E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetes mellitus tipo 2
Type 2 Diabetes Mellitus |
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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 |
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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 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. |
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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.
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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 |
Name of the genetic substudy: "A 24-week international, randomized, parallel-group, double-blind, placebo-controlled Phase III study with a 24-week extension period to evaluate the efficacy and safety of dapagliflozin therapy when added to the therapy of patients with type 2 diabetes with inadequate glycaemic control on insulin."
Date: 14 December 2007
Objectives: The purpose of the genetic research is to enable future exploratory pharmacogenetic research studies |
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E.3 | Principal inclusion criteria |
Inclusion criteria at enrolment (visit 1): 1. Provision of a written informed consent 2. Men and women diagnosed with type 2 diabetes 3. Age ≥18 - ≤80 years at time of consenting 4. Patients with inadequate glycaemic control, defined as documented HbA1c ≥7.5% and ≤10.5% and who are according to investigators judgement for a period of at least 8 weeks prior to enrolment on a stable insulin regimen with a mean insulin dose of least 30 IU of injectable insulin per day either without any other OADs or with a stable dose of OADs that have been approved in combination with insulin. Inclusion criteria before randomisation (visit 2): 1. Patients with HbA1c ≥7.5% and ≤10.5% according central laboratory values measured from sample taken at visit 1 and who are on a stable insulin regimen with a mean insulin dose of least 30 IU of injectable insulin per day either without any other OADs or with a stable dose of OADs that have been approved in combination with insulin. 2. Daily insulin requirements over the past seven days with insulin dose documentation that does not vary more than 10% on more than one occasion of the calculated mean daily insulin dose at visit two (For example for patient whose calculated mean daily insulin dose at visit 2 is 50 IU, daily doses in the preceding seven days with insulin dose documentation may not be <45 and >55 IU on more than one occasion). 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 and must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level >35mIU/mL).Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where the partner is sterile (eg vasectomy), should be considered to be of child bearing potential. 4. Body Mass Index (BMI) ≤ 45 kg/m2
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E.4 | Principal exclusion criteria |
Exclusion criteria at randomization visit (visit 2): 1. Clinical diagnosis of type 1 diabetes, MODY or secondary diabetes mellitus (eg chronic pancreatitis, partial pancreatectomy). 2. Symptoms of poorly controlled diabetes that in judgement of the investigator would preclude participation in this trial including, but not limited to, marked polyuria and polydipsia with greater than 10% weight loss during the 3 months prior to enrolment. 3. History of diabetes insipidus 4. Use of inhaled insulin or injectable GLP-1 receptor agonists or DPP-4 inhibitors within 8 weeks of enrolment visit 5. 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 6. Known condition of congenital renal glucosuria 7. Total bilirubin >34.2 mmol/l, >2.0 mg/dl (ULN) 8. Creatine kinase ≥3xULN 9. Hemoglobin ≤10.0 g/dl (≤100 g/l) for men; hemoglobin ≤9.5 g/dl (≤95 g/l) for women 10. Thyroid-stimulating hormone (TSH) values outside normal range confirmed by abnormal T4 values 11. 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. 12. 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. 13. 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 14. Pregnant or breastfeeding patients 15. 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 16. History of bariatric surgery 17. 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 18. 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 19. Intolerance, contraindication or potential allergy to dapagliflozin or placebo or formulation recipients 20. 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% 21. Severe respiratory failure or severe emphysema 22. Severe uncontrolled hypertension defined as systolic BP ≥180 mm Hg and/or diastolic BP ≥110 mm Hg 23. Patients who, in the judgment of the investigator, may be at risk for dehydration 24. History of chronic hemolytic anemia or hemoglobinopathies (sickle cell anemia or thalassemias, sideroblatic anemia) 25. History of alcohol abuse or illegal drug abuse within the past 12 months 26. History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin carcinoma 27. Involvement in the planning and conduct of the study (applies to both AZ and BMS staff or staff at the study centre) 28. Previous enrolment or randomization to treatment in the present study 29. Received an investigational agent within 30 days prior to receiving study medication 30. Donation or transfusion of blood, plasma or platelets within the past 3 months prior to visit 1 31. Suspected or confirmed poor protocol or medication compliance as judged by the investigator 32. 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 |
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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. |
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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 | 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 | 8 |
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 |
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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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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 |