A 12-month, Randomized, Efficacy and Safety Study of 0.5 mg Ranibizumab vs Laser in Chinese Diabetic Macular Edema (DME) Patients (REFINE)

A 12-month, Randomized, Double-masked, Multicenter, Laser-controlled Phase III Study Assessing the Efficacy and Safety of 0.5 mg Ranibizumab Dosed PRN in Subjects With Visual Impairment Due to Diabetic Macular Edema in Chinese Patients

Study of efficacy and safety of 0.5 mg ranibizumab in Chinese patients with diabetic macular edema (DME)

Study Overview

• Status: Completed
• Conditions: Diabetic Macular Edema; Visual Impairment
• Intervention / Treatment: Drug: Ranibizumab (RFB002); Procedure: Sham laser; Procedure: Laser; Drug: Sham injection

Detailed Description

The purpose of this study was to provide efficacy and safety data on 0.5 mg ranibizumab intravitreal injections compared to laser photocoagulation in Chinese patients with visual impairment due to DME. Treatment was driven by achieving vision stabilization.

• Study Type: Interventional
• Enrollment (Actual): 384
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Beijing, China, 100053
    • Novartis Investigative Site
  • Beijing, China, 100034
    • Novartis Investigative Site
  • Beijing, China, 100050
    • Novartis Investigative Site
  • Beijing, China, 100176
    • Novartis Investigative Site
  • Chongqing, China, 400042
    • Novartis Investigative Site
  • Shanghai, China, 200080
    • Novartis Investigative Site
  • Shanghai, China, 200092
    • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100730
      • Novartis Investigative Site
    • Beijing, Beijing, China, 100044
      • Novartis Investigative Site
    • Beijing, Beijing, China, 100191
      • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Novartis Investigative Site
    • Guangzhou, Guangdong, China, 510632
      • Novartis Investigative Site
    • Shantou, Guangdong, China, 515041
      • Novartis Investigative Site
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150001
      • Novartis Investigative Site
  • Hubei
    • Wuhan, Hubei, China, 430070
      • Novartis Investigative Site
    • Wuhan, Hubei, China, 430022
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410011
      • Novartis Investigative Site
  • Jiangsu
    • Wuxi, Jiangsu, China
      • Novartis Investigative Site
  • Jiangxi
    • Nanchang, Jiangxi, China, 330019
      • Novartis Investigative Site
  • Shandong
    • Qingdao, Shandong, China, 2666000
      • Novartis Investigative Site
  • Shanxi
    • Xi'an, Shanxi, China, 710032
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Novartis Investigative Site
    • Tianjin, Tianjin, China, 300070
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Novartis Investigative Site
    • Hangzhou, Zhejiang, China, 310014
      • Novartis Investigative Site
    • Wenzhou, Zhejiang, China, 325027
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Male or female Chinese patients ≥ 18 years of age with diabetes mellitus and with HbA1c ≤10.0%
• Stable medication for diabetes within 3 months prior to Visit 1
• Visual impairment due to DME with BCVA score between 78 and 39 letters as measured by ETDRS-like charts at 4 meters

Key Exclusion Criteria:

• Stroke or myocardial infarction less than 3 months prior to screening visit
• Uncontrolled hypertension
• Active ocular infection or intraocular inflammation in any eye
• Treatment with any anti-angiogenic drugs within 3 months prior to baseline visit in any eye
• Active proliferative diabetic retinopathy in study eye
• Use of other investigational drugs within 30 days and systemic anti-VEGF drugs within 6 months prior to baseline visit
• Prior laser photocoagulation or intraocular procedure within 3 months prior to baseline in study eye
• History of intravitreal corticosteroid treatment in phakic study eye, and in aphakic or pseudophakic within 3 months prior to screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ranibizumab (RFB002); 3 initial intravitreal injections to the study eye at Day 1, Month 1 and Month 2, followed by as-needed intravitreal injections of ranibizumab 0.5 mg guided by VA stabilization, plus sham laser	Drug: Ranibizumab (RFB002); Ranibizumab 0.5 mg/0.05 mL for intravitreal injection; Other Names: Lucentis; Procedure: Sham laser; Imitation of an active laser
Active Comparator: Laser; Laser photocoagulation applied to the study eye at Day 1, followed by active laser photocoagulation at intervals no shorter than 3 months apart, plus sham injections	Procedure: Laser; Laser photocoagulation according to Early Treatment Diabetic Retinopathy Study (ETDRS) guidelines; Drug: Sham injection; Imitation of an intravitreal injection consisting of an empty vial and an injection syringe without a needle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Average Change From Baseline in Best-Corrected Visual Acuity (BCVA) (Letters) to Month 1 Through 12	Visual acuity with eyeglasses was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at an initial testing distance of 4 meters. A letter score was calculated based on the number of letters correctly identified at the specified distance. Twelve monthly BCVA values were averaged [(Month1+Month2+...+Month12)/12], and the baseline BCVA value was subtracted from the average. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis.	Baseline, Monthly from Month 1 through Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in BCVA (Letters) at Each Visit	Visual acuity with eyeglasses was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at an initial testing distance of 4 meters. A letter score was calculated based on the number of letters correctly identified at the specified distance. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis.	Baseline, Monthly from Month 1 through Month 12
Mean Change From Baseline in Central Sub-Field Thickness (CSFT) at Each Visit	CSFT (the average retinal thickness of the circular area within 1 millimeter diameter around the foveal center) was assessed using Optical Coherence Tomography (OCT). A negative change value indicates an improvement in macular edema, while a positive change value indicates a worsening. One eye (study eye) contributed to the analysis.	Baseline, Monthly from Month 1 through Month 12
Percentage of Patients With BCVA Gain of ≥ 10 and ≥ 15 Letters From Baseline at Month 12	Visual acuity with eyeglasses was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at an initial testing distance of 4 meters. A letter score was calculated based on the number of letters correctly identified at the specified distance. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis.	Baseline, Month 12
Percentage of Patients With BCVA Loss of < 10 and < 15 Letters From Baseline to Month 12	Visual acuity with eyeglasses was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at an initial testing distance of 4 meters. A letter score was calculated based on the number of letters correctly identified at the specified distance. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis.	Baseline, Month 12
Percentage of Patients With BCVA ≥ 73 Letters at Month 12	Visual acuity with eyeglasses was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at an initial testing distance of 4 meters. A letter score was calculated based on the number of letters correctly identified at the specified distance. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. BCVA ≥ 73 letters is approximately equivalent to 20/40 on a Snellen chart. One eye (study eye) contributed to the analysis.	Month 12
Mean Average Change in BCVA From Month 4 to Month 12 Compared to Month 3	Visual acuity with eyeglasses was assessed in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like charts at an initial testing distance of 4 meters. A letter score was calculated based on the number of letters correctly identified at the specified distance. Nine monthly BCVA values were averaged [(Month4+Month5+...+Month12)/9],and the Month 3 BCVA value was subtracted from the average. A positive change value indicates an improvement in visual acuity, while a negative change value indicates a worsening. One eye (study eye) contributed to the analysis.	Monthly from Month 3 through Month 12
Mean Change From Baseline in Patient-Reported Visual Functioning at Month 6 and Month 12, Composite Score	Visual functioning was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in visual functioning, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported General Health at Month 6 and Month 12	General health was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in general health, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported General Vision at Month 6 and Month 12	General vision was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in general vision, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Color Vision at Month 6 and Month 12	Color vision was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in color vision, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Peripheral Vision at Month 6 and Month 12	Peripheral vision was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in peripheral vision, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Ocular Pain at Month 6 and Month 12	Ocular pain was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in ocular pain, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Near Activities at Month 6 and Month 12	Near activities were assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in near activities, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Distance Activities at Month 6 and Month 12	Distance activities were assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in distance activities, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Social Functioning at Month 6 and Month 12	Social functioning was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in social functioning, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Mental Health at Month 6 and Month 12	Mental health was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in mental health, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Roles Difficulties at Month 6 and Month 12	Roles difficulties were assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in roles difficulties, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Dependency at Month 6 and Month 12	Dependency was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in dependency, while a negative change value indicates a worsening.	Baseline, Month 6, Month 12
Mean Change From Baseline in Patient-Reported Driving at Month 6 and Month 12	Driving was assessed by the patient using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) on a scale from 0 to 100, where 0 = worst possible score and 100 = best. A positive change value indicates a perceived improvement in driving, while a negative change value indicates a worsening. Note: Many patients did not answer the driving related question as they did not drive at all.	Baseline, Month 6, Month 12
Mean Number of Ranibizumab Re-treatments Received in the Study Eye From Month 3 Onward	A ranibizumab re-treatment was defined as an administration of ranibizumab injection at a scheduled visit following at least one non-missed visit where ranibizumab was not administered in the study eye due to visual acuity stabilization. This outcome measure was pre-specified for the Ranibizumab 0.5 mg arm only.	Monthly from Month 3 through Month 12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2014
• Primary Completion (Actual): January 17, 2017
• Study Completion (Actual): January 17, 2017

Study Registration Dates

• First Submitted: October 3, 2014
• First Submitted That Met QC Criteria: October 3, 2014
• First Posted (Estimate): October 8, 2014

Study Record Updates

• Last Update Posted (Actual): February 1, 2019
• Last Update Submitted That Met QC Criteria: January 30, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: diabetes; Chinese; macular edema; DME; vision impairment
• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Sensation Disorders; Macular Edema; Edema; Vision, Low; Vision Disorders; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: CRFB002D2305

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No