E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Obese insulin-resistant patients with Type 2 Diabetes mellitus (T2DM) and inadequate glycemic control (HbA1c ≥ 8.0% and ≤ 11.0%) |
Patienten mit Diabetes mellitus Typ 2 und inadäquater glykämischer Kontrolle (HbA1c ≥ 8.0% und ≤ 11.0%) |
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E.1.1.1 | Medical condition in easily understood language |
Obese insulin-resistant patients with Type 2 Diabetes mellitus (T2DM) and inadequate glycemic control (HbA1c ≥ 8.0% and ≤ 11.0%) |
Patienten mit Diabetes mellitus Typ 2 und inadäquater glykämischer Kontrolle (HbA1c ≥ 8.0% und ≤ 11.0%) |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
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 absolute change from baseline in HbA1c at week 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy |
Vergleich der absoluten Veränderung des HbA1c von Baseline zu Woche 28 zwischen Dapagliflozin in Kombination mit Exenatid, Placebo und Exenatid Monotherapie als Ergänzung zu einer hoch-dosierten intensivierten Insulintherapie |
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E.2.2 | Secondary objectives of the trial |
-compare the absolute change from baseline in HbA1c at week 14 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy -compare the change from baseline in total body weight at week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy - compare the change from baseline in BMI at week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy -compare the change in fasting plasma glucose (FPG) at week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy -compare the change in total daily insulin dose (TDID) at week 14 and 28 between Dapagliflozin plus Exenatide, Placebo or Exenatide monotherapy added to high-dose intensive insulin therapy
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed Consent can be obtained prior to any study procedures. 2. Patient is able to read, understand and sign the Informed Consent. 3. HbA1c ≥ 8.0% and ≤ 11.0% based on laboratory results 4. Currently treated with a stable TDID ≥ 80 U at least 3 months prior to enrolment 5. Patients who are receiving metformin must be on a stable total daily dose ≥ 1500 mg or the maximum tolerated dose of metformin within 3 months prior to enrolment 6. BMI of ≥ 30 kg/m2 at enrolment 7. Male or female and ≥18 and ≤75 years old at time of informed consent 8. For female patients: - Not breastfeeding. - Negative pregnancy test result (human chorionic gonadotropin, beta subunit [βhCG]) at Visit 0 (Screening) and Visit 1 (randomization) -not applicable to hysterectomized and post-menopausal females. - 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 appropriate birth control (defined as a method which results in a low failure rate, ie, less than 1% per year, when used consistently and correctly, such as implants, injectables, hormonal contraceptives [pills, vaginal rings, or patches], some intrauterine contraceptive devices [levonorgestrel-releasing or copper-T], tubal ligation or occlusion, or a vasectomized partner) during the entire duration of the study. As applicable, all methods must be in effect prior to receiving the first dose of study medication. - Must practice appropriate birth control as stated above for 10 weeks after the last dose of study medication. 9. Patients who are receiving the following medications must be on a stable treatment regimen for a minimum of 2 months prior to Visit 0 (Screening): - Antihypertensive agents - Thyroid replacement therapy - Antidepressant agents |
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E.4 | Principal exclusion criteria |
1. Diagnosis of Type 1 Diabetes 2. History of diabetic ketoacidosis, hyperosmolar coma or corticosteroid-induced Type 2 diabetes 3. Patients with significant thyroid disease 4. Patients with history of acute or chronic pancreatitis 5. Clinically significant cardiovascular disease or procedure within 3 months prior to enrolment or expected to require coronary revascularization procedure 6. Presence of history of severe congestive heart failure (NYHA III and IV) 7. Creatinin-Clearance of < 60 ml/min based on local laboratory results 8. Concomitant medication with loop diuretics 9. Pregnant women 10. Administration of any other antidiabetic therapy, other than insulin (see inclusion criterion no.4 and 5) and metformin with a stable total daily dose ≥ 1500 mg or the maximum tolerated dose of metformin within 3 months prior to enrolment 11. History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥ 700 mg/dL (≥ 7.98 mmol/L) at Visit 0 (Screening). 12. History or presence of inflammatory bowel disease or other severe GI diseases, particularly those which may impact gastric emptying, such as gastroparesis or pyloric stenosis. 13. History of gastric bypass surgery or gastric banding surgery, or either procedure is planned during the time period of the study. Current use of gastric balloons is also excluded. 14. Significant hepatic disease, including, but not limited to, acute hepatitis, chronic active hepatitis, or severe hepatic insufficiency, including patients with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or total bilirubin (TB) >2 mg/dL (>34.2 μmol/L) (patients with TB >2 mg/dL [>34.2 μmol/L] and documented Gilbert’s syndrome will be allowed to participate). 15. Known history of hepatotoxicity with any medication 16. Known history of severe hepatobiliary disease. 17. Positive serological test for hepatitis B or hepatitis C. 18. Known or suspected human immunodeficiency virus (HIV) infection. 19. History of organ transplantation. 20. Presence or history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2) OR a family history of medullary thyroid carcinoma or MEN 2. 21. Malignancy (with the exception of basal and squamous cell carcinoma of the skin) within 5 years of Visit 0 (Screening). 22. Hemoglobinopathy, hemolytic anemia, or chronic anemia (haemoglobin concentration <11.5 g/dL [115 g/L] for males, <10.5 g/dL [105 g/L] for females) or any other condition known to interfere with the HbA1c methodology. 23. Has donated blood or had a significant blood loss within 2 months of first dose of study medication or is planning to donate blood during the study. 24. Has donated plasma within 7 days prior to first dose of study medication. 25. Any exposure to Exenatide (including BYETTA®, BYDUREON™, or exenatide suspension). 26. Any exposure to Dapagliflozin or any SGLT-2 inhibitor. 27. Has been treated, is currently being treated, or is expected to require or undergo treatment with any of the following treatment excluded medications: - Any DPP-4 inhibitor within 3 months prior to Visit 0 (Screening). - Any GLP-1 analog within 1 year prior to Visit 0 (Screening). - Systemic corticosteroids within 3 months prior to Visit 0 (Screening) by oral, intravenous, intra-articular, or intramuscular route; or potent, inhaled, or intrapulmonary (including ADVAIR®) steroids known to have a high rate of systemic absorption. For examples of excluded steroids, refer to Section 7.7. - Prescription or over-the-counter weight loss medications within 3 months prior to Visit 0 (Screening). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change in HbA1c from baseline to Week 28. |
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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) |
- Change in HbA1c from baseline (week 0) to week 14 - Change in total body weight from baseline (week 0) to week 14 and 28 - Change in BMI from baseline (week 0) to week 14 and 28 - Change in FPG from baseline (week 0) to week 14 and 28 -Change in TDID from baseline (week 0) to week 14 and 28 (approaching a target FPG of 100-120mg/dL/ 5.6-6.7 mmol/L) - Proportion of patients achieving HbA1c of ≤ 7% at week 28 compared to baseline |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Change in HbA1c from baseline (week 0) to week 14 - Change in total body weight from baseline (week 0) to week 14 and 28 - Change in BMI from baseline (week 0) to week 14 and 28 - Change in FPG from baseline (week 0) to week 14 and 28 -Change in TDID from baseline (week 0) to week 14 and 28 (approaching a target FPG of 100-120mg/dL/ 5.6-6.7 mmol/L) - Proportion of patients achieving HbA1c of ≤ 7% at week 28 compared to baseline |
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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 | 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) | Yes |
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 | 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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
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 | 16 |
E.8.9.1 | In the Member State concerned days | |