A Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes With Inadequately Controlled Hypertension on an ACEI or ARB and an Additional Antihypertensive Medication

Study Overview
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Brief Summary
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The purpose of this study is to learn if BMS-512148 (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 (ACEI) or an Angiotensin Receptor Blocker (ARB).The safety of this treatment will also be studied

Official Title
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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 (ACE) Inhibitor or Angiotensin Receptor Blocker (ARB) and an Additional Antihypertensive Medication

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo matching Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Males and females, 18 to 89 years old, with type 2 diabetes with inadequate glycemic control HbA1c between 7-10.5% and uncontrolled hypertension Systolic Blood Pressure (SBP) 140-165 and Diastolic Blood Pressure (DBP) 85-105 Subjects must have a mean 24 hr blood pressure ≥ 130/80 determined by Ambulatory Blood Pressure Monitoring (ABPM) within 1 week prior to Day 1 visit Stable dose of oral antidiabetic agent (OAD) for at least 6 weeks [12 wks for Thiazolidinedione (TZD)] or a stable daily dose of insulin, as a monotherapy or in combination with another OAD, for 8 weeks, and a stable dose of ACEI or ARB and 1 additional antihypertensive medication for at least 4 weeks C-peptide ≥ 0.8 ng/mL Body Mass Index ≤ 45.0 kg/m2 Serum creatinine < 1.50 mg/dL for men or < 1.40 mg/dL for women Exclusion Criteria: Aspartate aminotransferase (AST) and /or Alanine aminotransferase (ALT) > 3.0*upper limit of normal (ULN) Serum total bilirubin ≥ 1.5*ULN Creatinine kinase > 3*ULN Symptoms of severely uncontrolled diabetes History of malignant or accelerated hypertension Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin 10 mg<br>Dapagliflozin 10 mg tablets | Drug: Dapagliflozin<br>* Tablets, Oral, 10 mg, once daily, Up to 12 weeks<br>* Other names: Farxiga™;|
| Placebo Comparator: Placebo matching Dapagliflozin<br>Placebo tablets matching dapagliflozin tablets | Drug: Placebo matching Dapagliflozin<br>* Tablets, Oral, 0 mg, once daily, Up to 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure for 12 Week Double-Blind Treatment Period - Randomized Participants | Systolic blood pressure (SBP) was measured in millimeters of mercury (mmHg) on Day -1, Day 1, Weeks 2, 4, 8, and 12 of the Double Blind Period. Blood pressure (BP) values were obtained after the participant was seated for quietly for 10 minutes; a mean of 3 replicate measurements was taken 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 obtained (total = 5) and incorporated into the calculated mean. BP was measured in both arms. If the BP was higher in one arm than the other, then this arm was used; if no difference, the participant's dominant arm was used for all future BP measurements. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Participants refrained from ingestion of caffeine, alcohol, or nicotine at least 10 hours prior to their visit and having their BP measured. | Baseline to Week 12 | 
| Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) for 12 Week Double-Blind Treatment Period - Randomized Participants | Adjusted mean change in glycosylated hemoglobin ( HbA1c) from baseline at Week 12 was calculated. HbA1c was measured as percent of hemoglobin by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. HbA1c values were obtained at enrollment and lead-in (Day -28) periods, and at Day 1, Weeks 4, 8, and 12, in the double-blind period. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in 24-hour Ambulatory Systolic Blood Pressure at Week 12 Last Observation Carried Forward (LOCF) | Ambulatory 24 hour (hr) blood pressure monitoring (ABPM) was performed at baseline, which was during the lead-in period (between Day -7 and Day -1 prior to randomization) and 1 week prior to the Week 12 visit/end of treatment visit. If no Week 12 measurement was available, the last available earlier post-baseline measurement was used (LOCF) for analysis. Initiation of the 24-hr ABPM began between 6am and 11am to ensure trough BP measurements were obtained.The ABPM units were calibrated, and used per the manufacturer's and central ABPM vendor instructions. BP was measured in mmHg. Participants had to have a mean 24-hour ABPM ≥ 130/80 mmHg prior to randomization. All medication was withheld on the morning of the study visit and brought to the visit site by the participant. Once the ABPM cuff was in place, all morning medication was taken while at the site. | Baseline, Week 12 | 
| Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure (DBP) for 12 Week Double-Blind Treatment Period - Randomized Participants | Diastolic BP was measured in millimeters of mercury (mmHg) on Day -1, Day 1, Weeks 2, 4, 8, and 12 of the Double Blind Period. Diastolic BP values were obtained after the participant was seated for quietly for 10 minutes; a mean of 3 replicate measurements was taken 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 obtained (total = 5) and incorporated into the calculated mean. BP was measured in both arms. If the pressure was higher in one arm than the other, then this arm was used; if no difference, the participant's dominant arm was used for all future BP measurements. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Participants refrained from ingestion of caffeine, alcohol, or nicotine at least 10 hours prior to their visit and having their BP measured. | Baseline to Week 12 | 
| Adjusted Mean Change From Baseline in 24-hr Ambulatory Diastolic Blood Pressure at Week 12 (LOCF) | Ambulatory 24 hour (hr) BP monitoring (ABPM) was performed at baseline, which was during the lead-in period (between Day -7 and Day -1 prior to randomization) and 1 week prior to the Week 12 visit/end of treatment visit. If no Week 12 measurement was available, the last available earlier post-baseline measurement was used (LOCF). Initiation of the 24-hr ABPM began between 6am and 11am to ensure trough BP measurements were obtained. The ABPM units were calibrated, and used per the manufacturer's and central ABPM vendor instructions. BP was measured in mmHg. Participants had to have a mean 24-hour ABPM ≥ 130/80 mmHg prior to randomization. All medication was withheld on the morning of the study visit and brought to the visit site by the participant. Once the ABPM cuff was in place, all morning medication was taken while at the site. | Baseline, Week 12 | 
| Adjusted Mean Change From Baseline in Serum Uric Acid at Week 12 in Double-Blind Treatment Period - Randomized Participants | Adjusted mean change in serum uric acid from baseline at Week 12 was calculated. Serum uric acid was measured in milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Serum uric acid measurements were obtained at qualification and lead-in (Day -28) periods, and at Day 1, Weeks 4, 8, and 12, in the double-blind period but only the change from baseline at Week 12 was considered a secondary endpoint and is presented. | Baseline, Week 12 | 
| Number of Participants With Deaths,Serious Adverse Events (SAEs), Adverse Events (AEs), Hypoglycemia Events, Discontinuation Due to AEs, SAEs and Hypoglycemia, During the 12 Week Double Blind Period, Including Data After Rescue | Medical Dictionary for Regulatory Activities (MedDRA), version 15.1 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 missing relationship to study drug as per the investigator. Events captured from baseline to last double blind dose plus 4 days for AEs, plus 30 days for SAEs during the Double Blind 12 Week Period. 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. | Baseline to last dose of 12 weeks of double blind medication plus 30 days if SAE or plus 4 days if AE/hypoglycemic event | 
| Number of Participants With Marked Chemistry Laboratory Abnormalities in 12 Week Double Blind Treatment Period, Including Data After Rescue | Samples obtained: Day 1, Weeks 4, 8,12 in Double Blind Period. Baseline: last assessment prior to start of first dose of double-blind treatment. Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); greater than (>) less than (<); Units per liter (U/L), Marked abnormality Low (High): hemoglobin <6 (>18 females or >20 males) g/dL; creatinine (>=1.5*preRX, >=2.5 mg/dL); glucose < 54 or (> 350) mg/dL; albumin <= 2 or (> 6) g/dL; creatine kinase >5*ULN; albumin/creatinine ratio (>1800 mg/G); calcium <7.5 (>1 and >0.5 from PreRX) mg/dL; bicarbonate <=13 meq/dL; potassium <=2.5 (>6) meq/L; magnesium <1 (>4) mEq/L; sodium < 130 mEq/L (>150 mEq/L; phosphorus (>=5.6 mg/dL age 17-65, >=5.1 is >=66 years); Albumin/creatinine ratio (>1800 mg/g). Note: Hepatic tests are presented separately in next outcome measure. | Baseline (Day 1) to last dose double blind medication (Week 12) plus 4 days | 
| Number of Participants With Elevated Liver Laboratory Tests in Participants Treated With Double Blind 10 mg Dapagliflozin or Placebo , Including Data After Rescue | Laboratories were obtained at Day 1, Weeks 4, 8 and 12 in the Double Blind Period. Baseline: last assessment prior to start of first dose of double-blind treatment. Includes laboratory values measured after the first date of double-blind treatment and up to and including the last day of double blind treatment plus 30 days. Upper limit of normal (ULN);, alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP). Marked abnormality (High): AST and ALT (>3*ULN); ALP (>1.5*ULN); bilirubin (>1.5*ULN). Participants with abnormally elevated liver laboratory tests were followed 30 days after the last dose of study drug. | Baseline (Day 1) to last dose double blind medication (Week 12) Plus 30 days | 
| Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 12 (LOCF), Including Data After Rescue | 12-Lead electrocardiograms (ECGs) were performed at Enrollment, Day 1 of Double Blind Period and Week 12/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator as normal or abnormal. Baseline (BL) was Day 1 prior to dosing or last observation prior to dosing. | Baseline, Week 12 | 
| Proportion of Participants With Orthostatic Hypotension at Baseline and Week 12, Including Data After Rescue | Orthostatic hypotension was defined as a decrease from supine to standing of > 20 mmHg in systolic BP or >10 mmHg in diastolic BP. Proportion was calculated from number of participants with orthostatic hypotension (n) divided by the number of treated participants (N). n/N presented as a percent (%). Baseline was Day 1 of the double blind Period. Measurements for orthostatic hypotension were taken on Day 1 and at Week 12 visit and does not reflect AEs reported by the investigator. | Baseline (Day 1), Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 2, Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders, Metabolic Diseases, Angiotensin Receptor Inhibitors, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Cardiovascular Agents, Pharmacological Actions