| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| 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 |
DINAMOTM (main study)
The objective of this study is to assess the efficacy and safety of an empagliflozin dosing regimen and one dose of linagliptin versus placebo after 26 weeks of treatment in children and adolescents with type 2 diabetes mellitus treated with metformin and/or insulin or who are not tolerating metformin.
DINAMOTM Mono (ancillary study)
The objective of this study is to explore the effect of an empagliflozin dosing regimen and one dose of linagliptin as Monotherapy in children and adolescents with type 2 diabetes mellitus. |
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| E.2.2 | Secondary objectives of the trial |
| In addition, this study will assess long term safety of empagliflozin and linagliptin after 52 weeks of treatment. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients aged 10 to 17 years (inclusive) at the time of randomisation (Visit 2)
2. Male and female patients
3. Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient’s legal representative information sheet as well as in Section 4.2.2.3.
4. Signed and dated written informed consent provided by the patient’s parent(s) (or legal guardian) and patient’s assent in accordance with ICH-GCP and local legislation prior to admission to the trial (informed assent will be sought according to the patient’s age, level of maturity, competence and capacity)
5. Documented diagnosis of T2DM for at least 12 weeks at Visit 1A
6. Insufficient glycaemic control as measured by the central laboratory at Visit 1A:
a. DINAMOTM: HbA1c ≥ 6.5% and ≤ 10.5%
b. DINAMOTM Mono: HbA1c ≥ 6.5% and ≤ 9.0%
7. a. DINAMOTM: Patients treated with
- diet and exercise plus metformin at a stable dose for 8 weeks prior to Visit 2
AND/OR
- diet and exercise plus stable basal or MDI insulin therapy, defined as a weekly average variation of the basal insulin dose ≤ 0.1 IU/kg over 8 weeks prior to Visit 2.
Patients treated with diet and exercise only and not tolerating metformin (defined as patients who were on metformin treatment for at least 1 week and had to discontinue metformin due to metformin-related side effects as assessed by the investigator) are also eligible in this trial.
b. DINAMOTM Mono: Drug-naïve patients or patients not on active treatment (including a metformin washout for at least 12 weeks prior to Visit 2)
8. BMI ≥ 85th percentile for age and sex according to WHO references at Visit 1B
9. Non-fasting serum C-peptide levels ≥ 0.6 ng/ml as measured by the central laboratory at Visit 1A
10. Negative for both islet cell antigen auto-antibodies (IA-2) and glutamic acid decarboxylase (GAD) auto-antibodies as measured by the central laboratory at Visit 1A
11. Compliance with trial medication intake must be between 75% and 125% during the open-label placebo run-in period |
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| E.4 | Principal exclusion criteria |
1. Any history of acute metabolic decompensation such as diabetic ketoacidosis within 8 weeks prior to Visit 1A and up to randomisation (mild to moderate polyuria at the time of randomisation is acceptable)
2. Diagnosis of monogenic diabetes (e.g. MODY)
3. History of pancreatitis
4. Diagnosis of metabolic bone disease
5. Gastrointestinal disorders that might interfere with study drug absorption according to investigator assessment
6. Secondary obesity as part of a syndrome (e.g. Prader-Willi syndrome)
7. Any antidiabetic medication (with the exception of metformin and/or insulin background therapy for DINAMOTM) within 8 weeks prior to Visit 1A and until Visit 2
8. Treatment with weight reduction medications (including anti-obesity drugs) within 3 months prior to Visit 1A and until Visit 2
9. History of weight-loss surgery or current aggressive diet regimen (according to investigator assessment) at Visit 1A and until Visit 2
10. Treatment with systemic corticosteroids for > 1 week within 4 weeks prior to Visit 1A and up to Visit 2
Inhaled or topical use of corticosteroids (e.g. for asthma/chronic obstructive pulmonary disease) is acceptable.
11. Change in dose of thyroid hormones within 6 weeks prior to Visit 1A or planned change or initiation of such therapy before Visit 2
12. Known hypersensitivity or allergy to the investigational products or their excipients
13. Impaired renal function defined as estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73m² (according to Zappitelli formula) as measured by the central laboratory at Visit 1A
14. Indication of liver disease defined by serum level of either alanine transaminase (ALT), aspartate transaminase (AST) or alkaline phosphatase above 3 fold upper limit of normal (ULN) at Visit 1A as measured by the central laboratory at Visit 1A
15. History of belonephobia (needle phobia)
16. Any documented active or suspected malignancy or history of malignancy within 5 years prior to Visit 1A, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix
17. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia)
18. Any other acute or chronic medical or psychiatric condition or laboratory abnormality that, based on investigator’s judgement, would jeopardize patient safety during trial participation or would affect the study outcome
19. Medical contraindications to metformin according to the local label (for patient on metformin background therapy)
20. Patient not able or cannot be supported by his/her parent(s) or legal guardian to understand and comply with study requirements based on investigator’s judgement
21. Previous randomisation in this trial
22. Currently enrolled in another investigational device or drug trial, or less than 30 days since ending another investigational device or drug trial(s), or receiving other investigational treatment(s)
23. Chronic alcohol or drug abuse within 3 months prior to Visit 1A or any condition that, in the investigator’s opinion, makes them an unreliable trial patient or unlikely to complete the trial
24. Female patients who are pregnant, nursing, or who plan to become pregnant in the trial |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Change from baseline in HbA1c (%) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1) Change from baseline in fasting plasma glucose (mg/dl)
2) Change from baseline in body weight (kg)
3) Change from baseline in systolic blood pressure (SBP)
4) Change from baseline in diastolic blood pressure (DBP) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) 26 weeks
2) 26 weeks
3) 26 weeks
4) 26 weeks |
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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 | Yes |
| 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) | 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 | 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 | 33 |
| 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 |
| Argentina |
| Brazil |
| Canada |
| China |
| Colombia |
| Germany |
| Israel |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Portugal |
| Russian Federation |
| Thailand |
| United Kingdom |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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