E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetes mellitus type 2 |
Diabetes Typ 2 |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 Diabetes |
Typ 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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012594 |
E.1.2 | Term | Diabetes |
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 |
To compare the glucagon response of a treatment with metformin monotherapy (baseline), a SGLT-2 inhibitor, a DPP-4 inhibitor and a combination of a SGLT-2 inhibitor and a DPP-4 inhibitor during normo-, hyper- and hypoglycaemia in a controlled clamp setting under stable metformin therapy. |
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E.2.2 | Secondary objectives of the trial |
To compare the effect of treatment with metformin monotherapy (baseline), an add-on SGLT-2 inhibitor, an add-on DPP-4 inhibitor and an add-on combination of a SGLT-2 inhibitor and a DPP-4 inhibitor on endogenous glucose production, peripheral glucose uptake, lipolysis, insulin sensitivity, metabolites, and glucose regulating hormones during normo-, hyper- and hypoglycaemia in a controlled clamp setting under stable metformin therapy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female aged 18-64 years (both inclusive) at the time of signing informed consent. • Subjects diagnosed with type 2 diabetes and on stable treatment for a period of 90 days prior to screening with metformin as monotherapy. Stable is defined as un-changed dose. • Body mass index (BMI) between 20.0 and 35.0 kg/m2 (both inclusive). • HbA1c between 47.5 and 85.8 mmol/mol (6.5 – 10.0%) (both inclusive).
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E.4 | Principal exclusion criteria |
• Treatment with any glucose lowering agent(s) other than metformin in a period of 90 days before screening. An exception is short-term treatment (≤ 7 days in total) with insulin due to intercurrent illness. • Clinically significant abnormal haematology, biochemistry, lipids, hormones, coagu-lation and urinalysis. • Acute symptomatic (according to investigator’s judgement) urinary tract infection or genital infection, chronic or recurrent (≥ 3 annual episodes) cystitis. • Uncontrolled hypertension defined as sitting blood pressure at screening (after resting for 5 min) outside the range of 90−160 mmHg for systolic or 50−100 mmHg for diastolic. • Chronic liver failure with severe liver dysfunction as assessed by the investigator.
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E.5 End points |
E.5.1 | Primary end point(s) |
ΔGlucagon: Change in glucagon concentration from 5.5 mmol/L low insulin to 11.1 mmol/L: Glucagon11.1-Glucagon. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At each plateau of the hyper-, normo- and hypoglycaemic clamp |
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E.5.2 | Secondary end point(s) |
AUCGlucagon: area under the complete glucagon concentration curve during the clamp procedure. GlucagonPG, glucagon concentration at different assessment plateaus (e.g. 11.1 mmol/L) ΔGlucagona,b, change in glucagon concentration between different glucose levels (e.g. change from 5.5 mmol/L low insulin to 11.1 mmol/L) EGPplateau, mean endogenous glucose production (EGP) at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L) ΔEGPa,b, change in EGP between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L) AUCGIR, area under the glucose infusion rate (GIR) curve at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L) ΔGIRa,b, change in AUCGIR between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L) PGUplateau, mean peripheral glucose uptake (PGU) at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L) ΔPGUa,b, change in PGU between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L) Lipoplateau, mean lipolysis at different assessment plateaus (e.g. assessment plateau 11.1 mmol/L) Δlipoa,b, change in lipolysis between different assessment plateaus (e.g. change from assessment plateau 5.5 mmol/L low insulin to 11.1 mmol/L) MetabolPG, concentration of lactate, free fatty acids, glycerol and ketone bodies at different assessment plateaus(e.g. 11.1 mmol/L) ΔMetabola,b, change in concentration of lactate, free fatty acids, glycerol and ketone bodies between different glucose levels (e.g. change from 5.5 mmol/L low insulin to 11.1 mmol/L) CounterPG, concentration of adrenaline, noradrenaline, growth hormone and cortisol at different assessment plateaus (e.g. 11.1 mmol/L) ΔCountera,b, change in concentration of adrenaline, noradrenaline, growth hormone and cortisol between different glucose levels (e.g. change from 5.5 mmol/L low insulin to 11.1 mmol/L)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At each plateau of the hyper-, normo- and hypoglycaemic clamp |
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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) | 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 | No |
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 | 3 |
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 | 7 |
E.8.9.1 | In the Member State concerned days | |