JCHR

 For Protocol, click here

 Slides

Informed Consent Form

1.1    Study Objectives

To compare the efficacy of intravitreous aflibercept with intravitreous bevacizumab + deferred aflibercept if needed in eyes with CI DME and moderate vision loss. 

 

1.2    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

·         The study eye must meet the following criteria:

o   Visual acuity (VA) letter score in the study eye < 69 and = 24 (approximate Snellen equivalent 20/50 to 20/320)

o   Ophthalmoscopic evidence of center-involved DME (i.e., involving the center of the macula)

o   Center-involved macular thickening on optical coherence tomography (OCT)

• Zeiss Cirrus central subfield (CSF): =290µm in women or = 305µm in men
• Heidelberg Spectralis central subfield: = 305µm in women or =320µm in men

o   No history of 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 in the past 4 months (such as focal/grid macular photocoagulation, intravitreous or peribulbar corticosteroids)

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

o   No history of major ocular surgery in the study eye within prior 4 months or anticipated within the next 6 months following randomization

 

C.    Treatment Groups

Subjects will be assigned randomly (1:1) to one of the following two groups:

 

·         2.0 mg intravitreous aflibercept

·         1.25 mg intravitreous bevacizumab + deferred intravitreous 2.0 mg aflibercept if eye meets switch criteria

 

Study participants may have one or two study eyes, if both eyes are eligible at the time of randomization.  Study participants with two study eyes will be randomized to receive aflibercept in one eye and bevacizumab + deferred aflibercept (if switch criteria is met) in the other eye.  Further details on randomization are located in section 2.4.

           

D.    Sample Size

A minimum of 312 eyes (260 participants assuming 20% have two study eyes) are expected to be enrolled into the randomized trial. 

 

E.     Duration of Follow-up: 2 years

 

F.     Follow-up and Treatment Schedule

·         Follow-up visits occur every 4 weeks up to the 1 year visit

·         Study eyes in both groups will be evaluated for an injection at each study visit according to the same retreatment protocol (DRCR.net anti-VEGF retreatment algorithm). 

·         At 12, 16, and 20 weeks, study eyes in the bevacizumab treatment group that meet all of the following switch criteria will be switched to treatment with aflibercept

o   OCT CSF thickness = machine and gender specific thresholds

§  Zeiss Cirrus: =290µm in women or = 305µm in men

§  Heidelberg Spectralis: = 305µm in women or =320µm in men

o   VA not improved at least 5 letters from the prior two visits  

o   OCT CSF not improved at least 10% from the prior two visits

o   VA is 20/50 or worse

·         At and after 24 weeks, study eyes in the bevacizumab treatment group (that have not already switched to aflibercept) that meet all of the following switch criteria will switch to aflibercept

o   OCT CSF thickness = machine and gender specific thresholds

§  Zeiss Cirrus: =290µm in women or = 305µm in men

§  Heidelberg Spectralis: = 305µm in women or =320µm in men

o   VA not improved at least 5 letters from the prior two visits  

o   OCT CSF not improved at least 10% from the prior two visits

o   VA is 20/32 or worse

·         After 1 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

 

G.    Primary Efficacy Outcomes

·         The primary analysis is a treatment group comparison of mean change in visual acuity over 2 years, area under the curve (AUC) adjusted for baseline visual acuity. 

 

I. Main Safety Outcomes

Ocular: endophthalmitis, retinal detachment, traumatic cataract due to injection, vitreous hemorrhage, inflammation, neovascular glaucoma, iris neovascularization

Systemic: death, serious adverse event, hospitalization, Antiplatelet Trialists’ Collaboration (APTC) events

 

J. Schedule of Study Visits and Examination Procedures

Visit	0	4w-48w Visits Every 4 w	52w	Between 52w-104w Visits Every 4-16w*	104w
E-ETDRS Best Corrected Visual Acuitya	X	X	X	X	X
OCTb	X	X	X	X	X
Eye Examc	X	X	X	X	X
Fundus Photographyd	X		X		X
Blood pressure	X		X		X
Hemoglobin A1ce	X		X		X

E-ETDRS, Electronic Early Treatment Diabetic Retinopathy Study; OCT, optical coherence tomography

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.

^aBoth 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.

^bStudy eye only.

^cBoth eyes at baseline, 52 weeks and 104 weeks; study eye only at all other follow-up visits.  Includes slit lamp exam (including assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy.

^dDigital 7-fields, 4WF or UWF; study eye only. 

    ^eDoes 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.

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