| 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 |
| The primary objective of this study is to assess the efficacy of 2.5 mg, 5 mg and 10 mg dapagliflozin compared to placebo as add-on therapy to insulin in improving glycaemic control in subjects with type 2 diabetes who have inadequate glycaemic control on ≥ 30 IU injectable insulin daily for at least 8 weeks prior to enrolment, as determined by the change in HbA1c levels from baseline to Week 24. |
|
| E.2.2 | Secondary objectives of the trial |
Four key secondary objectives are identified a priori for special consideration in this study for each dose of dapagliflozin:
- to examine whether treatment with dapagliflozin in combination with insulin is superior in reducing Fasting Plasma Glucose (FPG) as compared to insulin treatment alone after 24 weeks of treatment.
- to examine whether treatment with dapagliflozin in combination with insulin is superior in reducing body weight or causing less weight gain as compared to insulin treatment alone after 24 weeks of treatment.
- to examine whether treatment with dapagliflozin in combination with insulin leads to higher percentage of patients with calculated mean daily insulin dose reduction from baseline to week 24 as compared to insulin treatment alone.
- to examine whether treatment with dapagliflozin in combination with insulin leads to a lower absolute calculated mean daily insulin dose as compared to insulin therapy alone, from baseline to week 24.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of a written informed consent
2. Men and women diagnosed with type 2 diabetes
3. Men and women who are ≥ 18 year old at time of consenting
4. Body Mass Index (BMI) ≤ 45 kg/m2
5. Inadequate glycaemic control, defined as HbA1c ≥7.5% and ≤10.5% and who are on a stable calculated mean daily insulin dose of least 30 IU of injectable insulin for at least 8 weeks prior to enrolment. Patients may also be treated with maximally two OADs under the approved prescribing information. OAD treatment should be at a stable dose for a period of at least 8 weeks. Patients on metformin therapy should be on at least 1500 mg/day or at the maximally tolerable dose for a period of at least 8 weeks prior to enrolment. Patients on other OADs should be on at least half maximum daily recommended dose for a period of at least 8 weeks prior to enrolment.
6. 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. |
|
| E.4 | Principal exclusion criteria |
1. Clinical diagnosis of type 1 diabetes, MODY or secondary diabetes mellitus.
2. History of diabetes insipidus
3. Use of inhaled insulin or injectable GLP-1 receptor agonists or DPP-4 inhibitors within 8 weeks of enrolment visit
4. Calculated Creatinine Clearance <50 ml/min/1.73m2 (calculated by Cockcroft-Gault formula) or a measured serum creatinine value of >2mg/dl (177 μmol/l). Patients on concomitant metformin therapy will be excluded if serum creatinine ≥1.5 mg/dl (133 mmol/l) for male subjects and ≥1.4 mg/dl (124 mmol/l) for female subjects
5. Known condition of congenital renal glucosuria
6. Total bilirubin >34.2 mmol/l, >2.0 mg/dl (ULN)
7. Creatine kinase ≥3xULN
8. Hemoglobin ≤10.0 g/dl (≤100 g/l) for men; hemoglobin ≤9.5 g/dl (≤95 g/l) for women
9. Thyroid-stimulating hormone (TSH) values outside normal range
10. Positive serologic evidence of current infectious liver disease including patients being positive for Hepatitis B viral antibody IgM, Hepatitis B surface antigen and Hepatitis C virus antibody.
11. Any clinically significant abnormality identified on physical examination, ECG or laboratory tests, which in the judgement of the investigator would compromise the patients’ safety or successful participation in the clinical study.
12. Significant cardiovascular history within the past 6 months prior to the screening visit, defined as: myocardial infarction, unstable angina pectoris, transient ischemic attack, unstable or previously undiagnosed arrhythmia, cardiac surgery or revascularization (coronary angioplasty or bypass grafts), or cerebrovascular accident
13. Pregnant or breastfeeding patients
14. Treatment with glucocorticoids equivalent to oral prednisolone >10 mg (betametasone >1.2 mg/dexametasone >1.5 mg/hydrocortisone >40 mg)/day within 30 days prior to enrolment; topical or inhaled corticosteroids are allowed
15. History of bariatric surgery
16. 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
17. Treatment for Human immunodeficiency virus (HIV)/use of antiviral drugs (delavirdine, indinavir, nelfinavir, ritonavir, saquinavir) and/or known immunocompromised status, including patients who have undergone organ transplantation
18. Intolerance, contraindication or potential allergy to dapagliflozin or placebo or formulation excepients
19. Congestive heart failure defined as New York Heart Association (NYHA) class III or IV (see Appendix D), and/or left ventricular ejection fraction of ≤40%
20. Severe respiratory failure or severe emphysema
21. Severe uncontrolled hypertension defined as systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg
22. Patients who, in the judgment of the investigator, may be at risk for dehydration
23. History of chronic hemolytic anemia or hemoglobinopathies (sickle cell anemia or thalassemias, sideroblatic anemia)
24. History of alcohol abuse or illegal drug abuse within the past 12 months
25. History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin carcinoma
26. Involvement in the planning and conduct of the study (applies to both AZ and BMS staff or staff at the study centre
27. Previous enrolment or randomization to treatment in the present study
28. Received an investigational agent within 30 days prior to receiving study medication
29. Donation or transfusion of blood, plasma or platelets within the past 3 months prior to visit 1
30. Suspected or confirmed poor protocol or medication compliance as judged by the investigator
31. Severe hepatic insufficiency and/or significant abnormal liver function defined as Aspartate aminotransferase (AST) >3 x upper limit of normal (ULN) and/or Alanine aminotransferase (ALT) >3 x ULN
32. Treatment with more than two additional OADs
33. Urine albumin:creatinine ratio (UACR)>1800 mg/g (>203.4 mg/mmol/Cr) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome variable is the absolute change in HbA1c from baseline to week 24 of the 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 | Yes |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 110 |
| 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 | 2 |
| 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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