A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RISE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00473330
First received: May 13, 2007
Last updated: August 25, 2014
Last verified: August 2014
Results First Received: December 10, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Diabetes Mellitus
Macular Edema
Interventions: Drug: Ranibizumab
Drug: Sham injection

  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
Patients were recruited from study sites in the United States and Argentina. There were 10 patients from Argentina.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.
Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.
Sham Injection/Ranibizumab 0.5 mg Patients received a sham intravitreal injection monthly for 24 months. Patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.

Participant Flow for 3 periods

Period 1:   Core Study
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
STARTED     125     125     127  
COMPLETED     98     100     86  
NOT COMPLETED     27     25     41  
Adverse Event                 4                 4                 1  
Death                 6                 4                 4  
Lost to Follow-up                 5                 5                 10  
Physician Decision                 2                 1                 3  
Subject Non-compliance                 1                 2                 1  
Subject Required Other Therapy                 0                 1                 3  
Subject's Decision                 9                 8                 19  

Period 2:   Open-label Extension Through Month 48
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
STARTED     89 [1]   79 [1]   77 [1]
COMPLETED     63     59     50  
NOT COMPLETED     26     20     27  
Adverse Event                 0                 0                 2  
Death                 2                 0                 0  
Lost to Follow-up                 1                 0                 2  
Physician's Decision                 2                 1                 3  
Subject's Decision                 1                 3                 3  
Sponsor’s Decision to Terminate Study                 18                 15                 16  
Subject Non-compliance                 2                 1                 0  
Subject Required Other Therapy                 0                 0                 1  
[1] Not all participants who completed the core study entered the optional open-label extension.

Period 3:   Open-label Extension Through Month 60
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
STARTED     89 [1]   79 [1]   77 [1]
COMPLETED     1     1     0  
NOT COMPLETED     88     78     77  
Adverse Event                 0                 0                 2  
Death                 2                 2                 1  
Lost to Follow-up                 3                 0                 4  
Physician's Decision                 2                 1                 3  
Subject's Decision                 1                 3                 4  
Sponsor’s Decision to Terminate Study                 77                 71                 62  
Subject Non-compliance                 2                 1                 0  
Subject Required Other Therapy                 1                 0                 1  
[1] Not all participants who completed the core study entered the optional open-label extension.



  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.
The Baseline Characteristics of the patients enrolled in the open-label extension phase (N=88, 83, 84 patients originally randomized to the ranibizumab 0.3 mg, ranibizumab 0.5 mg, and sham injection groups, respectively) were similar to the Baseline Characteristics of the patients enrolled in the core study.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months.
Total Total of all reporting groups

Baseline Measures
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Total  
Number of Participants  
[units: participants]
  125     125     127     377  
Age  
[units: years]
Mean ± Standard Deviation
  61.7  ± 8.9     62.8  ± 10.0     61.8  ± 9.8     62.1  ± 9.6  
Gender  
[units: participants]
       
Female     52     60     53     165  
Male     73     65     74     212  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24   [ Time Frame: Baseline to Month 24 ]

Measure Type Primary
Measure Title Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24
Measure Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Baseline to Month 24  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 24 months.
Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 24 months.
Sham Injection Patients received a sham intravitreal injection monthly for 24 months.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection  
Number of Participants Analyzed  
[units: participants]
  125     125     127  
Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24  
[units: Percentage of patients]
Number ( 95% Confidence Interval )
  44.8  
  ( 36.1 to 53.5 )  
  39.2  
  ( 30.6 to 47.8 )  
  18.1  
  ( 11.4 to 24.8 )  


Statistical Analysis 1 for Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] <0.0001
Difference in percentage at Month 24 [4] 24.3
95% Confidence Interval ( 13.8 to 34.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  An adjustment was made for multiple treatment comparisons of the ranibizumab dose groups with the control group.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2 for Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.0002
Difference in percentage at Month 24 [4] 20.9
95% Confidence Interval ( 10.7 to 31.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  An adjustment was made for multiple treatment comparisons of the ranibizumab dose groups with the control group.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.



2.  Secondary:   Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48   [ Time Frame: Baseline to Month 48 ]

Measure Type Secondary
Measure Title Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48
Measure Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time Frame Baseline to Month 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  125     125     127     127  
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48  
[units: Letters]
Mean ± Standard Deviation
       
Month 24     12.5  ± 14.1     11.9  ± 12.1     2.6  ± 13.9     NA  ± NA [1]
Month 36     14.2  ± 12.8     11.0  ± 12.9     NA  ± NA [1]   4.3  ± 14.9  
Month 48 (n=62,56,0,48)     13.8  ± 12.2     14.4  ± 11.8     NA  ± NA [1]   10.2  ± 11.2  
[1] NA = not applicable, see reporting groups.


Statistical Analysis 1 for Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] ANOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] 9.6
95% Confidence Interval ( 6.1 to 13.0 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] ANOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] 9.4
95% Confidence Interval ( 6.2 to 12.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48   [ Time Frame: Months 24, 36, and 48 ]

Measure Type Secondary
Measure Title Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48
Measure Description VA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the EDTRS chart.
Time Frame Months 24, 36, and 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  125     125     127     127  
Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48  
[units: Percentage of patients]
Number ( 95% Confidence Interval )
       
Month 24     60.0  
  ( 51.4 to 68.6 )  
  63.2  
  ( 54.7 to 71.7 )  
  37.8  
  ( 29.4 to 46.2 )  
  NA  
  ( NA to NA ) [1]
Month 36     63.2  
  ( 54.7 to 71.7 )  
  59.2  
  ( 50.6 to 67.8 )  
  NA  
  ( NA to NA ) [1]
  42.5  
  ( 33.9 to 51.1 )  
Month 48 (n=62,56,0,48)     62.9  
  ( 49.7 to 74.8 )  
  73.2  
  ( 59.7 to 84.2 )  
  NA  
  ( NA to NA ) [1]
  54.2  
  ( 39.2 to 68.6 )  
[1] NA = not applicable, see reporting groups.


Statistical Analysis 1 for Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] <0.0001
Difference in percentage at Month 24 [4] 24.4
95% Confidence Interval ( 13.4 to 35.4 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2 for Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] <0.0001
Difference in percentage at Month 24 [4] 25.1
95% Confidence Interval ( 14.0 to 36.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.



4.  Secondary:   Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48   [ Time Frame: Baseline to Month 48 ]

Measure Type Secondary
Measure Title Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48
Measure Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Baseline to Month 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  125     125     127     127  
Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48  
[units: Percentage of patients]
Number ( 95% Confidence Interval )
       
Month 24     97.6  
  ( 94.9 to 100 )  
  97.6  
  ( 94.9 to 100 )  
  89.8  
  ( 84.5 to 95.0 )  
  NA  
  ( NA to NA ) [1]
Month 36     99.2  
  ( 97.6 to 100 )  
  97.6  
  ( 94.9 to 100 )  
  NA  
  ( NA to NA ) [1]
  91.3  
  ( 86.4 to 96.2 )  
Month 48 (n=62,56,0,48)     100.0  
  ( 94.2 to 100.0 )  
  100.0  
  ( 93.6 to 100.0 )  
  NA  
  ( NA to NA ) [1]
  97.9  
  ( 88.9 to 99.9 )  
[1] NA = not applicable, see reporting groups.


Statistical Analysis 1 for Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.0086
Difference in percentage at Month 24 [4] 8.2
95% Confidence Interval ( 2.4 to 14.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2 for Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.0126
Difference in percentage at Month 24 [4] 7.8
95% Confidence Interval ( 2.0 to 13.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.



5.  Secondary:   Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline   [ Time Frame: Baseline to Month 36 ]

Measure Type Secondary
Measure Title Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline
Measure Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time Frame Baseline to Month 36  
Safety Issue No  

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.
Subgroup of the intent-to-treat population: All randomized patients with focal edema at baseline, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.
Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  54     55     57     57  
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline  
[units: Letters]
Mean ± Standard Deviation
       
Month 24     11.9  ± 14.2     9.8  ± 11.3     2.0  ± 14.3     NA  ± NA [1]
Month 36     14.3  ± 11.2     9.7  ± 12.6     NA  ± NA [1]   4.6  ± 14.4  
[1] NA = not applicable, see reporting groups.


Statistical Analysis 1 for Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] ANOVA
P Value [3] 0.0005
Mean Difference (Final Values) [4] 9.7
95% Confidence Interval ( 4.3 to 15.1 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] ANOVA
P Value [3] 0.0011
Mean Difference (Final Values) [4] 8.2
95% Confidence Interval ( 3.3 to 13.0 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.



6.  Secondary:   Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48   [ Time Frame: Baseline to Month 48 ]

Measure Type Secondary
Measure Title Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48
Measure Description Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time Frame Baseline to Month 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  125     125     127     127  
Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48  
[units: µm]
Mean ± Standard Deviation
       
Month 24     -250.6  ± 212.2     -253.1  ± 183.7     -133.4  ± 209.0     NA  ± NA [1]
Month 36     -261.2  ± 196.5     -269.1  ± 178.9     NA  ± NA [1]   -200.1  ± 215.6  
Month 48 (n=59,55,0,47)     -233.3  ± 186.8     -301.2  ± 155.6     NA  ± NA [1]   -281.3  ± 171.5  
[1] NA = not applicable, see reporting groups.


Statistical Analysis 1 for Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -107.9
95% Confidence Interval ( -149.2 to -66.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -119.1
95% Confidence Interval ( -159.6 to -78.5 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36   [ Time Frame: Baseline to Month 36 ]

Measure Type Secondary
Measure Title Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36
Measure Description The severity of diabetic retinopathy was graded on a 10-point scale by the central reading center by comparing patient fundus photographic images with a set of standard images. 1=diabetic retinopathy (DR) severity level 10, 12 (DR absent), 2=DR severity level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only), 3=DR severity level 35A-35F (mild non-proliferative [NP]DR), 4=DR severity level 43A, 43B (moderate NPDR), 5=DR severity level 47A-47D (moderately severe NPDR), 6=DR severity level 53A-53E (severe NPDR), 7=DR severity level 60, 61A, 61B (mild proliferative [P]DR), 8=DR severity level 65A-65C (moderate PDR), 9=DR severity level 71A-71D (high-risk PDR), 10=DR severity level 90 (cannot grade). A lower score indicates less severe diabetic retinopathy.
Time Frame Baseline to Month 36  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.
Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  117     115     115     115  
Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36  
[units: Percentage of patients]
Number ( 95% Confidence Interval )
       
Month 24 (n=117, 115, 115)     0.9  
  ( 0.0 to 2.5 )  
  1.7  
  ( 0.0 to 4.1 )  
  4.3  
  ( 0.6 to 8.1 )  
  NA  
  ( NA to NA ) [1]
Month 36 (n-117, 115, 115)     1.7  
  ( 0.0 to 4.1 )  
  1.7  
  ( 0.0 to 4.1 )  
  NA  
  ( NA to NA ) [1]
  4.3  
  ( 0.6 to 8.1 )  
[1] NA = not applicable, see reporting groups.


Statistical Analysis 1 for Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.1590
Difference in percentage at Month 24 [4] -3.0
95% Confidence Interval ( -6.7 to 0.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2 for Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.2721
Difference in percentage at Month 24 [4] -2.5
95% Confidence Interval ( -6.5 to 1.4 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.



8.  Secondary:   Percentage of Patients With Resolution of Leakage at Month 24   [ Time Frame: Baseline to Month 24 ]

Measure Type Secondary
Measure Title Percentage of Patients With Resolution of Leakage at Month 24
Measure Description Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center.
Time Frame Baseline to Month 24  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection  
Number of Participants Analyzed  
[units: participants]
  123     123     126  
Percentage of Patients With Resolution of Leakage at Month 24  
[units: Percentage of patients]
Number ( 95% Confidence Interval )
  30.1  
  ( 22.0 to 38.2 )  
  26.0  
  ( 18.3 to 33.8 )  
  1.6  
  ( 0.0 to 3.8 )  


Statistical Analysis 1 for Percentage of Patients With Resolution of Leakage at Month 24
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] <0.0001
Difference in percentage at Month 24 [4] 29.5
95% Confidence Interval ( 21.1 to 38.0 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2 for Percentage of Patients With Resolution of Leakage at Month 24
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] Cochran-Mantel-Haenszel
P Value [3] <0.0001
Difference in percentage at Month 24 [4] 24.2
95% Confidence Interval ( 16.7 to 31.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.



9.  Secondary:   Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36   [ Time Frame: Baseline to Month 36 ]

Measure Type Secondary
Measure Title Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36
Measure Description The need for macular laser treatment was evaluated by the masked (evaluating) physician. Macular laser was administered per protocol-specified objective and subjective criteria starting at Month 3.
Time Frame Baseline to Month 36  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.
Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  125     125     127     127  
Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36  
[units: Treatments]
Mean ± Standard Deviation
       
Month 24     0.8  ± 1.2     0.8  ± 1.3     1.8  ± 1.8     NA  ± NA [1]
Month 36     0.8  ± 1.4     0.9  ± 1.5     NA  ± NA [1]   1.9  ± 1.8  
[1] NA = not applicable, see reporting groups.


Statistical Analysis 1 for Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36
Groups [1] Ranibizumab 0.3 mg vs. Sham Injection
Method [2] ANOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -1.0
95% Confidence Interval ( -1.4 to -0.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36
Groups [1] Ranibizumab 0.5 mg vs. Sham Injection
Method [2] ANOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -1.1
95% Confidence Interval ( -1.5 to -0.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
[4] Other relevant estimation information:
  No text entered.



10.  Secondary:   Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48   [ Time Frame: Baseline to Month 48 ]

Measure Type Secondary
Measure Title Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48
Measure Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Baseline to Month 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  125     125     127  
Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48  
[units: Percentage of patients]
Number ( 95% Confidence Interval )
     
Month 36     51.2  
  ( 42.4 to 60.0 )  
  41.6  
  ( 33.0 to 50.2 )  
  22.0  
  ( 14.8 to 29.3 )  
Month 48 (n=62,56,48)     50.0  
  ( 37.0 to 63.0 )  
  48.2  
  ( 34.7 to 62.0 )  
  22.9  
  ( 12.0 to 37.3 )  

No statistical analysis provided for Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48



11.  Secondary:   Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48   [ Time Frame: Month 36 to Month 48 ]

Measure Type Secondary
Measure Title Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48
Measure Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time Frame Month 36 to Month 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata. PRN) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  62     56     48  
Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48  
[units: Letters]
Mean ± Standard Deviation
  -1.7  ± 7.5     0.8  ± 7.1     1.3  ± 5.4  

No statistical analysis provided for Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48



12.  Secondary:   Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48   [ Time Frame: Month 36 to Month 48 ]

Measure Type Secondary
Measure Title Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48
Measure Description BCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame Month 36 to Month 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata. PRN) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  62     56     48  
Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48  
[units: Percentage of participants]
Number ( 95% Confidence Interval )
  93.5  
  ( 84.3 to 98.2 )  
  96.4  
  ( 87.7 to 99.6 )  
  100.0  
  ( 92.6 to 100.0 )  

No statistical analysis provided for Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48



13.  Secondary:   Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48   [ Time Frame: Month 36 to Month 48 ]

Measure Type Secondary
Measure Title Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48
Measure Description Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time Frame Month 36 to Month 48  
Safety Issue No  

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.
Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata. PRN) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Sham Injection/Ranibizumab 0.5 mg Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.

Measured Values
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
Number of Participants Analyzed  
[units: participants]
  59     55     47  
Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48  
[units: µm]
Mean ± Standard Deviation
  23.3  ± 119.0     4.2  ± 78.6     29.6  ± 89.2  

No statistical analysis provided for Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48




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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
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