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Ranibizumab and Bevacizumab for Diabetic Macular Edema

Sponsor
National Eye Institute (NEI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01610557
Collaborator
The Emmes Company, LLC (Industry)
56
Enrollment
2
Locations
4
Arms
33.1
Duration (Months)
28
Patients Per Site
0.8
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
56 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase II Randomized Study to Compare Anti-VEGF Agents in the Treatment of Diabetic Macular Edema (CADME)
Study Start Date :
May 1, 2012
Actual Primary Completion Date :
Feb 1, 2015
Actual Study Completion Date :
Feb 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Group 1 - Ranibizumab-Ranibizumab-Bevacizumab Injection Series

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
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).

Drug: Bevacizumab
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).
Experimental: Group 2 - Ranibizumab-Bevacizumab-Bevacizumab Injection Series

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
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).

Drug: Bevacizumab
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).
Experimental: Group 3 - Bevacizumab-Bevacizumab-Ranibizumab Injection Series

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
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).

Drug: Bevacizumab
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).
Experimental: Group 4 - Bevacizumab-Ranibizumab-Ranibizumab Injection Series

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
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).

Drug: Bevacizumab
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).

Outcome Measures

Primary Outcome Measures

  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) [Baseline and 36 Weeks]

    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.

Secondary Outcome Measures

  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]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
INCLUSION CRITERIA:

To be eligible, the following inclusion criteria must be met, where applicable.

  1. Participant is 18 years of age or older.

  2. 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.

  1. Participant must understand and sign the protocol's informed consent document.

  2. 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.

  3. 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.

  1. Participant has at least one eye that meets the study eye eligibility criteria.
EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present.

  1. Participant is in another investigational study and actively receiving investigational product for DME.

  2. Participant has a known hypersensitivity to sodium fluorescein dye.

  3. 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).

  4. Participant has a history of chronic renal failure requiring dialysis or kidney transplant.

  5. Participant has a history of liver failure.

  6. Participant has a known hypersensitivity to bevacizumab, ranibizumab or any of their components.

  7. 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.

  1. 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.

  2. 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:

  1. Eye has a BCVA ETDRS score between 20/32 and 20/400.

  2. 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.

  3. Eye has retinal thickness in the central subfield on baseline OCT measurement greater than or equal to 330 microns, as measured by Cirrus OCT.

  4. Eye has clear ocular media and adequate pupillary dilation sufficient for adequate fundus photographs.

STUDY EYE EXCLUSION CRITERIA:
  1. 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.

  1. 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).

  2. 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.).

  3. Eye has a history of panretinal scatter photocoagulation (PRP) within three months prior to enrollment.

  4. Eye has a history of prior pars plana vitrectomy prior to enrollment.

  5. Eye has a history of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within three months prior to enrollment.

  6. Eye has a history of Yttrium-Aluminum-Garnet (YAG) capsulotomy performed within two months prior to enrollment.

  7. Eye had laser photocoagulation treatment, or received intravitreal or periocular steroids within three months prior to enrollment.

  8. Eye has a history of intravitreal anti-VEGF agents within eight weeks prior to enrollment.

  9. Eye has had greater than four intravitreal anti-VEGF injections within one year prior to enrollment.

  10. Eye has high-risk proliferative DR requiring laser photocoagulation treatment.

Contacts and Locations

Locations

Site City State Country Postal Code
1 National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland United States 20892
2 Bristol Eye Hospital Bristol United Kingdom

Sponsors and Collaborators

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

Investigators

  • Principal Investigator: Henry E Wiley, M.D., National Eye Institute (NEI)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

Responsible Party:
National Eye Institute (NEI)
ClinicalTrials.gov Identifier:
NCT01610557
Other Study ID Numbers:
  • 120134
  • 12-EI-0134
First Posted:
Jun 4, 2012
Last Update Posted:
Aug 19, 2016
Last Verified:
Aug 1, 2016
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Keywords provided by National Eye Institute (NEI)
Diabetic Macular Edema
Ranibizumab
Bevacizumab
Additional relevant MeSH terms:
Macular Edema
Edema
Bevacizumab
Ranibizumab

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail 56 participants enrolled: 50 participants had one eye randomly assigned (unilateral participants) and 6 participants had two eyes enrolled (bilateral participants) for a total of 62 eyes analyzed at baseline. Bilateral participants had the right eye randomly assigned; the left eye assigned to the group with the schedule inverse to the right eye.
Arm/Group Title 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 Ranibizumab/Bevacizumab As Needed
Arm/Group Description 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. 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. 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. 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. Post-36-Week Extension Phase: Eyes assigned to Group 1 or Group 2 in the crossover phase were injected with ranibizumab on an as-needed basis. Eyes assigned to Group 3 or Group 4 in the crossover phase were injected with bevacizumab on an as-needed basis. 53 participants attended at least one follow-up visit in the post-36-week extension phase: 49 participants who had one eye enrolled and 4 participants who had two eyes enrolled.
Period Title: 36-Week Randomized Crossover Phase
STARTED 16 13 14 13 0
COMPLETED 16 12 14 13 0
NOT COMPLETED 0 1 0 0 0
Period Title: 36-Week Randomized Crossover Phase
STARTED 0 0 0 0 55
COMPLETED 0 0 0 0 52
NOT COMPLETED 0 0 0 0 3

Baseline Characteristics

Arm/Group Title 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 Total
Arm/Group Description 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. 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. 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. 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. Total of all reporting groups
Overall Participants 17 15 16 14 62
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]
62.4
65.9
62.3
61.8
63
Sex: Female, Male (Count of Participants)
Female
4
23.5%
8
53.3%
7
43.8%
5
35.7%
24
38.7%
Male
13
76.5%
7
46.7%
9
56.3%
9
64.3%
38
61.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
2
11.8%
0
0%
1
6.3%
0
0%
3
4.8%
Not Hispanic or Latino
15
88.2%
15
100%
14
87.5%
14
100%
58
93.5%
Unknown or Not Reported
0
0%
0
0%
1
6.3%
0
0%
1
1.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
0
0%
0
0%
Asian
1
5.9%
0
0%
1
6.3%
1
7.1%
3
4.8%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
0
0%
Black or African American
2
11.8%
2
13.3%
2
12.5%
2
14.3%
8
12.9%
White
12
70.6%
13
86.7%
11
68.8%
10
71.4%
46
74.2%
More than one race
1
5.9%
0
0%
2
12.5%
0
0%
3
4.8%
Unknown or Not Reported
1
5.9%
0
0%
0
0%
1
7.1%
2
3.2%
Diabetes Type (eyes) [Number]
Diabetes Type 1
2
2
1
2
7
Diabetes Type 2
15
13
15
12
55
Hemoglobin A1C (%) (percentage of glycosylated hemoglobin) [Mean (Full Range) ]
Mean (Full Range) [percentage of glycosylated hemoglobin]
8.1
8.4
7.9
7.8
8.1
Best-corrected visual acuity (ETDRS letters) [Mean (Full Range) ]
Mean (Full Range) [ETDRS letters]
65
61
65
65
64
Optical Coherence Tomography (OCT) Central Subfield Mean Thickness (micrometers) [Mean (Full Range) ]
Mean (Full Range) [micrometers]
484
444
471
508
477

Outcome Measures

1. Primary Outcome
Title Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to 36 Weeks (Crossover Phase of the Study)
Description 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.
Time Frame Baseline and 36 Weeks

Outcome Measure Data

Analysis Population Description
A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.
Arm/Group Title Bevacizumab Ranibizumab
Arm/Group Description Represents the estimated effect of bevacizumab for a 3-month period, adjusted for period and baseline value. Represents the estimated effect of ranibizumab for a 3-month period, adjusted for period and baseline value.
Measure Participants 55 55
Measure eyes 61 61
Mean (95% Confidence Interval) [ETDRS letters]
5.3
6.6
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab, Ranibizumab
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.039
Comments
Method Linear mixed-effects model
Comments
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.3
Confidence Interval (2-Sided) 95%
0.07 to 2.5
Parameter Dispersion Type:
Value:
Estimation Comments The difference represents the estimated difference between ranibizumab and bevacizumab, adjusted for baseline visual acuity, study period, and clinical site and a subject effect for eyes nested within subject.
2. Secondary Outcome
Title 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)
Description 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.
Time Frame Baseline and 36 Weeks

Outcome Measure Data

Analysis Population Description
A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.
Arm/Group Title Bevacizumab Ranibizumab
Arm/Group Description Represents the estimated effect of bevacizumab for a 3-month period, adjusted for period and baseline value. Represents the estimated effect of ranibizumab for a 3-month period, adjusted for period and baseline value.
Measure Participants 55 55
Measure eyes 61 61
Mean (95% Confidence Interval) [micrometers]
-89
-137
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab, Ranibizumab
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.001
Comments
Method Linear mixed-effects model
Comments
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -48
Confidence Interval (2-Sided) 95%
-65 to -31
Parameter Dispersion Type:
Value:
Estimation Comments The difference represents the estimated difference between ranibizumab and bevacizumab, adjusted for baseline visual acuity, study period, and clinical site and a subject effect for eyes nested within subject.

Adverse Events

Time Frame Data were collected from 56 participants randomly-assigned to Groups 1 through 4 during the 36-week crossover period. After 36 weeks, data were collected from 53 participants who completed at least one post-36-week visit.
Adverse Event Reporting Description 36-week crossover period:Of the 56 participants, 50 had one eye and 6 had two eyes enrolled; data collected from the 6 participants with two eyes enrolled are reflected in the group to which the participant's right eye was randomly assigned. Post-36-weeks:Of the 53 participants, data were collected from 49 with one eye and 4 with two eyes enrolled.
Arm/Group Title 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 Ranibizumab As Needed (Post-36-Week Extension) Bevacizumab As Needed (Post-36-Week Extension) Ranibizumab and Bevacizumab As Needed (Post-36-Week Extension)
Arm/Group Description 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. 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. 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. 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. Post-36-Week Extension Phase: Eyes assigned to Group 1 or Group 2 in the crossover phase were injected with ranibizumab on an as-needed basis. Participants with one eye assigned in either Group 1 or Group 2 who had at least one follow-up visit in the post-36-week extension are included in the number of participants at risk. Participants for whom two eyes were assigned (bilateral participants) are not included. Post-36-Week Extension Phase: Eyes assigned to Group 3 or Group 4 in the crossover phase were injected with bevacizumab on an as-needed basis. Participants with one eye assigned in either Group 3 or Group 4 who had at least one follow-up visit in the post-36-week extension are included in the number of participants at risk. Participants for whom two eyes were assigned (bilateral participants) are not included. Post-36-Week Extension Phase: Eyes assigned to Group 1 or Group 2 in the crossover phase were injected with ranibizumab on an as-needed basis. Eyes assigned to Group 3 or Group 4 in the crossover phase were injected with bevacizumab on an as-needed basis. Participants with two eyes assigned who had at least one follow-up visit in the post-36-week extension are included in the number of participants at risk. Participants for whom one eye was assigned (unilateral participants) are not included.
All Cause Mortality
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 Ranibizumab As Needed (Post-36-Week Extension) Bevacizumab As Needed (Post-36-Week Extension) Ranibizumab and Bevacizumab As Needed (Post-36-Week Extension)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
Serious Adverse Events
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 Ranibizumab As Needed (Post-36-Week Extension) Bevacizumab As Needed (Post-36-Week Extension) Ranibizumab and Bevacizumab As Needed (Post-36-Week Extension)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 3/16 (18.8%) 1/13 (7.7%) 1/14 (7.1%) 1/13 (7.7%) 1/25 (4%) 0/24 (0%) 0/4 (0%)
Cardiac disorders
Arrhythmia 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Hepatobiliary disorders
Cholecystitis 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Infections and infestations
Osteomyelitis 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Cellulitis 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Localised infection 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Pneumonia 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Investigations
Blood glucose increased 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Nervous system disorders
Cerebral haemorrhage 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Syncope 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Other (Not Including Serious) Adverse Events
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 Ranibizumab As Needed (Post-36-Week Extension) Bevacizumab As Needed (Post-36-Week Extension) Ranibizumab and Bevacizumab As Needed (Post-36-Week Extension)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 13/16 (81.3%) 12/13 (92.3%) 9/14 (64.3%) 9/13 (69.2%) 13/25 (52%) 12/24 (50%) 4/4 (100%)
Cardiac disorders
Cardiac failure congestive 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Ear and labyrinth disorders
Vertigo 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Eye disorders
Blepharitis 0/16 (0%) 0 1/13 (7.7%) 2 1/14 (7.1%) 2 1/13 (7.7%) 2 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Blepharospasm 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Cataract 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Conjunctival haemorrhage 0/16 (0%) 0 2/13 (15.4%) 2 2/14 (14.3%) 2 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Conjunctivitis 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Corneal erosion 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Dry eye 1/16 (6.3%) 2 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Eye pain 2/16 (12.5%) 2 2/13 (15.4%) 2 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Eye pruritis 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Eyelid oedema 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Lenticular opacities 0/16 (0%) 0 1/13 (7.7%) 2 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Posterior capsule opacification 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Retinal haemorrhage 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 2/4 (50%) 2
Vision blurred 0/16 (0%) 0 2/13 (15.4%) 3 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Vitreous detachment 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Vitreous haematoma 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Vitreous haemorrhage 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 3/24 (12.5%) 4 0/4 (0%) 0
Gastrointestinal disorders
Abdominal discomfort 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 1/4 (25%) 1
Colitis 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Constipation 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 2/24 (8.3%) 2 0/4 (0%) 0
Diarrhoea 1/16 (6.3%) 1 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Tongue ulceration 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Vomiting 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
General disorders
Adverse drug reaction 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Chest pain 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Influenza like illness 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 2/24 (8.3%) 2 0/4 (0%) 0
Malaise 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Oedema peripheral 1/16 (6.3%) 1 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Peripheral swelling 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 2 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Pyrexia 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Hepatobiliary disorders
Early satiety 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Hepatic cirrhosis 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Immune system disorders
Drug hypersensitivity 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Hypersensitivity 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Infections and infestations
Cellulitis 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Ear infection 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Gastroenteritis viral 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 1/24 (4.2%) 1 1/4 (25%) 1
Influenza 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Localised infection 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Lower respiratory tract infection 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Nasopharyngitis 0/16 (0%) 0 1/13 (7.7%) 1 1/14 (7.1%) 1 3/13 (23.1%) 3 1/25 (4%) 1 0/24 (0%) 0 1/4 (25%) 1
Otitis media 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Pneumonia 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Respiratory tract infection 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Respiratory tract infection viral 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Sinusitis 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Tonsillitis 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Upper respiratory tract infection 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Urinary tract infection 1/16 (6.3%) 1 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 1/25 (4%) 1 2/24 (8.3%) 2 0/4 (0%) 0
Viral infection 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Injury, poisoning and procedural complications
Chest injury 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Corneal abrasion 1/16 (6.3%) 2 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 1/24 (4.2%) 1 0/4 (0%) 0
Fall 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Procedural nausea 2/16 (12.5%) 2 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Stress fracture 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Wound 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Wrist fracture 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 2/13 (15.4%) 2 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Investigations
Albumin urine present 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Blood iron decreased 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Intraocular pressure increased 2/16 (12.5%) 2 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Lymphocte count decreased 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Metabolism and nutrition disorders
Dehydration 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Gout 1/16 (6.3%) 1 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Hyperkalaemia 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Musculoskeletal and connective tissue disorders
Arthralgia 2/16 (12.5%) 2 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Back pain 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Musculoskeletal pain 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 2/13 (15.4%) 2 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Myalgia 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Neck pain 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Pain in extremity 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 2/24 (8.3%) 2 1/4 (25%) 1
Rheumatoid arthritis 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 0/4 (0%) 0
Nervous system disorders
Diabetic neuropathy 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Dizziness 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Hyposmia 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
IIIrd nerve paralysis 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
IVth nerve paralysis 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Sciatica 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Subarachnoid haemorrhage 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
VIIth nerve paralysis 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Psychiatric disorders
Anxiety 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Depressed mood 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Depression 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Reproductive system and breast disorders
Breast mass 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Respiratory, thoracic and mediastinal disorders
Asthma 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 1/4 (25%) 1
Cough 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 1/25 (4%) 1 0/24 (0%) 0 1/4 (25%) 1
Epistaxis 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Sinus congestion 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Skin and subcutaneous tissue disorders
Blister 1/16 (6.3%) 1 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Dermatitis contact 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Rash 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Skin lesion 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 1 0/4 (0%) 0
Surgical and medical procedures
Cyst removal 0/16 (0%) 0 1/13 (7.7%) 1 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Vascular disorders
Hypertension 0/16 (0%) 0 0/13 (0%) 0 1/14 (7.1%) 1 1/13 (7.7%) 1 0/25 (0%) 0 0/24 (0%) 0 0/4 (0%) 0
Hypotension 0/16 (0%) 0 0/13 (0%) 0 0/14 (0%) 0 0/13 (0%) 0 0/25 (0%) 0 1/24 (4.2%) 2 0/4 (0%) 0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

No outcome data should be presented until after a manuscript is accepted for publication.

Results Point of Contact

Name/Title Henry E Wiley, MD, Principal Investigator
Organization National Eye Institute (NEI) at National Institutes of Health (NIH)
Phone (301) 451-4260
Email wileyhe@mail.nih.gov
Responsible Party:
National Eye Institute (NEI)
ClinicalTrials.gov Identifier:
NCT01610557
Other Study ID Numbers:
  • 120134
  • 12-EI-0134
First Posted:
Jun 4, 2012
Last Update Posted:
Aug 19, 2016
Last Verified:
Aug 1, 2016