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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: Ranibizumab
* Procedure: Laser photocoagulation
* Drug: Sham ranibizumab
* Procedure: Sham laser photocoagulation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adjunctive treatment<br>Adjunctive administration of ranibizumab 0.5 mg intravitreal injections and active laser. | Drug: Ranibizumab<br>* 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.<br>Procedure: Laser photocoagulation<br>* Active laser treatment administered at day 1. Subsequent laser treatments administered if needed at intervals no shorter than 3 months from previous laser treatment.<br>|
| Experimental: Monotherapy treatment<br>Monotherapy ranibizumab 0.5 mg intravitreal injections plus sham laser. | Drug: Ranibizumab<br>* 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.<br>Procedure: Sham laser photocoagulation<br>* Sham laser treatment administered at day 1.<br>|
| Active Comparator: Laser control<br>Active laser treatment plus sham intravitreal injections. | Procedure: Laser photocoagulation<br>* Active laser treatment administered at day 1. Subsequent laser treatments administered if needed at intervals no shorter than 3 months from previous laser treatment.<br>Drug: Sham ranibizumab<br>* Sham intravitreal injections to ranibizumab at day 1, month 1 and month 2. Intravitreal injections re-initiated if needed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DME, Diabetic, macula, edema, ranibizumab, REVEAL