| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Obesity defined as body mass index (BMI) 30-45 kg/m2
Obesity related metabolic disorders |
|
| E.1.1.1 | Medical condition in easily understood language |
| Obesity and its related metabolic disorders |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029885 |
| E.1.2 | Term | Obesity, unspecified |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 efficacy of dapagliflozin 10 mg once daily and exenatide 2 mg once weekly in combination compared to placebo on body weight after 24 weeks of treatment in obese subjects (by measuring change in body weight (kg) from baseline to 24 weeks) |
|
| E.2.2 | Secondary objectives of the trial |
Sec. Objective
-Assess the efficacy of dapagliflozin 10 mg once daily and exenatide 2 mg once weekly in comb. compared to placebo on body weight after 24 w of treatment in obese subjects (by measuring change in percentage body weight from baseline to 24 w)
Exploratory objectives
To assess:
-Proportion of subjects responding to treatment with dapagliflozin & exenatide in comb. when compared to placebo
-Efficacy of a 28-w open-label period w dapagliflozin & exenatide following 24 w blinded treatment with dapagliflozin & exenatide in comb. or placebo respectively, to maintain or enhance body weight reduction
-Efficacy of dapagliflozin & exenatide in comb. compared to placebo on total body fat mass, total lean body mass, percentage liver fat, visceral fat mass & subcutaneous fat mass, glucose tolerance, insulin secretion, insulin sensitivity and lipolysis regulation, blood lipid profile, blood pressure & other anthropometric measurements |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Provision of signed informed consent prior to any study specific procedures.
2) Female and/or male aged 18 to 70 years with body mass index (BMI) (measured as body weight (kg)/(height (m))2) 30 to 45 kg/m2.
3) Female subjects must meet all of the following criteria:
a) Not breastfeeding
b) Negative pregnancy test result (human chorionic gonadotropin, beta subunit [hCG]) at Visit 1 (Enrolment) (not applicable to hysterectomized females).
c) If of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year), must practice and be willing to continue to practice one of the following highly effective birth control methods during the entire duration of the study:
i. Diaphragm or partner use of condom in combination with combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• Oral
• Intravaginal
• Transdermal
ii. Diaphragm or partner use of condom in combination with progestogen-only hormonal contraception associated with inhibition of ovulation:
• Oral
• Injectable
• Implantable
iii. Placement of an intrauterine device
iv. Placement of an intrauterine hormone-releasing system
v. Bilateral tubal occlusion
vi. Vasectomised partner (provided that the partner is the sole sexual partner of the female subject and that the vasectomised partner has received medical assessment of the surgical success)
vii. Sexual abstinence (defined as refraining from heterosexual intercourse)
d) Must practice appropriate birth control as stated above for 10 weeks after the last dose of study medication
|
|
| E.4 | Principal exclusion criteria |
1) Involvement in the planning and/or conduct of the study.
2) Previous enrolment in the present study.
3) Participation in another clinical study with an IP during the last 3 months prior to Visit 1.
4) History of any clinically significant disease, disorder or condition which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study.
5) Previous or new diagnosis of diabetes mellitus. For subjects being diagnosed with diabetes at enrolment, this should be judged by an experienced diabetologist and be based on composite laboratory measures according to American Diabetes Association (ADA) guidelines. These criteria include FPG >7.0 mmol/l, 2h-PG at OGTT >11.1 mmol/l and/or HbA1c > 48 mmol/mol. Subjects with FPG ≥7.0 mmol/L or 2h-PG ≥11.1 mmol/l at Visit 1, should have a second FPG measurement on a separate day, and if diabetes diagnosis is confirmed the subject will be excluded.
6) Any clinically significant abnormalities in physical examination or clinical chemistry results as judged by the Investigator. The following specific exclusion criteria apply to the selected Clinical Chemistry results:
a) Creatinine clearance <60mL/min (estimated with Cockroft-Gault formula).
b) Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN.
c) Total bilirubin (TB) >2.0 mg/dL (34.2 µmol/L).
7) Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IgM, Hepatitis B surface antigen and Hepatitis C virus antibody.
8) Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
9) Acute Coronary Syndrome (ACS) within 2 months prior to Visit 1. Hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment. Acute Stroke or transient ischemic attack (TIA) within two months prior to Visit 1. Less than two months post coronary artery revascularization.
10) History of gastroparesis or pancreatitis
11) History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin cancer.
12) Body weight loss greater than 5% within 3 months prior to Visit 1.
13) Treatment with any drug known to affect body weight within the last month, e.g. systemic glucocorticoids, antipsychotics or orlistat.
14) Multiple Endocrine Neoplasia syndrome type 2.
15) Personal or family history of medullary thyroid carcinoma.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Percentage change in body weight (kg) from baseline to 24 weeks
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoint:
Change in percentage bodyweight from baseline to 24 weeks
Exploratory endpoints:
Proportion of subjects with at least 10% reduction in weight at 24 and proportion of subjects with at least 5% reduction in weight at 24
Change in body weight (kg and percentage) from baseline to 52 weeks
Changes in
-Liver fat (%)
-Liver volume (l)
-Total liver fat (l)
-Visceral Adipose Tissue (l)
-Subcutaneous Adipose Tissue (l)
-Total Adipose Tissue (l)
-Total lean tissue (l)
-Body fat (%)
and other important parameters such as insulin, glukagon and free fatty acids |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-blind 24 weeks treatment followed by an optional 28-week open-label extension study. |
|
| 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
|
|
| 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 | 15 |
| E.8.9.1 | In the Member State concerned days | |
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