Clinical trial NCT03531294: Intravitreal Aflibercept as Indicated by Real-Time Objective Imaging to Achieve Diabetic Retinopathy Improvement
Official title: Intravitreal Aflibercept as Indicated by Real-Time Objective Imaging to Achieve Diabetic Retinopathy Improvement
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetic Retinopathy
Lead sponsor: Greater Houston Retina Research
Sponsor class: OTHER
Collaborators: name: Regeneron Pharmaceuticals
name: The Cleveland Clinic
First posted: 2018-05-21
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The PRIME trial will assess the safety of 2 mg intravitreal aflibercept injections (IAI) to achieve and maintain DRSS improvements (2 or more steps) in patients with a baseline DRSS level of 47A to 71A inclusive through 104 weeks as determined by reading center determined DRSS gradings on OPTOS fundus photos and leakage index on OPTOS WF-FA.

Detailed description: Study eyes will be assigned randomly (1:1 ratio) to one of the following 2 treatment arms. Randomization of PDR subjects will be limited to 50% of each arm.

Group 1

Year 1 Subjects will be seen every month, 28 days (+ 7 days), for 52 weeks. All subjects will receive IAI at baseline, after eligibility is confirmed. Week 4 through week 48, subjects will be seen monthly and treated with IAI PRN (pro re nata) according to, same day, central reading center (CRC) determined DRSS level. Monthly treatment with IAI will continue until a greater than or equal to 2 step DRSS level improvement is achieved, relative to screening/baseline DRSS based on CRC assessment OPTOS fundus photos (FP). Subjects who have baseline proliferative diabetic retinopathy (PDR) (DRSS Level 61-71) will continue to receive monthly IAI until a greater than or equal to 2 step DRSS improvement is achieved as determined by CRC assessment of OPTOS fundus photos relative to screening/baseline DRSS, and PDR is quiescent according to the treating investigator. Treatment with IAI will be reinitiated if a 1 step worsening of DRSS occurs compared to best DRSS score achieved, determined by CRC evaluation of OPTOS fundus photos. If such worsening is detected, the subject would resume monthly IAI until best DRSS score or greater is achieved, as determined by CRC assessment of OPTOS fundus photos. In addition, retreatment will also be re-started if new onset neovascularization is identified and is continued until the PDR is quiescent according to the treating investigator.

Year 2 Beginning in year 2 (week 52) subjects will be seen every 56 days (+ 14 days) and treated with IAI PRN (pro re nata) utilizing the same criteria from year 1. All subjects will have a mandatory week 104 visit, where treatment will not be given.

Group 2

Year 1 Subjects will be seen every month, 28 days (+ 7 days), for 52 weeks. All subjects will receive IAI at baseline, after eligibility is confirmed. Week 4 through week 48, subjects will be seen monthly and treated with IAI PRN (pro re nata) according to, same day, CRC determination of DRSS initially, and subsequently of leakage index.

Monthly treatment with IAI will continue until a greater than or equal to 2 step DRSS level improvement is achieved, relative to screening/baseline DRSS based on CRC assessment OPTOS fundus photos (FP). Subjects who have baseline proliferative diabetic retinopathy (PDR) (DRSS Level 61-71) will continue to receive monthly IAI until a greater than or equal to 2 step DRSS improvement is achieved as determined by CRC assessment of OPTOS fundus photos relative to screening/baseline DRSS, and PDR is quiescent according to the treating investigator.

Leakage index as determined by CRC assessment of OPTOS WF-FA at the visit at which a greater than or equal to 2 step DRSS level improvement is achieved will be considered the threshold. Treatment with IAI will be reinitiated if the leakage index increases to 33% above the individual subject threshold leakage index level as determined by CRC evaluation of OPTOS WF-FA. If such worsening is detected, the subject would resume monthly IAI until the threshold leakage index as determined by CRC assessment of OPTOS WF-FA is reached. In addition, retreatment will also be re-started if new onset neovascularization is identified and is continued until the PDR is quiescent according to the treating investigator.

Year 2 Beginning in year 2 (week 52) subjects will be seen every 56 days (+ 14 days) and treated with IAI PRN (pro re nata) utilizing the same criteria from year 1. All subjects will have a mandatory week 104 visit, where treatment will not be given.

If images of insufficient quality are unable to be obtained, in Group 1 or Group 2, subjects will undergo treatment with IAI at principal investigators discretion or designee.

Subjects can have both eyes in the study, if eligibility is met. If both eyes are eligible, one eye will be randomized to group 1 while the other is randomized to group 2. If only one eye is eligible IAI will be provided for the fellow eye as needed according to the treating investigator.

Eligibility criteria: Inclusion Criteria:

1. Men or Women \> 18 years of age with type 1 or II diabetes mellitus
2. Diabetic Retinopathy, DRSS Level 47A to 71A, as assessed by CRC (enrollment of PDR levels will be limited to 50% of the total population)
3. BCVA in the study eye better than 20/800

Exclusion Criteria:

1. Any prior systemic anti-VEGF treatment or IVT anti-search vascular endothelial growth factor (VEGF) treatment in the study eye within 24 weeks of screening/baseline
2. Any intravitreal or peribulbar corticosteroids in the study eye within 12 weeks of screening/baseline
3. Any prior treatment with Ozurdex or Iluvien in the study eye
4. SD-OCT central subfield thickness (CST) \> 320 µm in the study eye
5. Central DME causing visual acuity loss, in which treatment can not be safely deferred for at least 6 months, in the investigator's judgment
6. Current visually significant vitreous hemorrhage in the study eye. Vitreous hemorrhage is allowed as long as DRSS level is 71A or lower.
7. History of panretinal photocoagulation (PRP) in the study eye
8. History of vitrectomy surgery in the study eye
9. Cataract surgery in the study eye within 8 weeks of screening/baseline
10. Pregnant or breast-feeding women
11. Sexually active men\* or women of childbearing potential\*\* who are unwilling to practiceadequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening/baseline; intrauterine device \[IUD\]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly).

    \* Contraception is not required for men with documented vasectomy.

    \*\* Postmenopausal women must be amenorrheic for at least 52 weeks in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
12. If currently receiving diaylisis, must have started treatment more than 12 weeks prior to screening/baseline
13. Uncontrolled blood pressure (defined as \> 190/110 mm Hg systolic/diastolic, while seated)

Primary outcomes:
measure: Incidence of Adverse Events for diabetic retinopathy subjects who receive intravitreal Aflibercept
timeFrame: 104 weeks
Secondary outcomes:
measure: Correlation of DRSS and leakage index
timeFrame: 104 weeks
measure: Correlation between Reading Center DRSS Level and Physician determined DR severity
timeFrame: 104 weeks
measure: Number of IAI
timeFrame: 104 weeks
measure: Mean number of IAI (NPDR VS PDR)
timeFrame: 104 weeks
measure: ETDRS-BCVA change
timeFrame: 104 weeks
measure: Changes in Visual Function
timeFrame: 104 weeks
measure: DRSS Change
timeFrame: 104 weeks
measure: Change in Non-Perfusion
timeFrame: 104 weeks
measure: Change in Vascular Leakage
timeFrame: 104 weeks
measure: Change in microaneurysms
timeFrame: 104 weeks
measure: Change in CST
timeFrame: 104 weeks
measure: DME development
timeFrame: 104 weeks
measure: PDR Development
timeFrame: 104 weeks
measure: Cytokine Levels
timeFrame: 104 weeks
Other outcomes:
Locations:
city: Houston
country: United States
facility: Retina Consultants of Houston/The Medical Center
state: Texas
city: The Woodlands
country: United States
facility: Retina Consultants of Houston
state: Texas
Study officials:
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