| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Diabetes tipo 2
Type 2 diabetes |
|
| 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 examine whether, after 52 weeks of oral administration of double-blind treatment, the absolute change from baseline in HbA1c level with dapagliflozin plus metformin is non-inferior to glipizide (sulphonylurea) plus metformin in patients with type 2 diabetes who have inadequate glycaemic control on 1500 mg/day or higher doses of metformin therapy alone.
Objectives after the 52-week extension period:
- To assess the same safety and tolerability parameters as for the first 52 weeks, over 104 weeks treatment
- To assess the maintenance of efficacy of dapagliflozin plus metformin over 104 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
- To show that dapagliflozin plus metformin reduces body weight compared to glipizide plus metformin after 52 weeks of treatment
- To show that dapagliflozin plus metformin treatment leads to fewer patients with hypoglycaemic events compared to glipizide plus metformin after 52 weeks of treatment |
|
| 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 |
The full title and date of the genetic study is:
"A 52-Week International, Multi-centre, Randomised, Parallel-group, Double-blind, Active-controlled, Phase III study with a 52-Week Extension Period to Evaluate the Efficacy and Safety of Dapagliflozin in Combination with Metformin compared with Sulphonylurea in Combination with Metformin in Adult Patients with Type 2 Diabetes who have Inadequate Glycaemic Control on Metformin Therapy Alone"
Date: 2007-10-25
The objective of the genetic study is to enable future exploratory pharmacogenetic research studies |
|
| E.3 | Principal inclusion criteria |
Inclusion criteria at enrolment (visit 1):
1.Provision of a written informed consent
2.Diagnosed with type 2 diabetes
3.Men or women who are ≥18 years of age at time of consenting upon visit 1
4.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.
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 partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential.
WOCBP 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.
5.Treated with OAD therapy that includes metformin for at least 8 weeks prior to enrolment; NB In addition to metformin patients are only allowed to be on one further OAD and only up to the half maximum dose available. This applies both to the administration of the other OAD as separate drug or as fixed dose combination.
Inclusion criteria at start of metformin dose-stabilisation period - if applicable
(visit 2, laboratory values from visit 1):
6.HbA1c >6.5% and ≤10.0%; NB Patients with HbA1c >6.5% to <7% will no longer be eligible when the cohort of randomised patients having HbA1c <7% is approximately 25% and the lower bound of HbA1c for enrolment will be set at HbA1c ≥7% for the remainder of the study.
7.FPG ≤270 mg/dL (≤14.4 mmol/L)
8.C-peptide level ≥1.0 ng/mL (≥0.375 nmol/L)
Inclusion criteria at placebo lead-in period (visit 4):
9.Treatment with metformin alone on a stable dose of 1500 mg/day up to 2500 mg/day for at least 8 weeks
For patients who entered the study on a stable dose of metformin monotherapy ≥1500 mg/day with no other OAD therapy in the last 8 weeks and who skipped the metformin dose-stabilisation period (laboratory values from visit 1):
10.HbA1c >6.5% and ≤10.0%; NB Patients with HbA1c >6.5% to <7% will no longer be eligible when the cohort of randomised patients having HbA1c <7% is approximately 25% and the lower bound of HbA1c for enrolment will be set at HbA1c ≥7% for the remainder of the study.
11.FPG ≤270 mg/dL (≤14.4 mmol/L)
12.C-peptide level ≥1.0 ng/mL (≥0.375 nmol/L)
Inclusion criteria at randomisation (visit 5, laboratory values from visit 4):
13.HbA1c >6.5% and ≤10.0%; NB Patients with HbA1c >6.5% to <7% will no longer be eligible when the cohort of randomised patients having HbA1c <7% is approximately 25% and the lower bound of HbA1c for enrolment will be set at HbA1c ≥7% for the remainder of the study.
14.FPG ≤270 mg/dL (≤14.4 mmol/L)
For inclusion in the optional genetic research, patients must fulfil the following criterion:
15.Provision of written informed consent for genetic research
If a patient declines to participate in the genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, for which they have consented.
|
|
| E.4 | Principal exclusion criteria |
Exclusion criteria at enrolment (visit 1):
1.Type 1 diabetes, history of diabetic ketoacidosis or hyperosmolar non-ketonic coma, or corticosteroid-induced type 2 diabetes
2.History of diabetes insipidus
3.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 3 months prior to enrolment, or other signs and symptoms.
4.History of unstable or rapidly progressing renal disease
5.Known condition of congenital renal glucosuria
6.History of severe hepatobiliary disease or hepatotoxicity with any medication
7.Pregnant or breastfeeding patients
8.BMI >45.0 kg/m2
9.Insulin therapy within one year of enrolment (with the exception of insulin therapy during a hospitalization or use in gestational diabetes)
10.Previous participation in a clinical trial with dapagliflozin and/or with any other SGLT2 inhibitor
11.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
12.History of bariatric surgery
13.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
14.Treatment for HIV/use of antiviral drugs (delavirdine, indinavir, nelfinavir, ritonavir, saquinavir) and/or known immunocompromised status, including patients who have undergone organ transplantation
15.Intolerance, contraindication or potential allergy to metformin, dapagliflozin, glipizide, or placebo or formulation excepients
16.Congestive heart failure defined as NYHA class III or IV (see Appendix D), unstable congestive heart failure and/or left ventricular ejection fraction of ≤ 40%
17. Significant cardiovascular history within the past 6 months upon visit 1 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
18.Severe respiratory failure or severe emphysema
19.Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg
20.Patients who, in the judgement of the Investigator, may be at risk for dehydration
21.History of chronic haemolytic anaemia with the exception of sickle cell trait or thalassemia minor
22.History of alcohol abuse or illegal drug abuse within the past 12 months
23.History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin carcinoma
24.Involvement in the planning and conduct of the study
25.Previous enrolment or randomisation to treatment in the present study
26.Participation in a clinical study during the last 90 days prior to visit 1
27.Donation of blood, plasma or platelets within the past 3 months prior to visit 1
28.Suspected or confirmed poor protocol or medication compliance as judged by the investigator
Exclusion criteria at start of metformin dose-stabilisation period (visit 2, laboratory values from visit 1):
29.Renal failure or renal dysfunction (Creatinine-Clearance <60 ml/min)
30.UACR >1,800 mg/g (>203.4 mg/mmol/Cr)
31.Severe hepatic insufficiency and/or significant abnormal liver function defined as AST >3 x upper limit of normal (ULN) and/or ALT >3 x ULN
32.TB >2 mg/dL (>34 µmol/L)
33.CK >3 x ULN
34.Haemoglobin ≤11.0 g/dL (≤110 g/L) for men; haemoglobin ≤10.0 g/dL (≤100 g/L) for women
35.TSH values outside normal range, to be further confirmed by abnormal free T4 values
36.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
37.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.
For patients who entered the study on a stable dose of metformin monotherapy ≥1500 mg/day with no other OAD therapy in the last 8 weeks and who skipped the metformin dose-stabilisation period, exclusion criteria 29 - 37 will be checked at visit 4 (lab.values from visit 1).
For exclusion criteria at randomisation (visit 5) and for the participation in the optional genetic research, see Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary outcome variable
- Change in HbA1c from baseline to week 52
|
|
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 | 3 |
| 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 | 3 |
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