JCHR

Protocol

Protocol slide set

Informed Consent Form

Observational Phase Informed Consent Form

 

 

Study Objective

The primary objective of the proposed research is to compare the safety and efficacy of (1) prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF, (2) observation + deferred intravitreal anti-VEGF, and (3) prompt intravitreal anti-VEGF in eyes with central-involved DME and good visual acuity defined as a Snellen equivalent of 20/25 or better (electronic-ETDRS letter score of 79 or better).

 

Study Design and Synopsis of Protocol

 A.    Study Design

  Randomized, controlled, phase III multi-center clinical trial.

 

B.     Major Eligibility Criteria

• Age >=18 years
• Type 1 or type 2 diabetes
• Ophthalmoscopic evidence of center-involved DME in study eye confirmed on OCT at two consecutive visits within 1 to 28 days; defined by OCT CSF thickness on one of the following spectral domain OCT machines:

                  OCT CSF thickness at the screening visit:

  Zeiss Cirrus: = 290µ in women, and = 305µ in men

  Heidelberg Spectralis: = 305µ in women, and = 320µ in men

OCT CSF thickness at the randomization visit:

  Zeiss Cirrus: = 275µ in women, and = 290µ in men

  Heidelberg Spectralis: = 290µ in women, and = 305µ in men

• Best corrected visual acuity letter score in study eye = 79 (approximate Snellen equivalent 20/25 or better) at two consecutive visits within 1 to 28 days
• No history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME in the study eye within the prior 12 months.

If treatment for DME was given more than 12 months prior:

a.  no more than 1 prior focal/grid macular photocoagulation session, AND

b.  no more than 4 prior intraocular injections, AND

c.  in the investigator's judgement, the eye may possibly benefit from all of the possible study treatments. 

 

C.    Observational Phase

 

Potential study participants who are not willing or able to participate in the randomized trial may be enrolled into an observational phase and subsequently reconsidered for randomization.  The objective of the observational phase is to collect additional data on the natural history of the cohort. 

D.    Treatment Groups

Study participants (one eye per participant) will be assigned randomly (1:1:1) to one of the three following groups:

• Prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF
• Observation + deferred intravitreal anti-VEGF
• Prompt intravitreal anti-VEGF

For eyes in the deferred intravitreal anti-VEGF groups (either observation or focal/grid photocoagulation), intravitreal anti-VEGF will be provided if visual acuity decreases by at least 10 letters from baseline visual acuity (defined as the mean of the screening and randomization visual acuity) at one study visit or 5 to 9 letters from the baseline visual acuity at two consecutive study visits, with vision loss presumed to be due to DME. Further details on the treatment schedule and criteria for retreatment are described in section 4.3 of the protocol. 

 

 E.    Sample Size

A minimum of 702 eyes (one per study participant)

  

F.     Duration of Follow-up

Primary endpoint will be at 2 years

 

G.     Follow-up Schedule

  Treatment Visits:

Prompt anti-VEGF group: visits every 4 weeks during first 24 weeks, visits every 4 to 16 weeks thereafter depending on treatment administered.

Deferred anti-VEGF groups (prompt focal/grid photocoagulation and observation groups): visits at week 8 and 16, followed by visits every 16 weeks thereafter.*

 *For the deferred groups, the follow-up visit interval will be decreased if macular edema is worsening on OCT or visual acuity drops 5 to 9 letters, to assess for continued vision loss needing anti-VEGF treatment.  Once anti-VEGF is initiated, visits will be every 4 weeks during the first 24 weeks of treatment and every 4 to 16 weeks thereafter.  Further details on the follow-up visit schedule are described in section 4.1 of the protocol.

   Outcome Visits:

   All participants will have visits at 1 and 2 years for outcome assessment.

 

H.    Main Efficacy Outcomes

Primary:   

• Percent of eyes that have lost at least 5 letters of visual acuity at 2 years compared with baseline visual acuity (mean of the two visual acuity letter scores within 1 to 28 days required for eligibility).

Secondary:

 At 1 and 2 years:

• Percent of eyes with at least 5, 10 and 15 letter losses in visual acuity from baseline visual acuity
• Percent of eyes with at least 5 letter gain in visual acuity from baseline visual acuity
• Mean change in visual acuity, adjusted for baseline visual acuity
• Mean change in OCT CSF thickness, adjusted for baseline mean thickness (mean of the two OCT central subfield thickness measurements within 1 to 28 days required for eligibility)
• Percent of eyes with at least a 1 and 2 log step increase or decrease on OCT CSF thickness
• Percent of eyes with OCT CSF thickness less than the gender-specific spectral domain equivalent of 250 µm on Zeiss Stratus and at least a 10% OCT CSF thickness decrease
• Number of injections and/or focal/grid photocoagulation sessions performed
• Number of scheduled and unscheduled visits
• Mean change in low-contrast visual acuity on Electronic Visual Acuity Tester
• Total cost of follow-up and treatment
• For eyes randomly assigned to deferred anti-VEGF, the percentage of eyes needing anti-VEGF treatment.

I. Schedule of Study Visits and Examination Procedures

	Screening*	0	Visits Every 4-16w**	52w	104w
Visit Window			(± 1-4w)	(± 2w)	(± 4w)
E-ETDRS best corrected visual acuity a	X	X	X	X	X
Low-contrast acuity on EVAb		X		X	X
OCT c	X	X	X	X	X
Eye Examd		X	X	X	X
7-field Fundus Photography c		X		X	X
Fluorescein Angiography g		X
Blood pressure		X
HbA1c e		X	Xf	X	X

 *= a screening visit is required within 1 to 28 days of randomization in order to confirm the OCT and visual acuity eligibility criteria at two consecutive visits

**= visits every 4 weeks during the first 24 weeks for eyes assigned to prompt anti-VEGF treatment or eyes in the deferred groups that have had intravitreal anti-VEGF treatment initiated for DME.  After 24 weeks from initial anti-VEGF treatment for DME, visits every 4 to16 weeks based on treatment administered.  For eyes assigned to deferred anti-VEGF, 2 subsequent 8-week visits after randomization, followed by every 16-week visits until there is worsening or anti-VEGF treatment is initiated.

a= both eyes at each visit; including protocol refraction in the study eye at each visit and in the non-study eye at annual 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= at sites with electronic visual acuity (EVA) low-contrast acuity testing capabilities

c= study eye only

d= both eyes at randomization and study eye only at each follow-up visit unless treatment is given in the non-study eye, at which point an ocular exam also will be performed on the non-study eye for safety assessment.  Includes slit lamp exam (including assessment of lens), measurement of intraocular pressure, and dilated ophthalmoscopy.

e= must be performed using the same lab (or DCA Vantage Analyzer) at baseline and follow-up

f= at 16 weeks (± 4 weeks) only

 

 

 

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