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A 12 Month Core Study to Assess the Efficacy and Safety of Ranibizumab (Intravitreal Injections) in Patients With Visual Impairment Due to Diabetic Macular Edema and a 24 Month Open-label Extension Study (RESTORE)

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ClinicalTrials.gov Identifier: NCT00687804
Recruitment Status : Completed
First Posted : June 2, 2008
Results First Posted : April 19, 2011
Last Update Posted : April 1, 2013
Sponsor:
Information provided by (Responsible Party):
Novartis

Tracking Information
First Submitted Date  ICMJE May 27, 2008
First Posted Date  ICMJE June 2, 2008
Results First Submitted Date  ICMJE January 19, 2011
Results First Posted Date  ICMJE April 19, 2011
Last Update Posted Date April 1, 2013
Study Start Date  ICMJE May 2008
Actual Primary Completion Date January 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 17, 2013)
  • Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 [ Time Frame: Baseline through the end of study (Month 12) ]
    Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
  • Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study [ Time Frame: Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months] ]
    Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
  • Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study [ Time Frame: Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months] ]
    Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
Original Primary Outcome Measures  ICMJE
 (submitted: May 30, 2008)
Change from baseline in visual acuity from baseline in 12-month treatment period, treatment with ranibizumab (10 mg/ml)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 17, 2013)
  • Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 [ Time Frame: Baseline to Month 12 ]
    Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
  • Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time [ Time Frame: Baseline to Month 12 ]
    Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
  • Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye [ Time Frame: Baseline to Month 12 ]
    Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation.
  • Core Study: Mean Change From Baseline in Patient-reported Visual Functioning [ Time Frame: Baseline to Month 12 ]
    The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) was used to measure a patient's subjective assessment of vision-related quality of life. 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.
  • Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies [ Time Frame: Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 months] ]
    Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
  • Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies [ Time Frame: Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 Months] ]
    Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about Adverse Events can be found in the Adverse Event section.
  • Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 [ Time Frame: Extension baseline (Month12 -end of core study), Month 36 (end of extension study) ]
    Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.
  • Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 [ Time Frame: Core baseline (Day 1 of the core study), Month 36 (end of extension study) ]
    Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2008)
  • 12 months treatment with ranibizumab (10 mg/ml) and laser photocoagulation as standard of care
  • Change in retinal thickness from baseline
  • Change in Visual acuity from Baseline
  • Quality of Life assessment at baseline, last visit
  • Safety assessment (Incidence of ocular and non-ocular adverse events at each visit)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A 12 Month Core Study to Assess the Efficacy and Safety of Ranibizumab (Intravitreal Injections) in Patients With Visual Impairment Due to Diabetic Macular Edema and a 24 Month Open-label Extension Study
Official Title  ICMJE A Randomized, Double-masked, Multicenter, Laser-controlled Phase III Study Assessing the Efficacy and Safety of Ranibizumab (Intravitreal Injections) as Adjunctive and Mono-therapy in Patients With Visual Impairment Due to Diabetic Macular Edema
Brief Summary

CRFB002D2301: The core study was designed to confirm the efficacy and safety of ranibizumab (0.5 mg) as adjunctive therapy when added to laser photocoagulation and/or mono-therapy in patients with visual impairment due to diabetic macular edema.

CRFB002D2301E1: A 24 month open-label extension study for participants who completed the 12 month core study evaluated the long-term safety and efficacy of ranibizumab (0.5 mg) as symptomatic treatment for visual impairment due to diabetic macular edema.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Macular Edema
Intervention  ICMJE
  • Drug: Ranibizumab
    0.5 mg ranibizumab administered by intravitreal injection.
  • Procedure: Laser
    Laser photocoagulation treatment
  • Procedure: Sham laser
    Sham to laser procedure.
  • Drug: Sham to ranibizumab
    Sham to ranibizumab administered as an intravitreal injection.
Study Arms  ICMJE
  • Experimental: Ranibizumab 0.5 mg

    Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met:

    Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits.

    Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician.

    Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.

    In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.

    Interventions:
    • Drug: Ranibizumab
    • Procedure: Laser
    • Procedure: Sham laser
  • Experimental: Ranibizumab 0.5 mg + laser

    Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met:

    Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits.

    Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician.

    Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.

    In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.

    Interventions:
    • Drug: Ranibizumab
    • Procedure: Laser
  • Active Comparator: Laser

    Laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met:

    Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits.

    Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.

    In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.

    Interventions:
    • Drug: Ranibizumab
    • Procedure: Laser
    • Drug: Sham to ranibizumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 21, 2010)
345
Original Estimated Enrollment  ICMJE
 (submitted: May 30, 2008)
315
Actual Study Completion Date  ICMJE January 2012
Actual Primary Completion Date January 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Visual acuity impairment
  • Diabetic macular edema in at least one eye
  • Type 1 or type 2 diabetes mellitus
  • Medication for the diabetes treatment must be stable for the last 3 months

Exclusion Criteria:

  • Patients with uncontrolled systemic or ocular diseases
  • Laser photocoagulation in the study eye for the last 3 months
  • Any history of any intraocular surgery in the study eye within the past 3 months
  • Blood pressure > 160/100 mmHg

Extension Inclusion Criteria:

-Completion of the Core Study

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   France,   Germany,   Greece,   Hungary,   Italy,   Netherlands,   Spain,   Switzerland,   Turkey,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00687804
Other Study ID Numbers  ICMJE CRFB002D2301
EUDRACT: 2007-004877-24
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis
Study Sponsor  ICMJE Novartis
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date March 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP