JCHR

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1.1  Study Objectives

The objectives of this study are to 1) evaluate and compare visual acuity outcomes over the course of the study of a prompt vitrectomy + PRP regimen and an intravitreous aflibercept  regimen in eyes with VH from PDR for which intervention is deemed necessary, and 2) characterize the follow-up course for the two treatment regimens, including but not limited to post-operative complications for the vitrectomy group, and number of injections needed and percent requiring vitrectomy in the intravitreous aflibercept group. 

1.2  Study Design and Synopsis of Protocol

 

A.    Study Design

• Multi-center randomized clinical trial

 

 

B.    Major Eligibility Criteria

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

o   Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic retinopathy, for which intervention is deemed necessary

·       Note: Prior PRP is neither a requirement nor an exclusion

• Best corrected visual acuity letter score 78 or worse (approximate Snellen equivalent 20/32 or worse) with at least light perception
  • Investigators should use particular caution when considering enrollment of an eye with visual acuity letter score 78 to 69 (approximate Snellen equivalent 20/32 to 20/40) to ensure that the need for vitrectomy and its potential benefits outweigh the potential risks. 
• No evidence of rhegmatogenous retinal detachment or evidence of traction retinal detachment involving or threatening the macula
  • If the density of the hemorrhage precludes a visual assessment on clinical exam to confirm eligibility, then it is recommended that assessment be performed with ultrasound as standard care.

o   No history of vitrectomy

 

C.    Treatment Groups

Eligible eyes, one per participant, will be assigned randomly (1:1) to one of the following groups:

 

1. Intravitreous 2 mg aflibercept injections
2. Prompt vitrectomy + PRP

For the intravitreous aflibercept group, the initial injection must be given on the day of randomization.  Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met (see section 4.3.1).  Vitrectomy and PRP can only be performed if protocol criteria are met (see sections 4.3.2 and 4.3.3).

For the prompt vitrectomy + PRP group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator’s usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage (see section 4.5.2).

 

D.    Sample Size

A minimum of 200 study eyes, one per participant, will be randomized. 

 

E.    Duration of Follow-Up

Primary outcome: 24 weeks

Total duration: 104 weeks

 

F.    Follow-up Schedule

Ø  Outcome Visits:

All participants in both groups will have visits at the following times post-randomization:

·       Year 1: 4, 12, 24, 36, 52 weeks

·       Year 2: 68 weeks, 84 weeks, 104 weeks

 

It is recognized that the time between initial treatment and outcome visits will differ between the two groups due to the timing of the initial treatment; however, the differential timing of treatments is representative of clinical care in which anti-VEGF can be given immediately and vitrectomy would need to be scheduled in advance.  Therefore, the area under the curve analysis will be representative of clinical care based on the time point that the decision is made to intervene. 

 

Ø  Treatment Visits:

·       Participants receiving intravitreous aflibercept also will have treatment assessment visits as often as every 4 weeks, depending on recent treatment administered.

 

Ø  Additional Visits:

·       Participants undergoing vitrectomy will have a study visit 1 week post-vitrectomy for safety evaluation.  Investigators may schedule an initial (e.g. 1 day) post-operative visit earlier as standard care at their discretion.

 

G.   Main Efficacy Outcomes

Treatment Group Comparisons

 

Primary Outcome:  Visual acuity area under the curve between randomization and 24 weeks

Additional Key Outcomes (at 24, 52, and 104 weeks unless otherwise indicated):

·       Visual acuity area under the curve between randomization and 52 and 104 weeks

·       Mean visual acuity at 4, 12, and 24 weeks, and annual visits

·       Percent 20/20 or better, 20/32 or better, 20/40 or better, 20/200 or worse, and 20/800 or worse at 4, 12, and 24 weeks, and annual visits

·       Proportion of eyes with at least 15 and at least 30 letter gains or losses from baseline

·       Rates of recurrent VH on clinical exam

·       Percentage of eyes with retinal neovascularization

·       Mean OCT central subfield thickness

·       Treatment and follow-up costs

·       Mean change in four Workplace Productivity and Activity Impairment Questionnaire (WPAIQ) scales and area under the curve analyses of the Work Productivity Loss and Activity Impairment scales at 4, 12, and 24 weeks, and annual visits

 

Key Outcomes within Treatment Groups

·       Percent undergoing vitrectomy (initial vitrectomy in aflibercept group or repeat vitrectomy in vitrectomy group)

·       Number of aflibercept injections performed

·       Percent receiving PRP (aflibercept group only)

 

The primary outcome of visual acuity area under the curve at 24 weeks was primarily selected for sample size considerations.  The long-term additional key outcomes and within-group outcomes will be equally important as the area under the curve outcome for evaluating the overall follow-up course for these two treatment approaches.  Therefore, publication is not planned until the full 104 week follow-up has closed. 

 

H.   Main Safety Outcomes

Ocular: endophthalmitis, retinal detachment, visually significant cataract, cataract surgery

Systemic: Antiplatelet Trialist Collaboration (APTC) events

I.      Schedule of Study Visits and Procedures

 

	0	1w post-vitrectomy*	Treatment Assessment Visits**	Non-Annual Outcome Visits†	24-Week Visit and Annual visits
Visit window		±3d	±1w	±1 to4w	±4w
E-ETDRS best corrected visual acuitya	X		X	X	X
OCTb	X		X	X	X
Ultrasoundc	X	X	X	X	X
Eye examd	X	X	X	X	X
Blood pressure	X				X
HbA1ce	X				X
Questionnairef	X			X	X
Vitreous/aqueous samplingg	X*

*Vitrectomy group at baseline and aflibercept group if vitrectomy is performed during follow-up

**Every 4 to 16 weeks, as needed, for eyes receiving aflibercept

†At 12, 36, 68 and 84 weeks

a=both eyes including protocol refraction in the study eye only at outcome visits and DME treatment visits and on both eyes 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=study eye only; at annual visits and if evaluating for DME treatment

c= study eye only if needed as part of standard care if the density of the vitreous hemorrhage precludes assessment of retinal detachment.

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

e=can be obtained up to 3 weeks after randomization; does not need to be repeated if HbA1c is available from within the prior 3 months

f= Workplace Productivity and Activity Impairment Questionnaire

g=if investigator has agreed to perform sample collection and participant consents to this ancillary component; participants will be given the option of providing vitreous sample only or both vitreous and aqueous samples at the time of vitrectomy.

 

 

 

 

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