E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 19.1 |
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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to compare the adjusted mean reduction in total body fat mass from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). |
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E.2.2 | Secondary objectives of the trial |
The key secondary objectives of this trial are to assess the adjusted mean change from baseline in:
1. Metabolic measures • HbA1c (the principal measure of glycaemic control). • 24 hour urinary glucose excretion • Hepatic glucose output, measured using hyperinsulinaemic, euglycaemic clamp and stable isotope infusions of 2H-glucose.
2. Measures of food intake, feeding behaviour and appetite using test meal study days.
3. Changes in body weight and fat volume and distribution using MRI/MRS • Visceral adipose tissue (VAT), • Subcutaneous adipose tissue (SAT) and • Liver fat
4. Changes in cardiovascular function • Indices of myocardial systolic and diastolic function using transthoracic echocardiography (Tissue Doppler Imaging) • Endothelial function: Flow mediated dilatation will be measured in response to an ischaemic stimulus using brachial ultrasound
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The inclusion criterion for this trial includes: • • Males or females, age 18-65 years, • A clinical diagnosis of type 2 diabetes, • Glycosylated haemoglobin (HbA1c) >6.5% but <11%, • Currently treated with either diet or any combination of metformin, DPP-IV inhibitors and sulphonylureas (excluding patients treated with pioglitazone or insulin). DPP-IV inhibitors will require wash out period of four weeks, • No current use of GLP1 receptor agonist or SGLT2 inhibitor treatment and • Provision of a signed informed consent form.
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E.4 | Principal exclusion criteria |
The exclusion criterion for this trial includes: • Type 1 diabetes mellitus, • History of diabetic ketoacidosis or hyperosmolar non-ketotic coma, • Renal impairment: eGFR less than 60 ml/minute/1.73m2, • Hyperthyroidism, • Hypothyroidism (subjects with a normal TSH and free T4, and on a stable dose of thyroxine for at least 3 months may be included), • Uncontrolled hypertension (SBP >160mmHg/DBP >110mmHg), • Congestive heart failure class III-IV, • Recent (< 6 months) myocardial infarction, • Severe hepatic impairment, • Significant cardiac dysrhythmias (including pacemaker or ICD), • Previous stroke, • Hypovolaemia, • Previous history of acute pancreatitis, • History of medullary thyroid cancer or bladder cancer, • Presence of any other medical condition that would, in the opinion of the investigator or their clinician, preclude safe participation in the study. This decision should be informed by dapagliflozin and exenatide precautions for use statements which will be provided to all clinicians and the research team, • Alcohol consumption in excess of daily recommended limits (21 units/week females, 28 units/week males), • Any history of internal metal, pacemakers, ferromagnetic metallic implants, intraocular foreign bodies or cerebral aneurysm clips (exclusion from MR scanning), • History of seizures or unexplained syncope.
Physical and Laboratory Test Findings • ALT > 3 x ULN • AST > 3 x ULN • Bilirubin > 2 x ULN • Haemoglobin ≤ 10.5 g/dL (≤ 105 g/L) for men; haemoglobin ≤ 9.5 g/dL (≤ 95 g/L) for women • eGFR <60 ml/minute/1.73m2 • Unexplained haematuria • Weight < 60kg and >150kg (due to MRI limitations) • BMI <30 kg/m2 and >50 kg/m2 • Recent major change in body weight (> 3kg loss or gain in preceding month)
Allergies and Adverse Drug Reactions • Subjects with a history of any serious hypersensitivity reaction to GLP1-RA or SGLT2 inhibitor, • Participant should have no allergies against metacresol (the preservative in insulin vial), • History of anaphylaxis to food, • Known food allergies or food intolerance, • Known hypersensitivity to heparin, • Known hypersensitivity to IV catheter equipment.
Sex and Reproductive Status • Females of childbearing age who are not using adequate contraceptive methods or who are planning a pregnancy in the next 6 months, • Women who are pregnant or breastfeeding.
Prohibited Treatments and/or Therapies • Diabetes treated with pioglitazone, SGLT2 inhibitors, GLP-1 analogues or insulin, • Use of other weight loss medication or any drug that might affect body weight or appetite (including antipsychotics, orlistat or corticosteroids), • Patients who are currently receiving a loop diuretic that cannot be discontinued.
Other Exclusion Criteria • Active or previous substance abuse or dependence, • Prisoners or subjects who are involuntarily incarcerated, • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of the study is to compare the adjusted mean reduction in total body fat mass from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of treatment (32 weeks of treatment) for each patient |
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E.5.2 | Secondary end point(s) |
1. Metabolic measures - HbA1c (the principal measure of glycaemic control) - 24 hour urinary glucose excretion - Hepatic glucose output, measured using hyperinsulinaemic, euglycaemic clamp and stable isotope infusions of 2H-glucose.
2. Measures of food intake, feeding behaviour and appetite using test meal study days
3. Changes in body weight and fat volume and distribution using MRI/MRS - Visceral adipose tissue (VAT) - Subcutaneous adipose tissue (SAT) - Liver fat
4. Changes in cardiovascular function - Indices of myocardial systolic and diastolic function using transthoracic echocardiography (Tissue Doppler Imaging) - Endothelial function: Flow mediated dilatation will be measured in response to an ischaemic stimulus using brachial ultrasound
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of treatment (32 weeks of treatment) for each patient |
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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 | No |
E.6.5 | Efficacy | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Information not present in EudraCT |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | 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 | 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.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |