Diabetic Retinopathy
Conditions
Brief summary
The study's main purpose is to asses the safety, tolerability, and effect of oral administration of RG7774 on the severity of diabetic retinopathy (DR) in participants with moderately severe to severe non-proliferative diabetic retinopathy (NPDR) and good vision.
Interventions
DRUGPlacebo
Participants will receive oral placebo matched to RG7774
DRUGRG7774
Participants will receive oral RG7774
Sponsors
Hoffmann-La Roche
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
* Able and willing to provide written informed consent and to comply with the study protocol according to International Conference of Harmonization (ICH) and local regulations * Male and female patients of at least 18 years of age * Treatment naïve with moderately severe to severe NPDR defined as ETDRS DRSS 47 or 53 * Patients are eligible with and without DME in either eye * BCVA score at screening of at least 70 letters in study eyes without DME and at least 75 letters in case DME is present * Clear ocular media and adequate pupillary dilation to allow acquisition of good quality retinal images. * Diagnosis of diabetes mellitus (DM) type 1 or type 2 * Hemoglobin A1c (HbA1c) \</= 12%. * A female is eligible to participate if she is not pregnant, not breastfeeding
Exclusion criteria
Ocular criteria for study eye: * Prior treatment for DR or other retinal diseases with any approved or investigational therapy, including but not limited to intravitreal steroids, intravitreal anti-VEGF, light therapy, periocular pharmacological intervention, and laser (e.g. focal, grid, micropulse, or pan-retinal) * Uncontrolled glaucoma * Any concurrent intraocular condition (e.g. retinal detachment, dense cataract, epiretinal membrane with traction, or vitreomacular traction, etc.) that in the opinion of the Investigator could reduce the potential for improvement, require medical surgical intervention or may confound the visual and functional assessment and interpretation of study results Concurrent ocular conditions in either eye: * Any active ocular infection * Any active intraocular inflammation General Criteria: * Previous systemic use of anti-VEGF drugs within 6 months prior to screening * Complications of diabetes such as end-stage renal disease or liver disease * Currently untreated diabetes mellitus or previously untreated patients who initiated oral or injectable anti-diabetic medication within 3 months prior to screening * Uncontrolled blood pressure (\[BP\] defined as systolic \> 180mmHg and/or diastolic \>100 mmHg while patient at rest) * History of concurrent cardio-vascular disease not considered well controlled by the Investigator * Any major illness or major surgical procedure within one month before screening * History of or currently active other diseases, metabolic dysfunction, physical examination finding, malignancies not considered cured, or clinical laboratory findings giving reasonable suspicion of a condition that contraindicated the use of the investigational medicinal drug or that might affect interpretation of the results of the study or renders the patient at high risk for treatment complications in the opinion of the investigator * Known hypersensitivity to any of the excipients of the drug used, fluorescein dye or dilating eye drops * Use of systemic medications known to be toxic to the lens, retina or optic nerve (e.g., deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and ethambutol) used during the 6-month period prior to screening or likely need to be used
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With >/= 2-Step Improvement in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR Severity Scale (DRSS) From Baseline at Week 36 Measured in the Study Eye | Week 36 | The ETDRS DRSS is a standardized grading test to measure diabetic retinopathy progression, where higher scores indicate a higher risk of vision loss. The DRSS ranges from level 10 (no diabetic retinopathy) to level 85 (advanced diabetic retinopathy) |
| Percentage of Participants With Adverse Events (AEs) | Up to 1 year (baseline through follow-up period) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-Event for Vision-Threatening DR in the Study Eye | Up to Day 277 | Vision-threatening DR was defined as anterior segment neovascularization (ASNV), new proliferative diabetic retinopathy (PDR), new diabetic macular edema (DME), and pre-existing DME requiring treatment. Time-to-event was defined as the time where 50% of the population develops a DR vision-threatening event. |
| Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | Week 36 | This is a descriptive summary of the incidence of new ASNV, new PDR, new DME, and pre-existing DME, all of which indicate disease progression. Each row presents the proportion of participants amongst the overall population for each event. |
| Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye at Week 36 | Baseline; Week 36 | BCVA was measured by a qualified VA examiner prior to pupil dilation using modified ETDRS Charts 1, 2, and R. The adjusted mean is reported for each group. |
Countries
Australia, Poland, Puerto Rico, Slovakia, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received an oral dose of placebo matched to RG7774 once daily (QD) | 47 |
| Vicasinabin 30 mg QD Participants received 30 mg of oral RG7774 QD | 48 |
| Vicasinabin 200 mg QD Participants received 200 mg of oral RG7774 QD | 44 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 4 | 1 | 3 |
| Overall Study | Non-Compliance with Study Drug | 1 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Protocol Deviation | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo | Vicasinabin 30 mg QD | Vicasinabin 200 mg QD | Total |
|---|---|---|---|---|
| Age, Continuous | 58.9 Years STANDARD_DEVIATION 9.3 | 57.3 Years STANDARD_DEVIATION 10 | 56.5 Years STANDARD_DEVIATION 10.5 | 57.6 Years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 18 Participants | 15 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 30 Participants | 29 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 40 Participants | 46 Participants | 35 Participants | 121 Participants |
| Sex: Female, Male Female | 17 Participants | 18 Participants | 16 Participants | 51 Participants |
| Sex: Female, Male Male | 30 Participants | 30 Participants | 28 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 47 | 0 / 48 | 0 / 44 |
| other Total, other adverse events | 13 / 47 | 21 / 48 | 15 / 43 |
| serious Total, serious adverse events | 8 / 47 | 3 / 48 | 5 / 43 |
Outcome results
Primary
Percentage of Participants With Adverse Events (AEs)
Time frame: Up to 1 year (baseline through follow-up period)
Population: The Safety population is defined as all participants who give informed consent, receive at least one dose of study medication (active or placebo) and were grouped according to the actual treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Adverse Events (AEs) | 72.3 Percentage of participants |
| Vicasinabin 30 mg QD | Percentage of Participants With Adverse Events (AEs) | 64.6 Percentage of participants |
| Vicasinabin 200 mg QD | Percentage of Participants With Adverse Events (AEs) | 81.4 Percentage of participants |
Primary
Proportion of Participants With >/= 2-Step Improvement in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR Severity Scale (DRSS) From Baseline at Week 36 Measured in the Study Eye
The ETDRS DRSS is a standardized grading test to measure diabetic retinopathy progression, where higher scores indicate a higher risk of vision loss. The DRSS ranges from level 10 (no diabetic retinopathy) to level 85 (advanced diabetic retinopathy)
Time frame: Week 36
Population: The mITT population is defined as all participants who give informed consent, are randomized, and receive at least one dose of study treatment (active or placebo). For the mITT population, data were analyzed according to the treatment participants were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Participants With >/= 2-Step Improvement in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR Severity Scale (DRSS) From Baseline at Week 36 Measured in the Study Eye | 7.89 Percentage of participants |
| Vicasinabin 30 mg QD | Proportion of Participants With >/= 2-Step Improvement in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR Severity Scale (DRSS) From Baseline at Week 36 Measured in the Study Eye | 9.52 Percentage of participants |
| Vicasinabin 200 mg QD | Proportion of Participants With >/= 2-Step Improvement in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR Severity Scale (DRSS) From Baseline at Week 36 Measured in the Study Eye | 5.71 Percentage of participants |
p-value: 0.858695% CI: [-11.86, 14.23]Cochran-Mantel-Haenszel
p-value: 0.638895% CI: [-15.18, 9.31]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye at Week 36
BCVA was measured by a qualified VA examiner prior to pupil dilation using modified ETDRS Charts 1, 2, and R. The adjusted mean is reported for each group.
Time frame: Baseline; Week 36
Population: The mITT population is defined as all participants who give informed consent, are randomized, and receive at least one dose of study treatment (active or placebo). For the mITT population, data were analyzed according to the treatment participants were randomized to.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye at Week 36 | 0.12 Number of letters | Standard Error 0.747 |
| Vicasinabin 30 mg QD | Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye at Week 36 | -0.45 Number of letters | Standard Error 0.697 |
| Vicasinabin 200 mg QD | Change From Baseline in Best Corrected Visual Acuity (BCVA) in the Study Eye at Week 36 | -0.22 Number of letters | Standard Error 0.744 |
Secondary
Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye
This is a descriptive summary of the incidence of new ASNV, new PDR, new DME, and pre-existing DME, all of which indicate disease progression. Each row presents the proportion of participants amongst the overall population for each event.
Time frame: Week 36
Population: The mITT population is defined as all participants who give informed consent, are randomized, and receive at least one dose of study treatment (active or placebo). For the mITT population, data were analyzed according to the treatment participants were randomized to.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New ASNV | 0 Percentage of participants |
| Placebo | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New PDR | 0 Percentage of participants |
| Placebo | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New DME | 0 Percentage of participants |
| Placebo | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | Pre-existing DME requiring treatment | 4.3 Percentage of participants |
| Vicasinabin 30 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | Pre-existing DME requiring treatment | 10.4 Percentage of participants |
| Vicasinabin 30 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New ASNV | 0 Percentage of participants |
| Vicasinabin 30 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New DME | 4.2 Percentage of participants |
| Vicasinabin 30 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New PDR | 6.3 Percentage of participants |
| Vicasinabin 200 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | Pre-existing DME requiring treatment | 6.8 Percentage of participants |
| Vicasinabin 200 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New PDR | 0 Percentage of participants |
| Vicasinabin 200 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New DME | 0 Percentage of participants |
| Vicasinabin 200 mg QD | Incidence of New Anterior Segment Neovascularization (ASNV), New Proliferative Diabetic Retinopathy (PDR), New Diabetic Macular Edema (DME), and Pre-Existing DME Requiring Intervention in the Study Eye | New ASNV | 0 Percentage of participants |
Secondary
Time-to-Event for Vision-Threatening DR in the Study Eye
Vision-threatening DR was defined as anterior segment neovascularization (ASNV), new proliferative diabetic retinopathy (PDR), new diabetic macular edema (DME), and pre-existing DME requiring treatment. Time-to-event was defined as the time where 50% of the population develops a DR vision-threatening event.
Time frame: Up to Day 277
Population: The mITT population is defined as all participants who give informed consent, are randomized, and receive at least one dose of study treatment (active or placebo). For the mITT population, data were analyzed according to the treatment participants were randomized to.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time-to-Event for Vision-Threatening DR in the Study Eye | NA Days |
| Vicasinabin 30 mg QD | Time-to-Event for Vision-Threatening DR in the Study Eye | 267.0 Days |
| Vicasinabin 200 mg QD | Time-to-Event for Vision-Threatening DR in the Study Eye | NA Days |