| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with type 2 diabetes mellitus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with type 2 diabetes mellitus |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate whether diabetic retinopathy (DR) progression rate is slowed down by SGLT2 inhibitor treatment and thus a lower microaneurysm formation rate in subjects treated with Empagliflozin (intervention) compared to subjects treated with Glimepiride (control), both on top of standard blood glucose lowering treatment, will be achieved after 12 months. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate whether (temporal)
• change of ETDRS stage,
• change in intraocular lipid content,
• change in retinal thickness measured by optical coherence tomography (OCT),
• change in retinal perfusion of microvasculature within the retina (flow in OCT-A, if software/ version of OCT allows for measurement)
• development of macular edema,
• change in BCVA (letters),
• change in glucose homeostasis,
• change in body composition,
• change in blood pressure,
differ between the two treatment groups
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. women and men between 18 - 80 years of age
2. type 2 diabetes mellitus
3. early to moderate stage diabetic retinopathy (ETDRS: 20 (microaneurysms only) to 35 (microaneurysms/emorrhages and/or hard exsudates) in one or both eyes
4. stable HbA1c (± 0.5%) for at least 12 weeks
5. antidiabetic treatment with either diet, metformin, DPP4, GLP1, pioglitazone, acarbose, or respective combinations
6. HbA1c ≥ 6.5 and ≤ 10.0 %
7. body mass index < 46 kg/m2
8. office blood pressure ≤ 150/95 mmHg (confirmed on a second day; 24h ambulatory blood pressure measurement (ABPM) is allowed to check accuracy of office values; inclusion with 24h mean blood pressure ≤ 145/90 mm Hg is possible); patients with hypertension should be treated according to current treatment guidelines
9. either women without childbearing potential defined by:
o at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy
o hysterectomy
o ≥ 50 years and in postmenopausal state > 1 year
o < 50 years and in postmenopausal state > 1 year with serum FSH > 40 IU/l and serum estrogen < 30 ng/l or a negative estrogen test, both at screening
or women of childbearing potential with a negative serum ß-hCG pregnancy test at screening who agree to meet one of the following criteria from the time of screening, during the study and for a period of 4 days following the last administration of study medication:
o correct use of one of the following accepted contraception methods: hormonal contraceptives (combined oral contraceptives, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release), intrauterine device (IUD/IUS) or a double barrier method, e.g. condom and occlusive cap (diaphragm or cervical/vault caps) with spermicide (foam, gel, film, cream or suppository)
o true abstinence (periodic abstinence and withdrawal are not acceptable methods of contraception)
o sexual relationship only with female partners
o sterile male partners
10. signed written informed consent and willingness to comply with treatment and follow-up procedures
11. capability of understanding the investigational nature, potential risks and benefits of the clinical trial
|
|
| E.4 | Principal exclusion criteria |
1. Type 1 diabetes
2. uncontrolled diabetes mellitus type 2 with fasting glucose > 13.3 mmol/l confirmed on a second day
3. known or suspected hypersensitivity to empagliflozin, glimepiride, or any excipients; and / or known or suspected hypersensitivity to sulfonylureas, sulfonamides or SGLT2 inhibitors in general
4. history of multiple severe hypoglycemic episodes within the last two years
5. use of Insulin, SGLT2-inhibitor, sulfonylurea derivate or a glinide within past 3 months
6. clinical significant macular edema in both eyes and indication for intravitreal anti-VEGF treatment for both eyes at screening or baseline visit. Eyes with a small amount of intraretinal or subretinal fluid (seen in OCT) but no need for intravitreal treatment as judged by the investigator (according to current practice patterns) may be included. Eyes with a history of intravitreal treatment of macular edema which do not need ongoing intravitreal treatment at the time of screening may be included.
7. eye diseases or pathologies that prevent clear ophthalmoscopy and evaluation of study parameters, thus not allowing study participation according to the investigator´s judgment, such as (but not only) vitreous hemorrhage, mature cataract, macular pathologies other than diabetic maculopathy
8. history of ketoacidosis or metabolic acidosis
9. use of loop diuretics
10. history of > 1 urogenital infection/year
11. any history of stroke, TIA, instable angina pectoris or myocardial infarction within last 3 months prior to baseline visit
12. congestive heart failure NYHA III and IV
13. severe valvular or left ventricular outflow obstruction disease needing intervention;
14. atrial fibrillation/flutter with a mean ventricular response rate at rest >100 beats per minute
15. chronic lower urinary tract infections (but not simple asymptomatic bacteriuria)
16. eGFR < 60 ml/min/1,73 m2 (MDRD-formula, confirmed on a second day)
17. chronic diarrhea, any clinical signs of volume depletion or a hematocrit > 48 % (women) and > 53 % (men)
18. elevated risk for volume depletion, e.g. history of severe volume depletion that required medical therapy
19. chronic liver disease (including known active hepatitis) and/or screening alanine transaminase (ALT) or aspartate transaminase (AST) > 3 x ULN (confirmed on a second day)
20. Subjects with known seropositivity to human immunodeficiency virus.
21. acute illness at screening or randomization according to judgement by the investigator or patient
22. drug or alcohol abuse
23. psychosomatic or psychiatric diseases requiring hospitalization during the last 12 months
24. clinical evidence of current malignancy with exception of basal cell or squamous cell carcinoma of the skin, and cervical intraepithelial neoplasia (5 years prior to randomization)
25. any medical or surgical intervention planned for the next 13 months after randomization not allowing study participation according to the investigator´s judgment
26. current participation in any other clinical trial or participation in another clinical trial within 30 days before screening
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Microaneurysm (MA) formation rate over 12 months, i.e. number of newly developed microaneurysms within 12 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. change in diabetic retinopathy stage (≥ 2 step change on ETDRS severity score)
2. change in microaneurysm count
3. Microaneurysm formation rate after 6 months (compared to baseline)
4. change in retinal thickness (as measured by OCT)
5. change in retinal perfusion of microvasculature within the retina (flow in OCT-A, if software/ version of OCT allows for measurement),
6. number of patients/eyes showing a progression to clinically significant macular edema (CSME) with the need for (intravitreal) treatment during 12 months
7. change in intraocular lipid content (hard exsudates)
8. change in composite clinical outcome evaluating progression to proliferative DR (PDR) based on photography, angiography plus clinically important events defining PDR (e.g. vitreous haemorrhage)
9. change in best corrected visual acuity (BCVA [ETDRS letters])
10. change in HbA1c
11. change in fasting glucose
12. change in body weight and body fat mass
13. change in ambulatory blood pressure
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. weeks 27 and 52
2. weeks 27 and 52
3. 6 months
4. weeks 27 and 52
5. weeks 27 and 52
6. throughout the study
7. weeks 27 and 52
8. weeks 27 and 52
9. weeks 27 and 52
10. weeks 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 52 and 55
11. weeks 2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 52 and 55
12. weeks 27, 52 and 55
13. weeks 27 and 52 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
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