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Diabetic Macular EdemaPhase 2NCT01610557

Ranibizumab and Bevacizumab for Diabetic Macular Edema

A Phase 2 study testing Ranibizumab and Bevacizumab in people with Diabetic Macular Edema, run by National Eye Institute (NEI) at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Diabetic Macular Edema
What is being tested?
Ranibizumab and Bevacizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
56 participants
Where
2 sitesin 2 countries
Study dates
May 2012to Feb 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • To be eligible, the following inclusion criteria must be met, where applicable.
  • 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.
Show all 14Show fewer
  • 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.

Who cannot join

  • A participant is not eligible if any of the following exclusion criteria are present.
  • 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.
Show all 33Show fewer
  • 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:
  • The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below. Participants for whom both eyes meet all of the inclusion criteria and none of the exclusion criteria listed below may have both eyes enrolled in the study if they and the investigator so choose. If both eyes meet all of the inclusion criteria and none of the exclusion criteria listed below, and if the participant and the investigator decide that only one eye should be enrolled in the study, the study eye will be selected by the investigator in consultation with the participant.
  • STUDY EYE INCLUSION 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.
  • STUDY EYE EXCLUSION CRITERIA:
  • Eye has macular edema considered to be due to a cause other than diabetes.
  • An eye is not eligible if:
  • The macular edema is considered to be related to cataract extraction; or
  • Clinical examination and/or OCT suggest that vitreoretinal interface disease (e.g., a taut posterior hyaloid or epiretinal membrane) is the primary cause of the macular edema.
  • Eye has an ocular condition present such that, in the opinion of the investigator, visual acuity would not improve from resolution of macular edema (e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, non-retinal condition).
  • Eye has an ocular condition present (other than DR) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc.).
  • Eye has a history of panretinal scatter photocoagulation (PRP) within three months prior to enrollment.
  • Eye has a history of prior pars plana vitrectomy prior to enrollment.
  • Eye has a history of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within three months prior to enrollment.
  • Eye has a history of Yttrium-Aluminum-Garnet (YAG) capsulotomy performed within two months prior to enrollment.
  • Eye had laser photocoagulation treatment, or received intravitreal or periocular steroids within three months prior to enrollment.
  • Eye has a history of intravitreal anti-VEGF agents within eight weeks prior to enrollment.
  • Eye has had greater than four intravitreal anti-VEGF injections within one year prior to enrollment.
  • Eye has high-risk proliferative DR requiring laser photocoagulation treatment.

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

United Kingdom1 site

  • Bristol Eye Hospital

    Bristol

Other trials in United Kingdom

About this study

Official title: A Phase II Randomized Study to Compare Anti-VEGF Agents in the Treatment of Diabetic Macular Edema (CADME)

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.
Read more

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.
Read the detailed description

Objective: Diabetic retinopathy (DR) remains a leading cause of visual impairment. A frequent manifestation of DR is diabetic macular edema (DME) for which laser photocoagulation has been the only proven treatment for the last several decades. Studies have shown that anti-vascular endothelial growth factor (VEGF) injections such as bevacizumab or ranibizumab have been efficacious in treating patients with DME. However, there has been no direct comparison of these agents to determine whether one treatment is more effective than the other. The objective of this study is to compare the treatment efficacy of ranibizumab versus bevacizumab in eyes with DME.

Study Population: Sixty (60) participants with macular edema secondary to diabetes and any stage of DR (other than those requiring scatter laser photocoagulation for proliferative DR) in one or both eyes will be enrolled in this randomized study.

Design: In this Phase II, multi-center, comparative, double-masked study, eyes will be randomly assigned to receive ranibizumab or bevacizumab. During the initial phase of the study participants will participate in a three-period, 36-week, crossover study in which study eyes will be assigned to one of four treatment groups (i.e., treatment sequences). The two drugs and three periods form a RRB/RBB/BBR/BRR pattern as follows:

  • Group 1 (RRB pattern) eyes will receive a series of intravitreal injections of ranibizumab at baseline and Weeks 4, 8, 12, 16 and 20, then crossover to receive a series of intravitreal injections of bevacizumab at Weeks 24, 28 and 32.
  • Group 2 (RBB pattern) eyes will receive a series of intravitreal injections of ranibizumab at baseline and Weeks 4 and 8, then crossover to receive a series of intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32.
  • Group 3 (BBR pattern) eyes will receive a series of intravitreal injections of bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20, then crossover to receive a series of intravitreal injections of ranibizumab at Weeks 24, 28 and 32.
  • Group 4 (BRR pattern) eyes will receive a series of intravitreal injections of bevacizumab at baseline and Weeks 4 and 8, then crossover to receive a series of intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32.

Participants for whom one eye is enrolled in the study will have this eye randomly assigned to one of the four groups above. Participants for whom both eyes are enrolled in the study will have the right eye randomly assigned to one of the four groups above; the left eye will be assigned to the group with the schedule inverse to that for the right eye. For example, if the right eye is randomly assigned to Group 1 (RRB pattern), the left eye will be automatically assigned to Group 3 (BBR pattern). Thus, at each treatment, the right eye for a participant enrolling both eyes in the study will always receive a different investigational product than the left eye. Following this crossover phase, eyes will be returned to the treatment (ranibizumab or bevacizumab) to which they were originally assigned and treated on an as-needed basis through a common termination date one year from enrollment of the last-enrolled participant at the National Eye Institute (NEI) and through Year 1 at the Bristol Eye Hospital (BEH). Both the treating investigators and participants will be masked to the group assignments. The primary outcome will be assessed at Weeks 12, 24, 36 and Year 1.

Outcome Measures: The primary outcome measure is the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA). Changes in BCVA from baseline to four weeks following the end of each of the three periods (i.e., Weeks 12, 24 and 36) and at Year 1 will be used for the primary analysis.

Secondary outcomes (assessed between the baseline and Week 12 visits, Weeks 12 and 24 visits and Weeks 24 and 36 visits and at Year 1) will include the mean changes in central macular thickness and central retinal volume by treatment group as measured by optical coherence tomography (OCT); the slope of the changes in BCVA, central macular thickness and retinal volume; the proportion of eyes with visual improvement ≥ 10 letters; the proportion of eyes with visual improvement ≥ 15 letters; the proportion of eyes with ≥ 0.1 log unit loss or gain in logOCT; the proportion of eyes with ≥ 0.05 log unit loss or gain in logOCT; changes in fluid leakage in the macula as demonstrated by fluorescein angiography; and changes in macular structural improvement (i.e., resolution of cystic changes) as measured by OCT. The digital OCT images collected between the Baseline and Week 36 visits will be graded by a masked, external Reading Center.

Other secondary outcomes will include the proportion of eyes meeting criteria for significant worsening, treatment success, or treatment failure, the frequency of re-injection among eyes in the treatment-as-needed phase of the study, and the proportion of eyes receiving focal/grid laser photocoagulation or other adjuvant treatment during the course of the study.

Safety outcomes include the number and severity of adverse events. The number of eyes withdrawn from the investigational product due to vision loss or adverse events and the number of eyes deemed to have worsening disease will also contribute to the assessment of safety.

Keywords
Diabetic Macular Edema, Ranibizumab, Bevacizumab

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RanibizumabDrug

    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).

  • BevacizumabDrug

    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).

Study groups in NCT01610557
Study groupRoleWhat they receive
Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection SeriesExperimentalGroup 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.
Receives: Drug: Ranibizumab; Drug: Bevacizumab
Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection SeriesExperimentalGroup 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.
Receives: Drug: Ranibizumab; Drug: Bevacizumab
Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection SeriesExperimentalGroup 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.
Receives: Drug: Ranibizumab; Drug: Bevacizumab
Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection SeriesExperimentalGroup 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.
Receives: Drug: Ranibizumab; Drug: Bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline and 36 Weeks

Secondary outcomes (1)

  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)

    Optical Coherence Tomography (OCT) scans were graded in masked fashion by Duke University Reading Center (Durham, North Carolina). Per the initial protocol specifications, OCT scans were to be performed on a Cirrus OCT machine; however, some scans were performed on a Spectralis OCT machine at one of the sites due to technical difficulties. The protocol was amended to allow for Cirrus and Spectralis OCT scans at subsequent visits at the affected site. Spectralis values were then converted to Cirrus central subfield mean thickness (CSMT) values through a validated linear conversion function.

    Measured: Baseline and 36 Weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2012 (estimated)
  2. Study startMay 2012
  3. Primary completionFeb 2015
  4. Study completionFeb 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
56 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01610557
Sponsor's protocol ID
120134
Other IDs
12-EI-0134
Status last verified
Aug 2016
First submitted
31 May 2012
Last updated
9 Dec 2022
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • 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.

    PubMed 6521986

  • 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.

    PubMed 19167079

  • 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.

    PubMed 2866759

  • 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.

    PubMed 26875003

  • 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.

    PubMed 34967834

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ranibizumab and Bevacizumab in people with Diabetic Macular Edema, run by National Eye Institute (NEI) at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Apr 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to 36 Weeks (Crossover Phase of the Study) (time frame: Baseline and 36 Weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01610557, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2022.

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