Evaluation of Safety and Efficacy of Dapagliflozin in subjects with Type 2 Diabetes who have Inadequate Glycaemic Control on background combination of Metformin and Sulfonylurea

• Register: EUCTR
• Last refreshed on: 8 October 2021
• Main ID: EUCTR2011-002231-26-ES
• Date of registration: 03/10/2011
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: Evaluation of Safety and Efficacy of Dapagliflozin in subjects with Type 2 Diabetes who have Inadequate Glycaemic Control on background combination of Metformin and Sulfonylurea
• Scientific title: A 24-week, Multicentre, Randomised, Double-Blind, Placebo-Controlled, International Phase III Study with a 28-week Extension Period to Evaluate the Safety and Efficacy of Dapagliflozin 10mg once daily in Patients with Type 2 Diabetes who have Inadequate Glycaemic Control on a background combination of Metformin and Sulfonylurea - NA
• Date of first enrolment: 18/11/2011
• Target sample size: 216
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-002231-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Canada, Czech Republic, Germany, Poland, Slovakia, Spain

Contacts

• Name: Clinical Study Information
• Affiliation: AstraZeneca

• Name: Clinical Study Information
• Affiliation: AstraZeneca

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 172
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 44

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 ?mol/L) for male patients and ?1.4 mg/dL (124 ?mol/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 we

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Type II diabetes mellitus
MedDRA version: 14.0 Level: LLT Classification code 10012613 Term: Diabetes mellitus non-insulin-dependent System Organ Class: 10027433 - Metabolism and nutrition disorders

Intervention(s)

Product Name: Dapagliflozin
Product Code: BMS-512148
Pharmaceutical Form: Film-coated tablet
CAS Number: 960404-48-2
Current Sponsor code: BMS-512148-05
Other descriptive name: Dapagliflozin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: see E.5.1

Main Objective: 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.

Secondary Objective: 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.

Primary end point(s): Efficacy
Primary outcome variable:
· Change in HbA1c from baseline to week 24.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: see 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.

Secondary ID(s)

2011-002231-26-DE

D1693C00005

Source(s) of Monetary Support

AstraZeneca AB

Ethics review

Status: Approved
Approval date: 11/11/2011
Contact:

Results

• Results available: Yes
• Date Posted: 12/05/2016
• Date Completed: 12/08/2013
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-002231-26/results