| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029505 |
| E.1.2 | Term | Non-insulin-dependent diabetes mellitus |
|
| 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 compared to placebo as add-on therapy to glimepiride in improving glycaemic control in subjects with type 2 diabetes, as determined by the change in A1C levels from baseline to Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives
− To show that dapagliflozin plus glimepiride results in greater reductions in body
weight or less weight gain after 24 weeks of treatment when compared to placebo plus glimepiride.
− To show that dapagliflozin plus glimepiride results in greater reductions in the 2-h
post-challenge plasma glucose level as a response to an oral glucose tolerance test
(OGTT) from baseline to Week 24.
− To show that dapagliflozin plus glimepiride results in a larger proportion of subjects
achieving an A1C < 7% after 24 weeks of treatment compared to placebo plus glimepiride.
− To show that dapagliflozin plus glimepiride results in greater reductions in body
weight or less weight gain in subjects with baseline BMI ≥ 27 kg/m2 after 24 weeks of treatment when compared to placebo plus glimepiride.
− To show that dapagliflozin plus glimepiride leads to greater reductions in FPG after 24 weeks of treatment compared to placebo plus glimepiride.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of a written informed consent
2. Males and females ¡Ý 18 years of age at time of consenting
3. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 4 weeks after
the study in such manner that the risk of pregnancy is minimized.
4. Diagnosed with Type 2 diabetes
5. Subjects on a stable sulphonylurea monotherapy dose that is at least half the
maximal recommended dose for a minimum of 8 weeks duration prior to the
enrolment visit.
N.B. Subjects on glimepiride dose higher than 4 mg/day are not eligible for the
study.
Inclusion criteria before lead-in period (Visit 2, laboratory values from Visit 1):
6. Inadequate glycaemic control, defined as A1C ≥ 7.0 % and ≤ 10%
7. FPG ≤ 15 mmol/L (≤ 270 mg/dL)
8. C-peptide ≥ 1.0 ng/mL (0.33 nmol/L; 333.3 pmol/L)
Inclusion criteria at randomization (Visit 5, laboratory values from Visit 4 or Visit 1 for patients who skipped the lead-in period):
9. A1C ≥ 7% and ≤ 10%
10. FPG ≤ 15 mmol/L (≤ 270 mg/dL)
11. C-peptide ≥ 1.0 ng/mL (0.33 nmol/L; 333.3 pmol/L |
|
| E.4 | Principal exclusion criteria |
1. Type 1 diabetes, diabetes insipidus, corticosteroid-induced type 2 diabetes, and
history of diabetic ketoacidosis or hyperosmolar non-ketonic coma
2. Symptoms of poorly controlled diabetes that would preclude participation in this
trial including but not limited to marked polyuria and polydipsia with greater than
10% weight loss during the three months prior to enrolment, or other signs and
symptoms
3. Use of glimepiride dose higher than 4 mg/day at enrolment and 8 weeks prior to the enrolment
4. AST > 3 x ULN
5. ALT > 3 x ULN
6. Serum total bilirubin > 34 μmol/L (> 2.0 mg/dL)
7. Calculated Creatinine-Clearance < 50 ml/min (calculated by Cockcroft-Gault
formula) or a measured serum creatinine value of > 177 µmol/L (2mg/dL)
8. Urine albumin:creatinine ratio (UACR) > 1,800 mg/g (> 203.4 mg/mmol)
9. Creatine kinase (CK) > 3 x ULN
10. Haemoglobin ≤ 100 g/L (≤ 10.0 g/dL) for men; haemoglobin ≤ 95 g/L (≤ 9.5 g/dL) for women
11. Severe uncontrolled hypertension defined as systolic BP ≥ 180 mm Hg and/or
diastolic BP ≥ 110 mm Hg
N.B. If subject’s BP is higher than recommended target for BP control the
antihypertensive therapy should be optimised according to the local standards
of care.
12. Thyroid-stimulating hormone (TSH) values outside normal range, to be further
confirmed by abnormal free T4 values. Subjects with abnormal free T4 values will
be excluded.
13. Significant cardiovascular history within the past 6 months prior to the enrolment
visit (myocardial infarction, unstable angina, transient ischaemic attack (TIA),
unstable or previously undiagnosed arrhythmia, unstable chronic heart failure,
cardiac surgery or revascularization (CABG/PTCA))
14. History of malignancy within the last 5 years, excluding successful treatment of
basal or squamous cell skin carcinoma or in-situ carcinoma of the cervix
15. History of blood lipid induced eruptive xanthomas or hypertriglyceridaemia
induced pancreatitis
16. History of unstable or rapidly progressing renal disease
17. Known condition of congenital renal glycosuria
18. History of chronic haemolytic anemia, with the exception of sickle cell trait (SA) or
thalassemia minor.
19. Subjects who, in the judgement of the Investigator, may be at risk for dehydration
20. Pregnant or breastfeeding subjects
21. Body mass index (BMI) > 45.0 kg/m2
22. Suspicion that the patient is infected according to World Health Organisation
(WHO) risk categories 2 to 4 (See Appendix C)
23. Treatment with chronic insulin, within 24 weeks prior to Visit 1 (however, one
temporary period of daily insulin injections no longer than 7 days is allowed)
24. Replacement or chronic systemic treatment with corticosteroid, defined as any dose of systemic corticosteroid taken for > 4 weeks within 3 months prior to enrolment visit
25. History of bariatric surgery.
26. Administration of weight loss medication, including but not limited to sibutramine,
phentermine, orlistat, rimonabant, benzphetamine, diethylpropion,
methamphetamine, and/or phendimetrazine, within 30 days prior to enrolment
27. Treatment for Human immunodeficiency virus (HIV)/use of antiviral drugs
(delavirdine, indinavir, nelfinavir, ritonavir, saquinavir) and/or known
immunocompromised status, including subjects who have undergone organ
transplantation
28. Known hypersensitivity to dapagliflozin or glimepiride. Intolerance to
a sulphonylurea at any time in the past, or pre-existing medical conditions that is
contraindicated for the use of a sulphonylurea
29. History of drug-induced myopathy or drug-induced CK elevation
30. Severe hepatic disease, including chronic active hepatitis. Positive serologic
evidence of current infectious liver disease including subjects being positive for
Hepatitis B viral antibody IgM, Hepatitis B surface antigen and Hepatitis C virus
antibody
31. History of drug-induced liver enzyme elevations
32. History of alcohol or drug abuse within the last 5 years
33. Any clinically significant abnormality or other serious or unstable medical or
psychological condition identified in the subjects’ medical history, on physical
examination or laboratory tests that, in the judgement of the investigator, would
compromise the subjects’ safety or successful participation in the Clinical Study
34. Involvement in the planning and conduct of the study (applies to AstraZeneca and Bristol-Myers Squibb staff or staff at the study site)
35. Previous enrolment or randomisation of treatment in the present study
36. Previous participation in a clinical trial with dapagliflozin (BMS-512148) and/or any other SGLT2 inhibitor
37. Receiving any investigational product within 12 weeks prior to Visit 1 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome variable is the change in A1C from baseline to the end of the 24-week double-blind treatment period. |
|
| 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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