| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type II diabetes mellitus |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
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| 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 |
| The objective of the study is to investigate the efficacy, safety and tolerability of empagliflozin 10 mg qd and empagliflozin 25 mg qd compared to placebo given for 24 weeks in inadequately controlled T2DM patients on linagliptin 5 mg and maximum tolerated dose of metformin. The primary objective of efficacy evaluation is planned after 24 weeks of treatment. The study is designed to show superiority of the combination of empagliflozin and linagliptin FDC over linagliptin alone. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Diagnosis of type 2 diabetes mellitus prior to informed consent
2.Male and female patients on diet and exercise regimen who are pre-treated with an unchanged dose of immediate release metformin for at least 12 weeks prior to screening. Patients should be on ≥1500 mg/day of metformin or maximum tolerated dose (must be documented) or maximum dose as per local label
3.HbA1c ≥ 8.0% and ≤ 10.5% at Visit 1 for entering the 16 week treatment period.
4.HbA1c ≥ 7.0% and ≤ 10.5% at Visit 4 for randomisation into the 24 week double-blind treatment period.
5.Age ≥ 18 years at screening
6.Body Mass Index (BMI) ≤ 45 kg/m2 at Visit 1 (screening)
7.Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation |
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| E.4 | Principal exclusion criteria |
1.Uncontrolled hyperglycemia with a glucose level >270 mg/dl (>15 mmol/L) after an overnight fast during the open label treatment period (form Visit 2 to Visit 4) and placebo add on "run-in" periode (Visit 4 ot Visit 5) and confirmed by a second measurement (not on the same day and done either at the central or at local laboratory).
2.Any other antidiabetic drug within 12 weeks prior to Visit 2 (except metformin background therapy as defined via inclusion criterion 2). Use of other antidiabetic treatment (except study drug and metformin background medication) prior to randomization (Visit 5).
3.Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or TIA within 3 months prior to informed consent
4.Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening, linagliptin treatment and/or placebo add on “run-in” period
5.Impaired renal function, defined as eGFR <60 ml/min/1.73m2 (MDRD formula) as determined during screening, linagliptin treatment and/or placebo add on “run-in” period
6.Known hereditary galactose intolerance
7.Known contradications to metformin or linagliptin according to the local label
8.Any previous (within the past two years) or planned bariatric surgery (or any other weight loss surgery) or other gastrointestinal surgery that induce chronic malabsorption
9.Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
10.Known blood dyscrasias or any disorders causing hemolysis or unstable red blood cell count (e.g. malaria, babesiosis, hemolytic anemia) due to the short lifespan of the RBC and its impact on HbA1c.
11.Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) within 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight
12.Current treatment with systemic steroids (orally taken or parenteral) at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM
13.Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who:
- are nursing or pregnant or
- are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, complete sexual abstinence (if acceptable by local health authorities), double barrier method and vasectomized partner
14.Known allergy or hypersensitivity to DPP4 inhibitors or SGLT-2 inhibitors
15.Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to trial procedures or trial drug intake, in the judgment of the investigator
16.Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial or participation in the follow-up period of another trial (partipation in observational studies is permitted)
17.Any other clinical condition that, in the opinion of the investigator, would jeopardize patient’s safety while participating in this clinical trial
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint in this study is the change of HbA1c (HbA1c after 24 weeks of treatment at week 42 (Visit 9) from baseline (Visit 5)). HbA1c will be measured in the unit of % and mmol/mol. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 24 week double-blind treatment, from baseline at visit 5 to visit 9 |
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| E.5.2 | Secondary end point(s) |
Key Secondary endpoints are:
• Fasting plasma glucose (FPG) change from baseline (Visit 5) after 24 weeks of treatment ( at Visit 9).
• Body weight change from baseline (Visit 5) after 24 weeks of treatment (at Visit 9).
Other exploratory endpoints
• For the double blind 24 week treatment period
• Proportion of patients who achieve HbA1c <7.0% after 24 weeks of treatment (at Visit 9).
• Proportion of patients who achieve HbA1c <6.5% after 24 weeks of treatment (at Visit 9).
• Proportion of patients who achieve HbA1c lowering by at least 0.5% after 24 weeks of treatment (at Visit 9).
• HbA1c reduction from baseline (visit 5) by visit over time.
• The change from baseline (visit 5) in fasting plasma glucose (FPG) by visit over time.
• Weight change from baseline (visit 5) by visit over time.
• The change from baseline (visit 5) in waist circumference at 24 weeks (at Visit 9).
• Mean systolic blood pressure change from baseline (visit 5) at 24 weeks (at Visit 9).
• Mean diastolic blood pressure change from baseline (visit 5) at 24 weeks (at Visit 9).
• Change in systolic and diastolic blood pressure from baseline (visit 5) by visit over time.
Composite endpoint of the following conditions (all three fulfilled)
• Change from baseline HbA1c of more than -0.5%;
• Systolic BP reduction from baseline of 3 mmHg or more
• Weight reduction from baseline of 2% or more
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 24 week double-blind treatment, from baseline at visit 5 to visit 9 |
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| 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 | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| France |
| Korea, Democratic People's Republic of |
| New Zealand |
| Norway |
| Philippines |
| Spain |
| Taiwan |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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