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 | 14.1 |
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 |
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 |
Paediatric patients, aged 10 to 17 years at the time of randomisation (i.e. Visit 2)
Documented diagnosis of type 2 diabetes mellitus at least 3 months prior to randomisation (i.e. Visit 2)
Insufficient glycaemic control (i.e. an HbA1c > 7.0% and ≤ 10.0%) at screening despite treatment with diet and exercise and/or metformin (above or equal to 1000 mg per day (or the maximum tolerated dose) at a stable dose and dosing frequency for 8 weeks prior to randomisation)
Negative for islet cell antigen (ICA) auto-antibodies and glutamic acid decarboxylase (GAD) auto-antibodies prior to randomisation (i.e. Visit 2)
C-peptide levels (serum) ≥ 1.5 ng/ml (at 90 min following a Boost challenge) at Visit 2
Compliance during the open-label placebo run-in period between 75% and 125%.
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 |
Uncontrolled hyperglycaemia with a glucose level > 240 mg/dl (> 13.3 mmol/l) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
History of acute metabolic decompensation, such as diabetic ketoacidosis, within 3 months of screening
Current insulin therapy, or having received insulin for > 4 weeks within the 3 months prior to randomisation
Treatment with weight reduction medications (including anti-obesity treatments) within 3 months prior to randomisation
Chronic treatment – treatment duration of more than two weeks - with medication known to affect glucose metabolism within 3 months prior to randomisation
Anticipated need for treatment with PGP (P-glycoprotein) and CYP 3A4 inhibitors or inducers during the study.
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
Clinically significant hepatic disease (defined as persistent serum levels of ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening
Gastrointestinal disorders that might interfere with study drug absorption
Patients presenting a secondary obesity as part of a syndrome (e.g. : Prader-Willi syndrome)
Female patients who are nursing or are pregnant
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
Patients with a history of belonephobia (needle phobia) in this age group
Patients with anaemia defined as shown below and as determined at screening:
•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%
Active alcohol or drug abuse within the 3 months prior to informed consent
Patients whose parent(s) (or legal guardian) will be unable to support the reporting of adverse event information
Patients whose home circumstances will mean they are unable to store the study rescue medication (insulin) appropriately
Known hypersensitivity or allergy to the investigational product or its excipients or placebo
Participation in another trial with an investigational drug within 2 months prior to informed consent
Patients considered unreliable by the Investigator concerning the requirements for follow-up during the study and/or compliance with study medication administration
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
Contraindications to metformin according to the local label (for patient on metformin background therapy)
Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer 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) |
The secondary efficacy endpoint in this trial is the change from baseline in fasting plasma glucose (mmol/L) after 12 weeks of treatment
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 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 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Australia |
Canada |
Korea, Republic of |
Mexico |
New Zealand |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |