Diabetic Macular Edema
Conditions
Keywords
Diabetes, Macular Edema
Brief summary
The primary objective of the study is to assess the ocular and systemic adverse events of ranibizumab (Lucentis)for DME (diabetic macular edema) following previous treatment with intravitreal bevacizumab (Avastin).
Detailed description
This is an open-label, Phase I/II study of intravitreally administered 0.3mg ranibizumab (Lucentis) in subjects with DME (diabetic macular edema) previously treated with intravitreal bevacizumab (Avastin) with a randomized comparative dosing strategy, monthly vs treat-and-extend. Thirty patients total will be enrolled in the study, 15 in each group. This study will have a 1-year treatment period. The recruitment period will occur over 1 year with total potential study duration of 2 years.
Interventions
DRUGRanibizumab
Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.
Sponsors
Genentech, Inc.
Justis Ehlers
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects will be eligible if the following criteria are met: * Ability to provide written informed consent and comply with study assessments for the full duration of the study * Age \> 18 years * ETDRS best-corrected visual acuity of 20/25 to 20/320 in the study eye * Willing, committed, and able to return for ALL clinic visits and complete all study related procedures * At least 6 previous bevacizumab injections for diabetic macular edema in the last 12 months in the study eye. * At least 2 bevacizumab injections within 10 weeks and the most recent bevacizumab injection within 6 weeks of baseline study visits in the study eye. * Persistent foveal-involving diabetic macular edema based on presence of intraretinal and/or subretinal fluid by SDOCT in the foveal center at study entry in the study eye.
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from this study: * Pregnancy (positive pregnancy test) or lactation * Premenopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization or use of oral contraceptives, barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel, an IUD (intrauterine device), or contraceptive hormone implant or patch. * Intravitreal steroid or periocular steroid treatment within 3 months of study entry in the study eye. * Focal/grid laser photocoagulation treatment within 3 months of study entry in the study eye. * Panretinal photocoagulation treatment within 3 months of study entry in the study eye. * Prior vitrectomy in the study eye * History of retinal detachment in the study eye * Prior trabeculectomy or other filtration surgery in the study eye * Active intraocular inflammation in either eye * Active ocular or periocular infection in either eye * Active scleritis or episcleritis in either eye * History of any other retinal vascular disease (e.g., retinal vein occlusion, retinal artery occlusion) in the study eye. * Coexistent retinal disease other than diabetic retinopathy (e.g., AMD (age related macular degeneration), inherited retinal disease) in the study eye. * Intraocular surgery within 3 months of study entry in the study eye. * History of corneal transplant or corneal dystrophy in the study eye. * Significant media opacities in study eye which may interfere with visual acuity in the study eye. * Participation as a subject in any clinical study within 3 months of study entry. * History of allergy to topical iodine * Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated * Participation in another simultaneous medical investigation or trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Non-severe Ocular Adverse Events | 12 months | As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results. |
| Number of Participants With Severe Ocular Adverse Events | 12 months | As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs. |
| Number of Participants With Non-severe Non-ocular Adverse Event | 12 months | As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results. |
| Number of Participants With Severe Non-ocular Adverse Event | 12 months | As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Loss in Vision Greater Than or Equal to 15 Letters | Months 6 and 12 | Number of participants that lost greater than or equal to 15 letters of vision in their study eye at months 6 and 12. |
| Participants With BCVA at 20/40 or Better | Months 6 and 12 | Number of participants with 20/40 or better best-corrected visual acuity in their study eye at months 6 and 12. |
| Mean Change in BCVA | Months 6 and 12 | Mean change in best-corrected visual acuity as assessed by the number of letters read correctly on the electronic ETDRS eye chart from baseline to months 6 and 12. |
| Number of Participants With Nonperfusion | 3, 6 and 12 months | Number of participants with peripheral nonperfusion in their study eye from baseline to months 3, 6, and 12 (i.e. presence of ischemia). |
| Number of Participants With Angiographic Leakage | 3, 6 and 12 months | Number of participants with angiographic leakage in their study eye measured from baseline to months 3, 6 and 12 (i.e. presence of leakage). |
| Mean Change in Central Foveal Thickness | Months 6 and 12 | Mean absolute change from baseline central foveal thickness at months 6 and 12 as measured by SDOCT (defined as the average thickness within the central 1 mm subfield) |
| Anatomically Dry Eyes by SDOCT | Months 6 and 12 | Number of participants with an anatomically dry study eye by SDOCT at months 6 and 12 |
| Gain in Vision Greater Than or Equal to 15 Letters | Months 6 and 12 | Number of participants that gained greater than or equal to 15 letters of vision in their study eye at months 6 and 12. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group I - Monthly Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group.
Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema. | 15 |
| Group II - Treat-and-Extend Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results.
Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months. | 12 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Group II - Treat-and-Extend | Group I - Monthly | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 10 Participants | 17 Participants |
| Age, Continuous | 63.8 years STANDARD_DEVIATION 6.4 | 62.5 years STANDARD_DEVIATION 6 | 63.1 years STANDARD_DEVIATION 6.1 |
| Region of Enrollment United States | 12 Participants | 15 Participants | 27 Participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 12 |
| other Total, other adverse events | 15 / 15 | 12 / 12 |
| serious Total, serious adverse events | 6 / 15 | 3 / 12 |
Outcome results
Primary
Number of Participants With Non-severe Non-ocular Adverse Event
As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.
Time frame: 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Infectious advsere event | 1 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Nervous system adverse event | 2 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Cardiac adverse event | 8 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Psychiatric adverse event | 0 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Metabolic adverse event | 3 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Renal and urinary adverse event | 5 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | General adverse event | 14 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Reproductive adverse event | 1 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Musculoskeletal adverse event | 12 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Respiratory adverse event | 1 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Gastrointestinal adverse event | 6 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Skin and subcutaneous adverse event | 8 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Cyst, polyp and tumor adverse event | 3 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Vascular adverse event | 4 Participants |
| Group I - Monthly | Number of Participants With Non-severe Non-ocular Adverse Event | Blood and lymphatic adverse event | 1 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Vascular adverse event | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Blood and lymphatic adverse event | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Cardiac adverse event | 4 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Gastrointestinal adverse event | 1 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | General adverse event | 12 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Infectious advsere event | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Metabolic adverse event | 2 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Musculoskeletal adverse event | 8 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Cyst, polyp and tumor adverse event | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Nervous system adverse event | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Psychiatric adverse event | 1 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Renal and urinary adverse event | 3 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Reproductive adverse event | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Respiratory adverse event | 5 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Non-ocular Adverse Event | Skin and subcutaneous adverse event | 2 Participants |
Primary
Number of Participants With Non-severe Ocular Adverse Events
As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.
Time frame: 12 months
Population: Patients who exited the study early were accounted by using a last observation carried forward approach.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Dry eyes | 3 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Redness | 1 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Flashes | 3 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Pruritus | 2 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Elevated IOP | 4 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Tearing | 1 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Vitreous Floaters | 3 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Non-severe ocular adverse events | 0 Participants |
| Group I - Monthly | Number of Participants With Non-severe Ocular Adverse Events | Blurry Vision | 9 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Non-severe ocular adverse events | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Blurry Vision | 5 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Elevated IOP | 3 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Flashes | 3 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Vitreous Floaters | 2 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Redness | 2 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Pruritus | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Tearing | 1 Participants |
| Group II - Treat-and-Extend | Number of Participants With Non-severe Ocular Adverse Events | Dry eyes | 2 Participants |
Comparison: All analyses were performed with a significance level of 0.05 being assumed for all tests.p-value: <0.05t-test, 2 sided
Primary
Number of Participants With Severe Non-ocular Adverse Event
As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.
Time frame: 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Number of Participants With Severe Non-ocular Adverse Event | Hospitalizations | 6 Participants |
| Group I - Monthly | Number of Participants With Severe Non-ocular Adverse Event | TIA | 1 Participants |
| Group I - Monthly | Number of Participants With Severe Non-ocular Adverse Event | Stroke | 1 Participants |
| Group II - Treat-and-Extend | Number of Participants With Severe Non-ocular Adverse Event | Hospitalizations | 3 Participants |
| Group II - Treat-and-Extend | Number of Participants With Severe Non-ocular Adverse Event | TIA | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Severe Non-ocular Adverse Event | Stroke | 0 Participants |
Primary
Number of Participants With Severe Ocular Adverse Events
As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs.
Time frame: 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Number of Participants With Severe Ocular Adverse Events | Endophthalmitis | 0 Participants |
| Group I - Monthly | Number of Participants With Severe Ocular Adverse Events | Retinal Detachment | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Severe Ocular Adverse Events | Endophthalmitis | 0 Participants |
| Group II - Treat-and-Extend | Number of Participants With Severe Ocular Adverse Events | Retinal Detachment | 0 Participants |
Secondary
Anatomically Dry Eyes by SDOCT
Number of participants with an anatomically dry study eye by SDOCT at months 6 and 12
Time frame: Months 6 and 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Anatomically Dry Eyes by SDOCT | Month 6 | 0 Participants |
| Group I - Monthly | Anatomically Dry Eyes by SDOCT | Month 12 | 0 Participants |
| Group II - Treat-and-Extend | Anatomically Dry Eyes by SDOCT | Month 6 | 0 Participants |
| Group II - Treat-and-Extend | Anatomically Dry Eyes by SDOCT | Month 12 | 1 Participants |
Secondary
Gain in Vision Greater Than or Equal to 15 Letters
Number of participants that gained greater than or equal to 15 letters of vision in their study eye at months 6 and 12.
Time frame: Months 6 and 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Gain in Vision Greater Than or Equal to 15 Letters | Month 6 | 0 Participants |
| Group I - Monthly | Gain in Vision Greater Than or Equal to 15 Letters | Month 12 | 1 Participants |
| Group II - Treat-and-Extend | Gain in Vision Greater Than or Equal to 15 Letters | Month 6 | 2 Participants |
| Group II - Treat-and-Extend | Gain in Vision Greater Than or Equal to 15 Letters | Month 12 | 2 Participants |
Secondary
Loss in Vision Greater Than or Equal to 15 Letters
Number of participants that lost greater than or equal to 15 letters of vision in their study eye at months 6 and 12.
Time frame: Months 6 and 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Loss in Vision Greater Than or Equal to 15 Letters | Month 6 | 1 Participants |
| Group I - Monthly | Loss in Vision Greater Than or Equal to 15 Letters | Month 12 | 1 Participants |
| Group II - Treat-and-Extend | Loss in Vision Greater Than or Equal to 15 Letters | Month 6 | 0 Participants |
| Group II - Treat-and-Extend | Loss in Vision Greater Than or Equal to 15 Letters | Month 12 | 0 Participants |
Secondary
Mean Change in BCVA
Mean change in best-corrected visual acuity as assessed by the number of letters read correctly on the electronic ETDRS eye chart from baseline to months 6 and 12.
Time frame: Months 6 and 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group I - Monthly | Mean Change in BCVA | Month 6 | .7 ETDRS letters | Standard Deviation 8.1 |
| Group I - Monthly | Mean Change in BCVA | Month 12 | 2.1 ETDRS letters | Standard Deviation 8.3 |
| Group II - Treat-and-Extend | Mean Change in BCVA | Month 6 | .7 ETDRS letters | Standard Deviation 8.1 |
| Group II - Treat-and-Extend | Mean Change in BCVA | Month 12 | 7.4 ETDRS letters | Standard Deviation 10.4 |
Secondary
Mean Change in Central Foveal Thickness
Mean absolute change from baseline central foveal thickness at months 6 and 12 as measured by SDOCT (defined as the average thickness within the central 1 mm subfield)
Time frame: Months 6 and 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group I - Monthly | Mean Change in Central Foveal Thickness | Month 6 | -28.8 microns | Standard Deviation 173.4 |
| Group I - Monthly | Mean Change in Central Foveal Thickness | Month 12 | -80.9 microns | Standard Deviation 184.7 |
| Group II - Treat-and-Extend | Mean Change in Central Foveal Thickness | Month 6 | 104.1 microns | Standard Deviation 165.6 |
| Group II - Treat-and-Extend | Mean Change in Central Foveal Thickness | Month 12 | -124 microns | Standard Deviation 157.6 |
Secondary
Number of Participants With Angiographic Leakage
Number of participants with angiographic leakage in their study eye measured from baseline to months 3, 6 and 12 (i.e. presence of leakage).
Time frame: 3, 6 and 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Number of Participants With Angiographic Leakage | 3 month | 15 Participants |
| Group I - Monthly | Number of Participants With Angiographic Leakage | 6 month | 15 Participants |
| Group I - Monthly | Number of Participants With Angiographic Leakage | 12 month | 15 Participants |
| Group II - Treat-and-Extend | Number of Participants With Angiographic Leakage | 3 month | 12 Participants |
| Group II - Treat-and-Extend | Number of Participants With Angiographic Leakage | 6 month | 12 Participants |
| Group II - Treat-and-Extend | Number of Participants With Angiographic Leakage | 12 month | 12 Participants |
Secondary
Number of Participants With Nonperfusion
Number of participants with peripheral nonperfusion in their study eye from baseline to months 3, 6, and 12 (i.e. presence of ischemia).
Time frame: 3, 6 and 12 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Number of Participants With Nonperfusion | 3 months | 13 Participants |
| Group I - Monthly | Number of Participants With Nonperfusion | 6 months | 13 Participants |
| Group I - Monthly | Number of Participants With Nonperfusion | 12 months | 12 Participants |
| Group II - Treat-and-Extend | Number of Participants With Nonperfusion | 12 months | 9 Participants |
| Group II - Treat-and-Extend | Number of Participants With Nonperfusion | 3 months | 9 Participants |
| Group II - Treat-and-Extend | Number of Participants With Nonperfusion | 6 months | 10 Participants |
Secondary
Participants With BCVA at 20/40 or Better
Number of participants with 20/40 or better best-corrected visual acuity in their study eye at months 6 and 12.
Time frame: Months 6 and 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I - Monthly | Participants With BCVA at 20/40 or Better | Month 6 | 1 Participants |
| Group I - Monthly | Participants With BCVA at 20/40 or Better | Month 12 | 0 Participants |
| Group II - Treat-and-Extend | Participants With BCVA at 20/40 or Better | Month 6 | 2 Participants |
| Group II - Treat-and-Extend | Participants With BCVA at 20/40 or Better | Month 12 | 2 Participants |