Please select the eligibility criteria that correspond to the clinical trial below.
Title: Effects of Fenofibrate on Endothelial Progenitor Cell Levels in Diabetic Patients With Retinopathy. A Randomized Controlled Trial.
Brief Summary: Long-standing diabetes is often complicated by retinopathy. The mechanisms that induce the development of diabetic retinopathy are incompletely understood and include alterations in bone marrow derived vasculogenic cells called "endothelial progenitor cells".

Fenofibrate is a PPAR-alpha agonist used for the treatment of mixed dislipidemia and hypertriglyceridemia. In a trial conducted in type 2 diabetic patients, the drug fenofibrate has reduced retinopathy-related endpoints suggesting a direct effect of the drug on the mechanisms that drive the development of this complication.

Herein, the investigators hypothesize that fenofibrate treatment can increase circulating EPC levels in diabetic patients with retinopathy, compared to placebo.


Options:
A: Key Inclusion Criteria:

1. Men or women ≥18 years of age with type 1 or 2 diabetes mellitus who have moderately severe to severe nonproliferative diabetic retinopathy (NPDR) \[(diabetic retinopathy severity scale (DRSS) levels 47 or 53)\], confirmed by the central reading center, in whom panretinal photocoagulation (PRP) can be safely deferred for at least 6 months per the investigator
2. Best corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in the study eye of ≥69 letters (approximate Snellen equivalent of 20/40 or better)

Key Exclusion Criteria:

1. Presence of diabetic macular edema (DME) threatening the center of the macula in the study eye
2. Evidence of retinal neovascularization on clinical examination or Fluorescein Angiography (FA)
3. Any prior focal or grid laser photocoagulation or any prior PRP in the study eye
4. Any prior systemic anti-vascular endothelial growth factor (VEGF) treatment or intravitreal (IVT) anti-VEGF treatment in the study eye
5. Any prior intraocular steroid injection in the study eye
6. Current anterior segment neovascularization (ASNV), vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye

Note: Other inclusion/ exclusion criteria apply
B: Inclusion Criteria:

* Type 1 or type 2 diabetes
* Diabetic retinopathy
* Age 18-70
* Both sexes

Exclusion Criteria:

* Age \<18 or \>70 at enrollment
* Hereditary muscle disorders
* Uncontrolled hypothyroidism
* Elevated alcohol consumption
* Renal failure
* Hepatic failure
* Allergy to fenofibrate or excipients
* Acute / chronic pancreatitis
* Pregnancy and lactation.
C: 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 digital imaging as judged by the investigator. Reading center grading of less than ETDRS level 43 or greater than 53 is an exclusion.

   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. No evidence 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. No evidence 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.
D: Inclusion Criteria:

Age \>= 18 years -Individuals \< 18 years old are not being included because proliferative diabetic retinopathy (PDR) is so rare in this age group that the diagnosis of PDR may be questionable.

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:

* Current regular use of insulin for the treatment of diabetes
* Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes
* Documented diabetes by American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria (see Procedures Manual for definitions) Able and willing to provide informed consent.

Meets at least all of the following ocular criteria criteria:

* Presence of PDR which the investigator intends to manage with PRP alone but for which PRP can be deferred for at least 4 weeks in the setting of intravitreal ranibizumab, in the investigator's judgment.
* Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score \> 24 (approximate Snellen equivalent 20/320) on the day of randomization.
* Media clarity, pupillary dilation, and study participant cooperation sufficient to administer PRP and obtain adequate fundus photographs and optical coherence tomography (OCT).

  * Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality

Exclusion Criteria:

Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant.

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).

* Individuals in poor glycemic control who, within the last 4 months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 months should not be enrolled.

Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval for the indication being studied.

* Study participants cannot receive another investigational drug while participating in the study.

Known allergy to any component of the study drug.

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.

Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization.

Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

* These drugs should not be used during the study.

For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 3 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.

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 (DRCR.net) certified clinical center during the 3 years of the study.

Individual has any of the following ocular characteristics:

* History of prior panretinal photocoagulation (prior PRP is defined as ≥ 100 burns outside of the posterior pole)
* Tractional retinal detachment involving the macula.

  -- A tractional retinal detachment is not an exclusion if it is outside of the posterior pole (not threatening the macula) and in the investigator's judgment, is not a contraindication to intravitreal ranibizumab treatment and also does not preclude deferring PRP for at least 4 weeks in the setting of intravitreal ranibizumab
* Exam evidence of neovascularization of the angle (neovascularization of the iris alone is not an exclusion if it does not preclude deferring PRP for at least 4 weeks in the investigator's judgment).
* If macular edema is present, it is considered to be primarily due to a cause other than diabetic macular edema.

  -- An eye should not be considered eligible if:
  * macular edema is present that is considered to be related to ocular surgery such as cataract extraction or
  * clinical exam and/or OCT suggest that vitreoretinal interface abnormalities disease (e.g., a taut posterior hyaloid or epiretinal membrane) is the primary cause of any macular edema.
* 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, neovascular glaucoma, etc.).

  -- A vitreous or preretinal hemorrhage is not an exclusion if it is out of the visual axis and in the investigator's judgment is not having any affect on visual acuity.
* Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye were otherwise normal).
* History of intravitreal anti-VEGF treatment at any time in the past 2 months.
* History of corticosteroid treatment (intravitreal or peribulbar) at any time in the past 4 months.

  --If the investigator believes that there may still be a substantial effect 4 months after prior treatment (e.g., dose of intravitreal triamcinolone higher than 4 mg), the eye should not be included.
* History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
* History of (yttrium-aluminum-garnet) YAG capsulotomy performed within 2 months prior to randomization.
* Aphakia.
* Uncontrolled glaucoma (in investigator's judgment).
* Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis

Answer: B