A Study Evaluating Dosing Regimens for Treatment With Intravitreal Ranibizumab Injections in Subjects With Macular Edema Following Retinal Vein Occlusion

A Multicenter Randomized Study Evaluating Dosing Regimens for Treatment With Intravitreal Ranibizumab Injections in Subjects With Macular Edema Following Retinal Vein Occlusion

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01277302

Enrollment

202

Registered

2011-01-14

Start date

2011-02-28

Completion date

2012-10-31

Last updated

2014-04-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Macular Edema

Brief summary

This was a Phase IV multicenter, randomized, open-label study, with masking of the vision examiner, of the efficacy and safety of intravitreal ranibizumab 0.5 mg in subjects with macular edema following Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO).

Detailed description

This study consisted of 2 study periods, a 7-month fixed treatment period, followed by an 8-month alternate dose regimen period. Subjects could receive up to a maximum of 15 monthly injections of ranibizumab 0.5 mg during the study, 7 injections (Day 0 and at 6 monthly visits) in the fixed treatment period and a maximum of 8 injections in the alternate dose regimen period. During the fixed treatment period, subjects received 7 monthly intravitreal ranibizumab 0.5 mg injections. During the alternate dose regimen period, from Month 7 through Month 14, subjects were evaluated monthly to determine whether they achieved the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria. Subjects continued to receive monthly ranibizumab 0.5 mg monthly injections until the VA-OCT stability criteria were first met. Upon meeting the VA-OCT stability criteria for the first time during the alternate dose regimen period, subjects were randomly assigned in a 1:1 ratio to one of 2 dose regimens, the PRN (pro re nata, as-needed) or the Monthly regimen. PRN randomized subjects: Subjects received no injection at the randomization visit and at future monthly visits where the VA-OCT stability criteria were met and received a ranibizumab 0.5 mg injection at future monthly visits if the VA-OCT stability criteria were not met. Monthly randomized subjects: Subjects continued to receive ranibizumab 0.5 mg injections at each monthly visit. Monthly non-randomized subjects: Subjects who did not meet the VA-OCT stability criteria at any month from Month 7 through Month 14 were not randomized and received 8 monthly intravitreal ranibizumab 0.5 mg injections.

Interventions

DRUGRanibizumab

Liquid ranibizumab (10 mg/ml) was supplied in a sterile solution in single-use vials.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study. Ocular Inclusion Criteria (Study Eye) * Foveal center-involved macular edema secondary to branch retinal vein occlusion (BRVO) (including hemi-retinal retinal vein occlusion \[HRVO\]) or central retinal vein occlusion (CRVO). * Best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts of 20/40 to 20/320 (Snellen equivalent) in the study eye. * Mean central subfield thickness \> 300 µm on 2 spectral-domain optical coherence tomography measurements (screening and Day 0 \[first day of treatment\]).

Exclusion criteria

* History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0. * History of any systemic anti-vascular endothelial growth factor (VEGF) or pro-VEGF treatment within 6 months prior to Day 0. * History of allergy to fluorescein. * History of allergy to ranibizumab injection or related molecule. * Relevant systemic disease that may be associated with increased systemic VEGF levels. History of successfully treated malignancies is not an exclusion criterion. * Uncontrolled blood pressure. * Pregnancy or lactation. * Daily use of oral corticosteroids to treat a chronic condition. * Required treatment with injectable corticosteroids to treat a musculoskeletal condition. * Participation in an investigational trial within 30 days prior to Day 0 that involved treatment with any drug or device that has not received regulatory approval at the time of study entry. Ocular

Design outcomes

Primary

Measure	Time frame	Description
Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15	Baseline to Month 15	BCVA was measured in the study eye 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. The reported data are the observed changes from Baseline in BCVA at Months 7 and 15. For the statistical analysis, the interaction term of treatment by time in a longitudinal model was used to assess whether there was a difference in the trend of change from Baseline in the visual acuity scores from Month 7 to Month 15 between the 2 randomized treatment groups, Monthly and PRN.

Secondary

Measure	Time frame	Description
Percentage of Participants Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline	Month 7 to Month 15	BCVA was measured in the study eye 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.
Percentage of Participants With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better	Month 7 to Month 15	VA was measured in the study eye 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.
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 1 to Month 15	BCVA was measured in the study eye 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.
Visual Acuity Change From Previous Month During the Alternate Dose Regimen Period in Subjects Who Met the VA-OCT Stability Criteria at the Previous Month	Month 7 through Month 15	BCVA was measured in the study eye 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. This outcome measure is not relevant for subjects in the non-randomized group because they never met the VA-OCT stability criteria.
Percentage of Participants With a Central Foveal Thickness of ≤ 300 µm	Month 7 to Month 15	Central foveal thickness was assessed monthly in the study eye using spectral-domain optical coherence tomography. Central foveal thickness was computed using the automated Cirrus Review software (DOCTR CZM Cirrus OCT Grader Reading Manual, Version 1.02). All participants in the Monthly and PRN groups had a baseline central foveal thickness \> 300 µm at baseline.
Mean Change From Baseline in Central Foveal Thickness	Month 1 to Month 15	Central foveal thickness was assessed monthly in the study eye using spectral-domain optical coherence tomography. Central foveal thickness was computed using the automated Cirrus Review software (DOCTR CZM Cirrus OCT Grader Reading Manual, Version 1.02). All participants in the Monthly and PRN groups had a baseline central foveal thickness \> 300 µm at baseline. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Percentage of Participants With Intraretinal Edema	Month 7 to Month 15	The presence of intraretinal edema was defined as the presence of subretinal fluid, cystoid spaces, or central retinal thickness ≥ 300 µm as evaluated in spectral-domain optical coherence tomography images by the Digital Angiography Reading Center, the central reading center. At baseline, all participants in the Monthly and PRN groups had presence of edema.
Percentage of Participants Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline	Month 7 to Month 15	BCVA was measured in the study eye 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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Ranibizumab 0.5 mg Monthly - Randomized Subjects Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	85
Ranibizumab 0.5 mg PRN - Randomized Subjects Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	86
Ranibizumab 0.5 mg Monthly - Non-randomized Subjects Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.	31
Total	202

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
7-Month Fixed Treatment Period	Lost to Follow-up	0	0	2
7-Month Fixed Treatment Period	Subject Decision to Withdraw	0	0	8
7-Month Fixed Treatment Period	Subject Non-compliance	0	0	1
7-Month Fixed Treatment Period	Subject Required Other Drug Therapy	0	0	1
8-Month Alternate Dose Regimen Period	Death	0	1	0
8-Month Alternate Dose Regimen Period	Lost to Follow-up	1	1	3
8-Month Alternate Dose Regimen Period	Relocation	1	0	1
8-Month Alternate Dose Regimen Period	Subject Decision to Withdraw	3	0	1
8-Month Alternate Dose Regimen Period	Subject Non-compliance	0	2	1

Baseline characteristics

Characteristic	Total	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Age, Continuous	66.3 years STANDARD_DEVIATION 12.4	67.3 years STANDARD_DEVIATION 12.1	65.2 years STANDARD_DEVIATION 12.8	66.3 years STANDARD_DEVIATION 12.3
Sex: Female, Male Female	84 Participants	38 Participants	37 Participants	9 Participants
Sex: Female, Male Male	118 Participants	47 Participants	49 Participants	22 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	70 / 85	61 / 86	18 / 31
serious Total, serious adverse events	12 / 85	14 / 86	11 / 31

Outcome results

Primary

Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15

BCVA was measured in the study eye 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. The reported data are the observed changes from Baseline in BCVA at Months 7 and 15. For the statistical analysis, the interaction term of treatment by time in a longitudinal model was used to assess whether there was a difference in the trend of change from Baseline in the visual acuity scores from Month 7 to Month 15 between the 2 randomized treatment groups, Monthly and PRN.

Time frame: Baseline to Month 15

Population: Intent-to-treat population, randomized: All enrolled participants who received at least 1 ranibizumab injection in the study and were randomized into the Monthly or PRN treatment groups. The analysis was based on observed data without imputation for missing values.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15	Month 7 (n=85, 86)	17.5 Letters	Standard Deviation 12.6
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15	Month 15 (n=80, 82)	18.7 Letters	Standard Deviation 14.1
Ranibizumab 0.5 mg PRN - Randomized Subjects	Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15	Month 7 (n=85, 86)	19.7 Letters	Standard Deviation 12.6
Ranibizumab 0.5 mg PRN - Randomized Subjects	Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15	Month 15 (n=80, 82)	21.0 Letters	Standard Deviation 14.1

Comparison: The null hypothesis was that there was no difference in the trend of change from Baseline in the visual acuity scores from Month 7 to Month 15 between the 2 treatment groups as assessed by the interaction term of treatment by time in a longitudinal model.p-value: 0.5091Longitudinal mixed model

Secondary

Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score

Time frame: Month 1 to Month 15

Population: Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 15 (n=80, 82, 13)	18.7 Letters	Standard Deviation 14.1
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 7 (n=85, 86, 17)	17.5 Letters	Standard Deviation 12.6
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 1 (n=85, 86, 29)	12.2 Letters	Standard Deviation 10.3
Ranibizumab 0.5 mg PRN - Randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 7 (n=85, 86, 17)	19.7 Letters	Standard Deviation 12.6
Ranibizumab 0.5 mg PRN - Randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 1 (n=85, 86, 29)	11.2 Letters	Standard Deviation 10.4
Ranibizumab 0.5 mg PRN - Randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 15 (n=80, 82, 13)	21.0 Letters	Standard Deviation 14.1
Ranibizumab 0.5 mg Monthly - Non-randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 1 (n=85, 86, 29)	10.7 Letters	Standard Deviation 14
Ranibizumab 0.5 mg Monthly - Non-randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 15 (n=80, 82, 13)	14.5 Letters	Standard Deviation 14.7
Ranibizumab 0.5 mg Monthly - Non-randomized Subjects	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score	Month 7 (n=85, 86, 17)	14.7 Letters	Standard Deviation 12

Secondary

Mean Change From Baseline in Central Foveal Thickness

Central foveal thickness was assessed monthly in the study eye using spectral-domain optical coherence tomography. Central foveal thickness was computed using the automated Cirrus Review software (DOCTR CZM Cirrus OCT Grader Reading Manual, Version 1.02). All participants in the Monthly and PRN groups had a baseline central foveal thickness \> 300 µm at baseline. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.

Time frame: Month 1 to Month 15

Arm	Measure	Group	Value (MEAN)	Dispersion
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 7 (n=85, 86, 17)	-279.7 µm	Standard Deviation 167.4
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 1 (n=85, 86, 29)	-243.0 µm	Standard Deviation 172.5
Ranibizumab 0.5 mg Monthly - Randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 15 (n=80, 82, 13)	-289.9 µm	Standard Deviation 177.2
Ranibizumab 0.5 mg PRN - Randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 7 (n=85, 86, 17)	-265.2 µm	Standard Deviation 185.9
Ranibizumab 0.5 mg PRN - Randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 1 (n=85, 86, 29)	-214.9 µm	Standard Deviation 166.7
Ranibizumab 0.5 mg PRN - Randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 15 (n=80, 82, 13)	-247.8 µm	Standard Deviation 207.5
Ranibizumab 0.5 mg Monthly - Non-randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 1 (n=85, 86, 29)	-157.9 µm	Standard Deviation 181.8
Ranibizumab 0.5 mg Monthly - Non-randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 15 (n=80, 82, 13)	-93.2 µm	Standard Deviation 225.2
Ranibizumab 0.5 mg Monthly - Non-randomized Subjects	Mean Change From Baseline in Central Foveal Thickness	Month 7 (n=85, 86, 17)	-113.9 µm	Standard Deviation 184.9

Secondary