E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
"Hepatocyte nuclear factor 1-alfa diabetes", also called "Maturity onset diabetes of the young type 3"'. It is a monogenic form of inherited diabetes. |
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E.1.1.1 | Medical condition in easily understood language |
An inherited form of diabetes where only a single gene is affected. The disease resembles type 2 diabetes, but the patients are younger. |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10026948 |
E.1.2 | Term | Maturity-onset diabetes of the young |
E.1.2 | System Organ Class | 100000004861 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of this trial is to investigate the effect of glimepiride + linagliptin vs. glimepiride + placebo on glycaemic variability in patients with hepatocyte nuclear factor 1-alpha (HNF1A) diabetes in a double-blind, randomised, cross-over trial. HNF1A-diabetes is also known as maturity onset diabetes of the young type 3 (MODY3). |
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E.2.2 | Secondary objectives of the trial |
Among other to investigate longterm glycaemic control (HbA1c) and risk of hypoglycaemia during treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with hepatocyte nuclear factor 1-alpha (HNF1A) diabetes caused by heterozygous mutation in HNF1A confirmed by Sanger sequencing of the gene • Monotherapy with diet or a stable dose of glimepiride of (≥0.5 mg per day) during four weeks • Patients on glimepiride HbA1c ≥6.5% (HbA1c ≥47 mmol/mol); treatment naïve patients HbA1c ≥7.0% (HbA1c ≥53 mmol/mol) • Age ≥18 years of age • Capability to perform a 30 minute light bicycle test at a heart rate of 100-120 beats per min • Fertile females: use of anticonception (intrauterine contraceptive devices or hormonal contraception) • Informed consent |
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E.4 | Principal exclusion criteria |
• Glucose-lowering drugs other than glimepiride • Uraemia, end-stage renal disease or estimated glomerular filtration rate <30 ml/min/1.73m2 and/or albuminuria • Liver disease and/or alanine amino transferase (ALAT) and/or aspartate amino transferase (ASAT) >2 × upper normal serum levels • Anaemia (males blood haemoglobin <8.0 mmol/l and females <7.0 mmol/l) • History of acute and/or chronic pancreatitis • Pregnancy or breast feeding • Inability to complete the study • Known allergic reaction to study medication • Intention to become pregnant |
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean amplitude of glycaemic excursions (MAGE)
The primary endpoint is the absolute difference in MAGE between the two treatments (glimepiride + linagliptin vs. glimepiride + placebo) at the end of each treatment period calculated from six days (144 hours) of continuous glucose monitoring (CGM). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline and end of both treatment periods. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints include differences between the two treatments (glimepiride + linagliptin vs. glimepiride + placebo) in:
• Other parameters of glycaemic variability including low blood glucose index (LBGI), standard deviation of mean glucose, time spent in hypoglycaemia and time spent in hyperglycaemia calculated from six days of CGM at the end of each treatment period . • Difference between baseline and end of treatment in parameters of glycaemic variability including MAGE, LBGI, standard deviation of mean glucose, time spent in hypoglycaemia, time spent in hyperglycaemia from six days of CGM monitoring. • Glycaemic excursion and endocrine function during a 4-hour meal and bicycle test • Plasma/serum concentrations of insulin, C-peptide, glucagon, GIP, GLP-1, growth hormone (GH), cortisol, epinephrine and norepinephrine during a 4-hour meal and bicycle test • Number and severity of hypoglycaemic events during meal and bicycle tests • Number and severity of hypoglycaemic events during treatment periods • Fasting plasma glucose (FPG) at the end of each treatment period • Glycated haemoglobin (HbA1c) at end of trial • Change in bodyweight from baseline • Change in fructosamine at end of treatment • Changes in cardiovascular biomarkers in urine • Changes in quality of life from baseline evaluated with Short Form 36 (SF-36) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At baseline and in the end of each treatment period. |
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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 | 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 | No |
E.8.1.6 | Cross over | Yes |
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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |