Influence of Diabetes Control on Treatment of Diabetic Macular Edema With Ranibizumab (DORO)

The aim of the prospective randomized study is to investigate whether a intensified diabetic control program leads to better final visual acuity and less frequent diabetic ocular complications in patients with diabetic retinopathy when compared with a normal diabetic treatment.

Study Overview

• Status: Terminated
• Conditions: Macular Edema, Cystoid; Visual Acuity Reduced Transiently
• Intervention / Treatment: Drug: ranibizumab

Detailed Description

Patients with diabetic macular edema (DME) will be treated with intravitreal ranibizumab injections and the effect of optimal control of internal factors (eg. glycemia, blood pressure etc) on final functional (best corrected visual acuity-CBVA) and morphological (central retinal thickness-CRT) will be investigated. Patients will be randomized into two groups: Group with intensified diabetic control will be follow and investigated monthly at department of diabetology, endocrinology and nutritional medicine (Campus Benjamin Franklin) in Berlin with aim to reach the optimal glycemic control defined as HbA1c < 6,5%. Further, triglycerides values < 140 mg/dl and blood pressure < 140/90 mmHg will be pursued. Second group of patients will be followed by their general practitioner and in the study center only blood samples will be taken quarterly without active medical intervention.

BCVA, CRT and the number of required ranibizumab injections will we evaluated and compared between both study groups.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 12203
    • Department of Ophthalmology, Charite, Berlin

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

Inclusion Criteria:

- Patients with diabetic macular edema relevant to visual acuity

• OCT central retinal thickness ≥ 250µm
• HbA1c > 6,5% at initial visit
• BCVA ≤0.8 and ≥0.05
• Age ≥18 years
• Written patient informed consent given

Exclusion Criteria:

• Previous treatment with intravitreal drugs in last 6 months
• Vitreous hemorrhage as a consequence of proliferative retinopathy
• Pregnancy
• Blood pressure of ≥ 180/100 (or uncontrolled pressures under pharmacological therapy)
• Chronic systemic or ocular inflammatory/autoimmune diseases (e.g. inflammatory bowel disease, Addison´s disease, Cushing Syndrome, Uveitis)
• Systemic cortisone or anti-VEGF therapy
• Acute systemic or ocular infectious diseases

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regular Glycemic Control; Diabetic macular edema will be treated with 3 monthly ranibizumab (0,5mg) injections followed by PRN regimen. Patients randomized into this group will be controlled by their general practitioner or private diabetologist (usual care). The glycemic control (blood measurements of HbA1c) will be performed at trial site (Department of diabetology, endocrinology and nutritional medicine) every 3 months. The site will not influence or change the diabetes medication given by general physician and serves as an observer only to monitor the diabetic control.	Drug: ranibizumab; Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Experimental: Intensified Glycemic Control; Diabetic macular edema will be treated with 3 monthly ranibizumab (0,5mg) injections followed by PRN regimen. Patients randomized into this group will be controlled at the trial site (Department of diabetology, endocrinology and nutritional medicine) during first year monthly, in the second study year every 3 months. The individual HbA1c will be targeted according to the general status reflecting other risk factors for the vasculopathy (e.g. BMI, smoking, blood pressure, lipid status). All effort will be done to reach the target blood pressure ≤ 140/90 mmHg and blood triglyceride level < 140 mg/dl: Further the patients will be educated to improve their eating habits in regard to reduce the carbohydrate intake.	Drug: ranibizumab; Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference of Best Corrected Visual Acuity Measured in ETDRS Letters Score Between Month 12 Baseline Visit	Measured by the difference in ETDRS letters score between month 12 and baseline according to internal guideline of Charité department of ophthalmology.	Baseline to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Treatments With Ranibizumab up to 6, 12, 18 and 24 Months of Treatment	For the number of treatments at 6, 12, 18 and 24 months, an ANOVA without any covariates was planned to be applied at each endpoint 6, 12, 18 and 24 months. As the time point 12 months for the evaluation of this secondary endpoint was reached only for patients of study arm B, a comparison of both study arms was not possible and thus statistical analysis of the endpoint was waived completely. None of the patients reached time points beyond month 12. Results are only shown descriptively. Ranibizumab injections were summed up per study arm as well as cumulative at each time point.	Baseline to 12 months
Difference of Best Corrected Visual Acuity Measured in ETDRS Letters Score Between Month 6, 12, 24 and Baseline Visit	As the time point 12 months for the evaluation of this secondary endpoint was reached only for patients of study arm B, a comparison of both study arms was not possible and thus analysis of the endpoint was waived completely. Time point 24 months was reached by none of the patients due to trial discontinuation. Results are only shown descriptively. Best-corrected visual acuity (BCVA) score is shown as change in ETDRS letters score at the distinct time point compared to baseline. Higher scores mean a better outcome.	Baseline to 12 months
Macular Thickness Change at 6, 12, 18 and 24 Months Compared to Baseline	As the time point 12 months for the evaluation of this secondary endpoint was reached only for patients of study arm B, a comparison of both study arms was not possible and thus analysis of the endpoint was waived completely. None of the patients reached time points beyond month 12 due to trial discontinuation. Results are only shown descriptively. Macular thickness (study eye) is shown as change in thickness [µm] compared to individual baseline value. A reduction in thickness means improvement.	Baseline to 12 months
Time to Reach Target HbA1c		24 months
Number of Panretinal Laser Photocoagulation (PRP) Treatments Necessary for Neovascular Complications	Need for PRP is up to the investigator's decision. Assessment was done on every visit. Intended time frame was baseline to 24 months. None of the patients reached time points beyond month 12 due to study discontinuation. Unit of measure is any separate investigator's decision to perform panretinal laser photocoagulation (PRP) for neovascular complications. Each PRP is counted separately.	Baseline to 12 months
Number of Participants With Retinal Detachment, Central Retinal Artery Occlusion, or Endophthalmitis and/or Ocular Adverse Events That Are Related to Treatment	All ocular adverse events presented from baseline to 24 months will be documented.	Baseline to 12 months
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment	All adverse events were documented. Causal relationship to study treatment was assessed by the investigators. Intended time frame was baseline to 24 months. None of the patients reached time points beyond 12 months due to study discontinuation.	Baseline to 12 months

Collaborators and Investigators

• Sponsor: Prof. Dr. Antonia M. Joussen
• Collaborators: Charite University, Berlin, Germany

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2016
• Primary Completion (Actual): September 7, 2018
• Study Completion (Actual): September 7, 2018

Study Registration Dates

• First Submitted: January 21, 2016
• First Submitted That Met QC Criteria: January 24, 2016
• First Posted (Estimate): January 28, 2016

Study Record Updates

• Last Update Posted (Actual): November 20, 2019
• Last Update Submitted That Met QC Criteria: October 31, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Diabetic Macular Edema, Ranibizumab, Visual Acuity, Diabetic Control
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Macular Edema; Edema; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: DORO001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO