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

NCT00687804 | Completed Phase 3 Results

• 2 other identifiers: CRFB002D2301EUDRACT: 2007-004877-24
• Study Type: interventional
• Target: 345
• Locations: 13 countries
• Sites: 13

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.

Conditions

Diabetic Macular Edema

Keywords

DME; Diabetic; macula; edema; ranibizumab; RESTORE

Outcome Measures

Primary Outcomes (3)

• 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

  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.

  Baseline through the end of study (Month 12)

• Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study

  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 baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]

• Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study

  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 baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]

Secondary Outcomes (8)

• Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12

  Baseline to Month 12

• Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time

  Baseline to Month 12

• Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye

  Baseline to Month 12

• Core Study: Mean Change From Baseline in Patient-reported Visual Functioning

  Baseline to Month 12

• Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies

  Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 months]

Study Arms (3)

Ranibizumab 0.5 mg

EXPERIMENTAL

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.

Drug: Ranibizumab; Procedure: Laser; Procedure: Sham laser

Ranibizumab 0.5 mg + laser

EXPERIMENTAL

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.

Drug: Ranibizumab; Procedure: Laser

Laser

ACTIVE COMPARATOR

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.

Drug: Ranibizumab; Procedure: Laser; Drug: Sham to ranibizumab

Interventions

Ranibizumab DRUG

0.5 mg ranibizumab administered by intravitreal injection.

Laser; Ranibizumab 0.5 mg; Ranibizumab 0.5 mg + laser

Laser PROCEDURE

Laser photocoagulation treatment

Laser; Ranibizumab 0.5 mg; Ranibizumab 0.5 mg + laser

Sham laser PROCEDURE

Sham to laser procedure.

Ranibizumab 0.5 mg

Sham to ranibizumab DRUG

Sham to ranibizumab administered as an intravitreal injection.

Laser

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• Completion of the Core Study

Sponsors & Collaborators

• Novartis: lead

Study Sites (13)

Novartis Investigative Site

Melbourne, Australia

Location

Novartis Investigative Site

Leuven, Belgium

Location

Novartis Investigative Site

Ontario, Canada

Location

Novartis Investigative Site

Paris, France

Location

Novartis Investigative Site

Düsseldorf, Germany

Location

Novartis Investigative Site

Athens, Greece

Location

Novartis Investigative Site

Budapest, Hungary

Location

Novartis Investigative Site

Florence, Italy

Location

Novartis Investigative Site

Amsterdam, Netherlands

Location

Novartis Investigative Site

Barcelona, Spain

Location

Novartis Investigational Site

Zurich, Switzerland

Location

Novartis Investigative Site

Ankara, Turkey (Türkiye)

Location

Novartis Investigative Site

Upton, United Kingdom

Location

Related Publications (6)

• Bressler NM, Varma R, Mitchell P, Suner 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.

  PMID: 26584450 DERIVED

• Mitchell P, Massin P, Bressler S, Coon CD, Petrillo J, Ferreira A, Bressler NM. Three-year patient-reported visual function outcomes in diabetic macular edema managed with ranibizumab: the RESTORE extension study. Curr Med Res Opin. 2015 Nov;31(11):1967-75. doi: 10.1185/03007995.2015.1081880. Epub 2015 Oct 6.

  PMID: 26327116 DERIVED

• Bressler NM, Varma R, Suner 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.

  PMID: 25148789 DERIVED

• Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, Gerstner O, Bouazza AS, Shen H, Osborne A, Mitchell P; RESTORE Extension Study Group. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014 May;121(5):1045-53. doi: 10.1016/j.ophtha.2013.11.041. Epub 2014 Feb 1.

  PMID: 24491642 DERIVED

• Mitchell P, Bressler N, Tolley K, Gallagher M, Petrillo J, Ferreira A, Wood R, Bandello F; RESTORE Study Group. Patient-reported visual function outcomes improve after ranibizumab treatment in patients with vision impairment due to diabetic macular edema: randomized clinical trial. JAMA Ophthalmol. 2013 Oct;131(10):1339-47. doi: 10.1001/jamaophthalmol.2013.4592.

  PMID: 23974915 DERIVED

• Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, Simader C, Burian G, Gerstner O, Weichselberger A; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):615-25. doi: 10.1016/j.ophtha.2011.01.031.

  PMID: 21459215 DERIVED

MeSH Terms

Conditions

Edema

Interventions

Ranibizumab; Lasers

Condition Hierarchy (Ancestors)

Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Optical Devices; Equipment and Supplies; Radiation Equipment and Supplies

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862 778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 27, 2008
• First Posted: June 2, 2008
• Study Start: May 1, 2008
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2012
• Last Updated: April 1, 2013
• Results First Posted: April 19, 2011

Record last verified: 2013-03

Locations

CH (1); TU (1); GB (1); ES (1); HU (1); NL (1); GR (1); BE (1); CA (1); FR (1); AU (1); DE (1); IT (1)