JCHR

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1.1         Study Objective

The objectives of this study are to 1) determine the efficacy and safety of intravitreous aflibercept injections versus sham injections (observation) for prevention of PDR or CI-DME in eyes at high risk for development of these complications and 2) compare long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that are observed initially, and treated only if high-risk PDR or CI-DME with vision loss develops.

 

1.2         Study Design and Synopsis of Protocol

 

A.    Study Design

•        Phase III, multi-center randomized clinical trial

 

B.     Major Eligibility Criteria

•        Age >=18 years
•        Type 1 or type 2 diabetes
•        Study eye with

o   Best corrected Electronic-ETDRS (E-ETDRS) visual acuity letter score in the study eye =79 (approximate Snellen equivalent 20/25 or better)

o   Severe NPDR (based on the 4:2:1 rule) on clinical examination and on digital imaging as judged by the investigator

• Reading Center grading of less than ETDRS level 43 or greater than 53 is an exclusion

o   No evidence of neovascularization on fluorescein angiography within the 7-modified ETDRS fields, confirmed by Reading Center grading.

o   No clinical exam evidence of neovascularization including active neovascularization of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is assessed).

o   No prior PRP (defined as = 100 burns placed previously outside of the posterior pole)

o   No CI-DME on clinical exam and OCT central subfield thickness below the following gender and OCT-machine specific thresholds:

·         Zeiss Cirrus: 290µm in women and  305µm in men

·         Heidelberg Spectralis: 305µm in women and 320µm in men

o   No history of DME or DR treatment with laser or intraocular injections of medication within the prior 12 months and no more than 4 prior intraocular injections at any time in the past.

C.    Treatment Groups

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

 

·         Sham injections

·         Intravitreous 2 mg aflibercept injections

 

Study participants may have one or two study eyes.  Study participants with two study eyes will receive intravitreous aflibercept in one eye and sham injection in the other eye. Further details on randomization are located in section 2.4.

 

Injections (intravitreous or sham) will be given at baseline, 1 and 2 months in all participants.  Thereafter, injections will be given at each 4-month visit until 2 years.  At and after the 2-year visit, retreatment with injections (intravitreous or sham) will be based on DR level, as assessed by the investigator. 

 

Treatment for DME or PDR, if developed, may only be given once protocol-specified criteria are met and will follow a protocol-specified regimen (see Section 4.4 and 4.5). 

 

D.    Sample Size

•        A minimum of 386 eyes (approximately 322 study participants assuming 20% have two study eyes)

 

E.     Duration of Follow-up

•        Primary outcome: 2 years
•        Total follow-up: 4 years

 

F.     Follow-up Schedule

•          All participants will have visits at 1 month, 2 months, and 4 months, followed by visits every 4 months thereafter through 4 years.
•          Eyes may be seen more frequently depending on disease progression and treatment administered.  Further details on the follow-up visit schedule are described in Section 3.1.

 

G.    Main Efficacy Outcomes

 

Primary outcome:   

 

 Development of PDR or DME, defined as the first occurrence of any of the following (composite time-to-event outcome):

·         NV within the 7-modified ETDRS fields on fundus photography or FA, confirmed by a masked grader at the central reading center

o   At non-annual visits, fundus photography and FA will only be submitted to the reading center to assess for this component of the primary outcome if the investigator thinks treatment is necessary.

·         NV of the iris (at least 2 cumulative clock hours), definitive NV of the angle, or neovascular glaucoma on clinical exam (photographic documentation not required)

·         Other outcomes presumed to be from PDR and documented: traction retinal detachment, vitreous hemorrhage, or pre-retinal hemorrhage greater than ½ disc area

·         Procedures undertaken for the treatment of PDR (when present or presumed to be present): PRP, anti-VEGF, or vitrectomy

·         CI-DME on clinical exam with at least 10% increase in central subfield thickness from baseline and either (1) at least a 10-letter decrease in visual acuity from baseline at a single visit or (2) 5-to-9-letter decrease in visual acuity from baseline at 2 consecutive visits at least 21 days apart, with vision loss presumed to be from DME

·         Non-topical treatment for DME performed without meeting the above criteria, including focal/grid laser or intravitreous injections for DME

 

The primary outcome analysis will be performed when the last randomized participant reaches 2 years of follow up, using all available follow up data. The treatment groups will be compared using the hazard ratio.

 

Other Key Outcomes:

·         Development of PDR or DME outcome through 4 years

·         Mean visual acuity change from baseline at 2 years

·         Mean visual acuity change from baseline at 4 years

 

See section 7.3 for methods of handling multiplicity. 

 

Additional secondary outcomes at 2 and 4 years:

·         Development of PDR or PDR-related outcome (as defined above within the composite time-to-event outcome)

·         Development of CI-DME with visual acuity impairment (as defined above within the composite time-to-event outcome)

·         Development of PDR or DME based only on the objective components defined in the composite outcome, including OCT, visual acuity, and reading center assessment of photos and FA (i.e. not including investigator-only assessments)

·         Development of each component of the composite outcome assessed individually

·         Proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at least 5 letters at consecutive study visits, consisting of the visits just before and the 2- or 4-year visit

·         Visual acuity area under the curve (AUC) between randomization and the 2- and 4-year visits

·         Mean change in OCT central subfield thickness from baseline

·         Mean change in OCT volume from baseline

·         Development of CI-DME on clinical exam with at least 10% increase in central subfield thickness and at least a 25-micron increase from baseline, regardless of visual acuity change

·         Proportion of eyes with at least 2-step worsening of DR severity level (scale for individual eyes) by central reading center from baseline

·         Proportion of eyes with at least 2-step improvement of DR severity level (scale for individual eyes) by central reading center from baseline

·         Proportion of eyes with at least 3-step worsening of DR severity level (scale for individual eyes) by central reading center from baseline

·         Proportion of eyes with at least 3-step improvement of DR severity level (scale for individual eyes) by central reading center from baseline

·         Level of retinopathy on color photos

·         Number of aflibercept injections performed

·         Follow-up costs and patient-centered outcomes from the Workplace Productivity and Activity Impairment Questionnaire

 

H.    Main Safety Outcomes

Ocular: endophthalmitis, inflammation, retinal detachment, traumatic cataract from injection, vitreous hemorrhage

 

Systemic: Antiplatelet Trialists’ Collaboration (APTC) events and hypertension

 

I.       Schedule of Assessment Visits and Examination Procedures

    

	Screening	Randomization	Follow-Up Visits*	Annual Visits
Visit Window		within 35 days of screening	(±1to8w)	(±8w)
Usual care visual acuitya	X
E-ETDRS best corrected visual acuityb		X	X	X
Questionnairesc		X		X
OCTd	X	X	X	X
Eye Exame	X	X	X	X
Fundus Photographyf	X		Xg	X
Fluorescein angiographyf	X		Xg	X
Blood pressure		X		X
HbA1ch		X		X
OCT angiographyi	X		Xg	X

*= Assessment Visits at 1 month (±1w), 2 months (±1w), 4 months (±8w) and every 4 months  (±8w) thereafter; additional study visits may occur for treatment of DME/PDR as needed

a=study eye only; refraction and/or electronic ETDRS testing may be performed at the discretion of the site for usual care visual acuity.

b=both eyes including protocol refraction in the study eye at each study visit. Protocol refraction in non-study eye is only required at baseline and 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.

c= only in participants with one study eye

d= study eye only at randomization and annual visits and at other study visits only if evaluating for DME treatment (see section 3.2 for more details) or prior to initiating more frequent anti-VEGF treatment for PDR, if the DME outcome was not confirmed previously.

e=both eyes at randomization; study eye only at each additional study visit including slit lamp exam, lens assessment, measurement of intraocular pressure, and dilated ophthalmoscopy

f= study eye only. Fundus photography is 7MF or 4WF and FA is using the widest approach available at the site.

g= fundus photography,  FA, and OCTA (if available at the site) is also required in the study eye at 4 months AND 1) the first time traction retinal detachment, vitreous hemorrhage, or preretinal hemorrhage is identified to confirm the primary outcome has been met, or 2) prior to initiating PRP or vitrectomy, if the primary outcome was not confirmed previously or 3) prior to initiating more frequent anti-VEGF treatment for either DME or PDR, if the primary outcome was not confirmed previously.  Fundus photography is 7MF or 4WF and FA is using the widest approach available at the site.

h= 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.

i=study eye only; only at sites with OCT angiography capabilities.   

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