JCHR

 

 Study Design and Synopsis of Protocol

 Click here to view protocol

 Click here to view protocol slide set

A.    Study Design

•  Randomized, controlled phase II 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:
  •  Visual acuity letter score in study eye ≤ 78 and ≥ 24 (approximate Snellen equivalent 20/32 to 20/320)
  •  Ophthalmoscopic evidence of center-involved DME
  •   OCT CSF thickness value (microns):
    •  Zeiss Cirrus: ≥290 in women; ≥305 in men
    •  Heidelberg Spectralis: ≥305 in women; ≥320 in men
  • At least three intravitreal anti-VEGF injections given within prior 20 weeks
  • No previous history of glaucoma or steroid intraocular pressure response in either eye

C.    Run-In Phase

All potential study participants will be required to participate in a 12-week run-in phase. In order to enter the run-in phase, all eligibility criteria must be assessed and met. During the run-in phase, study eyes will receive 3 study ranibizumab 0.3mg injections approximately 4 weeks apart. 

At the end of the run-in phase (12-week visit), eyes with persistent DME despite prior intravitreal anti-VEGF therapy that still meet eligibility criteria (see section 4.2 of the protocol) will be randomized. “Persistent DME” at end of the run-in phase is defined as meeting all of the following:

• CSF thickness (microns) on OCT meeting either one of the following two gender and OCT machine-specific criteria:
  
  • Zeiss Cirrus: ≥290 in women; ≥305 in men
    
  •  Heidelberg Spectralis: ≥305 in women; ≥320 in men
• Visual acuity letter score ≤ 78  and ≥24 (approximate Snellen equivalent 20/32 to 20/320)
• DME is the cause of OCT thickening and vision loss by the investigator’s judgment

 D.    Treatment Groups

Eligible study eyes at the end of the run-in phase will be assigned randomly (1:1) to one of the following groups:

•         Group A: Sham + intravitreal ranibizumab
•         Group B: Intravitreal dexamethasone +intravitreal ranibizumab

Study participants may have one or two study eyes.  Study participants with two study eyes will be randomized to receive continued anti-VEGF therapy (ranibizumab) in one eye and dexamethasone +ranibizumab in the other eye.

For both treatment groups, the initial ranibizumab injections must be given on the day of randomization. The sham or dexamethasone injection will be given within 0-8 days of the ranibizumab injection. Study eyes will be evaluated for retreatment every 4 weeks based on OCT and visual acuity. Further details on the treatment schedule and criteria for retreatment are included in section 4.8 of the protocol. 

E.     Sample Size

A minimum of 150 study eyes (from approximately 125 participants assuming 20% have two study eyes)

F.     Duration of Follow-up

• 12-week run-in phase prior to randomization
• Primary outcome at 24 weeks after randomization 

G.    Follow-up Schedule

• Follow-up visits occur every 4±1 weeks

H.    Main Efficacy Outcomes

At 24 weeks after randomization:

 

Primary:   

•  Mean change in visual acuity letter score, adjusted for visual acuity at time of randomization

Secondary:

• Percent of eyes with at least 10 and at least 15 letter gain (increase) or loss (decrease) in E-ETDRS letter score visual acuity
• Visual acuity area under the curve (AUC) between randomization and 24 weeks
• Mean change in OCT CSF thickness, adjusted for thickness at time of randomization
• Percent of eyes with ≥1 and ≥2 logOCT step gain or loss in CSF thickness
• Percent of eyes with OCT CSF thickness (in micros) < the following gender and OCT machine-specific values: <290 in women and <305 in men in Zeiss Cirrus; <305 in women and <320 in men in Heidelberg Spectralis
• OCT CSF thickness AUC between randomization and 24 weeks
•  Percent of eyes with worsening or improvement of diabetic retinopathy on clinical exam

I.       Main Safety Outcomes

Injected-related: endophthalmitis, retinal detachment, retinal tears, intraocular hemorrhage, increased intraocular pressure

Ocular drug-related: inflammation, increased intraocular pressure, need for ocular anti-hypertensive, glaucoma surgery, or other IOP-lowering procedures, development or worsening of cataract and cataract extraction, intraocular hemorrhage, migration of dexamethasone to the anterior chamber and subsequent corneal complications

Systemic drug-related: Deaths, participants with at least one hospitialization, participants with at least one SAE, and cardiovascular events, and cerebrovascular events as defined by Antiplatelet Trialists’ Collaboration

 

J.      Schedule of Study Visits and Examination Procedures

 

Visit Window	Enroll in Run-In	Run-In Visits*	Randomization 0	4w-24w**
		(+/− 1w)		(+/− 1w)
E-ETDRS best corrected visual acuity a	X	X	X	X
OCT b	X	X	X	X
Eye exam c	X	X	X	X
Blood pressure	X		X
HbA1cd			X

* Visits at 4 and 8 (±1) weeks during the run-in phase.  Randomization visit (0) occurs at 12 (± 1) weeks from enrollment.

**Visits every 4 (±1) weeks post-randomization.

    a= both eyes at each visit; includes protocol refraction in study eye at each visit and the non-study eye at the randomization visit and 24 week visit. 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

c=both eyes at enrollment and randomization and study eye only at each follow-up visit. Includes slit lamp exam (including assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy.

    d=does not need to be repeated if HbA1c is available from within the prior 3 months. If not available, can be performed within 3 weeks after randomization.

Back