E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type II diabetes mellitus |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012613 |
E.1.2 | Term | Diabetes mellitus non-insulin-dependent |
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 this study is to compare the change from baseline in haemoglobin A1c (HbA1c) to week 24 between dapagliflozin 10 mg in combination with metformin and sulfonylurea and placebo in combination with metformin and sulfonylurea. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives
· To compare the change from baseline in fasting plasma glucose (FPG) to week 24 between dapagliflozin and placebo.
· To compare the change from baseline in total body weight to week 24 between dapagliflozin and placebo.
· To compare the proportion of patients achieving a therapeutic glycaemic response, defined as HbA1c < 7.0%, at week 24 between dapagliflozin and placebo.
· To compare the change from baseline in seated systolic blood pressure (SBP) to week 8 between dapagliflozin and placebo. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The following criteria apply to the enrolment, placebo lead-in and randomisation visits (Visits 1, 2, 3, and 4).
1. Provision of informed consent prior to any study specific procedures.
2. Diagnosis of type 2 diabetes mellitus.
3. Men or women age ≥18 years old, the upper age limit should be based on local metformin label restrictions.
4. Stable dose combination therapy of metformin ³1500mg/day and at least half the maximum dose of a sulfonylurea for at least 8 weeks prior to enrolment.
5. HbA1c inclusion criteria:
· At enrolment (Visit 1) – laboratory values from screening visit:
≥7.7% and ≤11.0%.
· At the randomisation visit (Visit 4) – laboratory values from visit 3:
≥7.0% and ≤10.5%.
6. For women only: Women not of childbearing potential, or women of childbearing potential who comply with the following:
- Use a highly effective method of birth control (see below) to avoid pregnancy throughout the study and for up to 4 weeks after the study.
- Have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication and at each visit. |
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E.4 | Principal exclusion criteria |
The following criteria apply to the enrolment, placebo lead-in and randomisation visits (Visits 1, 2, 3, and 4)
Endocrine and metabolic disorders
Diagnosis of Type 1 diabetes mellitus, known diagnosis of MODY or secondary diabetes mellitus
History of diabetic ketoacidosis
Symptoms of poorly controlled diabetes including, but not limited to, marked polyuria, polydipsia, and/or greater than 10% weight loss during the 3 months prior to enrolment
FPG >270 mg/dL (>15 mmol/L) – assessed based on laboratory results from Visits 1, 2 and 3
BMI >45 kg/m2
History of bariatric surgery (ie, any surgery to treat obesity; for example, gastric banding or procedures that involve bypassing or transposing sections of the small intestine). History of liposuction is allowed
Diabetes insipidus
Thyroid-stimulating hormone (TSH) and free T4 values outside normal range; an abnormal TSH value needs to be followed up with a free T4 test. Patients with abnormal free T4 values will be excluded
Cardiovascular disorders
Recent Cardiovascular Events in a patient:
Acute Coronary Syndrome (ACS) within 2 months prior to enrolment
Hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment
Acute Stroke or TIA within 2 months prior to enrolment
Less than 2 months post coronary artery revascularization prior to enrolment
Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure.
Blood pressure:
At enrolment (Visit 1): Systolic BP ≥170 mmHg and/or diastolic BP ≥110 mmHg
At randomisation (Visit 4): Systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg
Kidney or urological disorders
Measured serum creatinine value of ≥1.5 mg/dL (133 μmol/L) for male patients and ≥1.4 mg/dL (124 μmol/L) for female patients or renal function that would preclude treatment with metformin according to local guidance
History of unstable or rapidly progressing renal disease
Familial renal glucosuria. This condition is diagnosed as glucosuria (>1.0 mmol/L urine) in the presence of normoglycaemia in patients without the diagnosis of diabetes mellitus
History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit, where according to the investigator a satisfactory evaluation of hematuria has not been conducted based on guidance in section 6.4.9.3
Hepatic disorders
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
Total bilirubin >2.0 mg/dL (34.2 µmol/L)
Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody
History of drug-induced liver enzyme elevations
History of severe hepatobiliary disease or hepatotoxicity with any medication
Hematologic/oncologic disorders/conditions
Haemoglobin <10 g/dL (<100 g/L) or 6.2 mmol/L for men; haemoglobin <9.0 g/dL (<90 g/L) or 5.9 mmol/L for women
History of chronic haemolytic anaemia or haemoglobinopathies (for example, sickle cell anaemia, thalassemia, sideroblastic anaemia). Mild haemolysis due to artificial heart valves or due to sickle cell trait is not an exclusion criterion except when haemoglobin levels are too low (as defined in haemoglobin criteria above)
Iron deficiency anaemia with iron therapy started in the past 12 weeks prior to enrolment visit, or a recent diagnosis of iron deficiency anaemia that requires therapeutic management within the next 24 weeks in the judgement of the investigator
Donation or transfusion of blood, plasma, or platelets within the past 12 weeks prior to enrolment
History of malignancy within the last 5 years prior to enrolment, excluding successful treatment of basal or squamous cell skin cancer
Infectious disease/immunologic disorders
Known immunocompromised status, including patients who underwent organ transplantation
Musculoskeletal disorders
Creatine Kinase (CK) >3x ULN
History of drug-induced myopathy or drug-induced CK elevation
Reproductive status
Pregnant or breastfeeding patients
Prohibited medications
Use of any anti-hyperglycaemic medications other than metformin or sulfonylurea during the 10 weeks prior to enrolment
Use of weight loss medication, including but not limited to sibutramine, phentermine, orlistat, rimonabant, benzphetamine, diethylproprion, methamphetamine, and/or phendimetrazine, within 30 days prior to enrolment
Treatment with systemic glucocorticoids equivalent to oral prednisolone ≥10 mg (betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day within 30 days prior to enrolment; Treatment with single injections of systemic glucocorticoids, topical or inhaled corticosteroids are allowed |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy
Primary outcome variable:
· Change in HbA1c from baseline to week 24. |
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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) |
Key secondary outcome variables:
· Change in fasting plasma glucose (FPG) from baseline to week 24.
· Change in total body weight from baseline to week 24.
· Proportion of patients achieving a therapeutic glycaemic response, defined as HbA1c <7.0% at week 24.
· Change in seated systolic blood pressure (SBP) from baseline to week 8.
Other secondary outcome variables:
· Proportion of patients discontinued for lack of efficacy or rescued for failing to maintain FPG below pre-specified rescue criteria at weeks 4, 8, 16 and 24.
· Change in HbA1c in patients with baseline HbA1c ≥8.0% from baseline to week 24.
· Change in HbA1c in patients with baseline HbA1c ≥9.0% from baseline to week 24.
· Change in FPG from baseline to week 8.
· Change in seated SBP from baseline to week 24.
· Proportion of patients with seated blood pressure of <130/80 mmHg at week 24 in patients with baseline elevated blood pressure (baseline SBP ≥130 mmHg and/or baseline diastolic blood pressure (DBP) ≥80 mmHg).
· Percent change in fasting lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) from baseline to week 24.
· Change in HOMA-2, HOMA-IR from baseline to week 24.
· Change in insulin, proinsulin and C-peptide values from baseline to week 24.
· Change in waist circumference from baseline to week 24.
· Effect of dapagliflozin versus placebo from baseline to week 24 on health-related quality of life (HRQL) as measured by Euro quality of life 5 Dimensions 3 levels (EQ-5D-3L).
· Scores of treatment satisfaction, individual satisfaction and perceived frequency of hyper/hypoglycaemia as measured by Diabetes Treatment Satisfaction Questionnaire status (DTSQs) at baseline, week 24 and at week 52.
· Scores of change of treatment satisfaction, individual satisfaction and perceived frequency of hyper/hypoglycaemia using the Diabetes Treatment Satisfaction Questionnaire change (DTSQc) observed with dapagliflozin versus placebo at week 52.
· To assess HRQL- (EQ-5D-3L), weight related quality of life (SHIELD-WQ-9, IWQOL-Lite) and treatment satisfaction (DTSQc and DTSQs) over 52 weeks of treatment.
Exploratory
· Effects of dapagliflozin and placebo on weight related quality of life as measured by SHIELD-WQ-9.
· Effects of dapagliflozin and placebo on weight related quality of life as measured by IWQOL-Lite.
Safety
· AEs, including adjudication of CV events, laboratory values, electrocardiogram, pulse, blood pressure, hypoglycaemic events and physical examination findings. |
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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) | 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 | 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 | 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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Canada |
Czech Republic |
Germany |
Poland |
Slovakia |
Spain |
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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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The end of the study is defined as ‘the last visit of the last patient undergoing the study’. |
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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 |