E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with type 2 diabetes. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with type 2 diabetes. |
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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 | 18.0 |
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 main objective of this study is to identify the dose of linagliptin (BI1356) in paediatric patients. |
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E.2.2 | Secondary objectives of the trial |
Other efficacy objectives include the comparison of the lowering effect of linagliptin 1mg, 5mg and placebo on the fasting plasma glucose (FPG) observed after 12 wk of treatment.
The study will also investigate the pharmacokinetics (PK), the pharmacodynamics (PD) and the PK/PD relationship of linagliptin in the paediatric population.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
no real substudy but two different PK/PD subgroups following PDCO request : sparse or rich sampling will be performed in this trial with respectively 3 or 7 blood samples taken, twice during the study (visit 2 and visit 4) |
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E.3 | Principal inclusion criteria |
1. Paediatric patients (children and adolescents), aged 10 to 17 years at the time of randomization (i.e. Visit 2).
2. Documented diagnosis of type 2 diabetes mellitus at least 3 months prior to randomisation (i.e. Visit 2).
3. 1. Patients with insufficient glycaemic control (i.e. an HbA1c > 6.5% and ≤ 10.5%) at screening (i.e. Visit 1A)
3.2. Patients treated with diet and exercise and/or metformin (≥ 1000 mg per day (or the maximum tolerated dose) at a stable dose and dosing frequency for 8 weeks prior to randomisation) and/or concomitant stable basal insulin (total daily dose must be ≤ 0.5U/kg with less than 10% of weekly dose
change for 12 weeks prior to randomisation).
4. Negative for islet cell antigen (ICA) auto-antibodies and glutamic acid decarboxylase (GAD) auto-antibodies prior to randomisation (i.e. Visit 2)
5. C-peptide levels (serum) ≥ 1.5 ng/ml (at 90 min following a Boost challenge) at Visit 1B
6. Compliance during the open-label placebo run-in period between 75% and 125%.
7. BMI>50th percentile for age and sex.
8. Written informed consent provided by the patient’s parent(s) (or legal guardian) and assent by the patient at the latest by the date of Visit 1A in accordance with GCP and local legislation. Informed assent will be sought according to the patient’s age, level of maturity, competence and capacity. All informed consent/assent forms will be consistent with ICH-GCP and local IEC/IRB requirements.
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E.4 | Principal exclusion criteria |
1. Uncontrolled hyperglycaemia with repeatedly elevated glucose levels (i.e. at least 2 glucose levels) > 240 mg/dl (> 13.3 mmol/l)as measured by the central laboratory after an overnight fast during placebo run-in (i.e. from Visit 1B to Visit 2).
2. History of acute metabolic decompensation, such as diabetic ketoacidosis, within 3 months of screening (i.e. Visit 1A)
3. Current short-acting insulin
or having received short-acting insulin for more than 3 days within 1 month
prior to randomisation (i.e. Visit 2).
4. Treatment with weight reduction medications (including anti-obesity treatments) within 3 months prior to randomisation (i.e. the date of Visit 2)
5. Chronic treatment – treatment duration of more than two weeks - with medication known to affect glucose metabolism (e.g. metformin or systemic corticosteroids) within 3 months prior to randomisation (i.e. Visit 2)
6. Anticipated need for treatment with PGP (P-glycoprotein) and CYP 3A4 inhibitors or inducers during the placebo run-in period (Visit 1B onwards) and randomised period (Visits 2-6) of the study (See Appendix 10.5 for a list of prohibited medications)
7. Clinically significant renal disease (defined as estimated Glomerular Filtration Rate [eGFR] < 60 ml/min/1.73m2, i.e. moderate and severe renal impairment, calculated according to the Schwarz formula) as determined at screening (i.e. Visit 1A)
8. Elevated serum levels of ALT (SGPT), AST (SGOT), alkaline phosphatase above 3 x upper limit of normal (ULN) or lipase and amylase above 1.5 fold ULN as determined at screening (i.e. Visit 1A)
9. Patients with an history of documented pancreatitis
10. Gastrointestinal disorders that might interfere with study drug absorption
11. Patients presenting a secondary obesity as part of a syndrome (e.g. : Prader-Willi syndrome)
12. Female patients who are nursing or are pregnant
13. Female patients who have reached menarche (i.e. ANY vaginal bleeding, however scant or irregular) with a positive pregnancy test or who are sexually active and not using a medically accepted contraceptive method. Acceptable methods of birth control are limited to: intra-uterine device (IUD); oral, implantable or injectable contraceptives and oestrogen patch; double-barrier method (spermicide plus diaphragm); or abstinence (if permitted by local authorities) at the discretion of the Investigator
14. Patients with a history of belonephobia (needle phobia) in this age group
15. Patients with anaemia defined as shown below and as determined at screening (Visit 1A):
• children aged up to 12: haemoglobin of < 11.5 g/dl and haematocrit < 35%
• females aged > 12 or who reached menarche before this age: haemoglobin of < 12 g/dl and haematocrit < 36%
• males aged > 12: haemoglobin of < 13 g/dl and haematocrit < 39%
16. Active alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation according to the Investigator opinion
17. Patients whose parent(s) (or legal guardian) will be unable to support the reporting of adverse event information (e.g. not fluent in an appropriate language, or no access to a telephone)
18. Patients whose home circumstances will mean they are unable to store the study rescue medication (insulin) appropriately (i.e. no access to reliable refrigeration)
19. Known hypersensitivity or allergy to the investigational product or its excipients or placebo
20. Patient with an history of hereditary angioedema or history of serious hypersensitivity reactions (i.e anaphylaxis, recurrent angioedema or bronchial hyperreactivity)
21. Participation in another trial with an investigational drug within 2 months prior to informed consent
22. Patients considered unreliable by the Investigator concerning the requirements for follow-up during the study and/or compliance with study medication administration
23. Any disease or clinically significant abnormality/clinical condition that may increase the risk associated with study participation or affect the study outcome, and in the judgement of the Investigator would make the patient inappropriate for entry into the study
24. Contraindications to metformin according to the local label (for patient on metformin background therapy)
25. Medical history of cancer (except for basal cell carcinoma) and/or treatment forcancer within the last 5 years
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in this trial is the change from baseline in HbA1c (%) after 12 weeks of treatment. Throughout the trial protocol, the term "baseline" refers to the last observation prior to the administration of any randomised study medication. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 12 weeks of treatment |
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E.5.2 | Secondary end point(s) |
1. The secondary endpoint is the change from baseline in fasting plasma glucose (mmol/L) after 12 weeks of treatment.
2. The key secondary endpoint in this trial is DPP-4 inhibition (%) at trough at steady state. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. After 12 weeks of treatment.
2. After 4 or 8 or 12 weeks of treatment. |
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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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 13 |
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 | Information not present in EudraCT |
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 |
Canada |
France |
Italy |
Korea, Republic of |
Mexico |
New Zealand |
Poland |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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For all patients completing the 12 week treatment period according to protocol, a follow up visit 7 (clinic visit) should be performed at the end of the follow up period of 7 days. In case of premature discontinuation from the 12 week treatment period, a Visit 6 should be performed and the patient should return for visit 7 (7 days after V 6).
EOT = LPO or early termination of the trial (if applicable) |
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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 | 5 |
E.8.9.1 | In the Member State concerned days | 8 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |