JCHR

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 A. Study Design

· Phase III, prospective, multi-center randomized clinical trial

 

 

B. Major Eligibility Criteria

 

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

o PDR for which PRP can be safely deferred for at least 4 weeks in the investigator's judgment

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

o Visual acuity letter score in the study eye >= 24 (approximate Snellen equivalent of 20/320 or better)

 

 

 

 

C. Treatment Groups

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

• Prompt panretinal photocoagulation
• Intravitreal 0.5 mg ranibizumab with deferred panretinal photocoagulation

Study participants may have one or two study eyes. Study participants with two study eyes will receive prompt PRP in one eye and ranibizumab with deferred PRP in the other eye. Further details on randomization are located in section 2.4 of the protocol.

For both treatment groups, intravitreal ranibizumab may be given as needed for DME. The treatment regimen for PDR and DME are described in sections 4.2-4.4 of the protocol.

 

D. Sample Size

 

A minimum of 380 eyes (approximately 316 study participants assuming 20% have two study eyes)

 

 

E. Duration of Follow-Up

• Primary outcome: 2 years
• Total follow-up: 5 years
   

F. Follow-up Schedule

• Year 1: For eyes assigned to the ranibizumab with deferred PRP group, follow-up visits occur every 4 weeks unless PRP is given. For eyes assgned to the prompt PRP group, follow-up visits occur every 16 weeks. Eyes may be seen more frequently for DME treatment as needed.
  
• Years 2 and 3: Follow-up visits occur every 4 to 16 weeks depending on disease progression and treatment administered.
  
• During years 4 and 5: Participants who agree will be followed according to the visit schedule in Years 2 and 3; otherwise, treatment and follow-up is performed as part of the study participant’s usual care.  All participants will have study visits at 4 and 5 years.
  

G. Main Efficacy Outcomes

Treatment Group Comparisons:

Primary: Mean change in visual acuity from baseline to 2 years

Secondary:

• Mean visual acuity over 2 years (area under the curve analysis)
• Proportion of eyes with 10 and 15 letter vision loss or gain
• Humphrey visual field (HVF) testing (at sites with HVF capabilities), NEI VFQ-25, and UAB-LLQ
• Need for supplemental PRP after completion or deferred or prompt initial PRP
• Need for vitrectomy
• Mean change in OCT central subfield thickness, other retinal thickness outcomes
• In eyes without central subfield involved DME at baseline, proportion with progression to central subfield involved DME
• Percent of eyes with vitreous hemorrhage
• Proportion with complete regression of neovascularization on fundus photography
• Associated treatment and follow-up costs 

 

 Assessment of treatment group receiving anti-VEGF with deferred PRP:

• Percent not requiring PRP in the deferred PRP group at 2 years

 Eyes with and without DME at randomization will be pooled for the primary analysis, however, separate exploratory analyses of subgroups based on baseline DME status will be conducted.

 

 

H. Main Safety Outcomes

Injection-related: endophthalmitis, tractional retinal detachment, rhegmatogenous retinal detachment, retinal tears, cataract, intraocular hemorrhage

  

 Ocular drug-related: inflammation, cataract, cataract surgery, increased intraocular pressure, new or worsening neovascular glaucoma, glaucoma medications, glaucoma surgery, new or worsening tractional retinal detachment, progression of tractional retinal detachment from extramacular to macular, new or worsening neovascularization of the iris

 

 

Systemic drug-related: hypertension, cardiovascular events, cerebrovascular events

 
 

I. Schedule of Assessment Visits and Examination Procedures

	0	Treatment Visits Every 4-16w*	Non-Annual Assessment Visits†	Annual Visits
Visit Window		(+/- 1w)	(+/- 2 to 4w)	(+/- 4w)
E-ETDRS best corrected visual acuitya	X	X	X	X
Binocular visual acuityb	X			X
Ancillary visual field testingc	X			X
Questionnaires d	X		X	X
OCT e	X	X		X
Eye Examf	X	X	X	X
Fundus Photography g	X			X
Blood pressure	X
HbA1ch	X

*= visits every 4 weeks (w) during the first year for eyes assigned to ranibizumab with deferred PRP; if intravitreal ranibizumab treatment is initiated for DME in either group, additional visits for DME treatment may occur every 4 to 16 weeks as needed.   After one year from initial ranibizumab treatment for PDR or once PRP is given, visits every 4-16 weeks based on disease progression and treatment administered

†=visits at 16(±2), 32(±2), 68(±4), 84(±4), 120(±4), and 136(±4).  For participants who agree to structured follow-up in Years 4 and 5, additional assessment visits at 172(±4), 188(±4), 224(±4), and 240(±4) weeks.

a= both eyes including protocol refraction in the study eye at each visit. Protocol refraction in nonstudy 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.

b = binocular vision test using habitual correction on the Electronic Visual Acuity Tester

c=Humphrey visual field testing (30-2 and 60-4 test patterns; at sites with HVF testing capabilities)

d= only in participants with one study eye; includes NEI VFQ-25, UAB LLQ, and TTO annually only; WPAI at 4w and each subsequent assessment visit

e= study eye only at annual visits for all eyes and at each follow-up visit for eyes in which DME treatment is initiated

f=both eyes at baseline; study eye only at each follow-up visit including slit lamp exam, lens assessment, measurement of intraocular pressure, and dilated ophthalmoscopy; examination of the angle required if NVI or increased intraocular pressure present.

    g= study eye only at baseline, annual visits AND prior to initiating PRP in the deferred group; 7SF or 4WF with additional fields as necessary to capture presence of neovascularization

    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.

 

 

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