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History of Changes for Study: NCT02634333
Anti-VEGF Treatment for Prevention of PDR/DME
Latest version (submitted October 27, 2021) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 December 15, 2015 None (earliest Version on record)
2 February 19, 2016 Recruitment Status, Study Status, Contacts/Locations, Study Description and Oversight
3 March 22, 2016 Study Status and Contacts/Locations
4 April 25, 2016 Study Status and Contacts/Locations
5 May 13, 2016 Contacts/Locations and Study Status
6 June 14, 2016 Study Status and Contacts/Locations
7 July 14, 2016 Contacts/Locations and Study Status
8 August 25, 2016 Study Status and Study Identification
9 September 8, 2016 Study Status and Eligibility
10 December 9, 2016 Study Status, Contacts/Locations, Sponsor/Collaborators and Study Identification
11 January 19, 2017 Study Status and Contacts/Locations
12 February 16, 2017 Study Status and Contacts/Locations
13 March 16, 2017 Study Status and Contacts/Locations
14 April 20, 2017 Contacts/Locations and Study Status
15 May 18, 2017 Study Status and Contacts/Locations
16 June 14, 2017 Study Status and Contacts/Locations
17 July 20, 2017 Study Status and Contacts/Locations
18 August 22, 2017 Contacts/Locations and Study Status
19 September 29, 2017 Study Status and Contacts/Locations
20 October 16, 2017 Study Status and Eligibility
21 October 27, 2017 Contacts/Locations and Study Status
22 January 25, 2018 Contacts/Locations and Study Status
23 February 23, 2018 Study Status and Contacts/Locations
24 May 9, 2018 Recruitment Status, Study Status, Contacts/Locations and Study Design
25 August 23, 2018 Outcome Measures and Study Status
26 September 20, 2019 Study Status
27 February 10, 2020 Study Status
28 March 30, 2020 Study Status and Contacts/Locations
29 July 22, 2020 Study Status
Show
Results Submission Events
30 October 27, 2021 Study Status, Outcome Measures, Document Section, Results and Study Design
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Study NCT02634333
Submitted Date:  December 15, 2015 (v1)

Open or close this module Study Identification
Unique Protocol ID: DRCR.net Protocol W
Brief Title: Anti-VEGF Treatment for Prevention of PDR/DME
Official Title: Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Secondary IDs:
Open or close this module Study Status
Record Verification: December 2015
Overall Status: Not yet recruiting
Study Start: January 2016
Primary Completion: January 2020 [Anticipated]
Study Completion: January 2022 [Anticipated]
First Submitted: December 11, 2015
First Submitted that
Met QC Criteria:
December 15, 2015
First Posted: December 18, 2015 [Estimate]
Last Update Submitted that
Met QC Criteria:
December 15, 2015
Last Update Posted: December 18, 2015 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: Jaeb Center for Health Research
Responsible Party: Sponsor
Collaborators: Regeneron Pharmaceuticals
Juvenile Diabetes Research Foundation
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary:

Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated with monthly anti-VEGF therapy (RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I), it is unknown whether or not an earlier but less frequent dosing regimen would result in similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in favorable visual acuity outcomes.

If this study demonstrates that intravitreous aflibercept treatment is effective and safe for reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for these complications, a new strategy to prevent vision threatening complications of diabetes will be available for patients. The application of intravitreous aflibercept earlier in the course of disease (i.e., at the time when an eye has baseline severe non-proliferative diabetic retinopathy) could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual outcomes, if PDR and DME are prevented.

The primary objectives of this protocol 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.

Secondary objectives include:

  • Comparing other visual acuity outcomes between treatment groups, such as 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 the consecutive study visit just before and at the 2- or 4-year visit
  • Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT central subfield thickness and volume from baseline
  • Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of diabetic retinopathy severity level (scale for individual eyes) by central reading center from baseline
  • Comparing associated treatment and follow-up exam costs between treatment groups
  • Comparing safety outcomes between treatment groups
Detailed Description:
Open or close this module Conditions
Conditions: Diabetic Retinopathy
Diabetic Macular Edema
Keywords: anti-vascular endothelial growth factor
nonproliferative diabetic retinopathy
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Prevention
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: Double (Participant, Outcomes Assessor)
Allocation: Randomized
Enrollment: 322 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Sham Comparator: Observation (Prompt Sham)
Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Procedure: Prompt Sham
A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Procedure: Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Other Names:
  • focal/grid photocoagulation
  • panretinal photocoagulation
Drug: Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea
Experimental: Prompt aflibercept
Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Drug: Prompt aflibercept
Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea
Procedure: Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Other Names:
  • focal/grid photocoagulation
  • panretinal photocoagulation
Drug: Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Cumulative probability of any of the following events (i.e. once an eye meets any one of the events, it will be considered to have met the primary outcome):
[ Time Frame: 2 years ]

  • Development of neovascularization (NV) on fundus photography or fluorescein angiogram
  • NV of the iris, definitive NV of the angle, or neovascular glaucoma development on clinical exam
  • Other outcomes from proliferative diabetic retinopathy (PDR) including: traction retinal detachment, vitreous hemorrhage, pre-retinal hemorrhage greater than ½ disc area
  • Procedures for the treatment of PDR: panretinal photocoagulation, anti-vascular endothelial growth factor, or vitrectomy
  • Center-involved diabetic macular edema on clinical exam with ≥10% increase in central subfield thickness from baseline and either 1) at least 10 letter decrease in visual acuity (VA) from baseline at a single visit or 2) 5 to 9 letter decrease in VA from baseline at 2-consecutive visits at least 21 days apart, from DME
  • Non-topical treatment for DME performed without meeting above criteria, including focal or grid laser or intravitreous injections
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Age >= 18 years
  2. Diagnosis of diabetes mellitus (type 1 or type 2)

    • Any one of the following will be considered to be sufficient evidence that diabetes is present:

    1. Current regular use of insulin for the treatment of diabetes
    2. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes
    3. Documented diabetes by American Diabetes Association and/or World Health Organization criteria
  3. Able and willing to provide informed consent.

Meets all of the following ocular criteria in at least one eye:

  1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)
  2. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evident on clinical examination and on 7-modified field or 4-wide field digital fundus photographs as judged by the investigator, confirmed by central Reading Center fundus photograph grading prior to randomization as ETDRS level 47B to 53E. Severe NPDR is defined as:
    1. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages), or
    2. At least 2 fields of definite venous beading in the midperipheral quadrants or at least 1 field at least as severe as Standard photograph 6A, or
    3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A
  3. Absence of neovascularization on clinical exam including active neovascularization of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is assessed).
  4. Absence of neovascularization (NV) on fluorescein angiography within the 7-modified ETDRS fields, confirmed by the central Reading Center prior to randomization.

    • The widest method of imaging available at the site must be used to document whether there is NV present in the periphery; however, presence of NV outside of the 7-modified ETDRS fields on ultrawide field imaging will not be an exclusion provided treatment is not planned.

  5. No center-involved diabetic macular edema (CI-DME) on clinical exam and optical coherence tomography (OCT) central subfield thickness must be below the following gender and OCT-machine specific thresholds:
    1. Zeiss Cirrus: 290 µm in women and 305 µm in men
    2. Heidelberg Spectralis: 305 µm in women and 320 µm in men
    3. Investigator and potential participant are comfortable withholding treatment for DME until there is at least a 10% increase in OCT central subfield thickness with confirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at two consecutive visits).
  6. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) treatment not required AND investigator and potential participant are willing to wait for development of high-risk characteristics (defined in protocol) to treat PDR.
  7. Media clarity, pupillary dilation, and study participant cooperation sufficient to obtain adequate fundus photographs, fluorescein angiogram, and OCT.
    • Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (including segmentation line placement)

Exclusion Criteria:

  1. History of chronic renal failure requiring dialysis or kidney transplant.
  2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).
  3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.
  4. Participation in an investigational trial that involved treatment within 30 days of randomization with any drug that has not received regulatory approval for the indication being studied.

    • Note: study participants cannot participate in another investigational trial that involves treatment with an investigational drug while participating in the study.

  5. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).
  6. Known allergy to fluorescein dye.
  7. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). • If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become eligible.
  8. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

    • These drugs should not be used during the study.

  9. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 2 years.

    • Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.

  10. Individual is expecting to move out of the area of the clinical center to an area not covered by another Diabetic Retinopathy Clinical Research Network certified clinical center during the next 2 years.

Individual has any of the following ocular characteristics in the eye(s) being evaluated:

  1. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
  2. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
  3. History of prior PRP (defined as ≥100 burns outside of the posterior pole).
  4. An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, vitreomacular traction, etc.).
  5. History of DME or diabetic retinopathy 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.

    • Enrollment will be limited to a maximum of 25% of the planned sample size with any history of treatment for DME and/or diabetic retinopathy. Once this number of eyes has been enrolled, any history of treatment for DME and/or diabetic retinopathy will be an exclusion criterion.

  6. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
  7. Any history of vitrectomy.
  8. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.
  9. Aphakia.
  10. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.
  11. Evidence of uncontrolled glaucoma.
    • Intraocular pressure must be <30, with no more than one topical glaucoma medication, and no documented glaucomatous field loss for the eye to be eligible.
Open or close this module Contacts/Locations
Locations:
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Links:
Available IPD/Information:

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