Ranibizumab and Bevacizumab for Diabetic Macular Edema

NCT01610557 | Completed Phase 2 Results DMC

• 2 other identifiers: 12013412-EI-0134
• Study Type: interventional
• Target: 56
• Locations: 2 countries
• Sites: 2

Brief Summary

Background:

• Diabetic macular edema is a common eye complication of diabetes. It causes the blood vessels in the retina at the back of the eye to leak, causing swelling. The macula is the center part of the retina that is important for seeing fine details and for tasks such as reading, driving, or sewing. Swelling of the macula leads to vision loss and possible blindness. Inflammation may play a role in diabetic macular edema. It is also possible that there is a problem with the blood vessels and the blood supply to cells of the retina.
• A chemical in the body called vascular endothelial growth factor (VEGF) is important in the formation of blood vessels in the body. Lowering VEGF levels may help treat diabetic macular edema by reducing abnormal leaking blood vessels in the eye. Drugs that can lower or block VEGF include ranibizumab and bevacizumab. Both drugs have been shown to help treat diabetic macular edema. Researchers want to see if one of the drugs works better than the other. Objective: To compare the effectiveness of ranibizumab and bevacizumab injections for diabetic macular edema. Eligibility: Individuals at least 18 years of age who have diabetic macular edema in at least one eye. Design:
• Participants will be screened with a physical exam and medical history. A full eye exam will be performed. Blood and urine samples will be collected.
• One eye will be selected as the study eye to receive treatment. If both eyes are affected, both eyes may be enrolled in the study and receive different drug treatments.
• The main part of the study will last for 9 months. At each study visit, participants will have physical exams and eye exams. They will answer questions about their health and any side effects from the drugs.
• Participants will be assigned to one of four groups. Two groups will have two series of ranibizumab and one series of bevacizumab shots. The other two groups will have two series of bevacizumab and one series of ranibizumab shots. A series is three eye injections of the same drug every 4 weeks. The injections will be given at these study visits. The series order will vary for the different groups.
• After 9 months, participants will continue to have additional study visits. If the treatment seems to be successful, the study doctor may increase the time between visits. Study injections may be given as needed every 4 weeks for up to 3 years.
• Participants may have laser treatments in a study eye if needed. After being in the study for 1 year, they may also have steroid injections or other treatments as directed for the macular edema.

Conditions

Diabetic Macular Edema

Keywords

Diabetic Macular Edema; Ranibizumab; Bevacizumab

Outcome Measures

Primary Outcomes (1)

• Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to 36 Weeks (Crossover Phase of the Study)

  The primary outcome for 3-months change in BCVA utilized data from Weeks 12, 24 and 36 aggregated in a linear mixed-effects model. This model included adjustments accounting for period (i.e., Weeks 12, 24 and 36), treatment in current period, treatment in prior period, and baseline BCVA to provide the estimated 3-month BCVA change. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.

  Baseline and 36 Weeks

Secondary Outcomes (1)

• Change in Central Retinal Thickness Assessed by Optical Coherence Tomography (OCT) Central Subfield Mean Thickness (CSMT) From Baseline to 36 Weeks (Crossover Phase of the Study)

  Baseline and 36 Weeks

Study Arms (4)

Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series

EXPERIMENTAL

Group 1 eyes were assigned to Ranibizumab-Ranibizumab-Bevacizumab (RRB) treatment sequence and received intravitreal injections of ranibizumab at baseline, Weeks 4, and 8 (period 1), and Weeks 12, 16 and 20 (period 2), then crossed over to receive intravitreal injections of bevacizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye.

Drug: Ranibizumab; Drug: Bevacizumab

Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series

EXPERIMENTAL

Group 2 eyes were assigned to Ranibizumab-Bevacizumab-Bevacizumab (RBB) treatment sequence and received intravitreal injections of ranibizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye.

Drug: Ranibizumab; Drug: Bevacizumab

Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series

EXPERIMENTAL

Group 3 eyes were assigned to Bevacizumab-Bevacizumab-Ranibizumab (BBR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20 (periods 1 and 2), then crossed over to receive intravitreal injections of ranibizumab at Weeks 24, 28 and 32 (period 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye.

Drug: Ranibizumab; Drug: Bevacizumab

Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series

EXPERIMENTAL

Group 4 eyes were assigned to Bevacizumab-Ranibizumab-Ranibizumab (BRR) treatment sequence and received intravitreal injections of bevacizumab at baseline and Weeks 4 and 8 (period 1), then crossed over to receive intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32 (periods 2 and 3). Participants for whom one eye was enrolled in the study had this eye randomly assigned to one of four groups. Participants for whom both eyes were enrolled had the right eye randomly assigned; the left eye was assigned to the group with the schedule inverse to that for the right eye.

Drug: Ranibizumab; Drug: Bevacizumab

Interventions

Ranibizumab DRUG

Series of three intravitreous injections of ranibizumab (0.3 mg)\* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. \*Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after FDA approval of the 0.3 mg dose for DME, the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series; Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series; Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series; Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series

Bevacizumab DRUG

Series of three intravitreous injections of ranibizumab (0.3 mg)\* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion. \*Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after FDA approval of the 0.3 mg dose for DME, the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).

Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series; Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series; Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series; Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant is 18 years of age or older.
• Participant has a diagnosis of diabetic 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 (ADA) and/or World Health Organization (WHO) criteria.
• Participant must understand and sign the protocol's informed consent document.
• Female participants of childbearing potential must not be pregnant or breast-feeding and must have a negative pregnancy test at screening and must agree to pregnancy testing throughout the study.
• Female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for four weeks after their last injection. Acceptable methods of contraception include:
• Hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring),
• Intrauterine device,
• Barrier methods (i.e., diaphragm, condom) with spermicide, or
• Tubal ligation.
• Participant has at least one eye that meets the study eye eligibility criteria.

You may not qualify if:

• Participant is in another investigational study and actively receiving investigational product for DME.
• Participant has a known hypersensitivity to sodium fluorescein dye.
• Participant has a condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure and glycemic control).
• Participant has a history of chronic renal failure requiring dialysis or kidney transplant.
• Participant has a history of liver failure.
• Participant has a known hypersensitivity to bevacizumab, ranibizumab or any of their components.
• Participant has a blood pressure of \> 180/110 (systolic above 180 OR diastolic above 110).
• If blood pressure is brought below 180/110 by anti-hypertensive treatment, a patient can become eligible.
• Participant has a history of treatment with oral steroids (greater than or equal to 10 mg of prednisone daily or equivalent) within three months prior to enrollment. Non-ocular depot and inhaled steroid treatments will not exclude a participant.
• Participant has a history of treatment with systemic anti-VEGF agents within four weeks prior to enrollment.
• STUDY EYE ELIGIBILITY CRITERIA:
• Eye has a BCVA ETDRS score between 20/32 and 20/400.
• Eye has definite retinal thickening or cystic changes due to DME based on clinical exam involving the center of the macula that is not refractory to further therapy as based on the investigator's clinical judgment.
• Eye has retinal thickness in the central subfield on baseline OCT measurement greater than or equal to 330 microns, as measured by Cirrus OCT.
• Eye has clear ocular media and adequate pupillary dilation sufficient for adequate fundus photographs.

Sponsors & Collaborators

• National Eye Institute (NEI): lead
• The Emmes Company, LLC: collaborator

Study Sites (2)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Bristol Eye Hospital

Bristol, United Kingdom

Location

Related Publications (5)

• Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984 Dec;91(12):1464-74. doi: 10.1016/s0161-6420(84)34102-1.

  PMID: 6521986 BACKGROUND

• Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology. 2009 Mar;116(3):497-503. doi: 10.1016/j.ophtha.2008.10.016. Epub 2009 Jan 22.

  PMID: 19167079 BACKGROUND

• Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806.

  PMID: 2866759 BACKGROUND

• Wiley HE, Thompson DJ, Bailey C, Chew EY, Cukras CA, Jaffe GJ, Lee RW, Loken EK, Meyerle CB, Wong W, Ferris FL 3rd. A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema. Ophthalmology. 2016 Apr;123(4):841-9. doi: 10.1016/j.ophtha.2015.11.021. Epub 2016 Feb 10.

  PMID: 26875003 RESULT

• Sun JK, Josic K, Melia M, Glassman AR, Bailey C, Chalam KV, Chew EY, Cukras C, Grover S, Jaffe GJ, Lee R, Nielsen JS, Thompson DJS, Wiley HE, Ferris FL 3rd; DRCR Retina Network. Conversion of Central Subfield Thickness Measurements of Diabetic Macular Edema Across Cirrus and Spectralis Optical Coherence Tomography Instruments. Transl Vis Sci Technol. 2021 Dec 1;10(14):34. doi: 10.1167/tvst.10.14.34.

  PMID: 34967834 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Ranibizumab; Bevacizumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Henry E Wiley, MD, Principal Investigator
• Organization: National Eye Institute (NEI) at National Institutes of Health (NIH)

wileyhe@mail.nih.gov

(301) 451-4260

Study Officials

• Henry E Wiley, M.D.

  National Eye Institute (NEI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 31, 2012
• First Posted: June 4, 2012
• Study Start: May 1, 2012
• Primary Completion: February 1, 2015
• Study Completion: February 1, 2015
• Last Updated: December 9, 2022
• Results First Posted: April 27, 2016

Record last verified: 2016-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); GB (1)