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

• Sponsor: Prof. Dr. Antonia M. Joussen (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02665689
• Collaborator: Charite University, Berlin, Germany (Other)
• Enrollment: 4
• Location: 1
• Arms: 2
• Actual Duration (Months): 31.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Visual Acuity Reduced Transiently; Macular Edema, Cystoid	Drug: ranibizumab	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: Observer-masking (assessment of BCVA, macular thickness, capillary drop-out) is done to guard against detection bias.
• Primary Purpose: Treatment
• Official Title: Influence of Diabetes Control on Treatment of Diabetic Macular Edema With Ranibizumab
• Actual Study Start Date: Jan 18, 2016
• Actual Primary Completion Date: Sep 7, 2018
• Actual Study Completion Date: Sep 7, 2018

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Difference of Best Corrected Visual Acuity Measured in ETDRS Letters Score Between Month 12 Baseline Visit [Baseline to 12 months]

   Measured by the difference in ETDRS letters score between month 12 and baseline according to internal guideline of Charité department of ophthalmology.

Secondary Outcome Measures

1. Number of Treatments With Ranibizumab up to 6, 12, 18 and 24 Months of Treatment [Baseline to 12 months]

   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.

2. Difference of Best Corrected Visual Acuity Measured in ETDRS Letters Score Between Month 6, 12, 24 and Baseline Visit [Baseline to 12 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 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.

3. Macular Thickness Change at 6, 12, 18 and 24 Months Compared to Baseline [Baseline to 12 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 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.

4. Time to Reach Target HbA1c [24 months]

5. Number of Panretinal Laser Photocoagulation (PRP) Treatments Necessary for Neovascular Complications [Baseline to 12 months]

   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.

6. Number of Participants With Retinal Detachment, Central Retinal Artery Occlusion, or Endophthalmitis and/or Ocular Adverse Events That Are Related to Treatment [Baseline to 12 months]

   All ocular adverse events presented from baseline to 24 months will be documented.

7. Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment [Baseline to 12 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Ophthalmology, Charite, Berlin	Berlin		Germany	12203

Sponsors and Collaborators

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

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 23, 2015

More Information

Publications

None provided.

• Responsible Party: Prof. Dr. Antonia M. Joussen, Prof. MD, Charite University, Berlin, Germany
• ClinicalTrials.gov Identifier: NCT02665689
• Other Study ID Numbers: DORO001
• First Posted: Jan 28, 2016
• Last Update Posted: Nov 20, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Prof. Dr. Antonia M. Joussen, Prof. MD, Charite University, Berlin, Germany: Diabetic Macular Edema, Ranibizumab, Visual Acuity, Diabetic Control
• Additional relevant MeSH terms: Macular Edema; Edema; Ranibizumab

Study Results

Participant Flow

Recruitment Details	The recruitment has been stopped prematurely in August 2018 by the sponsor after the enrolment of four patients because the enrollment pace was far below target.
Pre-assignment Detail	Screening period of seven days prior to randomization.

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Period Title: Overall Study
STARTED	2	2
COMPLETED	0	0
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control	Total
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	Total of all reporting groups
Overall Participants	2	2	4
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 50%	0 0%	1 25%
>=65 years	1 50%	2 100%	3 75%
Sex: Female, Male (Count of Participants)
Female	0 0%	2 100%	2 50%
Male	2 100%	0 0%	2 50%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Number of participants with history of ophthalmic disease (Count of Participants)
Count of Participants [Participants]	2 100%	2 100%	4 100%
Number of patients with medical history (Count of Participants)
Count of Participants [Participants]	2 100%	2 100%	4 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Of the four enrolled patients, only the two patients had 12-month visit. Since the time point for the evaluation of the primary endpoint was reached only for patients of study arm B, a comparison of both study arms was not possible and thus analysis of the primary endpoint was waived.

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	0	0

2. Secondary Outcome

Title	Number of Treatments With Ranibizumab up to 6, 12, 18 and 24 Months of Treatment
Description	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.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

At month 6, the two patients in study arm A had received six treatments each; the two patients in study arm B had received three and five treatments, respectively. At month 12, the two patients in study arm B had received three and six treatments, respectively. For none of the patients in study arm A, 12-month data was available.

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	2	2
Month 6	12	8
Month 12	9

3. Secondary Outcome

Title	Difference of Best Corrected Visual Acuity Measured in ETDRS Letters Score Between Month 6, 12, 24 and Baseline Visit
Description	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.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

BCVA score compared to baseline.

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	2	2
Participant 1, month 6	7
Participant 2, month 6	5
Participant 3, month 6	3
Participant 4, month 6	8
Participant 3, month 12	3
Participant 4, month 12	10

4. Secondary Outcome

Title	Macular Thickness Change at 6, 12, 18 and 24 Months Compared to Baseline
Description	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.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

For none of the patients in study arm A 12-month data was available. Time points beyond 6 months (18, 24 months) were reached by none of the patients due to trial discontinuation. Results are only shown descriptively.

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	2	2
Participant 1, month 6	-91
Participant 2, month 6	-319
Participant 3, month 6	10
Participant 4, month 6	-103
Participant 3, month 12	23
Participant 4, month 12	-101

5. Secondary Outcome

Title	Time to Reach Target HbA1c
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Originally, target HbA1c should have been defined individually for each patient by the investigator acc. to the patient's general status by risk factors for vasculopathy (Body-Mass-Index, smoking, blood pressure, lipid Status). However, definition of target HbA1c values was waived and only HbA1c values were documented (not shown here).

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	0	0

6. Secondary Outcome

Title	Number of Panretinal Laser Photocoagulation (PRP) Treatments Necessary for Neovascular Complications
Description	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.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	2	2
Number [number of PRPs across participants]	1 50%	1 50%

7. Secondary Outcome

Title	Number of Participants With Retinal Detachment, Central Retinal Artery Occlusion, or Endophthalmitis and/or Ocular Adverse Events That Are Related to Treatment
Description	All ocular adverse events presented from baseline to 24 months will be documented.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

Patients in study arm A discontinued before month 12. None of the patients reached time points beyond month 12 due to trial discontinuation.

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	2	2
Month 6	0 0%	0 0%
Month 12	0 0%

8. Secondary Outcome

Title	Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
Description	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.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Regular Glycemic Control	Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
Measure Participants	2	2
Number [participants]	0 0%	0 0%

Adverse Events

Time Frame	First administration of the IMP until 30 days after the patient has stopped the treatment. Treatment is given individually acc. to summary of product characteristics following a pro re nata (as needed) scheme. Therefore adverse event data will be collected until time points individually for each patient but not longer than total trial duration (24 months). Time frame per protocol was baseline to 24 months. None of the patients reached time points beyond 12 months due to study discontinuation.
Arm/Group Title	Regular Glycemic Control		Intensified Glycemic Control
Arm/Group Description	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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.		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. ranibizumab: Ranibizumab injections will be given for diabetic macular edema. In the experimental arm insulin injections and antihypertensiva will be applied.
All Cause Mortality
	Regular Glycemic Control		Intensified Glycemic Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)
Serious Adverse Events
	Regular Glycemic Control		Intensified Glycemic Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		1/2 (50%)
Cardiac disorders
Coronary artery disease	1/2 (50%)	1	0/2 (0%)	0
Infections and infestations
Otosalpingitis	0/2 (0%)	0	1/2 (50%)	1
Investigations
Blood pressure increased	0/2 (0%)	0	1/2 (50%)	1
Metabolism and nutrition disorders
Hypokalaemia	0/2 (0%)	0	1/2 (50%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/2 (0%)	0	1/2 (50%)	1
Nervous system disorders
Headache	0/2 (0%)	0	1/2 (50%)	1
Vascular disorders
Hypertensive crisis	0/2 (0%)	0	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Regular Glycemic Control		Intensified Glycemic Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		2/2 (100%)
Cardiac disorders
Heart valve stenosis	0/2 (0%)	0	1/2 (50%)	1
Ear and labyrinth disorders
Vertigo	0/2 (0%)	0	1/2 (50%)	1
Eye disorders
Diabetic retinal oedema	0/2 (0%)	0	1/2 (50%)	1
Diabetic retinopathy	0/2 (0%)	0	1/2 (50%)	1
Eye pain	0/2 (0%)	0	2/2 (100%)	2
Foreign body sensation in eyes	0/2 (0%)	0	2/2 (100%)	2
Macular oedema	0/2 (0%)	0	1/2 (50%)	1
Retinal exudates	0/2 (0%)	0	1/2 (50%)	1
Ocular discomfort	1/2 (50%)	1	0/2 (0%)	0
Blepharitis	1/2 (50%)	1	0/2 (0%)	0
Anterior chamber disorder	1/2 (50%)	1	0/2 (0%)	0
Conjunctival haemorrhage	1/2 (50%)	1	0/2 (0%)	0
Gastrointestinal disorders
Diarrhoea	0/2 (0%)	0	1/2 (50%)	1
Nausea	0/2 (0%)	0	1/2 (50%)	1
Vomiting	0/2 (0%)	0	1/2 (50%)	1
General disorders
Chest pain	0/2 (0%)	0	1/2 (50%)	1
Injection site pain	0/2 (0%)	0	1/2 (50%)	1
Injury associated with device	0/2 (0%)	0	1/2 (50%)	1
Infections and infestations
Bronchitis	0/2 (0%)	0	1/2 (50%)	1
Upper respiratory tract infection	1/2 (50%)	1	0/2 (0%)	0
Injury, poisoning and procedural complications
Procedural pain	0/2 (0%)	0	1/2 (50%)	2
Musculoskeletal and connective tissue disorders
Exostosis	0/2 (0%)	0	1/2 (50%)	1
Musculoskeletal pain	0/2 (0%)	0	1/2 (50%)	1
Oedema peripheral	0/2 (0%)	0	1/2 (50%)	1
Pain in extremity	0/2 (0%)	0	1/2 (50%)	1
Nervous system disorders
Headache	0/2 (0%)	0	1/2 (50%)	1
Product Issues
Device dislocation	1/2 (50%)	1	0/2 (0%)	0
Skin and subcutaneous tissue disorders
Night sweats	0/2 (0%)	0	1/2 (50%)	1

Limitations/Caveats

Recruitment was stopped prematurely by the sponsor after enrolment of four patients since enrollment pace was far below target. Due to the limited number of patients, no conclusions in respect to the study aims can be made.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.