E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 diabetes mellitus and inadequate glycemic control on a stable dose of metformin |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 diabetes not being controlled by current medication |
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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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049746 |
E.1.2 | Term | Insulin-requiring type II diabetes mellitus |
E.1.2 | System Organ Class | 100000004861 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063624 |
E.1.2 | Term | Type II diabetes mellitus inadequate control |
E.1.2 | System Organ Class | 100000004861 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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 examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU is non-inferior to titrated insulin glargine plus metformin with or without SU after 24 weeks of open-label treatment. |
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E.2.2 | Secondary objectives of the trial |
•To compare co-administered saxagliptin 5mg and dapagliflozin 10mg plus metformin with/without SU versus titrated insulin glargine plus metformin with/without SU after 24 weeks: - the mean change from baseline in total body weight - the proportion of confirmed hypoglycemia [defined as: a) plasma glucose ≤70 mg/dL (3.9 mmol/L); or b) signs / symptoms of hypoglycemia with self-monitored blood glucose ≤70 mg/dL (3.9 mmol/L)] - the proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%, without any hypoglycemia.
•To examine whether with co-administered saxagliptin 5mg and dapagliflozin 10mg plus metformin with/without SU is non-inferior to titrated insulin glargine plus metformin with/without SU after 24 weeks: - the change from baseline in the mean value of 24-hour glucose readings measured by Continuous Glucose Monitoring - the proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%. |
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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 |
Continuous Glucose Monitoring (CGM) Sub-Study In the this study, a sub-population of approximately 250 subjects with valid CGM data at the baseline assessment performed at Week -2 (approximately 125 subjects per treatment arm stratified by background SU use) who agree to participate (separate informed consent) will have a CGM sensor inserted subcutaneously to measure glucose levels in tissue fluid. The glucose sensor will be inserted and removed by trained personnel at the site. Subjects will wear the glucose sensor for 7 consecutive days at 4 different time periods during the study: • At baseline, prior to receiving study medication, between Week -2 and Week-1 • Between Week 2 and Week 3 of treatment • Between Week 11 and Week 12 of treatment • Between Week 23 and Week 24 of treatment. Subjects in the sub-study will have 4 site visits added to the regularly scheduled visits (Week -1, Week 3, Week 11 and Week 23). If CGM recording is insufficient at any of these timepoints, subjects may be required to wear the glucose sensor for an additional 7 day period to obtain sufficient data. Subjects in the CGM sub-study will be required to perform a 4-point SMBG profile on days of CGM monitoring when they are not performing the 6-point SMBG profile (see Section 5.3.1.2). This 4-point SMBG should be performed at the approximate times: before breakfast, before lunch, before dinner and before bedtime and the values recorded in the subject’s diary.
Detailed procedures (including calibration, insertion/removal and upload of data) will be described in an operations manual and site staff will be trained on the use of the CGM. Subjects will be instructed on use of the device according to the manufacturer’s instructions. |
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E.3 | Principal inclusion criteria |
• Males and females aged ≥ 18 years old at the time of screening visit. • Subjects with T2DM with inadequate glycemic control, defined as a central laboratory HbA1c ≥ 8 % and ≤ 12 % obtained at the screening visit. • Subjects must be taking a stable dose of metformin ≥ 1500 mg/day for at least 8 weeks prior to screening visit with or without a stable dose of SU of at least 50% maximal dose per local label for at least 8 weeks prior to screening visit. Subjects must not take any other antidiabetic therapy for more than 14 days (consecutive or not) during 12 weeks prior to screening. • BMI ≤ 45.0 kg/m2 at the screening visit. • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) at screening and within 24 hours prior to the start of study drug.
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E.4 | Principal exclusion criteria |
• Clinical diagnosis of Type 1 Diabetes. • History of diabetic ketoacidosis • History of unstable or rapidly progressing renal disease, hepatic insufficiency or current, acute or chronic pancreatitis. • Any of the following cardiovascular/vascular diseases within 3 months of enrollment visit: myocardial infarction (MI), coronary arterial bypass graft (CABG), percutaneous coronary intervention (PCI), valvular disease or repair, unstable angina or unstable congestive heart failure (CHF), transient ischemic attack (TIA), Class III or IV heart failure, known left ventricular ejection fraction of < 40%, or significant cerebrovascular disease. • Impairment of renal function (defined as creatinine clearance [CrCl] < 60 mL/min [estimated by Cockcroft-Gault] or serum creatinine [SCr] ≥ 1.5 mg/dL in male subjects or ≥ 1.4 mg/dL in female subjects). • Bladder cancer • Hematuria (confirmed by microscopy at screening) with no explanation as judged by the investigator up to randomization. • Other hematological or oncological diseases or conditions. • Participation in a commercial weight loss program or history of bariatric surgery. • Replacement or chronic systemic corticosteroid therapy. • Administration of any other investigational drug or participation in any interventional clinical study within (30) days prior to screening for this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in HbA1c at Week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline, prior to receiving study medication, between Week -2 and Week -1, Week 24 |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints for the short-term treatment period include: 1) Change from baseline in total body weight at Week 24 2) Proportion of subjects with confirmed hypoglycemia [defined as: a) plasma glucose ≤ 70 mg/dL (3.9 mmol/L); or b) signs / symptoms of hypoglycemia with self-monitored blood glucose ≤ 70 mg/dL (3.9 mmol/L)] at Week 24 3) Proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%, without any reported hypoglycemia (for the duration of the Short-term Period) at Week 24 4) In a sub-study, change from baseline in the mean value of 24-hour glucose readings measured by Continuous Glucose Monitoring (CGM) at Week 2 5) Proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0% at Week 24
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) At baseline, prior to receiving study medication, between Week -2 and Week -1, Week 24 2) Week 24 3) Week 24 4) At baseline, prior to receiving study medication, between Week -2 and Week -1, Week 24 5) Week 24 |
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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 | No |
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) | 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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
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
| 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 71 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Czech Republic |
Denmark |
Germany |
Hungary |
Mexico |
Poland |
Romania |
Russian Federation |
South Africa |
Spain |
Sweden |
United States |
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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 | 2 |
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 | 2 |
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 |