Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, Double-masked, Multicenter, Randomized, Sham Injection-controlled Study of the Efficacy and Safety of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus
Brief Summary: This study is a Phase III, double-masked, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection in patients with clinically significant macular edema with center involvement (CSME-CI) secondary to diabetes mellitus (Type 1 or 2). This study is identical in design to study NCT00473330 (Protocol ID FVF4170g).

The open-label extension phase of the study was stopped after receiving FDA approval of the study drug (ranibizumab) for diabetic macular edema.


Options:
A: Inclusion Criteria:

* Macular edema associated with diabetic retinopathy
* Decreased visual acuity attributable primarily to DME
* Diagnosis of diabetes mellitus

Exclusion Criteria:

* High risk proliferative diabetic retinopathy
* Cataract surgery within 3 months of Baseline, or any other previous intraocular surgery
* Uncontrolled glaucoma
* Current or history of ocular disease in the study eye other than DME
* Major illness or major surgical procedure within 1 month prior to Day 1
* Uncontrolled blood pressure
* Glycosylated hemoglobin (HbA1c) greater than (\>) 12 percent (%) at screening
* Untreated diabetes mellitus or initiation of oral anti-diabetic medication or insulin within 4 months prior to Day 1
B: Inclusion Criteria:

1. Age \>= 18 years Participants \<18 years old are not being included because proliferative diabetic retinopathy is so rare in this age group that the diagnosis may be questionable.
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:

* 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 4. Able and willing to provide informed consent. 5. Patient is willing and able to undergo vitrectomy within next 2 weeks and the vitrectomy can be scheduled within that time frame.

  6. Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic retinopathy, for which intervention is deemed necessary.
  * Note: Prior panretinal photocoagulation is neither a requirement nor an exclusion.
  * Subhyaloid hemorrhage alone does not make an eye eligible; however, presence of subhyaloid hemorrhage in addition to the criteria above will not preclude participation provided the investigator is comfortable with either treatment regimen.

    7. Immediate vitrectomy not required (investigator and participant are willing to wait at least 4 months to see if hemorrhage clears sufficiently with anti-vascular endothelial growth factor without having to proceed to vitrectomy).

    8. Visual acuity letter score ≤78 (approximate Snellen equivalent 20/32) and at least light perception.

    9. Investigators should use particular caution when considering enrollment of an eye with visual acuity letter score 69 to 78 (approximate Snellen equivalent 20/32 to 20/40) to ensure that the need for vitrectomy and its potential benefits outweigh the potential risks.

Exclusion Criteria:

* A potential participant is not eligible if any of the following exclusion criteria are present:

  1. History of chronic renal failure requiring dialysis (including placement of fistula if performed in preparation for 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. A condition that, in the opinion of the investigator, would preclude participant undergoing elective vitrectomy surgery if indicated during the study.
  5. 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.

     • Note: participants cannot receive another investigational drug while participating in the study.
  6. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine).
  7. Blood pressure \> 180/110 (systolic above 180 or diastolic above 110).
  8. If blood pressure is brought below 180/110 by anti-hypertensive treatment, potential participant can become eligible.
  9. Systemic anti-vascular endothelial growth factor or pro-vascular endothelial growth factor treatment within 4 months prior to randomization.

     • These drugs cannot be used during the study.
  10. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next two years.

      • Women who are potential participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.
  11. Potential participant is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the two years.
  12. Evidence of traction 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.
  13. Evidence of rhegmatogenous retinal detachment.

      • 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.
  14. Evidence of neovascular glaucoma (iris or angle neovascularization is not an exclusion).
  15. Known diabetic macular edema (DME), defined as either
  16. Optical coherence tomography central subfield thickness (microns):
  17. Zeiss Cirrus: ≥290 in women; ≥305 in men
  18. Heidelberg Spectralis: ≥305 in women; ≥320 in men OR
  19. Diabetic macular edema on clinical exam that the investigator believes currently requires treatment.
  20. History of intravitreous anti-vascular endothelial growth factor treatment within 2 months prior to current vitreous hemorrhage onset or after onset.
  21. History of intraocular corticosteroid treatment within 4 months prior to current vitreous hemorrhage onset or after onset.
  22. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or major ocular surgery other than vitrectomy anticipated within the next 6 months following randomization.
  23. History of vitrectomy.
  24. History of YAG capsulotomy performed within 2 months prior to randomization.
  25. Aphakia.
  26. Uncontrolled glaucoma (in investigator's judgment).
  27. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.
C: Inclusion Criteria:

* Willingness to provide written informed consent and, at U.S. sites, Health Insurance Portability and Accountability Act (HIPAA) authorization, and in other countries, as applicable according to national laws.
* Age ≥ 18 years.
* Diabetes mellitus (Type 1 or 2) .
* Retinal thickening secondary to diabetes mellitus (DME) involving the center of the fovea with central macular thickness ≥ 275 µm in the center subfield as assessed on optical coherence tomography (OCT).
* Best corrected visual acuity (BCVA) score in the study eye of 20/40 to 20/320 approximate Snellen equivalent using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at an initial testing distance of 4 meters.
* Decrease in vision determined to be primarily the result of DME and not to other causes.
* For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study.
* Ability (in the opinion of the investigator) and willingness to return for all scheduled visits and assessments.

Exclusion Criteria:

* History of vitreoretinal surgery in the study eye.
* Panretinal photocoagulation (PRP) or macular laser photocoagulation in the study eye within 3 months of screening.
* Previous use of intraocular corticosteroids in the study eye (eg, triamcinolone acetonide \[TA\]) within 3 months of screening.
* Previous treatment with anti-angiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc) within 3 months of the Day 0 (first day of treatment) visit.
* Proliferative diabetic retinopathy (PDR) in the study eye, with the exception of inactive, regressed PDR.
* Iris neovascularization, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula in the study eye.

Concurrent Ocular Conditions

* Vitreomacular traction or epiretinal membrane in the study eye.
* Ocular inflammation (including trace or above) in the study eye.
* History of idiopathic or autoimmune uveitis in either eye.
* Structural damage to the center of the macula in the study eye that is likely to preclude improvement in VA following the resolution of macular edema, including atrophy of the retinal pigment epithelium (RPE), subretinal fibrosis, or organized hard-exudate plaque.
* Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization (CNV) of any cause (eg, age-related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia).
* Concurrent disease in the study eye that would compromise visual acuity or require medical or surgical intervention during the study period.
* Cataract surgery in the study eye within 3 months, yttrium-aluminum-garnet (YAG) laser capsulotomy within the past 2 months, or any other intraocular surgery within the 90 days preceding Day 0.
* Aphakia or absence of the posterior capsule in the study eye.
* Uncontrolled glaucoma or previous filtration surgery in the study eye.
* Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia.
* Evidence at examination of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye or current treatment for serious systemic infection.
* Uncontrolled blood pressure.
* History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0.
* Uncontrolled diabetes mellitus.
* Renal failure requiring dialysis or renal transplant.
* Participation in an investigational trial within 30 days prior to screening that involved treatment with any drug (excluding vitamins and minerals) or device.
* History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use an investigational drug, might affect interpretation of the results of the study, or renders the subject at high risk from treatment complications.
* Pregnancy or lactation.
* History of allergy to fluorescein.
* History of allergy to ranibizumab injection or related molecule.
D: Inclusion Criteria:

1. Diabetic patients older than 18 years
2. Presence of PDR (presence of retinal neovascularization, defined as active neovessels (fine retinal vessels with saccular dilatations or extremities covered with blood or associated with recurrent vitreous hemorrhage) with visual acuity better than 20/800 and with no previous laser treatment
3. Giving written informed consent.

Exclusion Criteria:

1. Presence of advanced PDR, i.e.: vitreous hemorrhage that would prevent documentation of the eye fundus or adequate retinal photocoagulation, or presence of traction retinal detachment
2. Presence of ring-shaped retinal neovascularization extending along both temporal arcades and the optic disc
3. Any abnormality of the vitreoretinal interface in the macular region for which the investigator would consider vitrectomy via pars plana to be necessary
4. Intravitreous injection of corticosteroids or of other antiangiogenic drugs 6 months before the evaluation for entry into the study
5. Inability to fixate and to conclude the automated static perimetry exam
6. Cataract surgery within the last three months
7. Posterior vitrectomy with scleral introflexion at any time
8. Acute ocular infection
9. Allerghy to fluorescein
10. Medical or psychological conditions that would prevent the patient from giving informed consent and concluding the study
11. Significant uncontrolled diseases which, in the opinion of the investigator, would exclude the patient from the study
12. Renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine levels \>2.0 mg/dl
13. Untreated diabetes mellitus
14. Severe (blood pressure systolic \> 160 mmHg or diastolic \> 100 mmHg) AND untreated hypertension
15. Inability to comply with study or follow-up procedures.
16. Impaired or limited legal capacity
17. Participation in another clinical study in the last 30 days.

Answer: C