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

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Genentech, Inc.

ClinicalTrials.gov Identifier:

NCT00473382

First received: May 13, 2007

Last updated: March 21, 2017

Last verified: March 2017

History of Changes

Results First Received: November 30, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, 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, Argentina, Peru, Columbia, Chile, and Peru. There were 47 patients from the Latin American countries.

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
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.
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.

Participant Flow for 3 periods

Period 1: Core Study

	Sham Injection/Ranibizumab 0.5 mg	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg
STARTED	130	125	127
COMPLETED	102	98	98
NOT COMPLETED	28	27	29
Adverse Event	3	1	1
Death	3	5	10
Lost to Follow-up	3	3	3
Physician Decision	1	2	2
Subject non-compliance	5	2	1
Subject needed other treatment	1	3	2
Subject's decision	12	11	10

Period 2: Open-label Extension Through Month 48

	Sham Injection/Ranibizumab 0.5 mg	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg
STARTED	88 ^[1]	83 ^[1]	84 ^[1]
COMPLETED	38	42	37
NOT COMPLETED	50	41	47
Adverse Event	0	0	1
Death	1	3	3
Lost to Follow-up	1	2	1
Subject's Decision	5	1	6
Sponsor’s Decision to Terminate Study	41	34	36
Subject Required Other Intervention	2	1	0

^[1]	Not all participants who completed the core study entered the optional open-label extension.

Period 3: Open-label Extension Through Month 60

	Sham Injection/Ranibizumab 0.5 mg	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg
STARTED	88 ^[1]	83 ^[1]	84 ^[1]
COMPLETED	2	1	2
NOT COMPLETED	86	82	82
Adverse Event	0	0	2
Death	1	7	4
Lost to Follow-up	1	3	1
Subject's Decision	7	1	6
Sponsor’s Decision to Terminate Study	75	70	69
Subject Required Other Intervention	2	1	0

^[1]	Not all participants who completed the core study entered the optional open-label extension.

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.
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
Overall Participants Analyzed [Units: Participants]	125	127	130	382

Age [Units: Years] Mean (Standard Deviation)	62.7 (11.1)	61.8 (10.1)	63.5 (10.8)	62.7 (10.7)

Sex: Female, Male [Units: Participants] Count of Participants
Female	52 41.6%	47 37.0%	64 49.2%	163 42.7%
Male	73 58.4%	80 63.0%	66 50.8%	219 57.3%

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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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 ]

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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 ]

Show Outcome Measure 3

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 ]

Show Outcome Measure 4

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 ]

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6. Secondary:

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

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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 ]

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8. Secondary:

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

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9. Secondary:

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

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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

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. 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.
Ranibizumab 0.5 mg	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 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.
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
Participants Analyzed [Units: Participants]	125	127	130	130
Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 [Units: Treatments] Mean (Standard Deviation)
Month 24	0.7 (1.4)	0.3 (0.7)	1.6 (1.6)	NA ^[1]
Month 36	0.9 (1.8)	0.4 (0.9)	NA ^[1]	1.7 (1.6)

[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
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	ANOVA
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	-0.9
95% Confidence Interval	-1.3 to -0.5

[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.
[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:
	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).
[4]	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.
[5]	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
Statistical Test Type ^[2]	Superiority or Other
Statistical Method ^[3]	ANOVA
P Value ^[4]	<0.0001
Mean Difference (Final Values) ^[5]	-1.3
95% Confidence Interval	-1.6 to -1.0

[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]	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:
	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).
[4]	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.
[5]	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 ]

Show Outcome Measure 10

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 ]

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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 ]

Show Outcome Measure 12

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 ]

Show Outcome Measure 13

Serious Adverse Events

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Other Adverse Events

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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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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact:

Name/Title: Medical Communications
Organization: Genentech, Inc.
phone: 800 821-8590
e-mail: genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Singh RP, Habbu K, Ehlers JP, Lansang MC, Hill L, Stoilov I. The Impact of Systemic Factors on Clinical Response to Ranibizumab for Diabetic Macular Edema. Ophthalmology. 2016 Jul;123(7):1581-7. doi: 10.1016/j.ophtha.2016.03.038. Epub 2016 May 24.

Pieramici DJ, Wang PW, Ding B, Gune S. Visual and Anatomic Outcomes in Patients with Diabetic Macular Edema with Limited Initial Anatomic Response to Ranibizumab in RIDE and RISE. Ophthalmology. 2016 Jun;123(6):1345-50. doi: 10.1016/j.ophtha.2016.02.007. Epub 2016 Mar 15.

Bressler NM, Varma R, Mitchell P, Suñer IJ, Dolan C, Ward J, Ferreira A, Ehrlich JS, Turpcu A. Effect of Ranibizumab on the Decision to Drive and Vision Function Relevant to Driving in Patients With Diabetic Macular Edema: Report From RESTORE, RIDE, and RISE Trials. JAMA Ophthalmol. 2016 Feb;134(2):160-6. doi: 10.1001/jamaophthalmol.2015.4636.

Boyer DS, Nguyen QD, Brown DM, Basu K, Ehrlich JS; RIDE and RISE Research Group. Outcomes with As-Needed Ranibizumab after Initial Monthly Therapy: Long-Term Outcomes of the Phase III RIDE and RISE Trials. Ophthalmology. 2015 Dec;122(12):2504-13.e1. doi: 10.1016/j.ophtha.2015.08.006. Epub 2015 Oct 9.

Bansal AS, Khurana RN, Wieland MR, Wang PW, Van Everen SA, Tuomi L. Influence of Glycosylated Hemoglobin on the Efficacy of Ranibizumab for Diabetic Macular Edema: A Post Hoc Analysis of the RIDE/RISE Trials. Ophthalmology. 2015 Aug;122(8):1573-9. doi: 10.1016/j.ophtha.2015.04.029. Epub 2015 Jun 4.

Bressler NM, Varma R, Suñer IJ, Dolan CM, Ward J, Ehrlich JS, Colman S, Turpcu A; RIDE and RISE Research Groups. Vision-related function after ranibizumab treatment for diabetic macular edema: results from RIDE and RISE. Ophthalmology. 2014 Dec;121(12):2461-72. doi: 10.1016/j.ophtha.2014.07.008. Epub 2014 Aug 20.

Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014 Sep;121(9):1783-9. doi: 10.1016/j.ophtha.2014.03.021. Epub 2014 Apr 24.

Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, Schlottmann PG, Rundle AC, Zhang J, Rubio RG, Adamis AP, Ehrlich JS, Hopkins JJ; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013 Oct;120(10):2013-22. doi: 10.1016/j.ophtha.2013.02.034. Epub 2013 May 22.

Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012 Sep;130(9):1145-52. doi: 10.1001/archophthalmol.2012.1043.

Responsible Party:	Genentech, Inc.
ClinicalTrials.gov Identifier:	NCT00473382 History of Changes
Other Study ID Numbers:	FVF4168g
Study First Received:	May 13, 2007
Results First Received:	November 30, 2012
Last Updated:	March 21, 2017

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