Multicenter Trial to Evaluate the Effect of Dapaglliflozin on the Incidence of Cardiovascular Events (DECLARE)

• Register: EUCTR
• Last refreshed on: 1 October 2018
• Main ID: EUCTR2013-000239-28-HU
• Date of registration: 02/10/2013
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: Multicenter Trial to Evaluate the Effect of Dapaglliflozin on the Incidence of Cardiovascular Events (DECLARE)
• Scientific title: DECLARE Dapagliflozin Effect on CardiovascuLAR Events A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in Patients with Type 2 Diabetes - DECLARE
• Date of first enrolment: 05/12/2013
• Target sample size: 17150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-000239-28
• 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): no Therapeutic use (Phase IV): yes

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Philippines, Poland, Romania, Russian Federation, Slovakia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Vietnam

Contacts

• Name: Information Center
• Affiliation: AstraZeneca

• Name: Information Center
• Affiliation: AstraZeneca

Key inclusion & exclusion criteria

Inclusion criteria:
For inclusion in the study patients should fulfill the following criteria:
1. Provision of informed consent prior to any study specific procedures (including run-in)
2. Female or male aged = 40 years
3. Diagnosed with T2DM (See Appendix E for details)
4. High Risk for CV event defined as having either established CV disease and/or multiple risk factors:
- Established CV Disease (See Appendix E for details)
OR
No known cardiovascular disease AND at least two cardiovascular risk factors in addition to T2DM, defined as:
- Age > 55 years in men and > 60 in women
AND presence of at least 1 of the following additional risk factors (see Appendix E for details)
- Dyslipidemia
- Hypertension
- Current Tobacco use
5. WOCBP must take precautions to avoid pregnancy throughout the study and for 4 weeks after intake of the last dose.
- WOCBP must have a negative urine pregnancy test. 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.
- WOCBP must be willing to use a medically accepted method of contraception that is considered reliable in the judgment of the Investigator.
For inclusion in the optional genetic research, patients must fulfill the criterion specified in Appendix H.
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 8575
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 8575

Exclusion criteria:
1. Use of the following excluded medications:
- Current or recent (within 24 months) treatment with pioglitazone and/or use of pioglitazone for a total of 2 years or more during lifetime
2. Acute cardiovascular event [e.g., acute coronary syndrome (ACS), transient ischemic attack (TIA), stroke, any revascularization, decompensated HF, sustained ventricular tachycardia <8 weeks prior to randomization. Patients with acute cardiovascular events can be enrolled in the run-in period as long as randomization does not occur within 8 weeks of the event
3. Systolic BP> 180 or diastolic BP > 100 mmHg at randomization. Patient should be excluded if either the systolic BP is elevated (> 180 mmHg) or the diastolic BP is elevated (> 100 mmHg) on both measurements (see section 6.4.8.1)
4. Diagnosis of Type 1 diabetes mellitus, MODY, or secondary diabetes mellitus
5. History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
6. History of any other malignancy within 5 years (with the exception of successfully treated non-melanoma skin cancers)
7. Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year)
8. Any conditions that, in the opinion of the Investigator, may render the patient unable to complete the study including but not limited to cardiovascular (NYHA class IV CHF, recurrent ventricular arrhythmias) or non-cardiovascular disease (e.g., active malignancy with the exception of basal cell carcinoma, cirrhosis, chronic lung disease, severe autoimmune disease) and/or a likely fatal outcome within 5 years
9. Pregnant or breast-feeding patients
10. Involvement in the planning and/or conduct of the study or other dapagliflozin studies (applies to AZ, BMS, Hadassah and Thrombolysis in Myocardial Infarction [TIMI] or representative staff and/or staff at the study site)
11. Previous enrollment or randomization in the present study
12. Active participation in another clinical study with IP and/or investigational device
13. Individuals at risk for poor protocol or medication compliance during run-in period (reasonable compliance defined as 80 – 120%, unless a reason for non-compliance is judged acceptable by the Investigator). If for any reason, the Investigator believes that the patient will not tolerate or be compliant with IP or study procedures, the patient should not be randomized and considered a run-in failure.
Patients will be excluded during run-in and should not be randomized if the following are observed from laboratory or observation during enrollment and run-in assessments:
14. HbA1c >12% or HbA1c < 6.5% from the central laboratory (nb, the proportion of subjects with an HbA1c between 6.5% and < 7.0% will be capped at approximately 5 % of the study)
15. AST or ALT >3x ULN or Total bilirubin >2.5 x ULN
16. CrCl < 60 ml/min (based on the Cockroft-Gault equation)
17. Hematuria (confirmed by microscopy at Visit 1) with no explanation as judged by the Investigator up to randomization. If bladder cancer is identified, patients are not eligible to participate.
18. Any reason the Investigator believes the patient is not likely to be compliant with the study medication and protocol.
Exclusion criteria for the optional genetic research
The exclusion criteria for the optional genetic research are provided in Appendix H.


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

Health Condition(s) or Problem(s) studied

Type II Diabetes mellitus
MedDRA version: 19.1 Level: LLT Classification code 10012613 Term: Diabetes mellitus non-insulin-dependent System Organ Class: 100000004861

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

Intervention(s)

Trade Name: Forxiga
Product Name: Dapagliflozin
Product Code: BMS-512148
Pharmaceutical Form: Film-coated tablet
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: The secondary objective is to determine whether treatment with dapagliflozin compared with placebo when added to current background therapy in patients with T2DM with either established cardiovascular disease or at least two cardiovascular risk factors in addition to T2DM will result in a reduction of:
· Hospitalization for Congestive Heart Failure
·The composite endpoint of cardiovascular death, MI, ischemic stroke, hospitalization for heart failure, hospitalization for unstable angina pectoris, or hospitalization for any revascularization.
· All-cause mortality
· Body weight from baseline

Main Objective: The primary efficacy objective is to determine whether treatment with dapagliflozin compared with placebo when added to current background therapy will result in a reduction in the incidence of the composite endpoint of cardiovascular death, myocardial infarction (MI), or ischemic stroke in patients with type 2 diabetes mellitus (T2DM) with either established cardiovascular disease or at least two cardiovascular risk factors in addition to T2DM.

Primary end point(s): The primary outcome efficacy variable of the study is the composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke (time to first event). These events will be adjudicated.

Timepoint(s) of evaluation of this end point: This is event triggered and will be evaluated at 1/3 of primary events, 2/3 of primary events and when we have 100% of the primary events, which means at 463, 927 and 1390 primary events

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Secondary endpoints will only be evaluated once – and that is when the study stops. It could be when we have 1/3 of primary events OR when we have 2/3 of primary events OR when we have all primary events.

Secondary end point(s): The secondary objective is to determine whether treatment with dapagliflozin compared with placebo when added to current background therapy in patients with T2DM with either established cardiovascular disease or at least two cardiovascular risk factors in addition to T2DM will result in a reduction of:
· Hospitalization for Congestive Heart Failure
· The composite endpoint of cardiovascular death, MI, ischemic stroke, hospitalization for heart failure, hospitalization for unstable angina pectoris, or hospitalization for any revascularization.
· All-cause mortality
· Body weight from baseline

Secondary ID(s)

D1693C00001

2013-000239-28-GB

NCT01730534

Source(s) of Monetary Support

AstraZeneca AB