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Ranibizumab and Bevacizumab for Diabetic Macular Edema

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01610557
First Posted: June 4, 2012
Last Update Posted: August 19, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
The EMMES Corporation
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )
Results First Submitted: February 11, 2016  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition: Diabetic Macular Edema
Interventions: Drug: Ranibizumab
Drug: Bevacizumab

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups
  Description
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.

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.

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.

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.

Ranibizumab/Bevacizumab As Needed

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.


Participant Flow for 2 periods

Period 1:   36-Week Randomized Crossover Phase
    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
STARTED   16 [1]   13 [2]   14 [3]   13 [4]   0 [5] 
COMPLETED   16   12 [6]   14   13   0 [5] 
NOT COMPLETED   0   1   0   0   0 
Withdrawal by Subject                0                1                0                0                0 
[1] Participants randomly assigned to Grp 1: 14 unilateral and 2 bilateral (left eye assigned to Grp 3)
[2] Participants randomly assigned to Grp 2: 12 unilateral and 1 bilateral (left eye assigned to Grp 4)
[3] Participants randomly assigned to Grp 3: 13 unilateral and 1 bilateral (left eye assigned to Grp 1)
[4] Participants randomly assigned to Grp 4: 11 unilateral and 2 bilateral (left eye assigned to Grp 2)
[5] Not applicable for 36-week double-masked randomized crossover phase
[6] Unilateral participant unable to return for visits after Wk 4 due to recovery from an adverse event

Period 2:   Post-36-Week Extension Phase
    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
STARTED   0 [1]   0 [1]   0 [1]   0 [1]   55 
COMPLETED   0 [1]   0 [1]   0 [1]   0 [1]   52 [2] 
NOT COMPLETED   0   0   0   0   3 
Withdrawal by Subject                0                0                0                0                3 
[1] Not applicable for the post-36-week extension phase
[2] 2 bilateral participants withdrew before their first post-36-week extension visit



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly.

Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes.


Reporting Groups
  Description
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.

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.

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.

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.

Total Total of all reporting groups

Baseline Measures
   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 
Overall Participants Analyzed 
[Units: Participants]
 17   15   16   14   62 
Age [1] 
[Units: Years]
Mean (Full Range)
 62.4 
 (39 to 85) 
 65.9 
 (39 to 87) 
 62.3 
 (39 to 83) 
 61.8 
 (51 to 82) 
 63 
 (39 to 87) 
[1] Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes.
Gender [1] 
[Units: Eyes]
         
Female   4   8   7   5   24 
Male   13   7   9   9   38 
[1] Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes.
Ethnicity (NIH/OMB) [1] 
[Units: Eyes]
         
Hispanic or Latino   2   0   1   0   3 
Not Hispanic or Latino   15   15   14   14   58 
Unknown or Not Reported   0   0   1   0   1 
[1] Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes.
Race (NIH/OMB) [1] 
[Units: Eyes]
         
American Indian or Alaska Native   0   0   0   0   0 
Asian   1   0   1   1   3 
Native Hawaiian or Other Pacific Islander   0   0   0   0   0 
Black or African American   2   2   2   2   8 
White   12   13   11   10   46 
More than one race   1   0   2   0   3 
Unknown or Not Reported   1   0   0   1   2 
[1] Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes
Diabetes Type [1] 
[Units: Eyes]
         
Diabetes Type 1   2   2   1   2   7 
Diabetes Type 2   15   13   15   12   55 
[1] Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes
Hemoglobin A1C (%) [1] 
[Units: Percentage of glycosylated hemoglobin]
Mean (Full Range)
 8.1 
 (6.2 to 11.5) 
 8.4 
 (5.8 to 12.2) 
 7.9 
 (6.2 to 10.6) 
 7.8 
 (5.8 to 10.3) 
 8.1 
 (5.8 to 12.2) 
[1] Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes.
Best-corrected visual acuity [1] 
[Units: ETDRS letters]
Mean (Full Range)
 65 
 (38 to 78) 
 61 
 (32 to 73) 
 65 
 (44 to 75) 
 65 
 (50 to 78) 
 64 
 (32 to 78) 
[1]

Best-corrected visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS chart.

Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes.

Optical Coherence Tomography (OCT) Central Subfield Mean Thickness [1] 
[Units: Micrometers]
Mean (Full Range)
 484 
 (334 to 720) 
 444 
 (366 to 602) 
 471 
 (362 to 606) 
 508 
 (358 to 653) 
 477 
 (334 to 720) 
[1]

Participants with both eyes enrolled are counted twice (by eye), once for each of the treatment sequences to which an eye was assigned randomly. Although 56 participants enrolled, 6 participants had two eyes enrolled for a total of 62 eyes.

Optical Coherence Tomography (OCT) scans were masked and graded at an external reading center (Duke University, Durham, North Carolina).



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   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 ]

Measure Type Primary
Measure 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)
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.

Reporting Groups
  Description
Bevacizumab Represents the estimated effect of bevacizumab for a 3-month period, adjusted for period and baseline value.
Ranibizumab Represents the estimated effect of ranibizumab for a 3-month period, adjusted for period and baseline value.

Measured Values
   Bevacizumab   Ranibizumab 
Participants Analyzed 
[Units: Participants]
 55   55 
Units Analyzed (Eyes) 
[Units: Eyes]
 61   61 
Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to 36 Weeks (Crossover Phase of the Study) 
[Units: ETDRS letters]
Mean (95% Confidence Interval)
 5.3 
 (3.2 to 7.4) 
 6.6 
 (4.5 to 8.7) 


Statistical Analysis 1 for Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to 36 Weeks (Crossover Phase of the Study)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Linear mixed-effects model
P Value [4] 0.039
Mean Difference (Final Values) [5] 1.3
95% Confidence Interval 0.07 to 2.5
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  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:   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)   [ Time Frame: Baseline and 36 Weeks ]

Measure Type Secondary
Measure 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)
Measure 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  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
A total of 56 participants (62 eyes) were enrolled and 55 participants (61 eyes) completed the 36-week crossover phase of the study.

Reporting Groups
  Description
Bevacizumab Represents the estimated effect of bevacizumab for a 3-month period, adjusted for period and baseline value.
Ranibizumab Represents the estimated effect of ranibizumab for a 3-month period, adjusted for period and baseline value.

Measured Values
   Bevacizumab   Ranibizumab 
Participants Analyzed 
[Units: Participants]
 55   55 
Units Analyzed (Eyes) 
[Units: Eyes]
 61   61 
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) 
[Units: Micrometers]
Mean (95% Confidence Interval)
 -89 
 (-116 to -62) 
 -137 
 (-164 to -110) 


Statistical Analysis 1 for 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)
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Linear mixed-effects model
P Value [4] <0.001
Mean Difference (Final Values) [5] -48
95% Confidence Interval -65 to -31
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[5] Other relevant estimation information:
  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.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


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
e-mail: wileyhe@mail.nih.gov


Publications of Results:
Other Publications:

Responsible Party: National Institutes of Health Clinical Center (CC) ( National Eye Institute (NEI) )
ClinicalTrials.gov Identifier: NCT01610557     History of Changes
Other Study ID Numbers: 120134
12-EI-0134
First Submitted: May 31, 2012
First Posted: June 4, 2012
Results First Submitted: February 11, 2016
Results First Posted: April 27, 2016
Last Update Posted: August 19, 2016