| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Efficacy of combination of Exenatide and Dapagliflozin compared to Dapagliflozin and Placebo and its effects on hepatic, myocardial and pancreatic fat distribution in patients with type 2 diabetes mellitus |
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| E.1.1.1 | Medical condition in easily understood language |
| Effects of Dapagliflozin and Exenatide versus Dapagliflozin and Placebo on liver, heart and pancreatic fat distribution in patients with type 2 diabetes mellitus. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| 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 investigate the effects on hepatic lipid content reduction of combination therapy with dapagliflozin (10mg daily) and exenatide (2mg weekly) compared to dapagliflozin (10mg daily) and placebo given for 24 weeks in patients with type 2 diabetes mellitus and insufficient glycaemic control. |
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| E.2.2 | Secondary objectives of the trial |
to investigate the effects on myocardial, pancreatic, abdominal and visceral lipid content reduction
to assess safety and tolerability of combination therapy with dapagliflozin and exenatide compared to dapagliflozine and placebo.
To assess effect of combination therapy with dapagliflozin and exenatide on quality of live and diabetes managment safisfaction compared to dapagliflozine and placebo.
To assess the effect of combination therapy with dapagliflozin and exenatide on glycaemic control, insulin resistance, blood pressure, glucagon level, weight loss and kidney function compared to dapagliflozine and placebo.
To assess the effect of combination therapy with dapagliflozin and exenatide on eating pattern, energy intake and expenditure, compared to dapagliflozine and placebo.
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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 |
Pancreas Fat Substudy: Optimization of the pancreatic fat measurement – transition from healthy volunteers to patients with T2DM
Amendment 1 in protocol version 1.7, date 08.07.2016
To optimize the measurement of the pancreatic fat, two different single voxel spectroscopic methods will be compared on 15 volunteering participants of the study at thebaseline MR measurement . Standard sequence used for the liver fat assessment will be applied on the pancreas and compared to the new one with the navigation based on the free breathing during the measurement. As the pancreas is small organ in comparison to the liver, slightly different breath hold than the one held during the localising images can result into improper volume used for the acquisition of the spectra, even outside of the pancreas or with inclusion of the visceral fat. Therefore navigated sequence, which is set to trigger the acquisition only during the specific position of the abdomen during the breathing cycle could provide more reliable results, although during longer measurement.
Measurements will be performed at 3T PrismaFit scanner from Siemens. Volunteers will be in the supine position on the spine coil, with the flex chest coil placed over the abdomen. After the localisation images, voxel will be placed into the tail of the pancreas, avoiding peripancreatic fat.
Water and lipid peaks in the spectra will be analysed in jMRUI and corrected for T2 and T1 relaxation and fat percentage will be calculated. Results will be compared to each other and to the DIXON fat-water images to decide which spectroscopic method provides more reliable results. |
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| E.3 | Principal inclusion criteria |
T2DM
Sex: male and female
HbA1c >=6.5 and <=11
Age >=18 and <=75 years
BMI>=25kg/m²
Metformin>=1000mg daily, 8 weeks stable dose
Please note: Type 2 diabetes mellitus patients treated with
less than 1000 mg metformin per day can only be included if
the investigator considers the patient to be on the maximum
tolerated dose and the investigator has documented the reason
why uptitration to 1000 mg was not possible
able and willing to not change diet and physical activity during enrolement in study
consent and able to give informed consent.
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| E.4 | Principal exclusion criteria |
other diabetes diagnosis than T2DM
patients on other antidiabetic medication (Sulfonylurea, Glitazone, insulin for more than 2 weeks (see below), SGLT2 inhibitors, GLP1 agonist, nateglinid, repaglinid, acarbose, DPP4 inhibitors)
Subjects currently or previously treated with insulin (with the exception of emergency situations in which insulin was given for less than 14 consecutive days, but not within the last 3 months before screening)
known intolerance against study medication
Contraindications including hypersensitivity known to metformin according to the local label
recurrent urinary tract infections
GFR < 60
Liver enzymes above 3 fold normal range
Bilirubin higher 3 fold normal range
Any other clinical condition that would jeopardize patients safety while participating in this clinical trial
disease at screening (other than NAFLD) such as relevant cardiovascular, gastrointestinal, hepatic, neurologic, psychiatric, endocrine (i.e. pancreatic) except T2DM, hematologic, malignant, infection or other major systemic diseases making implementation of the protocol or interpretation of the study results difficult
history of pancreatitis
Known autoimmune disease or chronic inflammatory condition
Myocardial infarction or stroke within 6 months prior to screening
Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g.malaria, babesiosis, haemolytic anaemia)
Other liver disease including chronic viral hepatitis (B or C), alcohol abuse, hemochromatosis, alpha-1antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, primary sclerosing cholangitis or primary biliary cirrhosis, or liver cirrhosis of any etiology
malignancy within the last 5 years before randomisation
medullary thyroid cancer
family history of multiple endocrine neoplasia syndrome
Alcohol or drug abuse 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
Presence of any absolute or relative contraindication for the conduct of an MRI investigation, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system,metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc.
History of bariatric surgery
Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 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
Subjects receiving antihypertensive medication and/or thyroid hormones, the dose(s) of which have not been stable for at least 6 weeks prior to baseline
Current treatment with systemic steroids at time of informed consent (Treatment with local and inhaled steroids is allowed)
Use of drugs potentially associated with NAFLD for more than 2 consecutive weeks in the 6 months prior to screening.
Use of anti-NASH drugs (thiazolidinediones, vitamin E, UDCA, SAM-e, betaine, milk thistle, anti-TNF therapies,) in the 3 months prior to randomization.
Donation of blood (> 400 mL) during the previous 3 months prior to the screening visit or during the duration of the study
Participation in another trial with an investigational drug within 30 days prior to informed consent.
Any subject who is the investigator or any subinvestigator, research assistant, pharmacist, study coordinator, other staff thereof, directly involved in the conduct of the protocol.
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 practising 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 (IUDs/IUSs), oral,
implantable or injectable contraceptives,sexual abstinence,( if
acceptable by local authorities) double barrier method and
vasectomised partner.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for the efficacy analysis is the liver fat [measured in percent] content at the end of the treatment period. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints are measurements on change in body fat , liver volume, visceral adipose tissue, subcutaneous adipose tissue, total adipose tissue and total lean tissue, myocardial and pancreatic fat from baseline to week 24 measured by MRI, the change in HbA1c from baseline after 24 weeks of treatment, the change in body weight from baseline after 24 weeks of treatment, the occurrence of confirmed symptomatic hypoglycaemic events during 24 weeks, the change in blood pressure (SBP and DBP) from baseline, after 24 weeks.
Other exploratory endpoints are the occurrence of treat to target efficacy i.e. HbA1c < 7.0 % or < 6.5 %, the occurrence of a relative efficacy response. i.e. HbA1c lowering of at least 0.5% after 24 weeks of treatment, the change from baseline HbA1c by visit over time, the change from baseline in FPG by visit over time, the change from baseline in mean daily glucose profile after 6, 12 and 24 weeks of treatment, the change in lipid profile from baseline after 24 weeks of treatment, the change in waist, hip and neck circumference from baseline after 24 weeks of treatment, the change in weight (>5% and >10% ) from baseline after 24 weeks of treatment, the change in insulin sensitivity and Insulin secretion, as well as glucose effectivness assessd by oGTT from baseline after 24 weeks of treatment, the change in glucagon levels, from baseline after 24 weeks of treatment, the change in energy intake and expenditure from baseline after 24 weeks of treatment, Sex/Gender differences in lipid accumulation, weight loss, glycaemia and the effect of combined treatment on changes.
the change in kidney function assessed by GFR from baseline after 24 weeks of treatment
Safety and tolerability endpoints
Safety of the treatment will be evaluated by AEs, laboratory tests, vital signs and ECG.
All subjects who received at least one dose of treatment will be included in the safety evaluation.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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) | 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 | 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 | 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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