Efficacy and Safety of Ranibizumab (Intravitreal Injections) in Patients With Visual Impairment Due to Diabetic Macular Edema

Diabetic Macular Edema Clinical Trial

— REVEAL  

Official title:

A Randomized, Double-masked, Multicenter, Laser Controlled Phase III Study Assessing the Efficacy and Safety of Ranibizumab (Intravitreal Injections) as Adjunctive and Monotherapy in Patients With Visual Impairment Due to Diabetic Macular Edema

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00989989
• Other study ID #: CRFB002D2303
• Status: Completed
• Phase: Phase 3
• First received: October 2, 2009
• Last updated: September 18, 2012
• Start date: September 2009
• Est. completion date: August 2011

Study information

• Verified date: September 2012
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Ministry of HealthChina: Food and Drug AdministrationSingapore: Clinical Trials & Epidemiology Research Unit (CTERU)Japan: Foundation for Biomedical Research and InnovationJapan: Institutional Review BoardJapan: Ministry of Education, Culture, Sports, Science and TechnologyJapan: Ministry of Health, Labor and WelfareJapan: Pharmaceuticals and Medical Devices AgencyHong Kong: Department of HealthTaiwan: Department of HealthKorea: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study was designed to confirm the efficacy and safety of ranibizumab (0.5 mg) as adjunctive therapy when added to laser photocoagulation and/or as monotherapy in Asian patients with visual impairment due to Diabetic Macular Edema (DME).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 396
• Est. completion date: August 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with Type 1 or Type 2 diabetes mellitus according to American Diabetes Association (ADA) or World Health Organization (WHO) guidelines with HbA1c not more than 10.0% at screening (Visit 1). Patients should be on diet, exercise, and/or pharmacological treatment for diabetes.

• Patients with visual impairment due to focal or diffuse Diabetic Macular Edema in at least one eye who are eligible for laser treatment in the opinion of the investigator. If both eyes are eligible, the one with the worse visual acuity, as assessed at Visit 1, will be selected for study treatment unless, based on medical reasons, the investigator deems the other eye the more appropriate candidate for study treatment.

• The study eye must fulfill the following criteria at Visit 1:

• Best-Corrected Visual Acuity (BCVA) score between 78 and 39 letters, inclusively, using Early Treatment of Diabetic Retinopathy (ETDRS) chart-like visual acuity testing charts at a testing distance of 4 meters (approximate Snellen equivalent of 20/32 to 20/160).

• Decrease in vision is due to DME and not due to other causes, in the opinion of the investigator.

• Medication for the management of diabetes must have been stable within 3 months prior to randomization and is expected to remain stable during the course of the study.

Exclusion Criteria:

• Ocular concomitant conditions/ diseases:

• Concomitant conditions in the study eye which could, in the opinion of the investigator, prevent the improvement of visual acuity on study treatment.

• Active intraocular inflammation in either eye.

• Any active infection in either eye.

• History of uveitis in either eye.

• Uncontrolled glaucoma in either eye.

• Ocular treatments:

• Panretinal laser photocoagulation in the study eye within 6 months prior to or during the study.

• Focal/grid laser photocoagulation in the study eye within 3 months prior to study entry.

• Systemic conditions or treatments:

• History of stroke

• Renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine level > 2.0 mg/dL.

• Untreated diabetes mellitus

• Blood pressure systolic > 160 mmHg or diastolic > 100 mmHg

• Compliance/ Administrative:

• Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Edema
• Macular Edema

Intervention

Drug:
• Ranibizumab
Ranibizumab 0.5 mg intravitreal injection at day 1, month 1 and month 2. If stable vision not reached at month 3, one injection per month continued until stable vision was reached. Intravitreal injections re-initiated if needed.

Procedure:
• Laser photocoagulation
Active laser treatment administered at day 1. Subsequent laser treatments administered if needed at intervals no shorter than 3 months from previous laser treatment.

Drug:
• Sham ranibizumab
Sham intravitreal injections to ranibizumab at day 1, month 1 and month 2. Intravitreal injections re-initiated if needed.

Procedure:
• Sham laser photocoagulation
Sham laser treatment administered at day 1.

Locations

Country	Name	City	State
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Changsha
China	Novartis Investigative Site	Chengdu
China	Novartis Investigative Site	Chongqing
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Hangzhou
China	Novartis Investigational Site	Shanghai
China	Novartis Investigative Site	Wenzhou
China	Novartis Investigative Site	Xi'an
Hong Kong	Novartis Investigative Site	Hong Kong
Japan	Novartis Investigative Site	Chiba
Japan	Novartis Investigative Site	Chiyoda-ku
Japan	Novartis Investigative Site	Chuo-ku
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Fukushima
Japan	Novartis Investigative Site	Hirakata
Japan	Novartis Investigative Site	Kita-gun
Japan	Novartis Investigative Site	Kobe
Japan	Novartis Investigative Site	Kyoto
Japan	Novartis Investigative Site	Mitaka
Japan	Novartis Investigative Site	Nagoya
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Otsu
Japan	Novartis Investigative Site	Shimotsuke
Japan	Novartis Investigative Site	Shinjuku-ku
Japan	Novartis Investigative Site	Suita
Japan	Novartis Investigative Site	Toyko
Japan	Novartis Investigative Site	Urayasu
Japan	Novartis Investigative Site	Wakayama
Japan	Novartis Investigative Site	Yamagata
Korea, Republic of	Novartis Investigative Site	Seoul
Singapore	Novartis Investigative Site	Singapore
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	LinKou
Taiwan	Novartis Investigative Site	Taipei

Sponsors (1)

Lead Sponsor	Collaborator
Novartis

Countries where clinical trial is conducted

China,  Hong Kong,  Japan,  Korea, Republic of,  Singapore,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Average Change From Baseline of Best-Corrected Visual Acuity (BCVA) Over 12 Months (From Month 1 to Month 12 Compared to Baseline)	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. The range of EDTRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement.	12 months	No
Secondary	Change From Baseline on Central Retinal Subfield Thickness (CRST) at Month 12	Central Retinal Subfield Thickness (CRST) was measured using Optical Coherence Tomography (OCT) in micrometers. A negative change from baseline of CRST indicates improvement.	12 months	No
Secondary	Percent of Participants With Anatomical Changes in Intra-retinal Cysts at End of Study Compared to Baseline	Presence or absence of intra-retinal cysts in any of the 6 sections of the study eye was measured using Optical Coherence Tomography (OCT). A complete resolution or decrease from baseline of intra-retinal cysts indicates improvement.	Up to 12 months	No
Secondary	Percent of Participants With Anatomical Changes in Sub-retinal Fluid at End of Study Compared to Baseline	Presence or absence of sub-retinal fluid in any of the 6 sections of the study eye was measured using Optical Coherence Tomography (OCT). A complete resolution or decrease from baseline of sub-retinal fluid indicates improvement.	Up to 12 months	No
Secondary	Percent of Participants With Visual Acuity Above 73 Letters at Month 12	Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart at baseline and month 12 while participants were in a sitting position at a testing distance of 4 meters. The range of EDTRS is 0 to 100 letters. BCVA above 73 letters at month 12 indicates a positive outcome.	12 months	No
Secondary	Percent of Participants Who Gained >= 10 Letters at Month 12 Compared to Baseline	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. The range of EDTRS is 0 to 100 letters. A gain of 10 or more BCVA letters from baseline indicates improvement. A BCVA of 84 letters or more at Month 12 indicates improvement.	12 months	No
Secondary	Percent of Participants Who Lost >= 10 Letters at Month 12 Compared to Baseline	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. The range of EDTRS is 0 to 100 letters. A loss of 10 or more BCVA letters from baseline indicates worsening.	12 months	No
Secondary	Percent of Participants Who Gained >= 15 Letters at Month 12 Compared to Baseline	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. The range of EDTRS is 0 to 100 letters. A gain of 15 or more BCVA letters from baseline indicates improvement. A BCVA of 84 letters or more at Month 12 indicates improvement.	12 months	No
Secondary	Percent of Participants Who Lost >= 15 Letters at Month 12 Compared to Baseline	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. The range of EDTRS is 0 to 100 letters. A loss of 15 or more BCVA letters from baseline indicates worsening.	12 months	No
Secondary	Best-Corrected Visual Acuity (BCVA) Mean Change From Baseline at Month 12	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. The range of EDTRS is 0 to 100 letters. A positive change from baseline of BCVA indicates improvement.	12 months	No
Secondary	Patient Outcome Measure Euro Quality of Life Questionnaire (EQ-5D)	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).	12 months	No