TREX-DME: A Safety and Efficacy Trial of a Treat and Extend Protocol Using Ranibizumab With and Without Laser Photocoagulation for Diabetic Macular Edema

• Sponsor: Palmetto Retina Center, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT01934556
• Collaborator: (none)
• Enrollment: 150
• Locations: 3
• Arms: 3
• Duration (Months): 53
• Patients Per Site: 50
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine if a "Treat and Extend" regimen (increasing the time between visits when the disease is stable and not getting worse) of Ranibizumab 0.3 mg injections inside the eye is safe and effective at treating patients with swelling of the retina from diabetes.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: Ranibizumab 0.3 mg intravitreal injection; Device: Guided Laser Photocoagulation	Phase 1/Phase 2

Detailed Description

This research study will compare the visual outcomes between a group of patients who are treated with monthly injections of Ranibizumab 0.3 mg and two groups of patients who are treated with the "Treat and Extend" regimen. One of the "Treat and Extend" groups will also receive laser therapy to determine if this has any additional beneficial effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Open Label, Multicenter, Randomized, Controlled Study of the Safety, Tolerability and Efficacy of Intravitreal Injections of 0.3 mg Ranibizumab Given Monthly Compared to a TReat and EXtend Protocol in Patients With Diabetic Macular Edema
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: Apr 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Monthly Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months.	Drug: Ranibizumab 0.3 mg intravitreal injection; Other Names: Ranibizumab Lucentis
Active Comparator: TREX (60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.	Drug: Ranibizumab 0.3 mg intravitreal injection; Other Names: Ranibizumab Lucentis
Active Comparator: GILA (60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.	Drug: Ranibizumab 0.3 mg intravitreal injection; Other Names: Ranibizumab Lucentis ; Device: Guided Laser Photocoagulation; Other Names: NAVILAS Guided Laser System

Outcome Measures

Primary Outcome Measures

1. Mean Change in Vision at 24 Months [2 Years]

   Mean change in ETDRS (Early Treatment in Diabetic Retinopathy Study) visual acuity at 24 months (week 92-week 107) from Day 0. Visual function of the study eye was assessed using the ETDRS protocol, which is a widely accepted international standard. A higher letter score represents better functioning"

Secondary Outcome Measures

1. Number of Participants With Adverse Events [2 years]

   Number of Participants with Adverse Events, ocular and non-ocular, in each of the study groups

2. Number of Intravitreal Injections [2 years]

   Total number of intravitreal injections required during the first 12 months (week 46 - week 57) and the entire 24-month (week 92 - week 107) study period.

3. Number of Office Visits [2 years]

   Total number of office visits and imaging studies performed during the first 12 months (week 46 - week 57) and the entire 24-month (week 92 - week 107) study period.

4. Change in Retinal Thickness [2 years]

   Mean change in central foveal thickness per SDOCT (Spectral Domain Optical Coherence Tomography) from randomization to 12 months (week46 - week 57) and randomization to 24 months (week 92 - week 107) study period.Change at month 24 reported.

5. Percentage of Eyes Gaining or Losing Vision [2 years]

   Percentage of eyes gaining or losing 3 lines of vision or more and 1 line of vision at 24 months (week 92 - week 107) from Day 0.

6. Percentage of Eyes Which Progress to Proliferative Diabetic Retinopathy [2 years]

   The percentage of eyes which show progression of proliferative diabetic retinopathy requiring panretinal photocoagulation and/or pars plana vitrectomy over the 24-month study period.

7. Percentage of Eyes Able to Begin Extension Phase Prior to Week 104 End-point Visit. [2 years]

   The percentage of eyes in the TREX (Treat and Extend) and GILA (Guided Laser) cohorts who are eligible to begin the extension phase prior to week 104 end-point visit.

8. Percentage of Eyes With a Secondary or Tertiary Baseline Retinal Thickness [2 years]

   For TREX and GILA Cohorts, the time to achieve a "Secondary or Tertiary Baseline" retinal thickness.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ability to provide written informed consent and comply with study assessments for the full duration of the study

• Age > 18 years of age Patient related considerations

• For sexually active women of childbearing potential, agreement to the use of an appropriate form of contraception (or abstinence) for the duration of the study

• Although no birth control method is 100% effective, the following are considered effective means of contraception: surgical sterilization, use of oral contraceptives, barrier contraception using either a condom or diaphragm with spermicidal gel, an intrauterine device, or contraceptive hormone implant or patch. A patient's primary care physician, obstetrician, or gynecologist should be consulted regarding an appropriate form of birth control.

• Ability and willingness to return for all scheduled visits and assessments

Disease related considerations

• The presence of center-involving diabetic macular edema on clinical exam and SDOCT

• Best corrected visual acuity in the study eye, using ETDRS testing, between 20/25 and 20/320 (Snellen equivalent), inclusive.

• Clear ocular media and adequate pupillary dilation to permit good quality fundus imaging.

Exclusion Criteria:

• General Exclusion Criteria

• Pregnancy (positive urine pregnancy test) or lactation.

• Premenopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization or use of oral contraceptives, barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel, an IUD (Intrauterine Device) , or contraceptive hormone implant or patch.

• Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated

• Participation in another simultaneous medical investigation or trial

Ocular Exclusion Criteria Prior Ocular Treatment

• History of active proliferative diabetic retinopathy in the study eye on clinical exam

• History of vitrectomy surgery, submacular surgery, or other intraocular surgical intervention for diabetic macular edema in the study eye

• Any previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection, anti-VEGF drugs including ranibizumab, or device implantation) in the study eye within 90 days of the screening visit.

• History of prior laser macular photocoagulation more than 90 days prior to screening will be eligible for study inclusion. However, if the investigator does not feel that additional laser photocoagulation can be safely performed or would benefit the patient, then the eye in consideration will be excluded.

• Evidence of vitreomacular interface abnormality or epiretinal membranes which may be responsible for macular edema

Concurrent Ocular Conditions

• Any concurrent intraocular condition in the study eye (e.g., cataract or macular degeneration) that, in the opinion of the investigator, could either: Require medical or surgical intervention during the 24-month study period to prevent or treat visual loss that might result from that condition; or if allowed to progress untreated, could likely contribute to loss of at least 2 Snellen equivalent lines of BCVA (Best Corrected Visual Acuity) over the 24-month study period.

• Active intraocular inflammation (grade trace or above) in the study eye

• Current vitreous hemorrhage in the study eye

• History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study eye

• Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

• Aphakia or absence of the posterior capsule in the study eye

• Intraocular surgery (including cataract surgery) in the study eye within 3 months preceding Day 0

• Uncontrolled glaucoma in the study eye (defined as IOP (Intraocular Pressure) ≥ 30 mmHg despite treatment with anti-glaucoma medication)

• History of glaucoma-filtering surgery in the study eye

• History of corneal transplant in the study eye

• History of pars plana vitrectomy

Concurrent Systemic Conditions

• Any history of use of systemic anti-VEGF (Vascular Endothelial Growth Factor) agents

• Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110 mmHg while patient is sitting) If a patient's initial reading exceeds these values, a second reading may be taken 30 or more minutes later. If the patient's blood pressure needs to be controlled by antihypertensive medication, the patient can become eligible if medication is taken continuously for at least 30 days prior to Day 0.

• Atrial fibrillation not managed by patient's primary care physician or cardiologist within 3 months of screening visit

• Women of childbearing potential not using adequate contraception (as defined in the inclusion criteria).

A woman is considered not to be of childbearing potential if she is postmenopausal, defined by amenorrhea for at least 1 year in a woman > 45 years old; or has undergone hysterectomy and/or bilateral oophorectomy.

• History of stroke within the last 3 months of screening visit

• 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 or that might affect interpretation of the results of the study or renders the patient at high risk for treatment complications

• Current treatment for active systemic infection

• Active malignancy

• History of allergy to fluorescein, not amenable to treatment

• Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded by the reading center

• Inability to comply with study or follow-up procedures

• Previous participation in any studies of investigational drugs within 1 month preceding Day 0 (excluding vitamins and minerals)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retina-Vitreous Associates Medical Group	Beverly Hills	California	United States	90211
2	Palmetto Retina Center	West Columbia	South Carolina	United States	29169
3	Retina Consultants of Houston	Houston	Texas	United States	77030

Sponsors and Collaborators

• Palmetto Retina Center, LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 23, 2015
• Informed Consent Form - Aug 27, 2015

More Information

Publications

None provided.

• Responsible Party: Palmetto Retina Center, LLC
• ClinicalTrials.gov Identifier: NCT01934556
• Other Study ID Numbers: ML28724
• First Posted: Sep 4, 2013
• Last Update Posted: Nov 17, 2020
• Last Verified: Oct 1, 2020

• Additional relevant MeSH terms: Macular Edema; Edema; Ranibizumab

Study Results

Participant Flow

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months.	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits and then underwent a treat and extend protocol of ranibizumab without navigated laser therapy.	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits and then underwent a treat and extend protocol of ranibizumab with navigated laser therapy.
Period Title: Overall Study
STARTED	30	60	60
COMPLETED	25	44	50
NOT COMPLETED	5	16	10

Baseline Characteristics

Arm/Group Title	Monthly	TREX	GILA	Total
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.	Total of all reporting groups
Overall Participants	30	60	60	150
Overall Eyes	30	60	60	150
Age (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	58.7	59.4	59.9	59.5
Sex: Female, Male (Count of Participants)
Female	16 53.3%	32 53.3%	24 40%	72 48%
Male	14 46.7%	28 46.7%	36 60%	78 52%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.7%	0 0%	1 0.7%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	12 40%	21 35%	18 30%	51 34%
White	12 40%	31 51.7%	31 51.7%	74 49.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	6 20%	7 11.7%	11 18.3%	24 16%
Region of Enrollment (participants) [Number]
United States	30 100%	60 100%	60 100%	150 100%
Body-Mass Index (Units of measure "kg/m^2") [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Units of measure "kg/m^2"]	32.2	31.9	30.9	31.6
Mean Duration of Diabetes (Years) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [Years]	15	13.5	13.5	14
Phakic Status (participants) [Number]
Number [participants]	23 76.7%	48 80%	46 76.7%	117 78%
Mean Best Corrected Visual Acuity (ETDRS Letters) (units on a scale) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [units on a scale]	67.5	65.5	67.0	66.5
Central Retinal Thickness (microns) (Microns) [Number]
Number [Microns]	415	452	484	452

Outcome Measures

1. Primary Outcome

Title	Mean Change in Vision at 24 Months
Description	Mean change in ETDRS (Early Treatment in Diabetic Retinopathy Study) visual acuity at 24 months (week 92-week 107) from Day 0. Visual function of the study eye was assessed using the ETDRS protocol, which is a widely accepted international standard. A higher letter score represents better functioning"
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

For those lost to follow-up, last observation carried forward

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Median (Inter-Quartile Range) [units on a scale]	72.5	75.0	75.0

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Number of Participants with Adverse Events, ocular and non-ocular, in each of the study groups
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Ocular Adverse Events : Blepharitis	0 0%	1 1.7%	0 0%
Ocular Adverse Events : Blurred Vision/Vision Loss	1 3.3%	6 10%	5 8.3%
Ocular Adverse Events : Cataract Progression	1 3.3%	5 8.3%	7 11.7%
Ocular Adverse Events : Chalazion	2 6.7%	0 0%	1 1.7%
Ocular Adverse Events : Conjunctivitis	1 3.3%	0 0%	1 1.7%
Ocular Adverse Events : Conjunctival hemorrhage	0 0%	2 3.3%	2 3.3%
Ocular Adverse Events : Corneal Abrasion	0 0%	0 0%	1 1.7%
Ocular Adverse Events : Corneal Edema	0 0%	2 3.3%	0 0%
Ocular Adverse Events : Diplopia	0 0%	0 0%	1 1.7%
Ocular Adverse Events : Dysphotopsia	0 0%	1 1.7%	0 0%
Ocular Adverse Events : Elevated IOP	3 10%	4 6.7%	3 5%
Ocular Adverse Events : Epiretinal Membrane	1 3.3%	1 1.7%	1 1.7%
Ocular Adverse Events : Eye discomfort/discharge	6 20%	9 15%	15 25%
Ocular Adverse Events : Eyelid Swelling	0 0%	3 5%	0 0%
Ocular Adverse Events : Glaucoma Progression	0 0%	1 1.7%	1 1.7%
Ocular Adverse Events : Hollenhorst Plaque	0 0%	1 1.7%	0 0%
Ocular Adverse Events : Macular Hole	0 0%	1 1.7%	0 0%
Ocular Adverse Events : Optic Neuropathy	1 3.3%	2 3.3%	0 0%
Ocular Adverse Events : Photophobia	0 0%	1 1.7%	0 0%
Ocular Adverse Events : Pingueculum	1 3.3%	0 0%	0 0%
Ocular Adverse Events : Secondary Cataract	3 10%	2 3.3%	2 3.3%
Ocular Adverse Events : Vitreous floaters	7 23.3%	6 10%	7 11.7%
Ocular Adverse Events : Punctate Keratitis	2 6.7%	3 5%	6 10%
Ocular Adverse Events : Retinal Hemorrhage	0 0%	1 1.7%	0 0%
Ocular Adverse Events : Vitreomacular Traction	1 3.3%	1 1.7%	0 0%
Ocular Adverse Events : Vitreous Hemorrhage	0 0%	4 6.7%	1 1.7%
Ocular Adverse Events : Vitritis	0 0%	1 1.7%	0 0%
Ocular Adverse Events : Worsening Retinopathy	1 3.3%	2 3.3%	2 3.3%
Nonocular AE: Acute Myocardial Infarction	0 0%	5 8.3%	2 3.3%
Nonocular AE: Angina Pectoris	0 0%	0 0%	5 8.3%
Nonocular AE: Arrhythmia	2 6.7%	1 1.7%	3 5%
Nonocular AE: Cardiomyopathy	0 0%	1 1.7%	0 0%
Nonocular AE: Congestive Heart Failure	0 0%	2 3.3%	4 6.7%
Nonocular AE: Coronary Artery Disease	0 0%	2 3.3%	2 3.3%
Nonocular AE: Pericardial Effusion	0 0%	0 0%	1 1.7%
Nonocular AE: Peripheral Edema	1 3.3%	6 10%	8 13.3%
Nonocular AE: Constipation	0 0%	2 3.3%	2 3.3%
Nonocular AE: Diverticulitis	1 3.3%	1 1.7%	0 0%
Nonocular AE: Diarrhea	2 6.7%	0 0%	1 1.7%
Nonocular AE: Elevated liver enzymes	1 3.3%	0 0%	0 0%
Nonocular AE: Nausea/emesis	1 3.3%	1 1.7%	2 3.3%
Nonocular AE: Gallstones	1 3.3%	1 1.7%	3 5%
Nonocular AE: Esophageal Reflux	2 6.7%	4 6.7%	3 5%
Nonocular AE: Hemorrhoids	1 3.3%	1 1.7%	0 0%
Nonocular AE: Incontinence	1 3.3%	0 0%	0 0%
Nonocular AE: Poor dentition	2 6.7%	3 5%	3 5%
Nonocular AE: Throat Irritation	3 10%	1 1.7%	1 1.7%
Nonocular AE: Anemia	1 3.3%	4 6.7%	7 11.7%
Nonocular AE: Hematoma	1 3.3%	0 0%	0 0%
Nonocular AE: Thrombocytopenia	0 0%	0 0%	1 1.7%
Nonocular AE: Allergy	5 16.7%	9 15%	5 8.3%
Nonocular AE: Appendicitis	1 3.3%	0 0%	0 0%
Nonocular AE: Epistaxis	1 3.3%	0 0%	1 1.7%
Nonocular AE: Fever	2 6.7%	2 3.3%	1 1.7%
Nonocular AE: Gastrointestinal infection	1 3.3%	3 5%	4 6.7%
Nonocular AE: Parotitis	0 0%	0 0%	1 1.7%
Nonocular AE: Skin Infection	6 20%	18 30%	20 33.3%
Nonocular AE: Respiratory Infection	12 40%	22 36.7%	14 23.3%
Nonocular AE: Sinusitis	5 16.7%	9 15%	3 5%
Nonocular AE: Urinary Tract Infection	4 13.3%	2 3.3%	1 1.7%
Nonocular AE: Elevated Creatinine	0 0%	0 0%	2 3.3%
Nonocular AE: Fatigue	3 10%	1 1.7%	0 0%
Nonocular AE: Graves disease	1 3.3%	0 0%	0 0%
Nonocular AE: Hyperammonemia	1 3.3%	0 0%	0 0%
Nonocular AE: Hypo/hyperglycemia	7 23.3%	12 20%	14 23.3%
Nonocular AE: Hyperlipidemia	5 16.7%	4 6.7%	6 10%
Nonocular AE: Hypo/hypercalcemia	0 0%	0 0%	1 1.7%
Nonocular AE: Hypo/hyperkalemia	0 0%	1 1.7%	5 8.3%
Nonocular AE: Hypothyroidism/nodule	1 3.3%	1 1.7%	0 0%
Nonocular AE: Hyperparathyroidism	0 0%	0 0%	1 1.7%
Nonocular AE: Hyperphosphatemia	0 0%	0 0%	2 3.3%
Nonocular AE: Hyperuricemia	0 0%	0 0%	1 1.7%
Nonocular AE: Testosterone deficiency	2 6.7%	1 1.7%	0 0%
Nonocular AE: Vitamin D Deficiency	1 3.3%	3 5%	2 3.3%
Nonocular AE: Weight Gain	1 3.3%	1 1.7%	0 0%
Nonocular AE: Arthritis	1 3.3%	1 1.7%	1 1.7%
Nonocular AE: Fractured Bone	2 6.7%	3 5%	9 15%
Nonocular AE: Hernia	0 0%	0 0%	1 1.7%
Nonocular AE: Musculoskeletal Pain	12 40%	16 26.7%	18 30%
Nonocular AE: Osteoporosis	0 0%	0 0%	1 1.7%
Nonocular AE: Skin burn	2 6.7%	2 3.3%	1 1.7%
Nonocular AE: Colon Cancer	1 3.3%	3 5%	1 1.7%
Nonocular AE: Lung Cancer	1 3.3%	0 0%	1 1.7%
Nonocular AE: Prostate Cancer	0 0%	1 1.7%	0 0%
Nonocular AE: Skin Cancer	1 3.3%	0 0%	2 3.3%
Nonocular AE: Cranial Nerve Palsy	0 0%	0 0%	2 3.3%
Nonocular AE: Cerebrovascular Accident	0 0%	0 0%	3 5%
Nonocular AE: Decreased Hearing	0 0%	1 1.7%	1 1.7%
Nonocular AE: Depression/Anxiety	0 0%	1 1.7%	3 5%
Nonocular AE: Dizziness	1 3.3%	3 5%	1 1.7%
Nonocular AE: Headache	6 20%	1 1.7%	3 5%
Nonocular AE: Insomnia	7 23.3%	7 11.7%	0 0%
Nonocular AE: Neuropathy	1 3.3%	0 0%	1 1.7%
Nonocular AE: Paresthesia	2 6.7%	1 1.7%	1 1.7%
Nonocular AE: Syncope/Presyncope	1 3.3%	2 3.3%	2 3.3%
Nonocular AE: Seizure	0 0%	1 1.7%	0 0%
Nonocular AE: Tinnitus	0 0%	1 1.7%	1 1.7%
Nonocular AE: Transient Ischemic Attack	0 0%	0 0%	1 1.7%
Nonocular AE: Kidney Stone	1 3.3%	2 3.3%	1 1.7%
Nonocular AE: Renal Insufficiency	1 3.3%	1 1.7%	6 10%
Nonocular AE: Acute Respiratory Failure	1 3.3%	1 1.7%	1 1.7%
Nonocular AE: Cough	2 6.7%	5 8.3%	5 8.3%
Nonocular AE: Dyspnea	0 0%	2 3.3%	2 3.3%
Nonocular AE: Lung Nodule	0 0%	1 1.7%	0 0%
Nonocular AE: Pneumonia	2 6.7%	4 6.7%	3 5%
Nonocular AE: Pulmonary Embolism	0 0%	0 0%	1 1.7%
Nonocular AE: Rhinorrhea	0 0%	0 0%	1 1.7%
Nonocular AE: Sleep apnea	0 0%	0 0%	1 1.7%
Nonocular AE: Orthostatic Hypotension	0 0%	1 1.7%	0 0%
Nonocular AE: Peripheral Vascular Disease	0 0%	0 0%	1 1.7%
Nonocular AE: Worsening Hypertension	10 33.3%	21 35%	26 43.3%

3. Secondary Outcome

Title	Number of Intravitreal Injections
Description	Total number of intravitreal injections required during the first 12 months (week 46 - week 57) and the entire 24-month (week 92 - week 107) study period.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Multiple imputation model for eyes lost to follow-up prior to week 104 visit.

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Median (Inter-Quartile Range) [Injections]	25.0	19.0	17.0

4. Secondary Outcome

Title	Number of Office Visits
Description	Total number of office visits and imaging studies performed during the first 12 months (week 46 - week 57) and the entire 24-month (week 92 - week 107) study period.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Multiple imputation model for eyes not reaching week 104 end-point visit.

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Median (Inter-Quartile Range) [Visits]	25.0	19.0	17.0

5. Secondary Outcome

Title	Change in Retinal Thickness
Description	Mean change in central foveal thickness per SDOCT (Spectral Domain Optical Coherence Tomography) from randomization to 12 months (week46 - week 57) and randomization to 24 months (week 92 - week 107) study period.Change at month 24 reported.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

For those not reaching week 104 end-point, last observation carried forward

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Median (Inter-Quartile Range) [Microns]	149	151	196

6. Secondary Outcome

Title	Percentage of Eyes Gaining or Losing Vision
Description	Percentage of eyes gaining or losing 3 lines of vision or more and 1 line of vision at 24 months (week 92 - week 107) from Day 0.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Measure Eyes	30	60	60
1-line vision gainers	13	28	32
1-line vision losers	5	1	3
3-line vision gainers	6	12	15
3-line vision losers	0	0	0

7. Secondary Outcome

Title	Percentage of Eyes Which Progress to Proliferative Diabetic Retinopathy
Description	The percentage of eyes which show progression of proliferative diabetic retinopathy requiring panretinal photocoagulation and/or pars plana vitrectomy over the 24-month study period.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Measure Eyes	30	60	60
Count of Units [Eyes]	1	2	2

8. Secondary Outcome

Title	Percentage of Eyes Able to Begin Extension Phase Prior to Week 104 End-point Visit.
Description	The percentage of eyes in the TREX (Treat and Extend) and GILA (Guided Laser) cohorts who are eligible to begin the extension phase prior to week 104 end-point visit.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Measure Eyes	30	60	60
Count of Units [Eyes]	0	49	55

9. Secondary Outcome

Title	Percentage of Eyes With a Secondary or Tertiary Baseline Retinal Thickness
Description	For TREX and GILA Cohorts, the time to achieve a "Secondary or Tertiary Baseline" retinal thickness.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Monthly	TREX	GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection	(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
Measure Participants	30	60	60
Measure Eyes	30	60	60
Count of Units [Eyes]	0	2	2

Adverse Events

Time Frame	2 years
Arm/Group Title	Monthly		TREX		GILA
Arm/Group Description	Monthly Cohort (30 eyes) - Study eyes will receive intravitreal injections of 0.3 mg ranibizumab every 4 weeks for 24 months. Ranibizumab 0.3 mg intravitreal injection		(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits. At the fourth visit (Week 12), if the central foveal thickness is ≤ 325 μm then the eye will receive 0.3 mg ranibizumab and begin the extension phase of the study. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD (Spectral Domain)-OCT criteria. Treatment is rendered at every visit. The time between visits is individualized based on each subject's response to treatment. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study. Ranibizumab 0.3 mg intravitreal injection		(60 eyes) - Monthly intravitreal injections of 0.3 mg ranibizumab for four visits combined with guided laser photocoagulation to all microaneurysms in the area of DME at visit 2 (Week 4) and then again every 3 months, if leakage is present on fluorescein angiography. If the central foveal thickness is ≤ 325 μm at visit 4 (Week 12), eyes will receive 0.3 mg ranibizumab and the extension phase will begin. For all subsequent visits in the extension phase, appropriate changes to the treatment interval with 0.3 mg ranibizumab (i.e. extend, maintain, reduce) will be made based on pre-specified SD-Optical coherence tomography criteria. If the central foveal thickness is > 325 μm at week 12, then the patient will continue to receive monthly intravitreal injections of 0.3 mg ranibizumab and possible guided laser every 3 months until the central foveal thickness is ≤ 325 μm. Once the central foveal thickness is ≤ 325 μm, then the study eye will begin the extension phase of the study.
All Cause Mortality
	Monthly		TREX		GILA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		5/60 (8.3%)		2/60 (3.3%)
Serious Adverse Events
	Monthly		TREX		GILA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/30 (36.7%)		30/60 (50%)		46/60 (76.7%)
Blood and lymphatic system disorders
Hematoma	1/30 (3.3%)	1	0/60 (0%)	0	0/60 (0%)	0
Thrombocytopenia	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Cardiac disorders
Myocardial Infarction	0/30 (0%)	0	4/60 (6.7%)	4	2/60 (3.3%)	2
Angina Pectoris	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Cardiac Arrhythmia	1/30 (3.3%)	1	0/60 (0%)	0	1/60 (1.7%)	1
Cardiomyopathy	0/30 (0%)	0	1/60 (1.7%)	1	0/60 (0%)	0
Congestive Heart Failure	0/30 (0%)	0	2/60 (3.3%)	2	4/60 (6.7%)	4
Coronary Artery Disease	0/30 (0%)	0	1/60 (1.7%)	1	1/60 (1.7%)	1
Pericardial Effusion	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Endocrine disorders
Hypo/Hyperglycemia	0/30 (0%)	0	2/60 (3.3%)	2	2/60 (3.3%)	2
Eye disorders
Vitreous Hemorrhage	0/30 (0%)	0	1/60 (1.7%)	1	0/60 (0%)	0
Gastrointestinal disorders
Appendicitis	1/30 (3.3%)	1	0/60 (0%)	0	0/60 (0%)	0
Hepatobiliary disorders
Gallstones	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Immune system disorders
Allergy	1/30 (3.3%)	1	0/60 (0%)	0	0/60 (0%)	0
Infections and infestations
Gastrointestinal Infection	0/30 (0%)	0	1/60 (1.7%)	1	1/60 (1.7%)	1
Parotitis	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Respiratory Infection	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Skin/Soft Tissue Infection	1/30 (3.3%)	1	3/60 (5%)	3	4/60 (6.7%)	4
Urinary Tract Infection	0/30 (0%)	0	1/60 (1.7%)	1	0/60 (0%)	0
Injury, poisoning and procedural complications
Fractured Bone	0/30 (0%)	0	1/60 (1.7%)	1	2/60 (3.3%)	2
Metabolism and nutrition disorders
Elevated Creatinine	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Hyperammonemia	1/30 (3.3%)	1	0/60 (0%)	0	0/60 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/30 (3.3%)	1	0/60 (0%)	0	0/60 (0%)	0
Musculoskeletal Pain	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	0/30 (0%)	0	1/60 (1.7%)	1	1/60 (1.7%)	1
Lung Cancer	1/30 (3.3%)	1	0/60 (0%)	0	1/60 (1.7%)	1
Prostate Cancer	0/30 (0%)	0	1/60 (1.7%)	1	0/60 (0%)	0
Nervous system disorders
Cranial Nerve Palsy	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Cerebrovascular Accident	0/30 (0%)	0	0/60 (0%)	0	3/60 (5%)	3
Syncope	0/30 (0%)	0	1/60 (1.7%)	1	1/60 (1.7%)	1
Transient Ischemic Attack	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Renal and urinary disorders
Urolithiasis	1/30 (3.3%)	1	1/60 (1.7%)	1	0/60 (0%)	0
Renal Failure	0/30 (0%)	0	1/60 (1.7%)	1	2/60 (3.3%)	2
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/30 (3.3%)	1	1/60 (1.7%)	1	1/60 (1.7%)	1
Dyspnea	0/30 (0%)	0	0/60 (0%)	0	1/60 (1.7%)	1
Pneumonia	0/30 (0%)	0	4/60 (6.7%)	4	3/60 (5%)	3
Vascular disorders
Orthostatic Hypotension	0/30 (0%)	0	1/60 (1.7%)	1	0/60 (0%)	0
Hypertension	1/30 (3.3%)	1	2/60 (3.3%)	2	6/60 (10%)	6
Other (Not Including Serious) Adverse Events
	Monthly		TREX		GILA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/30 (100%)		60/60 (100%)		60/60 (100%)
Blood and lymphatic system disorders
Anemia	1/30 (3.3%)	1	4/60 (6.7%)	4	7/60 (11.7%)	7
Cardiac disorders
Myocardial Infarction	0/30 (0%)	0	5/60 (8.3%)	5	2/60 (3.3%)	2
Angina Pectoris	0/30 (0%)	0	0/60 (0%)	0	5/60 (8.3%)	5
Cardiac Arrhythmia	2/30 (6.7%)	2	1/60 (1.7%)	1	3/60 (5%)	3
Congestive Heart Failure	0/30 (0%)	0	2/60 (3.3%)	2	4/60 (6.7%)	4
Ear and labyrinth disorders
Dizziness	1/30 (3.3%)	1	3/60 (5%)	3	1/60 (1.7%)	1
Endocrine disorders
Hypo/Hyperglycemia	7/30 (23.3%)	7	12/60 (20%)	12	14/60 (23.3%)	14
Testosterone Deficiency	2/30 (6.7%)	2	1/60 (1.7%)	1	0/60 (0%)	0
Eye disorders
Blurred Vision/Vision Loss	1/30 (3.3%)	1	6/60 (10%)	6	5/60 (8.3%)	5
Cataract Progression	1/30 (3.3%)	1	5/60 (8.3%)	5	7/60 (11.7%)	7
Chalazion	2/30 (6.7%)	2	0/60 (0%)	0	1/60 (1.7%)	1
Elevated Intraocular Pressure	3/30 (10%)	3	4/60 (6.7%)	4	3/60 (5%)	3
Eye Discomfort/Discharge	6/30 (20%)	6	9/60 (15%)	9	15/60 (25%)	15
Eyelid Swelling	0/30 (0%)	0	3/60 (5%)	3	0/60 (0%)	0
Secondary Cataract	3/30 (10%)	3	2/60 (3.3%)	2	2/60 (3.3%)	2
Vitreous Floaters	7/30 (23.3%)	7	6/60 (10%)	6	7/60 (11.7%)	7
Punctate Keratitis	2/30 (6.7%)	2	3/60 (5%)	3	6/60 (10%)	6
Vitreous Hemorrhage	0/30 (0%)	0	4/60 (6.7%)	4	1/60 (1.7%)	1
Gastrointestinal disorders
Diarrhea	2/30 (6.7%)	2	0/60 (0%)	0	1/60 (1.7%)	1
Esophageal Reflux	2/30 (6.7%)	2	4/60 (6.7%)	4	3/60 (5%)	3
Throat Irritation	3/30 (10%)	3	1/60 (1.7%)	1	1/60 (1.7%)	1
General disorders
Poor Dentition	2/30 (6.7%)	2	3/60 (5%)	3	3/60 (5%)	3
Fatigue	3/30 (10%)	3	1/60 (1.7%)	1	0/60 (0%)	0
Insomnia	7/30 (23.3%)	7	7/60 (11.7%)	7	0/60 (0%)	0
Hepatobiliary disorders
Gallstones	1/30 (3.3%)	1	1/60 (1.7%)	1	3/60 (5%)	3
Immune system disorders
Allergy	5/30 (16.7%)	5	9/60 (15%)	9	5/60 (8.3%)	5
Infections and infestations
Fever	2/30 (6.7%)	2	2/60 (3.3%)	2	1/60 (1.7%)	1
Gastrointestinal Infection	1/30 (3.3%)	1	3/60 (5%)	3	4/60 (6.7%)	4
Skin Infection	6/30 (20%)	6	18/60 (30%)	18	20/60 (33.3%)	20
Respiratory Infection	12/30 (40%)	12	22/60 (36.7%)	22	14/60 (23.3%)	14
Sinusitis	5/30 (16.7%)	5	9/60 (15%)	9	3/60 (5%)	3
Urinary Tract Infection	4/30 (13.3%)	4	2/60 (3.3%)	2	1/60 (1.7%)	1
Injury, poisoning and procedural complications
Fractured Bone	2/30 (6.7%)	2	3/60 (5%)	3	9/60 (15%)	9
Metabolism and nutrition disorders
Hyperlipidemia	5/30 (16.7%)	5	4/60 (6.7%)	4	6/60 (10%)	6
Hypo/Hyperkalemia	0/30 (0%)	0	1/60 (1.7%)	1	5/60 (8.3%)	5
Vitamin D Deficiency	1/30 (3.3%)	1	3/60 (5%)	3	2/60 (3.3%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	12/30 (40%)	12	16/60 (26.7%)	16	18/60 (30%)	18
Headache	6/30 (20%)	6	1/60 (1.7%)	1	3/60 (5%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	1/30 (3.3%)	1	3/60 (5%)	3	1/60 (1.7%)	1
Nervous system disorders
Paresthesia	2/30 (6.7%)	2	1/60 (1.7%)	1	1/60 (1.7%)	1
Psychiatric disorders
Depression/Anxiety	0/30 (0%)	0	1/60 (1.7%)	1	3/60 (5%)	3
Renal and urinary disorders
Renal Insufficiency	1/30 (3.3%)	1	1/60 (1.7%)	1	6/60 (10%)	6
Respiratory, thoracic and mediastinal disorders
Cough	2/30 (6.7%)	2	5/60 (8.3%)	5	5/60 (8.3%)	5
Pneumonia	2/30 (6.7%)	2	4/60 (6.7%)	4	3/60 (5%)	3
Skin and subcutaneous tissue disorders
Skin Burn	2/30 (6.7%)	2	2/60 (3.3%)	2	1/60 (1.7%)	1
Vascular disorders
Peripheral Edema	1/30 (3.3%)	1	6/60 (10%)	6	8/60 (13.3%)	8
Hypertension	10/30 (33.3%)	10	21/60 (35%)	21	26/60 (43.3%)	26

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.