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A Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes and Inadequately Controlled Hypertension on an Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker

This study has been completed.
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01137474
First received: June 3, 2010
Last updated: April 1, 2014
Last verified: April 2014
  Purpose

The purpose of this study is to learn whether dapagliflozin, after 12 weeks, can improve (decrease) blood pressure in patients with type 2 diabetes with uncontrolled hypertension who are on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The safety of this treatment will also be studied.


Condition Intervention Phase
Type 2 Diabetes
Drug: Dapagliflozin
Drug: Placebo-matching dapagliflozin
Drug: Oral antidiabetic agent
Drug: Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB)
Drug: With or without insulin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Subjects With Type 2 Diabetes With Inadequately Controlled Hypertension on an Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin Receptor Blocker (ARB)

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]
    Seated BP was to be measured at every visit. Data after rescue medication was excluded. The patient first rested for at least 10 minutes in the seated position. Seated blood BP was determined from the mean of 3 replicated measurements obtained at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were to be obtained (total=5) and incorporated into the calculated mean for systolic BP and diastolic BP. For the initial BP recording, BP was measured in both arms. If the BP was higher in 1 arm, that arm was used for BP measurement. If there was no difference in BP measurements between arms, the dominant arm was used for all future BP measurements. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.

  • Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]
    HbA1c was measured as percent of hemoglobin by a central laboratory. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.


Secondary Outcome Measures:
  • Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward) [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]
    Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24-hrs each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hr ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.

  • Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]
    All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.

  • Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]
    Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24 hours each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hour ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.

  • Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: No ]
    Central laboratory serum uric acid levels will be determined at the Enrollment, Day -28, Day 1, and at Week 4, 8, 12, and 13 visits. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.


Other Outcome Measures:
  • Number of Participants With Adverse Events (AEs), Hypoglycemic Events, Related AEs, Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Discontinuations Due to AEs, and Discontinuations Due to Hypoglycemic Events [ Time Frame: Day 1 of treatment to last dose plus 4 days for AEs and hypoglycemic events and plus 30 days for SAEs ] [ Designated as safety issue: Yes ]
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. Includes nonserious AEs with onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment plus 4 days and SAEs with onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment plus 30 days. Includes data after rescue. Only hypoglycemia reported as an SAE is included in AE/SAE categories. All reported hypoglycemia events within 4 days of last day of treatment are included as hypoglycemic events.

  • Number of Participants With Clinical Laboratory Results Meeting Criteria for Marked Abnormality [ Time Frame: Day 1 of treatment to last dose, plus 4 days ] [ Designated as safety issue: Yes ]
    Laboratory abnormalities were evaluated based on laboratory values meeting predefined marked abnormality (MA) criteria. Includes data after the start date of double-blind treatment up to and including the last day of double-blind treatment plus 4 days. BUN=blood urea nitrogen; preRX=pretreatment; unspecif=unspecified; ULN=upper limit of normal. High total calcium= ≥1 mg/dL from ULN and ≥0.5 mg/dL from preRX value; high inorganic phosphorus= ≥5.6 mg/dL if age 17-65 years or ≥5.1 mg/dL if age ≥66 years.

  • Changes From Baseline in Electrocardiogram (ECG) Findings at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: Yes ]
    The normality or abnormality of the ECG tracing, determined by the investigator, was summarized by normal or abnormal ECG tracing at Week 12 overall and at baseline. When the data at Week 12 were not available, the last observation before discontinuation of that patient was used for summary.

  • Changes From Baseline in Supine and Standing Systolic and Diastolic Blood Pressure (BP) at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: Yes ]
    Supine BP was measured prior to standing BP. The patient was to rest in the supine position for at least 5 minutes prior to measurement of BP. Supine BP was determined from 3 replicate measurements obtained at least 1 minute apart. The average BP was determined from these 3 replicate measurements. The patient then stood for 2 to 3 minutes. After this time, BP was measured with the arm supported at the antecubital fossa at heart level.

  • Changes From Baseline in Supine and Standing Heart Rate (HR) at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: Yes ]
    Supine HR was measured prior to the standing HR. The patient was to rest in the supine position for at least 5 minutes prior to measurement of HR. Supine HR will be determined from 3 replicate measurements obtained at least 1 minute apart. The average HR was determined from these 3 replicate measurements and reported in the case report form. The patient then stood for 2 to 3 minutes. All measurements were to occur at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine.

  • Changes From Baseline in 24-Hour Ambulatory Heart Rate at Week 12 [ Time Frame: From Baseline to Week 12 ] [ Designated as safety issue: Yes ]
    Changes from baseline in 24-hour mean ambulatory heart rate were summarized at each visit using descriptive statistics.

  • Number of Participants With Elevated Results of Liver Laboratory Tests [ Time Frame: Day 1 of double-blind treatment to last double-blind dose, plus 30 days ] [ Designated as safety issue: Yes ]
    ALT=alanine aminotransferase; ALP=alkaline phosphatase


Enrollment: 2996
Study Start Date: July 2010
Study Completion Date: February 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dapagliflozin, 10 mg
Oral tablets administered as 10 mg once daily for up to 12 weeks
Drug: Dapagliflozin
Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks
Other Name: BMS-512148
Drug: Oral antidiabetic agent Drug: Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB)
Patients were previously taking an ACE inhibitor or ARB
Drug: With or without insulin
Patients may or may not have been taking insulin
Placebo Comparator: Placebo-matching dapagliflozin
Oral tablets administered once daily in the morning
Drug: Placebo-matching dapagliflozin
Oral tablets administered as 0 mg once daily for up to 12 weeks
Drug: Oral antidiabetic agent Drug: Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB)
Patients were previously taking an ACE inhibitor or ARB
Drug: With or without insulin
Patients may or may not have been taking insulin
Experimental: Dapagliflozin, 2. 5 mg
Oral tablets administered as 2.5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)
Drug: Dapagliflozin
Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks
Other Name: BMS-512148
Drug: Oral antidiabetic agent Drug: Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB)
Patients were previously taking an ACE inhibitor or ARB
Drug: With or without insulin
Patients may or may not have been taking insulin
Experimental: Dapagliflozin, 5 mg
Oral tablets administered as 5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)
Drug: Dapagliflozin
Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks
Other Name: BMS-512148
Drug: Oral antidiabetic agent Drug: Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB)
Patients were previously taking an ACE inhibitor or ARB
Drug: With or without insulin
Patients may or may not have been taking insulin

  Eligibility

Ages Eligible for Study:   18 Years to 89 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key inclusion criteria

  • Participants willing and able to give signed and written informed consent
  • Males and females, aged 18 to 89 years, who have type 2 diabetes with inadequate glycemic control (hemoglobin A1c between 7% and 10.5%) and uncontrolled hypertension (systolic blood pressure of 140 to 165 mm Hg and diastolic blood pressure 85 to 105 mm Hg)
  • Stable dose of oral antidiabetic agent (OAD) for at least 6 weeks (12 weeks for thiazolidinedione) or a stable daily dose of insulin as monotherapy or in combination with another OAD, for 8 weeks, and a stable dose of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for at least 4 weeks
  • C-peptide level ≥0.8 ng/mL
  • Body mass index 45.0 kg/m^2

Key exclusion criteria

  • Aspartate aminotransferase or alanine aminotransferase level >3*upper limit of normal (ULN)
  • Serum total bilirubin level >1.5*ULN
  • Serum creatinine ≥2.0 mg/dL unless subject was on metformin, where exclusionary limits were serum creatinine ≥1.50 mg/dL for women and ≥1.40 mg/dL for men
  • Serum creatinine level <1.50 mg/dL for men or <1.40 mg/dL for women
  • Estimated creatinine clearance of <60 mL/min
  • Hemoglobin ≤10.0 g/dL for men and ≤9.0 g/dL for women
  • Creatine kinase >3*ULN
  • Positive for hepatitis B surface antigen
  • Positive for antihepatitis C virus antibody
  • Abnormal free T4 value
  • History of diabetes insipidus
  • 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 enrollment.
  • History of diabetic ketoacidosis or hyperosmolar nonketotic coma
  • History of malignant and accelerated hypertension
  • Known or suspected secondary hypertension
  • Any of the following within 6 months of enrollment visit:

    • Myocardial infarction
    • Cardiac surgery or revascularization (coronary artery bypass surgery /percutaneous transluminal coronary angioplasty)
    • Unstable angina
    • Unstable congestive heart disease New York Heart Association Class III or IV
    • Transient ischemic attack or significant cerebrovascular disease
    • Unstable or previously undiagnosed arrhythmia
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01137474

  Show 329 Study Locations
Sponsors and Collaborators
Bristol-Myers Squibb
AstraZeneca
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01137474     History of Changes
Other Study ID Numbers: MB102-073 ST, 2010-019797-32
Study First Received: June 3, 2010
Results First Received: February 7, 2014
Last Updated: April 1, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration
Canada: Health Canada
Mexico: Secretaria de Salud
Germany: Federal Institute for Drugs and Medical Devices
Australia: Department of Health and Ageing Therapeutic Goods Administration
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Hungary: National Institute of Pharmacy
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of the Russian Federation

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Hypertension
Cardiovascular Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Vascular Diseases
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Enzyme Inhibitors
Hypoglycemic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on November 27, 2014