Ranibizumab 0.5mg and 2.0mg to Treat Diabetic Macular Edema in Patients With Poor Response to Bevacizumab (REEF)

Open Label, Phase I/II, Residual Edema Evaluation With 0.5mg and 2.0mg Ranibizumab Formulations (REEF)

This is an open-label, Phase I/II study of intravitreally administered ranibizumab either 0.5-mg and/or 2.0-mg in subjects with clinical, angiographic, and ocular coherence tomography (OCT) evidence of diabetic retinopathy with associated diabetic macular edema following bevacizumab therapy. Thirty patients will be enrolled in this study.

Consented, enrolled subjects will receive multiple open-label intravitreal injections of 0.5 mg ranibizumab administered every 30 days (±7 days) for 3 injections during the mandatory treatment phase (Day 0, Month 1, and Month 2).

Subjects with complete resolution of diabetic macular edema after 3 intravitreal injections of 0.5 mg ranibizumab will be treated as necessary with 0.5 mg ranibizumab to treat recurrent macular edema for an additional 9 months (12 months from Day 0). The intent is to administer additional ranibizumab treatment if there is evidence of disease activity documented on OCT (e.g., intra-retinal fluid, subretinal fluid and/or cystic changes).

Subjects with residual diabetic macular edema following 3 intravitreal injections of 0.5 mg ranibizumab will be receive 3 intravitreal injections of 2.0 mg ranibizumab administered every 30 days (±7 days) for 3 injections at the Month 3, Month 4, and Month 5 study visits.

Beginning at the Month 6 study visit, subjects with complete resolution of diabetic macular edema following 3 intravitreal injections of 2.0 mg ranibizumab will treated as necessary with 2.0 mg ranibizumab injections only to treat recurrent macular edema for an additional 6 months (12 months from Day 0).

Subjects with residual diabetic macular edema following 3 consecutive intravitreal injections of 2.0 mg ranibizumab will be treated as necessary with 2.0 mg ranibizumab to treat persistent or recurrent macular edema for an additional 6 months (12 months from Day 0). Focal photocoagulation or intravitreal triamcinolone may be administered at the physician's discretion as an adjunct to ranibizumab injections beginning at Month 6 through Month 12 of the study.

All subjects will make monthly visits for 12 months for evaluation of safety and efficacy. All subjects will have their first injection of ranibizumab on Day 0 and undergo a safety visit one week (±2 days) after the first injection. At subsequent visits, the subject will have a safety evaluation at the monthly scheduled follow-up visit prior to any intravitreal injection. Subjects will be contacted by the site personnel 1-2 days after each injection to elicit reports of decreased vision or pain or unusual new ocular symptoms in the study eye.

Study Overview

• Status: Completed
• Conditions: Diabetic Macular Edema
• Intervention / Treatment: Drug: Ranibizumab

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Bakersfield, California, United States, 93309
      • California Retina Consultants
    • Oxnard, California, United States, 93030
      • California Retina Consultants
    • Santa Barbara, California, United States, 93103
      • California Retina Consultants
    • Santa Maria, California, United States, 93454
      • California Retina Consultants
  • Hawaii
    • Honolulu, Hawaii, United States, 69815
      • Retina Institute of Hawai'i

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ability to provide written informed consent and comply with study assessments for the full duration of the study
• Age > 18 years
• Diagnosis of diabetes mellitus (type 1 or 2)Any one of the following will be considered to be sufficient evidence that diabetes is present:Current regular use of insulin for treatment of diabetes or current regular use of oral anti-hyperglycemia agent for the treatment of diabetes
• Clinical evidence of retinal thickening due to macular edema involving the center of the macula, associated with diabetic retinopathy.
• Previous history of two consecutive intravitreal bevacizumab injections for the treatment of diabetic macular edema with documented incomplete resolution of central subfield thickening by OCT (consecutive injections administered < 7 weeks apart and within the past 12 months).
• Central diabetic macular edema present on clinical examination and OCT testing with central 1mm subfield thickness greater than 300 microns as measured on SD-OCT.
• Visual acuity score greater than or equal to 19 letters (20/400) and less than or equal to 73 letters (20/40) by the ETDRS visual acuity protocol.
• Media clarity, pupillary dilation and patient cooperation sufficient to allow OCT testing and retinal photography

Exclusion Criteria:

• Pregnancy (positive pregnancy test) or known to be pregnant; also pre-menopausal women not using adequate contraception.
• Participation in another ocular investigation or trial simultaneously
• Blood pressure > 180/110 (systolic above 180 OR diastolic above 110)
• Any condition that, in the opinion of the investigator, would preclude participation in the study (e.g. chronic alcoholism, drug abuse)
• Evidence of vitreoretinal interface abnormality after ocular exam or OCT that may be contributing to the macular edema
• An eye that, in the investigator's opinion, has no chance of improving in visual acuity following resolution of macular edema (e.g. presence of subretinal fibrosis or geographic atrophy)
• Presence of another ocular condition that may affect the visual acuity or macular edema during the course of the study (e.g. AMD, uveitis, Irvine-Gas)
• Evidence of neovascularization of the iris or retina
• Evidence of central atrophy or fibrosis in the study eye
• Presence of substantial cataract, one that might decrease the vision by 3 or more lines of vision at sometime during the study.
• History of vitreous surgery in the study eye
• History of cataract surgery within 6 months of enrollment.
• History of YAG capsulotomy within 2 months of enrollment.
• Visual acuity <20/400 in the fellow eye
• Uncontrolled glaucoma (pressure >30) despite treatment with glaucoma medications.
• History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 0.5mg and 2.0mgRanibizumab; Three consecutive intravitreal ranibizumab 0.5mg injections followed by three consecutive intravitreal ranibizumab 2.0mg injections if specific criteria is met.	Drug: Ranibizumab; 0.05ml of 0.5mg or 2.0mg ranibizumab injected intravitreally; Other Names: Lucentis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Mean Change in Visual Acuity Scores at Month 6 Compared to Baseline	To determine the mean change in the best-corrected visual acuity on an ETDRS visual acuity chart at a starting distance of 4 meters from baseline to 6 months.	baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in 1-mm Central Subfield (CST) Thickness as Measured by OCT at Month 6 Compared to Baseline	To determine the mean change in central 1-mm subfield thickness as measured by spectral-domain OCT from baseline to 6 months .	baseline and 6 months
Qualitative Assessment of Diabetic Macular Edema (DME)	To compare the percentage of subjects with compete or partial/no resolution of diabetic macular edema in response to the ranibizumab 0.5 and 2.0 mg doses.	Baeline and 6 months

Collaborators and Investigators

• Sponsor: California Retina Consultants
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Dante Pieramici, MD, California Retina Consultants

Publications and helpful links

General Publications

• Dhoot DS, Pieramici DJ, Nasir M, Castellarin AA, Couvillion S, See RF, Steinle N, Bennett M, Rabena M, Avery RL. Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study). Eye (Lond). 2015 Apr;29(4):534-41. doi: 10.1038/eye.2014.338. Epub 2015 Jan 30.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: February 7, 2011
• First Submitted That Met QC Criteria: February 9, 2011
• First Posted (Estimate): February 10, 2011

Study Record Updates

• Last Update Posted (Estimate): April 22, 2016
• Last Update Submitted That Met QC Criteria: March 23, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Diabetes; Retina; Edema; Macula
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Macular Edema; Edema; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: FVF4978s