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: July 31, 2013
Last verified: July 2013
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
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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
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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/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.

Participant Flow:   Overall 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 needed other treatment                 0                 1                 3  
Subject's decision                 9                 8                 19  



  Baseline Characteristics
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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.
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Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 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
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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 ]
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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 and 36   [ Time Frame: Baseline to Months 24 and 36 ]

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

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

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 Months 24 and 36 ]

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

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 Months 24 and 36 ]

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

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

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


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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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