Please select the eligibility criteria that correspond to the clinical trial below.
Title: Comparing the Effectiveness and Costs of Bevacizumab to Ranibizumab in Patients With Diabetic Macular Edema (The BRDME Study)
Brief Summary: The primary objective is to demonstrate the non-inferiority of bevacizumab to ranibizumab in the treatment of patients with DME (OCT central area thickness \> 275 μm) as determined by the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6.


Options:
A: Inclusion Criteria:

* Age ≥ 18 years
* Individuals \<18 years old are not being included because DME is so rare in this age group that the diagnosis of DME 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 and/or World Health Organization criteria (see Procedures Manual for definitions)
* At least one eye meets the following study eye criteria:

  * Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity letter score ≤ 78 (i.e., 20/32 or worse) and ≥ 24 (i.e., 20/320 or better) within eight days of randomization.
  * On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.
  * Diabetic macular edema present on optical coherence tomography (OCT) (central subfield thickness on OCT \>250 µm on Zeiss Stratus or the equivalent on spectral domain OCTs based on gender specific cutoffs), within eight days of randomization.
  * Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (for Zeiss Stratus, standard deviation of center point thickness should be ≤ 10% of the center point thickness and signal strength should be ≥ 6)
  * Media clarity, pupillary dilation, and individual cooperation sufficient for adequate fundus photographs
* Able and willing to provide informed consent.

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 four months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next four 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 at the time of study entry.

  • Note: 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 four months prior to randomization or anticipated use during the study.

  • These drugs cannot be used during the study.
* For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 24 months.
* 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 clinical center during the first 12 months of the study.

The following exclusions apply to the study eye only (i.e., they may be present for the nonstudy eye):

* Macular edema is considered to be due to a cause other than diabetic macular edema.
* An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are the primary cause of the macular edema.
* An ocular condition is present such that, in the opinion of the investigator, visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition).
* An ocular condition is present (other than diabetes) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).
* Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).
* History of an anti-VEGF treatment for DME in the past 12 months or history of any other treatment for DME at any time in the past four months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids).
* Enrollment will be limited to a maximum of 25% of the planned sample size with any history of anti-VEGF treatment for DME. Once this number of eyes has been enrolled, any history of anti-VEGF treatment for DME will be an exclusion criterion.
* History of pan-retinal photocoagulation within four months prior to randomization or anticipated need for pan-retinal photocoagulation in the six months following randomization.
* History of anti-VEGF treatment for a disease other than DME in the past 12 months.
* History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior four months or anticipated within the next six months following randomization.
* History of YAG capsulotomy performed within two months prior to randomization.
* Aphakia.
* Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.
B: Inclusion Criteria:

* Diabetic macular edema with center involvement in at least one eye
* Type 1 or type 2 diabetes mellitus diagnosed 2 years prior to screening
* Laser photocoagulation in the study eye can be withheld for at least 3 months after randomization

Exclusion Criteria:

* Patients with uncontrolled systemic or ocular diseases
* Have any history of any intraocular surgery in the study eye within the past 6 months preceding screening
* Conditions that require chronic concomitant therapy with systemic or topical ocular corticosteroids

Other protocol-defined inclusion/exclusion criteria applied to the study.
C: Inclusion Criteria:

* case with clear media IOP below 23 mm/Hg female after menopause at least for 12 months or had 2 contraceptive roots visual acuity between 20/50 to 20/320

Exclusion Criteria:

* no PRP or N.d YAG laser in past 6 months no intraocular surgery in past 12 months
* CVA in past 12 months blood sugar above 250
* active infection in extraocular adnexa
D: Inclusion Criteria:

1. Male or female patients \> 18 years of age who have signed an informed consent;
2. Patients with Type 1 or Type 2 diabetes mellitus (according to American Diabetes Association or World Health Organization (WHO) guidelines) with glycosylated haemoglobin (HbA1c) less than 12.0% at screening (Visit 1). Patients should be on a dietary, exercise and/or pharmacological program for diabetes. Treatment for diabetes must have been stable for at least 2 months;
3. Patients with visual impairment due to DME (within the EDTRS criteria of clinically significant macular edema) in at least one eye, with a central area thickness \>275 ìm, who are eligible for anti-VEGF treatment according to the investigator. If both eyes are eligible, the one with the worse visual acuity, as assessed at visit 1, will be selected by the investigator as the study eye;
4. BCVA equal or more than 24 and less or equal to 78 letters in the study eye at screening using ETDRS- like visual acuity testing charts at a testing distance of 4 meter (approximate Snellen equivalent of 20/32 to 20/320).

Exclusion Criteria:

1. Women of child-bearing potential.
2. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum pregnancy test (human chorionic gonadotropin \> 5 mIU/ml);
3. Inability to comply with study procedures;
4. Active intraocular inflammation (grade + or above) in either eye at enrolment;
5. Any active infection (e.g., conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis) in either eye at the time of enrolment;
6. History of uveitis in either eye at any time;
7. Structural damage within 600 m of the centre of the macula in the study eye likely to preclude improvement in visual acuity following in the resolution of macular edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), epiretinal membrane involving fovea or organized hard exudate plaques;
8. Uncontrolled glaucoma in the study eye at screening (IOP \> 24 mmHg on medication or according to investigator's judgment);
9. Neovascularization of the iris in the study eye;
10. Evidence of vitreomacular traction in the study eye;
11. Active untreated proliferative diabetic retinopathy in the study eye;
12. Any intraocular surgery in the study eye within 3 months prior to randomization;
13. History of vitrectomy in study eye regardless of time prior to randomization;
14. Planned medical or surgical intervention during the 6 months study period;
15. Panretinal laser photocoagulation in the study eye within 3 months prior to or during the study;
16. Focal/grid laser photocoagulation in the study eye 3 months prior to study entry;
17. Treatment with anti-angiogenic drugs in the study eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, VEGF-Trap, etc.) within 3 months prior to randomization;
18. Use of other investigational drugs at the time of enrolment, or within 3 month or 5 half-lives from enrolment, whichever is longer;
19. History of intravitreal corticosteroids in phakic eye within 18 months prior to randomization or in post-cataract surgery study eye (aphakic or pseudophakic, without damaged posterior capsule) within 4 months prior to randomization;
20. Ocular conditions in the study eye that require chronic concomitant therapy with topical ocular or systemically administered corticosteroids;
21. History of stroke or transient ischemic attack (TIA) within 6 months prior to enrolment;
22. Renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine levels \> 2.0 mg/dl at screening;
23. Blood pressure systolic \> 165 mm Hg or diastolic \> 105 mmHg at screening and randomization;
24. Hypertension or change in antihypertensive treatment within 1 month preceding randomization;
25. Current use of or likely need for systemic medications known to be toxic to the lens, retina or optic nerve, including deferoxamine, chloroquine/hydroxychloroquine (Plaquenil), tamoxifen, phenothiazines and ethambutol;
26. Known hypersensitivity to fluorescein, ranibizumab or bevacizumab or any component thereof or drugs of similar chemical classes;
27. Any type of advanced, severe or unstable disease or its treatment, that may interfere with primary and/or secondary variable evaluations including any medical condition that could be expected to progress, recur, or change to such an extend that it may bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk;
28. Concomitant conditions in the study eye which would, in the opinion of the investigator, prevent the improvement of visual acuity on study treatment;
29. Ocular disorders in the study eye that may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the 6-month study period, including cataract, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., AMD, ocular histoplasmosis, or pathologic myopia).

Answer: D