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Extension Study to Compare Long-term Efficacy and Safety of Ranibizumab Intravitreal Injections Versus Dexamethasone Intravitreal Implant in Patients With RVO

Primary Purpose

Retinal Vein Occlusion

Status
Completed
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
RFB002
Dexamethasone
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Retinal Vein Occlusion focused on measuring Macular Degeneration, Macular Edema, Retinal Vein Occlusion, Choroidal Neovascularization, Signs and Symptoms, Retinal Degeneration, Retinal Diseases, Eye Diseases, Venous Thrombosis Sensation Disorders, Dexamethasone acetate, Dexamethasone, Dexamethasone 21-phosphate, BB 1101, Anti-Inflammatory Agents, Therapeutic Uses, Vision, Low, Signs, Vision Disorders

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must have completed the core study assessments at month 6 of study CRFB002EDE17 or CRFB002EDE18, respectively

Exclusion Criteria:

  • Patients who experienced an uncontrollable rise in IOP during the core study CRFB002EDE17 respectively CRFB002EDE18, i.e. IOP could not be decreased to a stable level of < 25mmHg.
  • Use of other investigational drugs
  • Current use or likely need of systemic medications known to be toxic to the lens, retina or optic nerve
  • History of hypersensitivity to Ranibizumab or Ozurdex or any component of the ranibizumab respectively Ozurdey formulation
  • Any type of advanced, severe or unstable disease or its treatment, that could interfere with evaluations or put the patient at special risk
  • Women
  • who were pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5 mIU/mL)

  • who were menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception (Pearl Index <1**)*** during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche was required with sufficient lead time before randomization

    • definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy

      • examples of particularly reliable methods with Pearl Index (PI) <1, according to guidelines of "Deutsche Gesellschaft für Gynäkologie und Geburtshilfe":

        • Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9)
        • Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.)
        • Contraceptive patch (EVRA®, PI= 0.72 uncorr.; 0.9 corr.)
        • Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14)
        • Progestin-containing contraceptives (Implanon®, PI=0-0.08)
        • Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.)
        • Intra-uterine progestin device (Mirena®, PI=0.16)

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

Ranibizumab (Arm A)

Dexamethasone (Arm B)

Arm Description

The PRN injection scheme applied in the core study will also be followed during this extension study: Patients should be monitored monthly (starting at V1E) for VA and treatment is to be resumed when monitoring indicates loss of VA due to disease activity. Monthly injections should then be administered until stable VA is reached again for 3 consecutive monthly assessments (implying a minimum of 2 injections during stable VA). The interval between 2 doses should not be shorter than 1 month

A PRN re-treatment scheme will be applied for the Ozurdex arm during this extension study, i.e. patients may receive an implant at V1E or later as needed: Patients should be monitored monthly and if there is a decline from stable VA stability due to macular edema patients will receive another intravitreal implant. (700 µg; long acting release (LAR)) given that in the opinion of the investigator the patient would benefit from the re-treatment. However, a minimum period of 5 months in between implantations is required.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events as a Measure of Safety and Tolerability
The number of participants who experienced Adverse events, serious AE and death

Secondary Outcome Measures

Raw Mean Best Corrected Visual Acuity (BCVA) by Treatment Group
Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (EDTRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. The range of BCVA (EDTRS) is 0 to 100 letters. A positive change from baseline of BCVA indicates improvement
Percentage of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters at Month 12 Compared to Baseline
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increased score indicates improvement in acuity. This outcome assessed the percentage of participants who were gaining/losing ≥15, 10 or 5 more letters of visual acuity at month 12 as compared with baseline
Change in Central Subfield Thickness (CSRT) From Baseline to Month 12
High Resolution OCT was performed at every study visit by Spectral Domain OCT (if not available Time Domain OCT was acceptable) and the images were transferred to a digital video disc. These assessments were performed by trained and adequately qualified experts at the sites and prior to any study drug administration. CSFT is the average retinal thickness of the circular area with 1 mm diameter around the foveal center.
Change of Foveal Center Point Thickness (FCPT) From Baseline to Month 12
FCPT (foveal center point thickness) was assessed by central reading center to ensure error- corrected measurements of retinal thickness and volumes,
Change in Mean Visual Function Questionnaire (VFQ-25)
The VFQ-25 composite and subscale scores range from 0 to 100, a higher score indicating better functioning. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function.
Change in SF-36 Summary Scores
The SF-36 measures the impact of disease on overall quality of life and consists of eight subscales (physical function, pain, general and mental health, vitality, social function, physical and emotional health) which can be aggregated to derive a physical-component summary score and a mental-component summary score. Scores for each subscale range from 0 to 10, and the composite scores range from 0 to 100, with higher scores indicating better health. A positive change from Baseline score indicates improvement in quality of life.
Change in Euro Quality of Life Questionnaire (EQ-5D) VAS Summary Scores
The Euro Quality of Life Questionnaire (EQ-5D) standardized instrument was utilized to measure health outcomes related to mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Participants self-rate their health on a visual, vertical analogue scale from 0 to 100 where the endpoints are labeled "Best imaginable health state" (100) and "worst imaginable health state" (0).
Time to the First Retreatment of Both Treatment Arms
Time to the first retreatment

Full Information

First Posted
April 16, 2012
Last Updated
April 11, 2016
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01580020
Brief Title
Extension Study to Compare Long-term Efficacy and Safety of Ranibizumab Intravitreal Injections Versus Dexamethasone Intravitreal Implant in Patients With RVO
Official Title
An Open-label, Multi-center, 6-month Extension Study Comparing the Long-term Efficacy and Safety of Lucentis (Ranibizumab) Intravitreal Injections Versus Ozurdex (Dexamethasone) Intravitreal Implant in Patients With Visual Impairment Due to Macular Edema Following Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO) Who Have Completed the Respective Core Study (CRFB002EDE17 or CRFB002EDE18)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2016
Overall Recruitment Status
Completed
Study Start Date
May 2012 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The study is intended to characterize the clinical benefit regarding safety and efficacy of a long term treatment with Lucentis in comparison with Ozurdex over an additional 6 months and a 3-month follow-up period, following the initial 6-month treatment in the respective core studies CRFB002EDE17 (NCT01396057) and CRFB002EDE18 (NCT01396083).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Retinal Vein Occlusion
Keywords
Macular Degeneration, Macular Edema, Retinal Vein Occlusion, Choroidal Neovascularization, Signs and Symptoms, Retinal Degeneration, Retinal Diseases, Eye Diseases, Venous Thrombosis Sensation Disorders, Dexamethasone acetate, Dexamethasone, Dexamethasone 21-phosphate, BB 1101, Anti-Inflammatory Agents, Therapeutic Uses, Vision, Low, Signs, Vision Disorders

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
175 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ranibizumab (Arm A)
Arm Type
Experimental
Arm Description
The PRN injection scheme applied in the core study will also be followed during this extension study: Patients should be monitored monthly (starting at V1E) for VA and treatment is to be resumed when monitoring indicates loss of VA due to disease activity. Monthly injections should then be administered until stable VA is reached again for 3 consecutive monthly assessments (implying a minimum of 2 injections during stable VA). The interval between 2 doses should not be shorter than 1 month
Arm Title
Dexamethasone (Arm B)
Arm Type
Sham Comparator
Arm Description
A PRN re-treatment scheme will be applied for the Ozurdex arm during this extension study, i.e. patients may receive an implant at V1E or later as needed: Patients should be monitored monthly and if there is a decline from stable VA stability due to macular edema patients will receive another intravitreal implant. (700 µg; long acting release (LAR)) given that in the opinion of the investigator the patient would benefit from the re-treatment. However, a minimum period of 5 months in between implantations is required.
Intervention Type
Biological
Intervention Name(s)
RFB002
Intervention Description
0.5 mg/0.05 mL solution to be injected intravitreally. Ranibizumab was formulated as a sterile solution aseptically filled in a sterile glass vial. Each vial contained ranibizumab in an aqueous solution (pH 5.5) with histidine, trehalose and polysorbate 20.
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
Ozurdex (Dexamethasone): intravitreal implant as per commercial label (700 µg Dexamethasone; Dexamethasone was formulated as a rod shaped implant to be inserted into the eye by an applicator. The implant as well as the respective applicator were suitable for single use only. Dexamethasone had to be stored according to label instructions and it had to be kept in a secure locked facility
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Description
The number of participants who experienced Adverse events, serious AE and death
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Raw Mean Best Corrected Visual Acuity (BCVA) by Treatment Group
Description
Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (EDTRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. The range of BCVA (EDTRS) is 0 to 100 letters. A positive change from baseline of BCVA indicates improvement
Time Frame
Baseline, 6 months and 12 months
Title
Percentage of Patients Gaining / Losing ≥ 15 / 10 / 5 Letters at Month 12 Compared to Baseline
Description
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increased score indicates improvement in acuity. This outcome assessed the percentage of participants who were gaining/losing ≥15, 10 or 5 more letters of visual acuity at month 12 as compared with baseline
Time Frame
12 month
Title
Change in Central Subfield Thickness (CSRT) From Baseline to Month 12
Description
High Resolution OCT was performed at every study visit by Spectral Domain OCT (if not available Time Domain OCT was acceptable) and the images were transferred to a digital video disc. These assessments were performed by trained and adequately qualified experts at the sites and prior to any study drug administration. CSFT is the average retinal thickness of the circular area with 1 mm diameter around the foveal center.
Time Frame
Baseline , Month 12
Title
Change of Foveal Center Point Thickness (FCPT) From Baseline to Month 12
Description
FCPT (foveal center point thickness) was assessed by central reading center to ensure error- corrected measurements of retinal thickness and volumes,
Time Frame
Baseline, Month 12
Title
Change in Mean Visual Function Questionnaire (VFQ-25)
Description
The VFQ-25 composite and subscale scores range from 0 to 100, a higher score indicating better functioning. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function.
Time Frame
Baseline, 12 months
Title
Change in SF-36 Summary Scores
Description
The SF-36 measures the impact of disease on overall quality of life and consists of eight subscales (physical function, pain, general and mental health, vitality, social function, physical and emotional health) which can be aggregated to derive a physical-component summary score and a mental-component summary score. Scores for each subscale range from 0 to 10, and the composite scores range from 0 to 100, with higher scores indicating better health. A positive change from Baseline score indicates improvement in quality of life.
Time Frame
Baseline, month 12
Title
Change in Euro Quality of Life Questionnaire (EQ-5D) VAS Summary Scores
Description
The Euro Quality of Life Questionnaire (EQ-5D) standardized instrument was utilized to measure health outcomes related to mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Participants self-rate their health on a visual, vertical analogue scale from 0 to 100 where the endpoints are labeled "Best imaginable health state" (100) and "worst imaginable health state" (0).
Time Frame
Baseline, month 12
Title
Time to the First Retreatment of Both Treatment Arms
Description
Time to the first retreatment
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have completed the core study assessments at month 6 of study CRFB002EDE17 or CRFB002EDE18, respectively Exclusion Criteria: Patients who experienced an uncontrollable rise in IOP during the core study CRFB002EDE17 respectively CRFB002EDE18, i.e. IOP could not be decreased to a stable level of < 25mmHg. Use of other investigational drugs Current use or likely need of systemic medications known to be toxic to the lens, retina or optic nerve History of hypersensitivity to Ranibizumab or Ozurdex or any component of the ranibizumab respectively Ozurdey formulation Any type of advanced, severe or unstable disease or its treatment, that could interfere with evaluations or put the patient at special risk Women who were pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5 mIU/mL) who were menstruating and capable of becoming pregnant* and not practicing a medically approved method of contraception (Pearl Index <1**)*** during and up to at least 4 weeks after the end of treatment. A negative pregnancy test (serum) for all women and for girls entering menarche was required with sufficient lead time before randomization definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy examples of particularly reliable methods with Pearl Index (PI) <1, according to guidelines of "Deutsche Gesellschaft für Gynäkologie und Geburtshilfe": Combination pill with estrogen and gestagen (no mini-pill, PI=0.1-0.9) Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.) Contraceptive patch (EVRA®, PI= 0.72 uncorr.; 0.9 corr.) Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14) Progestin-containing contraceptives (Implanon®, PI=0-0.08) Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.) Intra-uterine progestin device (Mirena®, PI=0.16)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Augsburg
ZIP/Postal Code
85155
Country
Germany
Facility Name
Novartis Investigative Site
City
Bad Rothenfelde
ZIP/Postal Code
49214
Country
Germany
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
10713
Country
Germany
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigative Site
City
Bonn
ZIP/Postal Code
53127
Country
Germany
Facility Name
Novartis Investigative Site
City
Bremen
ZIP/Postal Code
28209
Country
Germany
Facility Name
Novartis Investigative Site
City
Chemnitz
ZIP/Postal Code
09113
Country
Germany
Facility Name
Novartis Investigative Site
City
Darmstadt
ZIP/Postal Code
64297
Country
Germany
Facility Name
Novartis Investigative Site
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Novartis Investigative Site
City
Duesseldorf
ZIP/Postal Code
40225
Country
Germany
Facility Name
Novartis Investigative Site
City
Düsseldorf
ZIP/Postal Code
40212
Country
Germany
Facility Name
Novartis Investigative Site
City
Frankfurt
ZIP/Postal Code
60318
Country
Germany
Facility Name
Novartis Investigative Site
City
Freiburg i. Br
ZIP/Postal Code
79106
Country
Germany
Facility Name
Novartis Investigative Site
City
Glauchau
ZIP/Postal Code
08371
Country
Germany
Facility Name
Novartis Investigative Site
City
Göttingen
ZIP/Postal Code
37075
Country
Germany
Facility Name
Novartis Investigative Site
City
Halle
ZIP/Postal Code
06114
Country
Germany
Facility Name
Novartis Investigative Site
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Novartis Investigative Site
City
Ingolstadt
ZIP/Postal Code
85049
Country
Germany
Facility Name
Novartis Investigative Site
City
Karlsruhe
ZIP/Postal Code
76133
Country
Germany
Facility Name
Novartis Investigative Site
City
Karlsruhe
ZIP/Postal Code
76199
Country
Germany
Facility Name
Novartis Investigative Site
City
Koeln
ZIP/Postal Code
50935
Country
Germany
Facility Name
Novartis Investigative Site
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Novartis Investigative Site
City
Ludwigshafen
ZIP/Postal Code
67063
Country
Germany
Facility Name
Novartis Investigative Site
City
Marburg
ZIP/Postal Code
35039
Country
Germany
Facility Name
Novartis Investigative Site
City
Minden
ZIP/Postal Code
32427
Country
Germany
Facility Name
Novartis Investigative Site
City
Muelheim
ZIP/Postal Code
45468
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenster
ZIP/Postal Code
48145
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Novartis Investigative Site
City
München
ZIP/Postal Code
80336
Country
Germany
Facility Name
Novartis Investigative Site
City
München
ZIP/Postal Code
81675
Country
Germany
Facility Name
Novartis Investigative Site
City
Recklinghausen
ZIP/Postal Code
45657
Country
Germany
Facility Name
Novartis Investigative Site
City
Regensburg
ZIP/Postal Code
93042
Country
Germany
Facility Name
Novartis Investigative Site
City
Sulzbach
ZIP/Postal Code
66280
Country
Germany
Facility Name
Novartis Investigative Site
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Novartis Investigative Site
City
Ulm
ZIP/Postal Code
89075
Country
Germany
Facility Name
Novartis Investigative Site
City
Wolfsburg
ZIP/Postal Code
38442
Country
Germany
Facility Name
Novartis Investigative Site
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany

12. IPD Sharing Statement

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Extension Study to Compare Long-term Efficacy and Safety of Ranibizumab Intravitreal Injections Versus Dexamethasone Intravitreal Implant in Patients With RVO

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