Neovascularization) and ME (Macular Edema) | 3 Month | -54.4 μm | Standard Deviation 104.55 |
| CNV (Choroidal Neovascularization) | Mean Change From Baseline in Change in Central Retinal Thickness for Patients With CNV (Choroidal Neovascularization) and ME (Macular Edema) | 12 Month | -56.4 μm | Standard Deviation 69.82 |
| ME (Macular Edema) | Mean Change From Baseline in Change in Central Retinal Thickness for Patients With CNV (Choroidal Neovascularization) and ME (Macular Edema) | 3 Month | -84.4 μm | Standard Deviation 178.28 |
| ME (Macular Edema) | Mean Change From Baseline in Change in Central Retinal Thickness for Patients With CNV (Choroidal Neovascularization) and ME (Macular Edema) | 12 Month | -102.0 μm | Standard Deviation 220 |
Secondary
Proportion of Patients With Angiographic Leakage
Angiography was taken via fluorescein angiography. Any increases of angiographic leakage was counted between baseline and month 3. Also any decreases of angiographic leakage was counted between baseline and 3 month.
Time frame: 3 months, 12 month
Population: Intent-to-treat population (ITT): all patients who received at least one application of study treatment and had at least one post-baseline efficacy assessment. The ITT population was the main analysis set for efficacy evaluations. The (n) represent the number of assessed value.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CNV (Choroidal Neovascularization) | Proportion of Patients With Angiographic Leakage | 3 Month Absent | 3 Participants |
| CNV (Choroidal Neovascularization) | Proportion of Patients With Angiographic Leakage | 12 Month Present | 2 Participants |
| CNV (Choroidal Neovascularization) | Proportion of Patients With Angiographic Leakage | 12 Month Absent | 3 Participants |
| CNV (Choroidal Neovascularization) | Proportion of Patients With Angiographic Leakage | 3 Month Present | 3 Participants |
| ME (Macular Edema) | Proportion of Patients With Angiographic Leakage | 12 Month Present | 0 Participants |
| ME (Macular Edema) | Proportion of Patients With Angiographic Leakage | 3 Month Absent | 3 Participants |
| ME (Macular Edema) | Proportion of Patients With Angiographic Leakage | 3 Month Present | 3 Participants |
| ME (Macular Edema) | Proportion of Patients With Angiographic Leakage | 12 Month Absent | 1 Participants |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | Proportion of Patients With Angiographic Leakage | 3 Month Present | 0 Participants |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | Proportion of Patients With Angiographic Leakage | 3 Month Absent | 1 Participants |
Secondary
Proportion of Patient With Vitreous Cavity Hemorrhage Occurrence for Patient With Proliferative Retinopathy
Occurrence of postoperative vitreous cavity hemorrhage
Time frame: 3 months, 12 month
Population: Intent-to-treat population (ITT): all patients who received at least one application of study treatment and had at least one post-baseline efficacy assessment. The ITT population was the main analysis set for efficacy evaluations. (n) is the number of participants with an observed value
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CNV (Choroidal Neovascularization) | Proportion of Patient With Vitreous Cavity Hemorrhage Occurrence for Patient With Proliferative Retinopathy | 3 Month Absent | 14 Participants |
| CNV (Choroidal Neovascularization) | Proportion of Patient With Vitreous Cavity Hemorrhage Occurrence for Patient With Proliferative Retinopathy | 3 Month Present | 3 Participants |
| CNV (Choroidal Neovascularization) | Proportion of Patient With Vitreous Cavity Hemorrhage Occurrence for Patient With Proliferative Retinopathy | 12 Month Absent | 12 Participants |
| CNV (Choroidal Neovascularization) | Proportion of Patient With Vitreous Cavity Hemorrhage Occurrence for Patient With Proliferative Retinopathy | 12 Month Present | 1 Participants |
Secondary
Ranibizumab Injection
Number of ranibizumab injections needed by decreased visual acuity and/or increasing retinal thickness in 3 months of observation period
Time frame: 3 months, 12 month
Population: Safety set population: all patients who received at least one application of study treatment and had at least one post-baseline safety assessment. The statement that a patient had no adverse events also constituted a safety assessment. All safety evaluations were carried out on the safety population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNV (Choroidal Neovascularization) | Ranibizumab Injection | 12 Month | 3.8 Number of injections | Standard Deviation 2.34 |
| CNV (Choroidal Neovascularization) | Ranibizumab Injection | 3 Month | 2.5 Number of injections | Standard Deviation 1.03 |
| ME (Macular Edema) | Ranibizumab Injection | 3 Month | 2.7 Number of injections | Standard Deviation 0.88 |
| ME (Macular Edema) | Ranibizumab Injection | 12 Month | 3.9 Number of injections | Standard Deviation 2.17 |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | Ranibizumab Injection | 3 Month | 1.7 Number of injections | Standard Deviation 0.79 |
| RI/NVG (Rubeosis Iridis and Neovacular Glaucoma) | Ranibizumab Injection | 12 Month | 3.0 Number of injections | Standard Deviation 1.96 |
| PDR/V | Ranibizumab Injection | 12 Month | 1.7 Number of injections | Standard Deviation 1.44 |
| PDR/V | Ranibizumab Injection | 3 Month | 1.6 Number of injections | Standard Deviation 1 |