Click Here to View the Protocol

Click Here to View the Protocol Slide Set

Click Here to View the One-Year Results Publication and Results Slide Set

Study Objective

The primary objective of the proposed research is to compare the efficacy and safety of  (1) intravitreal aflibercept, (2) intravitreal bevacizumab, and (3) intravitreal ranibizumab when given to treat central-involved DME in eyes with visual acuity of 20/32 to 20/320.

 

Study Design and Synopsis of Protocol

A. Study Design

Randomized, multi-center clinical trial.

 

B. Major Eligibility Criteria

• Age =18 years.
• Type 1 or type 2 diabetes.
• Central-involved DME in study eye (OCT CSF =250 µm on Zeiss Stratus or the equivalent on spectral domain OCT based on gender specific cutoffs) within eight days of randomization.
• Visual acuity letter score in study eye = 78 and =24 (approximate Snellen equivalent 20/32 to 20/320) within eight days of randomization.
• No history of an anti-VEGF treatment for DME in the past 12 months  in the study eye and no history of any other treatment for DME in the study eye at any time in the past four months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids).

   - Enrollment will be limited to a maximum of 25% of the planned sample size with any history of anti-VEGF treatment in the study eye. Once this number of eyes has been enrolled, any history of anti-VEGF treatment in the study eye will be an exclusion criterion.

• No history of major ocular surgery in the study eye within prior four months or anticipated within the next six months following randomization.

C. Treatment Groups

Study participants will be assigned randomly to one of the following three groups:

1)      2.0  mg intravitreal aflibercept

2)      1.25 mg intravitreal bevacizumab

3)      0.3 mg intravitreal ranibizumab

 Study participants can have only one study eye.  If both eyes are eligible at the time of randomization and one of the eyes has never received anti-VEGF treatment, that eye should be randomized.  If both eyes are eligible and have previously received anti-VEGF treatment or both eyes have never received anti-VEGF then the study eye will be selected by the investigator and the participant before randomization. 

 D. Sample Size

• The sample size is 660 study eyes (220 eyes per group)

 E. Duration of Follow-up

• Duration of follow-up is 2 years with the primary outcome at one year

 F. Follow-up Schedule

• Follow-up visits occur every four weeks up to the one year visit
• After one year, visits occur every 4 to 16 weeks depending on disease progression and treatment administered
• All participants will have follow-up visits at 1 and 2 years
• Participants will be requested to complete one optional visit 2-3days (+/- 1 day if the participant cannot return within 2-3 days) after either the first, second, or third injection 

G. Main Efficacy Outcomes

Primary:   Change in visual acuity from baseline to one year adjusted for baseline visual acuity.  

 

      Secondary:  

• Change in visual acuity at four months
• Change in visual acuity at 2 years
• Number of intravitreal injections given per protocol
• Proportion of eyes with two and three line gains or losses in visual acuity
• Change in OCT central subfield thickness and retinal volume
• Proportion of eyes with OCT central subfield thickness of <250 µm on Stratus OCT (or spectral domain equivalent)
• Of eyes with non-prolific diabetic retinopathy at baseline, proportion of eyes with regression of retinopathy severity level
• Proportion receiving panretinal photocoagulation, vitrectomy, or vitreous hemorrhage
• Change in blood pressure 2-3 days (+/- 1 day) after an injection and at 1 year
• Change in albumin/creatinine ratio for microalbuminuria 2-3 days (+/- 1 day)  after an injection and at 1 year

 

H. Main Safety Outcomes

• Injection-related: endophthalmitis, traction retinal detachment, rhegmatogenous retinal detachment, retinal tear, cataract, intraocular hemorrhage increased intraocular pressure.
• Ocular drug-related: inflammation,  new or worsening traction retinal detachment, progression of traction retinal detachment from extramacular to macular.
• Systemic drug-related: hypertension events, kidney, gastrointestinal events, and cardiovascular events as defined by the Antiplatelet Trialists’ Collaboration.

 

I. Schedule of Study Visits and Examination Procedures

 

Visit	0	4w-48w	52w	Between 52w-104w   Visits Every 4-16w*	104w
E-ETDRS best corrected visual acuity a	X	X	X	X	X
OCT  b	X	X	X	X	X
Eye Exam c	X	X	X	X	X
7-field Fundus Photography  d	X		X		X
Blood pressure	X	Xf	X
Hemoglobin A1c e	X
Urine Sample	X	Xf	X

 

A medical history will be elicited at baseline and an updated history at each visit.  Concomitant medications will be recorded at baseline and updated at each visit.  Adverse events will be recorded at each visit.

 a= both eyes at each visit; includes protocol refraction in study eye at each visit. Protocol refraction in nonstudy eye is only required at baseline, 52 week and 104 week visits.  E-ETDRS refers to electronic ETDRS testing using the Electronic Visual Acuity Tester that has been validated against 4-meter chart ETDRS testing.

b=study eye only

c=both eyes at baseline, 52 weeks and 104 weeks; study eye only (and nonstudy eye if treated with study drug) at all other follow-up visits.  Includes slit lamp exam (including assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy.

d=digital 7-fields or 4WF; study eye only 

    e=does not need to be repeated if Hemoglobin A1c is available from within the prior 3 months.  If not available, can be performed within 3 weeks after randomization.

 

 f=Participants will be asked to return for an optional visit 2-3 days (+/- 1 day) after the baseline injection to obtain a blood pressure measurement and urine sample. If the participant is unable or unwilling to return after the baseline injection he/she will be asked to return for an optional visit 2-3 (+/- 1 day)  days after either of the next 2 injections to have the blood pressure measured and urine sample collected.  Blood pressure will also be obtained at the first 4 week protocol visit after the post-injection blood pressure was obtained.

 

J. 5 Year Follow-up Extension Study

Participants would return for one follow-up visit 5 years (± 6 months) from original randomization for the following procedures to be performed: 

• Assessment of DME and diabetic retinopathy treatments since 2 year visit
• Ocular and medical history since 2 year visit
• Best-corrected E-ETDRS visual acuity
• Comprehensive, dilated eye exam 
• Optical coherence tomography 
• HbA1c
• Color fundus photographs 
• Assessment of APTC events since the 2 year visit

 

Back