24 Week Efficacy and Safety Study of Empagliflozin (BI 10773) in Hypertensive Black/African American Patients With Type 2 Diabetes Mellitus and Hypertension
Condition: Diabetes Mellitus, Type 2; Hypertension
MeSH terms: Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Empagliflozin low dose; placebo; Empagliflozin high dose
Intervention description: starting dose 10mg; forced titration after 4 weeks 25mg dose; starting dose 10mg; forced titration after 4 weeks 25mg dose; starting dose 10mg; forced titration after 4 weeks 25mg dose
Intervention MeSH terms: Empagliflozin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Enrollment: 166.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This trial is designed to investigate the efficacy and safety of empagliflozin compared with
      placebo in hypertensive black/African Americans with type 2 Diabetes Mellitus. Since
      hyperglycaemia and hypertension are key risk factors for both micro- and macrovascular
      complications, assessment of both glucose and BP lowering effects of empagliflozin in
      hypertensive African American patients with type 2 Diabetes Mellitus could provide clinically
      highly relevant, new information for the use of empagliflozin.

      Essential hypertension is four times more common in African Americans than in Caucasians.

      One of the risk factors for hypertension is sodium sensitivity and approximately one third of
      the essential hypertensive population is responsive to sodium intake. There is a higher
      association of hypertension with sodium sensitivity in African American patients with type 2
      Diabetes Mellitus.

      The treatment duration of this trial (24 weeks) will enable assessment of the clinically
      relevant endpoint of a decrease in HbA1c, a well accepted measurement of chronic glycaemic
      control and the key secondary endpoints of decreases in systolic BP (SBP) and diastolic BP
      (DBP) at 12 and 24 weeks.
    

Eligibility criteria:

        Inclusion criteria:

          -  Diagnosis of Type 2 Diabetes Mellitus (T2DM) prior to informed consent.

          -  Male and female black/African American patients on diet and exercise regimen who are
             EITHER drug-naïve (defined as absence of any oral antidiabetic therapy, glucagon like
             peptide-1 (GLP-1) analog or insulin for 12 weeks, 16 weeks for pioglitazone prior to
             randomisation) OR pre-treated with stable dose of

               -  Metformin only, or

               -  Sulfonylurea only, or

               -  Dipeptidyl peptidase-4 (DPP-4) inhibitor only, or

               -  metformin plus sulfonylurea, or

               -  metformin plus DPP-4 inhibitor. Treatment has to be unchanged for a minimum of 12
                  weeks prior to randomization. Dose for metformin: maximum tolerated dose The
                  maximum daily dose of Sulfonylurea (SU) or DPP-4 inhibitor should not exceed that
                  stated in the local label.

          -  HbA1c of >= 7.0% (53 mmol/mol) and ≤ 11.0% (97 mmol/mol) at Visit 1 (screening).

          -  Mean seated Systolic Blood Pressure (SBP) 140-180 mmHg at Visit 1 (screening).

          -  Successful completion of baseline Ambulatory Blood Pressure Monitor (ABPM) testing
             with a mean SBP 135-175 mmHg prior to randomisation.

          -  Treatment with stable doses of at least one but not more than 4 antihypertensive
             medication >= 4 weeks prior to randomisation.

          -  Age >= 18 years at Visit 1 (screening)

          -  Signed and dated written informed consent by date of Visit 1 in accordance with Good
             Clinical Practice (GCP) and local legislation

        Exclusion criteria:

          -  Uncontrolled hyperglycemia with a glucose level >270 mg/dl (>15.0 mmol/L) after an
             overnight fast during placebo run-in (includes Visit 2.1) and confirmed by a second
             measurement (not on the same day).

          -  Exposure to any other antidiabetic medication within 12 weeks prior to randomisation
             other than metformin, sulfonylurea, Dipeptidyl peptidase-4 (DPP-4) inhibitor,
             metformin plus sulfonylurea or metformin plus DPP-4 inhibitor.

          -  Current hypertension treatment with oral Minoxidil (topical minoxidil for hair growth
             is allowed).

          -  Mean seated Systolic Blood Pressure (SBP) ≥181 mmHg during placebo run-in visit and
             confirmed by a second measurement (not on the same day) preferably within one day.

          -  Upper arm circumference that exceeds the upper circumference level of the cuff size of
             either Ambulatory Blood Pressure Monitor (ABPM) and/or (BP) measurement device used in
             the study.

          -  Night shift workers who routinely sleep during the daytime and/or whose work hours
             include midnight.

          -  Diagnosis of autoimmune diabetes/Type I diabetes mellitus, monogenic (neonatal or
             maturity onset diabetes of the young (MODY)) diabetes or Type I diabetes in
             adults/latent autoimmune diabetes of adults (LADA) per investigator or patient medical
             history at the time of Visit 1 (screening).

          -  Known or suspected secondary hypertension (e.g. renal artery
             stenosis,phaeochromocytoma, Cushing's disease).

          -  History or evidence of hypertensive retinopathy (Keith-Wagener grade III or IV) and/or
             hypertensive encephalopathy.

          -  Clinically significant valvular heart disease or severe aortic stenosis in the opinion
             of the investigator.

          -  Acute coronary syndrome (non- ST wave elevated myocardial infarction (STEMI), STEMI
             and unstable angina pectoris), stroke or transient ischemic attack within 3 months
             prior to informed consent.

          -  Indication of liver disease, defined by serum levels of either Alanine
             Aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase(SGPT)), Aspartate
             Aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)), or alkaline
             phosphatase above 3 x upper limit of normal (ULN) as determined during screening
             and/or run-in phase.

          -  Impaired renal function, defined as Estimated Glomerular Filtration Rate (eGFR)< 45
             ml/min/1.73m2 (moderate renal impairment, chronic kidney disease epidemiology
             collaboration Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) as
             determined during screening and/or run-in phase.

          -  Bariatric surgery within the past two years and other gastrointestinal surgeries that
             induce chronic malabsorption.

          -  Medical history of cancer (except for basal cell carcinoma) and/or treatment for
             cancer within the last 5 years.

          -  Blood dyscrasias or any disorders causing hemolysis or unstable Red Blood Cells (e.g.
             malaria, babesiosis, haemolytic anaemia, thalassemia, sickle cell anaemia (sickle cell
             trait is allowed)).

          -  Medical history and signs and symptoms of diabetic autonomic neuropathy.

          -  Treatment with anti-obesity drugs 3 months prior to randomisation (i.e. surgery,
             aggressive diet regimen, etc.) leading to unstable body weight.

          -  Current treatment with systemic steroids at time of informed consent or change in
             dosage of thyroid hormones within 6 weeks prior to informed consent or any other
             uncontrolled endocrine disorder except Type 2 Diabetes Mellitus (T2DM) in the opinion
             of the investigator.

          -  Pre-menopausal women (last menstruation <=1 year prior to informed consent) who:

               -  are nursing or pregnant or

               -  are of child-bearing potential and are not practicing an acceptable method of
                  birth control, or do not plan to continue using this method throughout the study
                  and do not agree to submit to periodic pregnancy testing during participation in
                  the trial. Acceptable methods of birth control include tubal ligation,
                  transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable
                  or injectable contraceptives, complete sexual abstinence (if acceptable by local
                  authorities), double barrier method and vasectomised partner.

          -  Alcohol, drug or confectionary liquorice abuse within the 3 months prior to informed
             consent that would interfere with trial participation or any ongoing condition leading
             to a decreased compliance to study procedures or study drug intake in the
             investigator's opinion.

          -  Intake of an investigational drug in another trial within 30 days prior to intake of
             study medication in this trial; or participating in another trial (involving an
             investigational drug and/or follow-up) after discontinuing medication in that trial.

          -  Any other clinical condition that would jeopardize patient's safety while
             participating in this clinical trial in the opinion of the investigator.