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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: Ranibizumab 0.3 mg intravitreal injection
* Device: Guided Laser Photocoagulation


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Monthly<br>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<br> <br> * Other names: Lucentis;|
| Active Comparator: TREX<br>(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<br> <br> * Other names: Lucentis;|
| Active Comparator: GILA<br>(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<br> <br> * Other names: Lucentis;Device: Guided Laser Photocoagulation<br> <br> * Other names: NAVILAS Guided Laser System;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Vision at 24 Months | 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 | 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Number of Participants with Adverse Events, ocular and non-ocular, in each of the study groups | 2 years | 
| Number of Intravitreal Injections | 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. | 2 years | 
| Number of Office Visits | 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. | 2 years | 
| Change in Retinal Thickness | 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. | 2 years | 
| Percentage of Eyes Gaining or Losing Vision | 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. | 2 years | 
| Percentage of Eyes Which Progress to Proliferative Diabetic Retinopathy | 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. | 2 years | 
| Percentage of Eyes Able to Begin Extension Phase Prior to Week 104 End-point Visit. | 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. | 2 years | 
| Percentage of Eyes With a Secondary or Tertiary Baseline Retinal Thickness | For TREX and GILA Cohorts, the time to achieve a Secondary or Tertiary Baseline retinal thickness. | 2 years |