A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin)

Sponsor
Jaeb Center for Health Research (Other)
Overall Status
Completed
CT.gov ID
NCT00336323
Collaborator
National Eye Institute (NEI) (NIH)
121
34
5
20
3.6
0.2

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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, e.g., 20/25 to 20/50, 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 1.25 mg, which is the dose that has most commonly been used in clinical practice, and 2.5 mg, which has also been used though less commonly. A lower dose than 1.25 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

1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks

2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks

1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks)

1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 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 investigator's discretion.

Study Design

Study Type:
Interventional
Actual Enrollment :
121 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin)
Study Start Date :
Jun 1, 2006
Actual Primary Completion Date :
Nov 1, 2006
Actual Study Completion Date :
Feb 1, 2008

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: 1

Laser photocoagulation at baseline

Procedure: Laser Photocoagulation
Laser photocoagulation at baseline; If edema present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart

Experimental: 2

1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks

Drug: Bevacizumab
1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks
Other Names:
  • Avastin
  • anti-VEGF drug
  • Experimental: 3

    2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks

    Drug: Bevacizumab
    2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Other Names:
  • Avastin
  • anti-VEGF drug
  • Experimental: 4

    1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks)

    Drug: Bevacizumab
    1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks)
    Other Names:
  • Avastin
  • anti-VEGF drug
  • Experimental: 5

    1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks

    Drug: Bevacizumab
    1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
    Other Names:
  • Avastin
  • anti-VEGF drug
  • Outcome Measures

    Primary Outcome Measures

    1. Change in Central Subfield Retinal Thickness From Baseline Over All Study Visits [Baseline to 3,6,9, and 12 weeks]

      Change in central subfield retinal thickness from baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. The OCT scans were sent to the DRCR.net Reading Center for grading. Negative changes represent a decrease in retinal thickening.

    2. Percentage of Participants With <250 Microns or ≥ 50% Reduction in Retinal Thickening From Baseline Over All Study Visits [Baseline to 3,6,9, and 12 Weeks]

      Central subfield retinal thickness measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. The OCT scans were sent to the DRCR.net Reading Center for grading.

    Secondary Outcome Measures

    1. Change in Visual Acuity Letter Score From Baseline Over All All Study Visits [Baseline to 3,6,9, and 12 weeks]

      Change in visual acuity letter score as measured using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. At baseline and at each follow up visit, best corrected visual acuity was measured at 3 meters by a certified tester using an electronic procedure based on the E-ETDRS method. Letter score best value = 97 and worst value = 0; positive change represents an improvement in letter score.

    2. Distribution of Change in Visual Acuity Over All Study Visits [Baseline to 3,6,9, and 12 weeks]

      Visual acuity letter score as measured using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. At baseline and at each follow up visit, best corrected visual acuity was measured at 3 meters by a certified tester using an electronic procedure based on the E-ETDRS method. Letter score best value = 97 and worst value = 0; an increase in a letter score by 10 is considered clinically significant.

    Other Outcome Measures

    1. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Baseline Central Subfield Thickness [Baseline to 3 Weeks]

      Pooled Bevacizumab groups include the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    2. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Baseline Visual Acuity Letter Score [Baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    3. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Age at Baseline [Baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    4. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Gender [Baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    5. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to History of Treatment for Diabetic Macular Edema at Baseline [Baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    6. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Retinopathy Severity at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks + laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. Retinopathy severity based on investigator discretion on clinical examination.

    7. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Clinical Diabetic Macular Edema Characterization at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    8. Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Subretinal Fluid Presence at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    9. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Central Subfield Thickness at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    10. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Visual Acuity at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    11. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Age at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    12. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Gender [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    13. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to History of Treatment for Diabetic Macular Edema [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    14. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Retinopathy Severity at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    15. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Clinical Diabetic Macular Edema Characterization at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    16. Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Subretinal Fluid Presence at Baseline [baseline to 3 Weeks]

      Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.

    17. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had a >11% Decrease in Change of Central Subfield Thickness From Baseline to 3 Weeks [3 to 6 Weeks]

      The 1.25mg Bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Duration of effect of Bevacizumab was based on additional improvement versus maintained improvement versus worsening within 3 to 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in the DRCR.net paper, Reproducibility of macular thickness and volume using Zeiss optical coherence tomography in patients with diabetic macular edema.Ophthalmology 2007;114:1520-25.

    18. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had Within a ±11% Change of Central Subfield Thickness From Baseline to 3 Weeks [3 to 6 Weeks]

      The 1.25mg bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The pooled 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    19. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had a >11% Increase in Change of Central Subfield Thickness From Baseline to 3 Weeks [3 to 6 Weeks]

      The 1.25mg bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The pooled 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    20. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had a >11% Decrease in Change of Central Subfield Thickness From Baseline to 3 Weeks [3 to 6 Weeks]

      The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    21. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had Within a ±11% Change in Central Subfield Thickness From Baseline to 3 Weeks [3 to 6 Weeks]

      The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    22. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had a >11% Increase in Change of Central Subfield Thickness From Baseline to 3 Weeks [3 to 6 Weeks]

      The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    23. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had a >11% Decrease in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks [3 to 9 weeks]

      The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    24. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had Within ±11% Change of Central Subfield Thickness From 6 Weeks to 9 Weeks [3 to 9 weeks]

      The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    25. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had a >11% Increase in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks [3 to 9 weeks]

      The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    26. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had a >11% Decrease in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks [3 to 9 weeks]

      The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    27. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had Within ±11% Change of Central Subfield Thickness From 6 Weeks to 9 Weeks [3 to 9 weeks]

      The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    28. Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had Within >11% Increase in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks [3 to 9 weeks]

      The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    SUBJECT-LEVEL INCLUSION CRITERIA

    To be eligible, the following inclusion criteria (1-3) must be met:
    1. Age >= 18 years

    2. Diagnosis of diabetes mellitus (type 1 or type 2)

    3. Able and willing to provide informed consent.

    EXCLUSION

    A subject is not eligible if any of the following exclusion criteria (4-13) are present:

    1. Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant.

    2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).

    3. Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval at the time of study entry.

    4. Known allergy to any component of the study drug.

    5. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110).

    6. Major surgery within 28 days prior to randomization or major surgery planned during the next 6 months.

    7. Myocardial infarction, other cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 6 months prior to randomization.

    8. Systemic anti-VEGF or pro-VEGF treatment within 3 months prior to randomization.

    9. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 6 months.

    10. Subject is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the first 6 months of the study.

    STUDY EYE CRITERIA

    The subject must have one eye meeting all of the inclusion criteria (a-e) and none of the exclusion criteria (f-r) listed below.

    Subjects can have only one study eye. If both eyes are eligible, the study eye will be selected by the investigator and subject.

    The eligibility criteria for a study eye are as follows:

    INCLUSION

    1. Best corrected E-ETDRS visual acuity letter score of >= 24 (i.e., 20/320 or better) and <= 78 (i.e., 20/32 or worse) within 8 days of randomization.

    2. On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.

    3. OCT central subfield >=275 microns within 8 days of randomization.

    4. Media clarity, pupillary dilation, and subject cooperation sufficient for adequate fundus photographs.

    5. If prior macular photocoagulation has been performed, the investigator believes that the study eye may possibly benefit from additional photocoagulation.

    EXCLUSION

    The following exclusions apply to the study eye only (i.e., they may be present for the nonstudy eye):

    1. Macular edema is considered to be due to a cause other than diabetic macular edema.

    2. An ocular condition is present such that, in the opinion of the investigator, visual acuity would not improve from resolution of macular edema (e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, nonretinal condition).

    3. An ocular condition is present (other than diabetes) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.).

    4. Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).

    5. History of treatment for DME at any time in the past 3 months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, anti-VEGF drugs, or any other treatment).

    6. History of panretinal scatter photocoagulation (PRP) within 4 months prior to randomization.

    7. Anticipated need for PRP in the 6 months following randomization.

    8. History of prior pars plana vitrectomy.

    9. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 6 months or anticipated within the next 6 months following randomization.

    10. History of YAG capsulotomy performed within 2 months prior to randomization.

    11. Aphakia.

    12. Uncontrolled glaucoma (in investigator's judgment).

    13. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

    FELLOW EYE CRITERIA

    The fellow eye must meet the following criteria:
    1. Best corrected E-ETDRS visual acuity letter score >= 19 (i.e., 20/400 or better).

    2. No anti-VEGF treatment within the past 3 months and no expectation of such treatment in next 3 months.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Loma Linda University Health Care, Dept. of Ophthalmology Loma Linda California United States 92354
    2 Southern California Desert Retina Consultants, MC Palm Springs California United States 92262
    3 California Retina Consultants Santa Barbara California United States 93103
    4 Bay Area Retina Associates Walnut Creek California United States 94598
    5 Retina Vitreous Consultants Ft. Lauderdale Florida United States 33334
    6 Central Florida Retina Institute Lakeland Florida United States 33805
    7 Southeast Retina Center, P.C. Augusta Georgia United States 30909
    8 Illinois Retina Associates Joliet Illinois United States 60435
    9 Raj K. Maturi, M.D., P.C. Indianapolis Indiana United States 46280
    10 American Eye Institute New Albany Indiana United States 47150
    11 Retina and Vitreous Associates of Kentucky Lexington Kentucky United States
    12 Paducah Retinal Center Paducah Kentucky United States 42001
    13 Maine Vitreoretinal Consultants Bangor Maine United States 04401
    14 Elman Retina Group, P.A. Baltimore Maryland United States 21237
    15 Retina Consultants of Delmarva, P.A. Salisbury Maryland United States 21801
    16 Ophthalmic Consultants of Boston Boston Massachusetts United States 02114
    17 Joslin Diabetes Center Boston Massachusetts United States 02215
    18 Retina Center, PA Minneapolis Minnesota United States 55404
    19 Charlotte Eye, Ear, Nose and Throat Assoc., PA Charlotte North Carolina United States 28210
    20 Wake Forest University Eye Center Winston-Salem North Carolina United States 27157
    21 Retina Associates of Cleveland, Inc. Beachwood Ohio United States 44122
    22 Retina Northwest, PC Portland Oregon United States 97210
    23 Casey Eye Institute Portland Oregon United States 97239
    24 Penn State College of Medicine Hershey Pennsylvania United States 17033
    25 Retina Consultants Providence Rhode Island United States 02903
    26 Palmetto Retina Center Columbia South Carolina United States 29169
    27 Carolina Retina Center Columbia South Carolina United States 29223
    28 Southeastern Retina Associates, P.C. Knoxville Tennessee United States 37909
    29 West Texas Retina Consultants P.A. Abilene Texas United States 79605
    30 Retina Research Center Austin Texas United States 78705
    31 Texas Retina Associates Dallas Texas United States 75231
    32 Charles A. Garcia, PA & Associates Houston Texas United States 77002
    33 Texas Retina Associates Lubbock Texas United States 79424
    34 University of Washington Medical Center Seattle Washington United States 98195

    Sponsors and Collaborators

    • Jaeb Center for Health Research
    • National Eye Institute (NEI)

    Investigators

    • Study Chair: Ingrid U. Scott, M.D., M.P.H., Penn State College of Medicine

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00336323
    Other Study ID Numbers:
    • NEI-129
    • U10EY018817-03
    • U10EY014229-07
    • U10EY014231-09
    • EY14231, EY14269, EY14229
    First Posted:
    Jun 13, 2006
    Last Update Posted:
    Aug 26, 2016
    Last Verified:
    Aug 1, 2016

    Study Results

    Participant Flow

    Recruitment Details Thirty-six clinical sites across the United States recruited 121 subjects (109 met criteria for inclusion in the analyses) between June 2006 and August 2006.
    Pre-assignment Detail Unless otherwise noted, differences in number of Participants at different visits reflect a missed visit, not a drop-out.
    Arm/Group Title Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Arm/Group Description Laser photocoagulation at baseline: If edema is present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
    Period Title: Overall Study
    STARTED 19 22 24 22 22
    3 Week Visit 18 21 24 22 20
    6 Week Visit 18 22 24 22 20
    9 Week Visit 18 21 23 21 19
    12 Week Visit 19 21 24 22 20
    18 Week Visit 19 22 23 21 18
    24 Week Visit 18 20 22 22 19
    COMPLETED 19 21 23 22 19
    NOT COMPLETED 0 1 1 0 3

    Baseline Characteristics

    Arm/Group Title Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w Total
    Arm/Group Description Laser photocoagulation at baseline: If edema is present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks Total of all reporting groups
    Overall Participants 19 22 24 22 22 109
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    64
    63
    68
    60
    67
    65
    Sex: Female, Male (Count of Participants)
    Female
    9
    47.4%
    6
    27.3%
    9
    37.5%
    9
    40.9%
    10
    45.5%
    43
    39.4%
    Male
    10
    52.6%
    16
    72.7%
    15
    62.5%
    13
    59.1%
    12
    54.5%
    66
    60.6%
    Race/Ethnicity, Customized (participants) [Number]
    White
    10
    52.6%
    16
    72.7%
    20
    83.3%
    18
    81.8%
    19
    86.4%
    83
    76.1%
    African-American
    7
    36.8%
    3
    13.6%
    2
    8.3%
    3
    13.6%
    2
    9.1%
    17
    15.6%
    Hispanic or Latino
    2
    10.5%
    2
    9.1%
    2
    8.3%
    0
    0%
    1
    4.5%
    7
    6.4%
    Asian
    0
    0%
    0
    0%
    0
    0%
    1
    4.5%
    0
    0%
    1
    0.9%
    Unknown/ not reported
    0
    0%
    1
    4.5%
    0
    0%
    0
    0%
    0
    0%
    1
    0.9%
    Character of Diabetic Macular Edema (DME) (participants) [Number]
    Typical/Predominantly Focal
    6
    31.6%
    5
    22.7%
    2
    8.3%
    3
    13.6%
    4
    18.2%
    20
    18.3%
    Neither Predominantly Focal or Diffuse
    4
    21.1%
    5
    22.7%
    5
    20.8%
    6
    27.3%
    6
    27.3%
    26
    23.9%
    Typical/Predominantly Diffuse
    9
    47.4%
    12
    54.5%
    17
    70.8%
    13
    59.1%
    12
    54.5%
    63
    57.8%
    Cystoid Abnormalities on Optical Coherence Tomography (OCT) (participants) [Number]
    Yes
    18
    94.7%
    22
    100%
    24
    100%
    21
    95.5%
    21
    95.5%
    106
    97.2%
    No
    1
    5.3%
    0
    0%
    0
    0%
    1
    4.5%
    1
    4.5%
    3
    2.8%
    Diabetes Type (participants) [Number]
    Type 1
    1
    5.3%
    1
    4.5%
    3
    12.5%
    2
    9.1%
    1
    4.5%
    8
    7.3%
    Type 2
    18
    94.7%
    21
    95.5%
    21
    87.5%
    20
    90.9%
    21
    95.5%
    101
    92.7%
    Lens status (clinical examination) (participants) [Number]
    Phakic
    12
    63.2%
    15
    68.2%
    14
    58.3%
    12
    54.5%
    13
    59.1%
    66
    60.6%
    Pseudophakic
    7
    36.8%
    7
    31.8%
    10
    41.7%
    10
    45.5%
    9
    40.9%
    43
    39.4%
    Prior Panretinal Scatter Photocoagulation (participants) [Number]
    Yes
    3
    15.8%
    2
    9.1%
    3
    12.5%
    1
    4.5%
    4
    18.2%
    13
    11.9%
    No
    16
    84.2%
    20
    90.9%
    21
    87.5%
    21
    95.5%
    18
    81.8%
    96
    88.1%
    Prior Treatment for Diabetic Macular Edema (DME) in Study Eye (participants) [Number]
    None
    7
    36.8%
    5
    22.7%
    10
    41.7%
    5
    22.7%
    7
    31.8%
    34
    31.2%
    Focal photocoagulation alone
    4
    21.1%
    11
    50%
    9
    37.5%
    6
    27.3%
    9
    40.9%
    39
    35.8%
    Focal photocoagulation plus other treatment
    8
    42.1%
    3
    13.6%
    3
    12.5%
    11
    50%
    6
    27.3%
    31
    28.4%
    Other treatment without focal photocoagulation
    0
    0%
    3
    13.6%
    2
    8.3%
    0
    0%
    0
    0%
    5
    4.6%
    Retinopathy Severity (participants) [Number]
    Mild nonproliferative diabetic retinopathy (NPDR)
    1
    5.3%
    6
    27.3%
    3
    12.5%
    0
    0%
    4
    18.2%
    14
    12.8%
    Moderate NPDR
    5
    26.3%
    3
    13.6%
    1
    4.2%
    3
    13.6%
    3
    13.6%
    15
    13.8%
    Moderately severe NPDR
    5
    26.3%
    6
    27.3%
    8
    33.3%
    8
    36.4%
    9
    40.9%
    36
    33%
    Severe NPDR
    0
    0%
    1
    4.5%
    2
    8.3%
    4
    18.2%
    1
    4.5%
    8
    7.3%
    Mild proliferative diabetic retinopathy (PDR)
    4
    21.1%
    5
    22.7%
    6
    25%
    5
    22.7%
    4
    18.2%
    24
    22%
    Moderate PDR
    1
    5.3%
    0
    0%
    2
    8.3%
    0
    0%
    1
    4.5%
    4
    3.7%
    High Risk PDR
    2
    10.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    1.8%
    Missing
    1
    5.3%
    1
    4.5%
    2
    8.3%
    2
    9.1%
    0
    0%
    6
    5.5%
    Subretinal Fluid on Optical Coherence Tomography (OCT) (participants) [Number]
    Definite, center
    2
    10.5%
    2
    9.1%
    7
    29.2%
    2
    9.1%
    4
    18.2%
    17
    15.6%
    Definite, not center
    0
    0%
    1
    4.5%
    1
    4.2%
    0
    0%
    1
    4.5%
    3
    2.8%
    Questionable
    0
    0%
    1
    4.5%
    0
    0%
    2
    9.1%
    0
    0%
    3
    2.8%
    No evidence
    16
    84.2%
    18
    81.8%
    16
    66.7%
    18
    81.8%
    17
    77.3%
    85
    78%
    Missing
    1
    5.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.9%
    Baseline Visual Acuity (letter score) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [letter score]
    64
    65
    63
    64
    66
    64
    Duaration of Diabetes (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    17
    15
    18
    17
    20
    17
    Hemoglobin A1c (percent HbA1c) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [percent HbA1c]
    7.0
    7.4
    7.3
    6.7
    7.1
    6.9
    Optical Coherence Tomography (OCT) Central Subfield Thickness (microns) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [microns]
    441
    397
    446
    406
    389
    411
    Optical Coherence Tomography Retinal Volume (mm^3) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [mm^3]
    8.3
    9.5
    9.1
    8.9
    8.6
    8.6

    Outcome Measures

    1. Primary Outcome
    Title Change in Central Subfield Retinal Thickness From Baseline Over All Study Visits
    Description Change in central subfield retinal thickness from baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. The OCT scans were sent to the DRCR.net Reading Center for grading. Negative changes represent a decrease in retinal thickening.
    Time Frame Baseline to 3,6,9, and 12 weeks

    Outcome Measure Data

    Analysis Population Description
    The primary analysis included per protocol and intent to treat analysis. The intent to treat analysis included all randomized eyes. The last observation carried forward method was used to impute missing data. The per-protocol analysis was performed including only patients who receive treatment as per the protocol and complete the 9-week exam.
    Arm/Group Title Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Arm/Group Description Laser photocoagulation at baseline: If edema is present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
    Measure Participants 19 22 24 22 22
    3 Weeks
    21
    -35
    -86
    -3
    -13
    6 Weeks
    -40
    -35
    -42
    -17
    -20
    9 Weeks
    -53
    -74
    -56
    5
    -48
    12 Weeks
    -40
    -56
    -47
    -5
    -40
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline, 1.25 mg Injection at Baseline and at 6 Weeks
    Comments Comparison of central subfield thickness at the 3 week visit between the laser only treatment group to the 1.25 mg injection at baseline and at 6 weeks treatment group
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.009
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of central subfield thickness at the 3 week visit between the laser only treatment group to the 2.5mg injection at baseline and 6 weeks treatment group
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of the reduction in central subfield thickening in the 1.25mg injection at baseline and at 6 weeks treatment group with the 2.5mg injection at baseline and 6 weeks treatment group at the 3 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.66
    Comments Adjusted for baseline values
    Method Least squares regression
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of the reduction in central subfield thickening in the 1.25mg injection at baseline and at 6 weeks treatment group with the 2.5mg injection at baseline and 6 weeks treatment group at the 6 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.49
    Comments Adjusted for baseline values
    Method Least squares regression
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of the reduction in central subfield thickening in the 1.25mg injection at baseline and at 6 weeks treatment group with the 2.5mg injection at baseline and 6 weeks treatment group at the 9 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.45
    Comments Adjusted for baseline values
    Method Least squares regression
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of the reduction in central subfield thickening in the 1.25mg injection at baseline and at 6 weeks treatment group with the 2.5mg injection at baseline and 6 weeks treatment group at the 12 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.90
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    2. Secondary Outcome
    Title Change in Visual Acuity Letter Score From Baseline Over All All Study Visits
    Description Change in visual acuity letter score as measured using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. At baseline and at each follow up visit, best corrected visual acuity was measured at 3 meters by a certified tester using an electronic procedure based on the E-ETDRS method. Letter score best value = 97 and worst value = 0; positive change represents an improvement in letter score.
    Time Frame Baseline to 3,6,9, and 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Arm/Group Description Laser photocoagulation at baseline: If edema is present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
    Measure Participants 19 22 24 22 22
    3 Weeks
    -2
    5
    6
    2
    0
    6 Weeks
    1
    5
    6
    3
    0
    9 Weeks
    3
    7
    8
    1
    -2
    12 Weeks
    -1
    5
    7
    4
    0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of improvement in visual acuity between the 1.25mg injection at baseline and at 6 weeks treatment group and the 2.5mg injection at baseline and 6 weeks treatment group at the 3 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.42
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of improvement in visual acuity between the 1.25mg injection at baseline and at 6 weeks treatment group and the 2.5mg injection at baseline and 6 weeks treatment group at the 6 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.67
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of improvement in visual acuity between the 1.25mg injection at baseline and at 6 weeks treatment group and the 2.5mg injection at baseline and 6 weeks treatment group at the 9 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.48
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 1.25 mg Injection at Baseline and at 6 Weeks, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of improvement in visual acuity between the 1.25mg injection at baseline and at 6 weeks treatment group and the 2.5mg injection at baseline and 6 weeks treatment group at the 12 week visit
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.82
    Comments
    Method Least squares regression
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline, 1.25 mg Injection at Baseline and at 6 Weeks
    Comments Comparison of improvement in visual acuity through the 12 week visit between the laser only treatment group and the 1.25mg injection at baseline and at 6 weeks treatment group
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.01
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline, 2.5 mg Injection at Baseline and 6 Weeks
    Comments Comparison of improvement in visual acuity through the 12 week visit between the laser only treatment group and the 2.5mg injection at baseline and at 6 weeks treatment group
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    3. Primary Outcome
    Title Percentage of Participants With <250 Microns or ≥ 50% Reduction in Retinal Thickening From Baseline Over All Study Visits
    Description Central subfield retinal thickness measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. The OCT scans were sent to the DRCR.net Reading Center for grading.
    Time Frame Baseline to 3,6,9, and 12 Weeks

    Outcome Measure Data

    Analysis Population Description
    The primary analysis included per protocol and intent to treat analysis. The intent to treat analysis included all randomized eyes. The last observation carried forward method was used to impute missing data. The per-protocol analysis was performed including only patients who receive treatment as per the protocol and complete the 9-week exam.
    Arm/Group Title Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Arm/Group Description Laser photocoagulation at baseline: If edema is present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
    Measure Participants 19 22 24 22 22
    3 Weeks
    11
    57.9%
    37
    168.2%
    38
    158.3%
    10
    45.5%
    25
    113.6%
    6 Weeks
    17
    89.5%
    30
    136.4%
    22
    91.7%
    19
    86.4%
    25
    113.6%
    9 Weeks
    19
    100%
    38
    172.7%
    22
    91.7%
    10
    45.5%
    37
    168.2%
    12 Weeks
    21
    110.5%
    33
    150%
    33
    137.5%
    14
    63.6%
    25
    113.6%
    4. Secondary Outcome
    Title Distribution of Change in Visual Acuity Over All Study Visits
    Description Visual acuity letter score as measured using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. At baseline and at each follow up visit, best corrected visual acuity was measured at 3 meters by a certified tester using an electronic procedure based on the E-ETDRS method. Letter score best value = 97 and worst value = 0; an increase in a letter score by 10 is considered clinically significant.
    Time Frame Baseline to 3,6,9, and 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Arm/Group Description Laser photocoagulation at baseline: If edema is present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
    Measure Participants 19 22 24 22 22
    ≥ 10 letter improvement at 3 Weeks
    1
    5.3%
    4
    18.2%
    4
    16.7%
    2
    9.1%
    2
    9.1%
    ≥ 10 letters worse at 3 Weeks
    1
    5.3%
    1
    4.5%
    0
    0%
    1
    4.5%
    0
    0%
    ≥ 10 letter improvement at 6 Weeks
    2
    10.5%
    7
    31.8%
    7
    29.2%
    3
    13.6%
    3
    13.6%
    ≥ 10 letters worse at 6 Weeks
    2
    10.5%
    0
    0%
    1
    4.2%
    1
    4.5%
    4
    18.2%
    ≥ 10 letter improvement at 9 Weeks
    3
    15.8%
    6
    27.3%
    9
    37.5%
    3
    13.6%
    5
    22.7%
    ≥ 10 letters worse at 9 Weeks
    1
    5.3%
    1
    4.5%
    0
    0%
    0
    0%
    2
    9.1%
    ≥ 10 letter improvement at 12 Weeks
    3
    15.8%
    7
    31.8%
    6
    25%
    2
    9.1%
    4
    18.2%
    ≥ 10 letters worse at 12 Weeks
    1
    5.3%
    1
    4.5%
    0
    0%
    2
    9.1%
    2
    9.1%
    5. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Baseline Central Subfield Thickness
    Description Pooled Bevacizumab groups include the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame Baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    <400 microns
    -3
    ≥400 microns
    -102
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between eyes that had baseline central subfield thickness of <400 microns compared to those that had baseline central subfield thickness of ≥400 microns. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    6. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Baseline Visual Acuity Letter Score
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame Baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    <65 letters
    -35
    ≥65 letters
    -28
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between eyes that had baseline visual acuity letter score that was <65 letters compared to those that had baseline visual acuity letter score that was ≥65 letters. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.31
    Comments
    Method Least squares regression
    Comments Adjusted for baseline score
    7. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Age at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame Baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    ≤66 years
    -45
    >66 years
    -16
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between those that were ≤66 years old compared to those that were >66 years old at baseline. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.44
    Comments
    Method Least squares regression
    Comments
    8. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Gender
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame Baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    Female
    -28
    Male
    -35
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between females and males. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.55
    Comments
    Method Least squares regression
    Comments
    9. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to History of Treatment for Diabetic Macular Edema at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame Baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    No
    -40
    Yes
    -29
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between eyes that had no history of treatment for diabetic macular edema compared to those that had history or treatment for diabetic macular edema. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.16
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    10. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Retinopathy Severity at Baseline
    Description Pooled Bevacizumab group includes treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks + laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. Retinopathy severity based on investigator discretion on clinical examination.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    <Severe nonproliferative diabetic retinopathy
    -31
    Proliferative diabetic retinopathy or severe NPDR
    -31
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between eyes that had baseline retinopathy severity that was <severe nonproliferative diabetic retinopathy (NPDR) compared to those that had baseline retinopathy severity that was proliferative diabetic retinopathy or severe NPDR. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.53
    Comments
    Method Least squares regression
    Comments
    11. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Clinical Diabetic Macular Edema Characterization at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    Typical/Predominantly Focal
    -13
    Neither Predominantly Focal or Diffuse
    -8
    Typical/Predominantly Diffuse
    -82
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between eyes that had baseline clinical diabetic macular edema characterized as typical/predominantly focal, neither predominantly focal or diffuse, or typical/predominantly diffuse. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.93
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    12. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness in Bevacizumab Groups From Baseline to 3 Weeks According to Subretinal Fluid Presence at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. Negative values represent a reduction in central subfield thickness. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    Definite/Questionable
    -35
    No Evidence
    -29
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of central subfield thickness (microns) change from baseline to the 3 week visit between eyes that had baseline subretinal fluid that was definite/questionable compared to eyes that had no evidence of subretinal fluid at baseline. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.52
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    13. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Central Subfield Thickness at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    <400 microns
    1
    ≥400 microns
    5
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between eyes that had baseline central subfield thickness of <400 microns compared to eyes that had baseline central subfield thickness of ≥400 microns. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.22
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    14. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Visual Acuity at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    <65 letters
    3
    ≥65 letters
    1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between eyes that had a baseline visual acuity letter score of <65 letters compared to eyes that had baseline visual acuity letter score of ≥65 letters. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.006
    Comments
    Method Least squares regression
    Comments Adjusted for baseline values
    15. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Age at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    ≤66 years
    4
    >66 years
    2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between eyes that were ≤66 years old at baseline compared to eyes that were >66 years old at baseline. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.23
    Comments
    Method Least squares regression
    Comments
    16. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Gender
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    Female
    3
    Male
    3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between females and males. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.37
    Comments
    Method Least squares regression
    Comments
    17. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to History of Treatment for Diabetic Macular Edema
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    No
    5
    Yes
    2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between eyes that did not have a prior history of treatment for diabetic macular edema compared to eyes that did have a prior history of treatment for diabetic macular edema. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.04
    Comments
    Method Least squares regression
    Comments
    18. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Retinopathy Severity at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    <Severe nonproliferative diabetic retinopathy
    3
    Proliferative diabetic retinopathy or severe NPDR
    1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between eyes that had a baseline retinopathy severity of <severe nonproliferative diabetic retinopathy (NPDR) compared to eyes that had baseline retinopathy severity of proliferative diabetic retinopathy or severe NPDR. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.38
    Comments
    Method Least squares regression
    Comments
    19. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Clinical Diabetic Macular Edema Characterization at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    Typical/Predominantly Focal
    7
    Neither Predominantly Focal or Diffuse
    0
    Typical/Predominantly Diffuse
    3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between eyes that had a baseline clinical diabetic macular edema (DME) characterization of typical/predominantly focal compared to neither predominantly focal or diffuse characterization at baseline and compared to typical/predominantly diffuse characterization at baseline. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.45
    Comments
    Method Least squares regression
    Comments
    20. Other Pre-specified Outcome
    Title Change in Visual Acuity (Letters) in Bevacizumab Groups From Baseline to 3 Weeks According to Subretinal Fluid Presence at Baseline
    Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks, 2.5mg at baseline and at 6 weeks, 1.25mg at baseline only, and 1.25mg at baseline and 6 weeks plus laser at 3 weeks. The 4 bevacizumab groups (N=87) were pooled to compare differences in response at 3 weeks among subgroups of interest. The pooled Bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure. Positive values represent an improvement in letter score.
    Time Frame baseline to 3 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled Bevacizumab Groups
    Arm/Group Description Pooled Bevacizumab group includes the following treatment groups: 1.25mg at baseline and at 6 weeks; 2.5mg at baseline and at 6 weeks; 1.25mg at baseline only; and 1.25mg at baseline and 6 weeks plus laser at 3 weeks.
    Measure Participants 87
    Definite/Questionable
    6
    No Evidence
    1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Laser at Baseline
    Comments Comparison of change in visual acuity letter score from baseline to the 3 week visit between eyes that had a baseline subretinal fluid presence that was definite/questionable compared to eyes that there was no evidence of subretinal fluid at baseline. Eyes included all of those from the pooled Bevacizumab group.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.06
    Comments
    Method Least squares regression
    Comments
    21. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had a >11% Decrease in Change of Central Subfield Thickness From Baseline to 3 Weeks
    Description The 1.25mg Bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Duration of effect of Bevacizumab was based on additional improvement versus maintained improvement versus worsening within 3 to 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in the DRCR.net paper, Reproducibility of macular thickness and volume using Zeiss optical coherence tomography in patients with diabetic macular edema.Ophthalmology 2007;114:1520-25.
    Time Frame 3 to 6 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled 1.25mg Initial Bevacizumab Injection Groups
    Arm/Group Description The following are the treatment groups included in the Pooled 1.25mg Bevacizumab Groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only
    Measure Participants 14
    >11% Decreased Change from 3 Weeks to 6 Weeks
    1
    5.3%
    Within ± 11% Change from 3 Weeks to 6 Weeks
    11
    57.9%
    >11% Increased Change from 3 Weeks to 6 Weeks
    2
    10.5%
    22. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had Within a ±11% Change of Central Subfield Thickness From Baseline to 3 Weeks
    Description The 1.25mg bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The pooled 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 6 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled 1.25mg Initial Bevacizumab Injection Groups
    Arm/Group Description The following are the treatment groups included in the Pooled 1.25mg Bevacizumab Groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only
    Measure Participants 22
    >11% Decreased Change from 3 Weeks to 6 Weeks
    2
    10.5%
    Within ± 11% Change from 3 Weeks to 6 Weeks
    16
    84.2%
    >11% Increased Change from 3 Weeks to 6 Weeks
    4
    21.1%
    23. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Injection Only and Had a >11% Increase in Change of Central Subfield Thickness From Baseline to 3 Weeks
    Description The 1.25mg bevacizumab groups include the following treatment groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The pooled 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 6 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pooled 1.25mg Initial Bevacizumab Injection Groups
    Arm/Group Description The following are the treatment groups included in the Pooled 1.25mg Bevacizumab Groups: 1.25mg at baseline and 6 weeks; and 1.25mg at baseline only
    Measure Participants 2
    >11% Decreased Change from 3 Weeks to 6 Weeks
    1
    5.3%
    Within ± 11% Change from 3 Weeks to 6 Weeks
    1
    5.3%
    >11% Increased Change from 3 Weeks to 6 Weeks
    0
    0%
    24. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had a >11% Decrease in Change of Central Subfield Thickness From Baseline to 3 Weeks
    Description The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 6 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 2.5 mg Injection at Baseline and 6 Weeks
    Arm/Group Description 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 13
    >11% Decreased Change from 3 Weeks to 6 Weeks
    0
    0%
    Within ± 11% Change from 3 Weeks to 6 Weeks
    9
    47.4%
    >11% Increased Change from 3 Weeks to 6 Weeks
    4
    21.1%
    25. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had Within a ±11% Change in Central Subfield Thickness From Baseline to 3 Weeks
    Description The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 6 Weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 2.5 mg Injection at Baseline and 6 Weeks
    Arm/Group Description 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 10
    >11% Decreased Change from 3 Weeks to 6 Weeks
    0
    0%
    Within ± 11% Change from 3 Weeks to 6 Weeks
    9
    47.4%
    >11% Increased Change from 3 Weeks to 6 Weeks
    1
    5.3%
    26. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab and Had a >11% Increase in Change of Central Subfield Thickness From Baseline to 3 Weeks
    Description The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 6 Weeks

    Outcome Measure Data

    Analysis Population Description
    There were no participants with a change in central subfield thickness from 3 to 6 weeks in this treatment group that had a >11% increase in change of central subfield thickness from baseline to 3 weeks.
    Arm/Group Title 2.5 mg Injection at Baseline and 6 Weeks
    Arm/Group Description 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 0
    27. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had a >11% Decrease in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks
    Description The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 9 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 1.25 mg Injection at Baseline and at 6 Weeks
    Arm/Group Description 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 7
    >11% Decreased Change from 9 Weeks to 12 Weeks
    0
    0%
    Within ± 11% Change from 9 Weeks to 12 Weeks
    4
    21.1%
    >11% Increased Change from 9 Weeks to 12 Weeks
    3
    15.8%
    28. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had Within ±11% Change of Central Subfield Thickness From 6 Weeks to 9 Weeks
    Description The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 9 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 1.25 mg Injection at Baseline and at 6 Weeks
    Arm/Group Description 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 9
    >11% Decreased Change from 9 Weeks to 12 Weeks
    1
    5.3%
    Within ± 11% Change from 9 Weeks to 12 Weeks
    6
    31.6%
    >11% Increased Change from 9 Weeks to 12 Weeks
    2
    10.5%
    29. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 1.25mg Bevacizumab at 6 Weeks and Had a >11% Increase in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks
    Description The 1.25mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 1.25mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 9 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 1.25 mg Injection at Baseline and at 6 Weeks
    Arm/Group Description 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 2
    >11% Decreased Change from 9 Weeks to 12 Weeks
    0
    0%
    Within ± 11% Change from 9 Weeks to 12 Weeks
    2
    10.5%
    >11% Increased Change from 9 Weeks to 12 Weeks
    0
    0%
    30. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had a >11% Decrease in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks
    Description The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 9 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 2.5 mg Injection at Baseline and 6 Weeks
    Arm/Group Description 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 3
    >11% Decreased Change from 9 Weeks to 12 Weeks
    0
    0%
    Within ± 11% Change from 9 Weeks to 12 Weeks
    2
    10.5%
    >11% Increased Change from 9 Weeks to 12 Weeks
    1
    5.3%
    31. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had Within ±11% Change of Central Subfield Thickness From 6 Weeks to 9 Weeks
    Description The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 9 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 2.5 mg Injection at Baseline and 6 Weeks
    Arm/Group Description 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 17
    >11% Decreased Change from 9 Weeks to 12 Weeks
    2
    10.5%
    Within ± 11% Change from 9 Weeks to 12 Weeks
    14
    73.7%
    >11% Increased Change from 9 Weeks to 12 Weeks
    1
    5.3%
    32. Other Pre-specified Outcome
    Title Change in Central Subfield Thickness From 3 to 6 Weeks Among Eyes That Received 2.5mg Bevacizumab at 6 Weeks and Had Within >11% Increase in Change of Central Subfield Thickness From 6 Weeks to 9 Weeks
    Description The 2.5mg bevacizumab treatment group received an injection at both baseline and at 6 weeks. Change in central subfield thickness was categorized according to whether it exceeded 11%, the reliability limit for real change determined in another Diabetic Retinopathy Clinical Research Network study 16. The 2.5mg bevacizumab treatment group will be the only group/arm that has values, all other treatment groups/arms will have a null value for this outcome measure.
    Time Frame 3 to 9 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 2.5 mg Injection at Baseline and 6 Weeks
    Arm/Group Description 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks
    Measure Participants 2
    >11% Decreased Change from 9 Weeks to 12 Weeks
    1
    5.3%
    Within ± 11% Change from 9 Weeks to 12 Weeks
    1
    5.3%
    >11% Increased Change from 9 Weeks to 12 Weeks
    0
    0%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Arm/Group Description Laser photocoagulation at baseline: If edema is present at 12 weeks, can be treated with 2 intravitreal injections of 1.25 mg bevacizumab spaced 6 weeks apart 1.25 mg intravitreal injection of bevacizumab at baseline and 6 weeks 2.5 mg intravitreal injection of bevacizumab at baseline and 6 weeks 1.25 mg intravitreal injection of bevacizumab at baseline (sham injection at 6 weeks) 1.25 mg intravitreal injection of bevacizumab at baseline, laser photocoagulation at 3 weeks, and intravitreal injection of 1.25 mg bevacizumab at 6 weeks
    All Cause Mortality
    Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/19 (42.1%) 8/22 (36.4%) 6/24 (25%) 1/22 (4.5%) 6/22 (27.3%)
    Blood and lymphatic system disorders
    Anemia 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Cardiac disorders
    Arteriosclerosis coronary artery 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Chest pain 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    Congestive cardiac failure 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Hyperglycaemia 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Hypoglycaemia 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Intraventricular haemorrhage 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Myocardial infarction 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 3/22 (13.6%)
    Endocrine disorders
    Inadequate control of diabetes mellitus 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Gastrointestinal disorders
    Gastroenteritis 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Pancreatic carcinoma 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Vomiting 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    General disorders
    Death 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Delerium 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Endophthalmitis 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Glaucoma 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Syncope 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Vitrectomy 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Hepatobiliary disorders
    Cholelithiasis 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Infections and infestations
    Localised infection 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Musculoskeletal and connective tissue disorders
    Cellulitis 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Hip fracture 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Renal and urinary disorders
    Renal failure 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Renal impairment 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Metastatic lung cancer 0/19 (0%) 1/22 (4.5%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Pneumonia 2/19 (10.5%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Skin and subcutaneous tissue disorders
    Bacterial skin infection 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Skin ulcer or skin lesion 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Vascular disorders
    Cerebrovascular accident 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Peripheral vascular disorder 1/19 (5.3%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Other (Not Including Serious) Adverse Events
    Laser at Baseline 1.25 mg Injection at Baseline and at 6 Weeks 2.5 mg Injection at Baseline and 6 Weeks 1.25 mg Injection at Baseline Only 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 14/19 (73.7%) 16/22 (72.7%) 19/24 (79.2%) 20/22 (90.9%) 22/22 (100%)
    Blood and lymphatic system disorders
    Anemia 1/19 (5.3%) 1/22 (4.5%) 1/24 (4.2%) 1/22 (4.5%) 1/22 (4.5%)
    Hypercholesterolemia 1/19 (5.3%) 2/22 (9.1%) 0/24 (0%) 2/22 (9.1%) 0/22 (0%)
    blood glucose decreased 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    blood potassium increased 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    haemoglobin decreased 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    hyperkalaemia 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    hypoglycaemia 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    leukocytosis 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Cardiac disorders
    chest pain 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    chronic obstructive pulmonary disease 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    heart rate irregular 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    Ear and labyrinth disorders
    deafness 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Endocrine disorders
    Diabetes mellitus 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    diabetes mellitus inadequate control 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Eye disorders
    Angle Closure Glaucoma 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Anterior chamber cell 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Anterior chamber flare 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Blepharitis 1/19 (5.3%) 2/22 (9.1%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    Cataract nuclear 0/19 (0%) 2/22 (9.1%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Conjunctival hemorrhage 0/19 (0%) 5/22 (22.7%) 1/24 (4.2%) 6/22 (27.3%) 3/22 (13.6%)
    Diabetic Retinopathy 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Diabetic retinal edema 0/19 (0%) 5/22 (22.7%) 3/24 (12.5%) 2/22 (9.1%) 1/22 (4.5%)
    Diplopia 0/19 (0%) 2/22 (9.1%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    Eye irritation 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 2/22 (9.1%) 1/22 (4.5%)
    Eye pain 2/19 (10.5%) 4/22 (18.2%) 5/24 (20.8%) 3/22 (13.6%) 5/22 (22.7%)
    Foreign body sensation in eyes 1/19 (5.3%) 0/22 (0%) 2/24 (8.3%) 0/22 (0%) 2/22 (9.1%)
    Glaucoma 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Increased intraocular pressure 0/19 (0%) 1/22 (4.5%) 3/24 (12.5%) 3/22 (13.6%) 2/22 (9.1%)
    Lacrimation increased 1/19 (5.3%) 3/22 (13.6%) 2/24 (8.3%) 2/22 (9.1%) 1/22 (4.5%)
    Ocular hyperaemia 1/19 (5.3%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 2/22 (9.1%)
    Vision blurred 5/19 (26.3%) 6/22 (27.3%) 5/24 (20.8%) 5/22 (22.7%) 5/22 (22.7%)
    Visual acuity reduced 2/19 (10.5%) 4/22 (18.2%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    Visual disturbance 0/19 (0%) 0/22 (0%) 4/24 (16.7%) 2/22 (9.1%) 1/22 (4.5%)
    Vitreous floaters 0/19 (0%) 7/22 (31.8%) 8/24 (33.3%) 1/22 (4.5%) 3/22 (13.6%)
    Vitreous hemorrhage 0/19 (0%) 1/22 (4.5%) 5/24 (20.8%) 3/22 (13.6%) 2/22 (9.1%)
    cataract 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    cataract cortical 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    cataract operation 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    cataract operation complication 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    cataract subcapsular 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    conjunctivitis 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    conjunctivitis allergic 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    conjunctivitis viral 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    corneal abrasion 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    corneal oedema 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    desemets membrane disorder 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    dry eye 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    eye inflammation 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    eye pruritus 0/19 (0%) 1/22 (4.5%) 1/24 (4.2%) 1/22 (4.5%) 1/22 (4.5%)
    eyelid oedema 0/19 (0%) 1/22 (4.5%) 1/24 (4.2%) 0/22 (0%) 1/22 (4.5%)
    eyelid pain 1/19 (5.3%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    eyelid ptsosis 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    foreign body in eye 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    injection site irritaion 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    keratoconjunctivitis sicca 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    macular oedema 1/19 (5.3%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 1/22 (4.5%)
    maculopathy 1/19 (5.3%) 1/22 (4.5%) 2/24 (8.3%) 1/22 (4.5%) 0/22 (0%)
    oedema peripheral 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    optic nerve cupping 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    periorbital haematoma 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    photophobia 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    photopsia 0/19 (0%) 1/22 (4.5%) 1/24 (4.2%) 1/22 (4.5%) 0/22 (0%)
    posterior capsule opacification 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    pterygium 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    punctate keratitis 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    retinal degeneration 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    retinal detachment 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    retinal exudates 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    retinal laser coagulation 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    retinal neovascularisation 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    retinal oedema 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    retinal telagiectasia 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    vitrectomy 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    vitreous degeneration 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    vitreous detachment 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    vitreous opacities 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Gastrointestinal disorders
    Duodenitis 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Gastroenteritis viral 0/19 (0%) 2/22 (9.1%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    gastroenteritis 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    gastrooespohageal reflux disease 1/19 (5.3%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    General disorders
    Abdominal pain 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Anorexia 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Back injury 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Headache 1/19 (5.3%) 2/22 (9.1%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    Osteomyelitis 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Tooth abcess 0/19 (0%) 2/22 (9.1%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    anxiety 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    arthralgia 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    asbestosis 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    back pain 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    benign breast neoplasm 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    blister 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    blood creatine increased 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    breast cancer 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    caugh 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    chalazion 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    colon cancer 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    constipation 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    dizziness 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 1/22 (4.5%) 1/22 (4.5%)
    epistaxis 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    fall 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    haematochezia 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    herpes zoster 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    insomnia 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    intervertebral disc protrusion 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    joint dislocation 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    localised infection 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    nasopharyngitis 1/19 (5.3%) 0/22 (0%) 3/24 (12.5%) 0/22 (0%) 0/22 (0%)
    nausea 0/19 (0%) 1/22 (4.5%) 1/24 (4.2%) 0/22 (0%) 1/22 (4.5%)
    pain in extremity 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    pharyngolaryngeal pain 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    protein urine present 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    pruritus 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    reading disorder 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    respiratory tract congestion 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    rhinitis allergic 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    sinusitis 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    swollen tongue 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    upper respiratory tract infection 0/19 (0%) 1/22 (4.5%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Infections and infestations
    Localised infection 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Injury, poisoning and procedural complications
    Head injury 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Musculoskeletal and connective tissue disorders
    rheumatoid arthritis 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    prostate cancer 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    skin cancer 1/19 (5.3%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Nervous system disorders
    autonomic nervous system imbalance 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    nerve injury 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    trigeminal neuralgia 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Psychiatric disorders
    depression 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    Renal and urinary disorders
    renal failure 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    renal failure chronic 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    urinary incontinence 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    urinary tract infection 0/19 (0%) 1/22 (4.5%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Respiratory, thoracic and mediastinal disorders
    Bronchitis 2/19 (10.5%) 1/22 (4.5%) 0/24 (0%) 1/22 (4.5%) 1/22 (4.5%)
    Influenza 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 2/22 (9.1%) 1/22 (4.5%)
    Nasopharyngitis 1/19 (5.3%) 0/22 (0%) 3/24 (12.5%) 0/22 (0%) 0/22 (0%)
    Pneumonia 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    Skin and subcutaneous tissue disorders
    Skin ulcer 0/19 (0%) 0/22 (0%) 0/24 (0%) 1/22 (4.5%) 0/22 (0%)
    dermatitis allergic 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    dermatitis contact 1/19 (5.3%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 1/22 (4.5%)
    fungal skin infection 0/19 (0%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 1/22 (4.5%)
    peritonitis 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    rash 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    skin lesion excision 0/19 (0%) 0/22 (0%) 1/24 (4.2%) 0/22 (0%) 0/22 (0%)
    Vascular disorders
    Cerebrovascular accident 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    Hypertension 2/19 (10.5%) 2/22 (9.1%) 2/24 (8.3%) 1/22 (4.5%) 1/22 (4.5%)
    Peripheral vascular disease 1/19 (5.3%) 0/22 (0%) 0/24 (0%) 0/22 (0%) 0/22 (0%)
    deep vein thrombosis 0/19 (0%) 1/22 (4.5%) 0/24 (0%) 0/22 (0%) 0/22 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Name/Official Title: Adam Glassman, M.S., Director
    Organization Jaeb Center for Health Research, Diabetic Retinopathy Clinical Research Network
    Phone (813) 975-8690
    Email drcrnet@jaeb.org
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00336323
    Other Study ID Numbers:
    • NEI-129
    • U10EY018817-03
    • U10EY014229-07
    • U10EY014231-09
    • EY14231, EY14269, EY14229
    First Posted:
    Jun 13, 2006
    Last Update Posted:
    Aug 26, 2016
    Last Verified:
    Aug 1, 2016