| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diabetes mellitus type 2 is the medical condition to be investiagted |
|
| E.1.1.1 | Medical condition in easily understood language |
| A medical condition called diabetes which is characterized by elevated glucose levels. |
|
| 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 | 16.1 |
| 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 |
| The objective of the study is to investigate the efficacy, safety and tolerability of linagliptin 5 mg qd compared to placebo given for 24 weeks in inadequately controlled T2DM patients on empagliflozin 10 mg or 25 mg and maximum tolerated dose of metformin |
|
| E.2.2 | Secondary objectives of the trial |
| Fasting plasma glucose (FPG) change from baseline (Visit 5) at 24 weeks (or Visit 9) |
|
| 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 who have received diet and exercise counselling and who are pre-treated with an unchanged dose of immediate release metformin for at least 12 weeks prior to Visit 2.
Minimum dose for metformin is defined as:
• ≥1500 mg/day of metformin or
• maximum tolerated dose (the investigator must have documented the reason why uptitration to e.g. ≥ 1500 mg/day was not possible) or
• maximum dose according to the local label (the investigator must have documented the local label requirements in the medical records)
3. HbA1c ≥ 8.0% (64 mmol/mol) and ≤ 10.5% (91 mmol/mol) at Visit 1 for randomization into the 16 week treatment period.
4. HbA1c ≥ 7.0% (53 mmol/mol) and ≤ 10.5 % (91 mmol/mol) at Visit 4 for randomization into the 24 week treatment period.
5. Age ≥ 18 years
6. Body Mass Index (BMI) ≤45 kg/m2 at Visit 1 (screening) as calculated in the eCRF.
7. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation |
|
| E.4 | Principal exclusion criteria |
1. Uncontrolled hyperglycaemia with a glucose level >270 mg/dl (>15.0 mmol/L) after an overnight fast during the open label period (from Visit 2 to Visit 4) and placebo add on "run-in" period (Visit 4 to Visit 5) confirmed by a second measurement (not on the same day and done either at the central or local laboratory).
2. Any other antidiabetic drug within 12 weeks prior to Visit 2 randomization (except metformin background therapy as defined via inclusion criterion 2).
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) based on Visit 1 or Visit 4 laboratory parameters.
Note: Each value should be assessed independently of one another, i.e Visit 1 assessments will determine randomization to the open label treatment period and Visit 4 assessments will determine randomization to the double blind treatment period
5. Impaired renal function, defined as eGFR <60 ml/min/1.73 m2 (MDRD formula) as determined during screening (Visit 1) or placebo add on "run-in" (Visit 4)
Note: Each eGFR value should be assessed independently of one another, i.e Visit 1 assessments will determine randomization to the open label treatment period and Visit 4 randomization and assessments will determine randomization to the double blind treatment period
6. Known hereditary galactose intolerance
7. Known contraindications to metformin or linagliptin according to the local label (where marketed)
8. Any previous (within the past two years) or planned bariatric surgery (or any other weight loss surgery) or other gastrointestinal surgery that induces 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 haemolysis or unstable red blood cell count (e.g. malaria, babesiosis, haemolytic anaemia) 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 (other than inhaled or topical steroids) at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other documented 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 vasectomised 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
(participation 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change of HbA1c after 24 weeks of treatment (at week 24 or Visit 9) from baseline (Visit 5). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 24 weeks of treatment (Visit 9) from baseline (Visit 5). |
|
| E.5.2 | Secondary end point(s) |
| Fasting plasma glucose (FPG) change from baseline (Visit 5) at 24 weeks (or Visit 9) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 24 weeks of treatment (Visit 9) from baseline (Visit 5). |
|
| 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 | No |
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Canada |
| Italy |
| Portugal |
| Argentina |
| Australia |
| Germany |
| India |
| Spain |
| Sri Lanka |
| Peru |
| Russian Federation |
| Ukraine |
| United States |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 24 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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