E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients with IGT, type 2 diabetes mellitus and healthy subjects |
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E.1.1.1 | Medical condition in easily understood language |
patients with IGT (impaired glucose tolerance) and type 2 diabetes mellitus and healthy subjects |
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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 | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018429 |
E.1.2 | Term | Glucose tolerance impaired |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 assess the acute and chronic effects of empagliflozin (BI 10773) on fasting and postprandial
glucose homeostasis in patients with IGT and type 2 diabetes mellitus and assess the acute effects of empagliflozin in healthy subjects. This includes
the analysis of gut and pancreatic hormones, endogenous glucose production, beta cell function and urinary glucose excretion |
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E.2.2 | Secondary objectives of the trial |
Secondary and furhter endpoints:
- Change in rate of endogenous glucose production, urinary glucose excretion, gut and pancreatic hormonal control of glucose metabolism, beta cell function, insulin sensitivity, lipolysis, energy expenditure, weight and waist circumference and systolic and diastolic blood pressure after one dose, and after 28 days of treatment, change in fasting and postprandial plasma triglycerides, total and HDL cholesterol and plasma metabolites and change from baseline in HbA1c after 28 days of treatment.
Endpoint(s) of safety
Adverse events, hypoglycaemic events, protocol-specified significant adverse events, cardiovascular events and changes from baseline in clinical laboratory values |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria for patients (IGT and T2DM):
1a Male and female patients diagnosed with IGT according to the current ADA
guidelines as a two-hour glucose levels of 140 to 199 mg/dl (7.8 mmol/l to 11.1
mmol/l) on the 75-g oral glucose tolerance test, with an OGTT performed at the time
of the screening visit (Visit 1), or
1b Male and female patients diagnosed with type 2 diabetes mellitus prior to informed consent, on diet and exercise regimen who are drug-naive, defined as absence of any antihyperglycemic therapy for 12 weeks prior to the planned Day 1 of the trial, or,
1c Male and female patients diagnosed with type 2 diabetes mellitus prior to informed consent, who are pre-treated with metformin (only immediate release formulations permitted) background therapy, on a stable dose of metformin of at least 1500 mg per day, unchanged for at least 12 weeks prior to the planned Day 1 in the trial.
2 HbA1c at Visit 1 (screening):
a. For patients diagnosed of IGT: HbA1c < 6.5%
b. For patients diagnosed of T2DM: HbA1c ≥ 6.5 % and ≤ 10.5 %3 Age ≥ 18 at Visit 1.
4 BMI ≥ 20 and ≤ 40 Kg/m2 (Body Mass Index) at Visit 1.
5 For patients who are under current antihypertensive treatment, this must be stable
(with no changes in dosage) within 4 weeks prior to the planned Day 1 (Visit 4) in the trial.
6 Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation.
Inclusion criteria for healthy subjects:
1 Males or females matching the below mentioned criteria and otherwise healthy according to the investigator’s assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (BP, PR) and clinical laboratory tests.
2 HbA1c at Visit 1 (screening): HbA1c < 6.5%
3 Confirmed normal glucose tolerance (NGT) by OGTT
4 Age ≥ 45 and ≤ 55 at Visit 1.
5 BMI ≥ 30 and ≤ 40 Kg/m2 (Body Mass Index) at Visit 1.
6 Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation.
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E.4 | Principal exclusion criteria |
1. Acute coronary syndrome (non-STEMI, STEMI, unstable AP), stroke or TIA within 6 months prior to informed consent.
2. 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).
3. Any other antidiabetic drug within 12 weeks prior to starting the open-label active
treatment (Visit 4) except those defined as background via inclusion criterion 1c.
4. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST
(SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as
determined during screening and/or run-in phase.
5. Impaired renal function, defined as eGFR < 60 ml/min (moderate and severe renal
impairment) as determined during screening and/or run-in phase.
6. Medical history of insufficient bladder emptying (i.e. neurogenic bladder disorders).
7. Patients with Hb values outside of normal reference ranges measured at central laboratory during screening and/or run-in phase.
8. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption.
9. Medical history of cancer (except for basal cell carcinoma) and/or treatment for
cancer within the last 5 years.
10. For patients on metformin background therapy, the investigator must check for
potential exclusion criteria according to local metformin label.
11. Treatment with anti-obesity drugs 3 months prior to
informed consent or any other treatment at the time of screening (i.e. surgery,
aggressive diet regimen, etc.) leading to unstable body weight.
12. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other
uncontrolled endocrine disorder except T2DM. However, the use of inhaled steroids
(e.g., for asthma, COPD) is not an exclusion as these do not cause systemic steroid
action.
13. Alcohol or drug abuse (according to investigators judgment) within the 3 months prior to informed consent that would interfere with trial participation or any ongoing
condition leading to a decreased compliance to study procedures or study drug intake.
14. Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial.
15. Pre-menopausal women (last menstruation ⤠1 year prior to informed consent) who:
⢠Are nursing or pregnant or
⢠Are of child-bearing potential and are not practicing an acceptable method of
birth control, or do not plan to continue using this method throughout the
study and do not agree to submit to periodic pregnancy testing during
participation in the trial. Acceptable methods of birth control include tubal
ligation, transdermal patch, intra uterine devices/systems (IUD/IUSs), oral,
implantable or injectable contraceptives, sexual abstinence (if acceptable by
local authorities), double barrier method and vasectomised partner.
16. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints in this study are the fasting plasma glucose (FPG) and the change in glucose metabolism (fasting pre-meal and postprandial glucose) from baseline to the first administration of the study medication (all subjects), and to 28 days of treatment (IGT and T2DM patients).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to the first administration of the study medication, and to 28 days of treatment. The term 'baseline' refers to the last observation prior to the inclusion into the open-label active-treatment period. |
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E.5.2 | Secondary end point(s) |
Change in rate of endogenous glucose production from baseline after one dose, and after 28 days of treatment. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to the first administration of the study medication, and to 28 days of treatment. The term 'baseline' refers to the last observation prior to the inclusion into the open-label active-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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 | 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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It has been provided in the protocol (section 3.3.4) |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |