Ignite Creation Date:
2024-05-05 @ 4:53 PM
Last Modification Date:
2024-10-26 @ 9:25 AM
Study NCT ID:
NCT00336323
Status:
COMPLETED
Last Update Posted:
2016-08-26
First Post:
2006-06-09
Brief Title:
A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema Bevacizumab Avastin
Sponsor:
Jaeb Center for Health Research
Organization:
Jaeb Center for Health Research
Study Overview
Official Title:
A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema Bevacizumab Avastin
Status:
COMPLETED
Status Verified Date:
2016-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Bevacizumab
Brief Summary:
This study will provide preliminary data on the dose and dose interval related effects of intravitreally administered Avastin on retinal thickness and visual acuity in subjects with Diabetic Macular Edema DME to aid in planning a phase 3 trial
In addition this study will provide preliminary data on the safety of intravitreally administered Avastin in subjects with DME
In addition this study will provide preliminary data on the safety of intravitreally administered Avastin in subjects with DME
Detailed Description:
Diabetic retinopathy is a major cause of visual impairment in the United States Diabetic macular edema DME is a manifestation of diabetic retinopathy that produces loss of central vision Data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy WESDR estimate that after 15 years of known diabetes the prevalence of diabetic macular edema is approximately 20 in patients with type 1 diabetes mellitus DM 25 in patients with type 2 DM who are taking insulin and 14 in patients with type 2 DM who do not take insulin
In a review of three early studies concerning the natural history of diabetic macular edema Ferris and Patz found that 53 of 135 eyes with diabetic macular edema presumably all involving the center of the macula lost two or more lines of visual acuity over a two year period In the Early Treatment Diabetic Retinopathy Study ETDRS 33 of 221 untreated eyes available for follow-up at the 3-year visit all with edema involving the center of the macula at baseline had experienced a 15 or more letter decrease in visual acuity score equivalent to a doubling of the visual angle eg 2025 to 2050 and termed moderate visual loss
In the ETDRS focal photocoagulation direct treatment to microaneurysms and grid treatment to diffuse edema of eyes with clinically significant macular edema CSME reduced the risk of moderate visual loss by approximately 50 from 24 to 12 three years after initiation of treatment Therefore 12 of treated eyes developed moderate visual loss in spite of treatment Furthermore approximately 40 of treated eyes that had retinal thickening involving the center of the macula at baseline still had thickening involving the center at 12 months as did 25 of treated eyes at 36 months
Although several treatment modalities are currently under investigation the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation as demonstrated by the ETDRS intensive glycemic control as demonstrated by the Diabetes Control and Complications Trial DCCT and the United Kingdom Prospective Diabetes Study UKPDS and blood pressure control as demonstrated by the UKPDS In the DCCT intensive glucose control reduced the risk of onset of diabetic macular edema by 23 compared with conventional treatment Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control with a 58 risk reduction in the development of diabetic macular edema for the DCCT patients followed in the Epidemiology of Diabetes Interventions and Complications Study
The frequency of an unsatisfactory outcome with respect to proportion with vision improvement following laser photocoagulation in some eyes with diabetic macular edema has prompted interest in other treatment modalities One such treatment is pars plana vitrectomy These studies suggest that vitreomacular traction or the vitreous itself may play a role in increased retinal vascular permeability Removal of the vitreous or relief of mechanical traction with vitrectomy and membrane stripping may be followed by substantial resolution of macular edema and corresponding improvement in visual acuity However this treatment may be applicable only to a specific subset of eyes with diabetic macular edema that have a component of vitreomacular traction contributing to the edema It also requires a complex surgical intervention with its inherent risks recovery time and expense Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and use of intravitreal corticosteroids are under investigation The use of antibodies targeted at vascular endothelial growth factor VEGF such as in the current study is another treatment modality that has generated considerable interest and is currently being investigated in phase 3 trials of choroidal neovascularization in age-related macular degeneration with pegaptanib or ranibizumab or diabetic macular edema with pegaptanib
Increased VEGF levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy VEGF also known as vascular permeability factor has been demonstrated to increase vessel permeability by increasing the phosphorylation of tight junction proteins and has been shown to increase retinal vascular permeability in in vivo models Anti-VEGF therapy therefore may represent a useful therapeutic modality which targets the underlying pathogenesis of diabetic macular edema
Bevacizumab is currently approved for the treatment of metastatic colorectal cancer and published case reports and widespread clinical use have suggested its efficacy in the treatment of neovascular age-related macular degeneration and macular edema associated with diabetes and central retinal vein occlusion To date no evidence of ocular inflammation or other adverse events has been noted in association with intravitreal injection of bevacizumab However a study has not been conducted to evaluate its efficacy and safety In view of the widespread use of bevacizumab such a study is important to conduct
From a public health perspective an intravitreal bevacizumab study is also important to conduct because of the relatively low cost of the bevacizumab drug As noted earlier bevacizumab is marketed for systemic use for colon cancer The dose used in the eye is a fraction of the systemic dose and costs 25 to 50 per dose
The two doses of bevacizumab being evaluated in this study will be 125 mg which is the dose that has most commonly been used in clinical practice and 25 mg which has also been used though less commonly A lower dose than 125 mg would create difficulties with dilution and the accuracy of injection of a small volume
The optimal interval for the bevacizumab doses is not known Six weeks has been selected for this study as it is not believed that the effect will last longer than this Retinal thickening and visual acuity will be measured at 3 and 6 weeks to provide the requisite information to judge the duration of effect
There is expected to be a beneficial cumulative effect of multiple doses A total of two doses spaced 6 weeks apart was selected for the study with the primary outcome 3 weeks after the second dose
The decision as to whether to proceed to a phase 3 trial will be based on the observation of a substantial reduction in retinal thickening in the bevacizumab-treated eyes compared with the laser-treated eyes and at least a suggestion of benefit on visual acuity plus a safety profile of minimal risk
Description The study involves the enrollment of subjects over 18 years of age with diabetic macular edema Subjects will have one study eye randomly assigned with equal probability stratified by visual acuity to one of 5 treatment groups
Laser photocoagulation at baseline
125 mg intravitreal injection of bevacizumab at baseline and 6 weeks
25 mg intravitreal injection of bevacizumab at baseline and 6 weeks
125 mg intravitreal injection of bevacizumab at baseline sham injection at 6 weeks
125 mg intravitreal injection of bevacizumab at baseline laser photocoagulation at 3 weeks and intravitreal injection of 125 mg bevacizumab at 6 weeks
Follow-up includes 10 visits at 4 days 3 weeks 6 weeks 4 days following 6 weeks 9 weeks 12 weeks 18 weeks 24 weeks 41 weeks and 70 weeks At each visit visual acuity and ocular exams are completed on both eyes and an OCT is performed on the study eye except at the 4-day visits
During the first 12 weeks no other treatment for DME is given During weeks 13-24 treatment depends on the response to the treatment given during the first 12 weeks After 24 weeks follow-up is for safety and treatment is at the investigators discretion
In a review of three early studies concerning the natural history of diabetic macular edema Ferris and Patz found that 53 of 135 eyes with diabetic macular edema presumably all involving the center of the macula lost two or more lines of visual acuity over a two year period In the Early Treatment Diabetic Retinopathy Study ETDRS 33 of 221 untreated eyes available for follow-up at the 3-year visit all with edema involving the center of the macula at baseline had experienced a 15 or more letter decrease in visual acuity score equivalent to a doubling of the visual angle eg 2025 to 2050 and termed moderate visual loss
In the ETDRS focal photocoagulation direct treatment to microaneurysms and grid treatment to diffuse edema of eyes with clinically significant macular edema CSME reduced the risk of moderate visual loss by approximately 50 from 24 to 12 three years after initiation of treatment Therefore 12 of treated eyes developed moderate visual loss in spite of treatment Furthermore approximately 40 of treated eyes that had retinal thickening involving the center of the macula at baseline still had thickening involving the center at 12 months as did 25 of treated eyes at 36 months
Although several treatment modalities are currently under investigation the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation as demonstrated by the ETDRS intensive glycemic control as demonstrated by the Diabetes Control and Complications Trial DCCT and the United Kingdom Prospective Diabetes Study UKPDS and blood pressure control as demonstrated by the UKPDS In the DCCT intensive glucose control reduced the risk of onset of diabetic macular edema by 23 compared with conventional treatment Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control with a 58 risk reduction in the development of diabetic macular edema for the DCCT patients followed in the Epidemiology of Diabetes Interventions and Complications Study
The frequency of an unsatisfactory outcome with respect to proportion with vision improvement following laser photocoagulation in some eyes with diabetic macular edema has prompted interest in other treatment modalities One such treatment is pars plana vitrectomy These studies suggest that vitreomacular traction or the vitreous itself may play a role in increased retinal vascular permeability Removal of the vitreous or relief of mechanical traction with vitrectomy and membrane stripping may be followed by substantial resolution of macular edema and corresponding improvement in visual acuity However this treatment may be applicable only to a specific subset of eyes with diabetic macular edema that have a component of vitreomacular traction contributing to the edema It also requires a complex surgical intervention with its inherent risks recovery time and expense Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and use of intravitreal corticosteroids are under investigation The use of antibodies targeted at vascular endothelial growth factor VEGF such as in the current study is another treatment modality that has generated considerable interest and is currently being investigated in phase 3 trials of choroidal neovascularization in age-related macular degeneration with pegaptanib or ranibizumab or diabetic macular edema with pegaptanib
Increased VEGF levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy VEGF also known as vascular permeability factor has been demonstrated to increase vessel permeability by increasing the phosphorylation of tight junction proteins and has been shown to increase retinal vascular permeability in in vivo models Anti-VEGF therapy therefore may represent a useful therapeutic modality which targets the underlying pathogenesis of diabetic macular edema
Bevacizumab is currently approved for the treatment of metastatic colorectal cancer and published case reports and widespread clinical use have suggested its efficacy in the treatment of neovascular age-related macular degeneration and macular edema associated with diabetes and central retinal vein occlusion To date no evidence of ocular inflammation or other adverse events has been noted in association with intravitreal injection of bevacizumab However a study has not been conducted to evaluate its efficacy and safety In view of the widespread use of bevacizumab such a study is important to conduct
From a public health perspective an intravitreal bevacizumab study is also important to conduct because of the relatively low cost of the bevacizumab drug As noted earlier bevacizumab is marketed for systemic use for colon cancer The dose used in the eye is a fraction of the systemic dose and costs 25 to 50 per dose
The two doses of bevacizumab being evaluated in this study will be 125 mg which is the dose that has most commonly been used in clinical practice and 25 mg which has also been used though less commonly A lower dose than 125 mg would create difficulties with dilution and the accuracy of injection of a small volume
The optimal interval for the bevacizumab doses is not known Six weeks has been selected for this study as it is not believed that the effect will last longer than this Retinal thickening and visual acuity will be measured at 3 and 6 weeks to provide the requisite information to judge the duration of effect
There is expected to be a beneficial cumulative effect of multiple doses A total of two doses spaced 6 weeks apart was selected for the study with the primary outcome 3 weeks after the second dose
The decision as to whether to proceed to a phase 3 trial will be based on the observation of a substantial reduction in retinal thickening in the bevacizumab-treated eyes compared with the laser-treated eyes and at least a suggestion of benefit on visual acuity plus a safety profile of minimal risk
Description The study involves the enrollment of subjects over 18 years of age with diabetic macular edema Subjects will have one study eye randomly assigned with equal probability stratified by visual acuity to one of 5 treatment groups
Laser photocoagulation at baseline
125 mg intravitreal injection of bevacizumab at baseline and 6 weeks
25 mg intravitreal injection of bevacizumab at baseline and 6 weeks
125 mg intravitreal injection of bevacizumab at baseline sham injection at 6 weeks
125 mg intravitreal injection of bevacizumab at baseline laser photocoagulation at 3 weeks and intravitreal injection of 125 mg bevacizumab at 6 weeks
Follow-up includes 10 visits at 4 days 3 weeks 6 weeks 4 days following 6 weeks 9 weeks 12 weeks 18 weeks 24 weeks 41 weeks and 70 weeks At each visit visual acuity and ocular exams are completed on both eyes and an OCT is performed on the study eye except at the 4-day visits
During the first 12 weeks no other treatment for DME is given During weeks 13-24 treatment depends on the response to the treatment given during the first 12 weeks After 24 weeks follow-up is for safety and treatment is at the investigators discretion
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| EY14231 EY14269 EY14229 | US NIH GrantContract | None | httpsreporternihgovquickSearchU10EY014231-09 |
| U10EY018817-03 | NIH | None | None |
| U10EY014229-07 | NIH | None | None |
| U10EY014231-09 | NIH | None | None |