24 Week Efficacy and Safety Study of Empagliflozin (BI 10773) in Hypertensive Black/African American Patients With Type 2 Diabetes Mellitus and Hypertension

Study Overview
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Brief Summary
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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.

Official Title
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A Randomised, Double-blind, Placebo-controlled, Parallel Group, Efficacy and Safety Study of Empagliflozin (10mg, 25mg) Administered Orally, Once Daily Over 24 Weeks in Hypertensive Black/African American Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2, Hypertension

Intervention / Treatment
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* Drug: Empagliflozin low dose
* Drug: placebo
* Drug: Empagliflozin high dose


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>starting dose 10mg; forced titration after 4 weeks 25mg dose | Drug: Empagliflozin low dose<br>* starting dose 10mg; forced titration after 4 weeks 25mg dose<br>Drug: Empagliflozin high dose<br>* starting dose 10mg; forced titration after 4 weeks 25mg dose<br>|
| Placebo Comparator: Placebo<br>starting dose 10mg; forced titration after 4 weeks 25mg dose | Drug: placebo<br>* starting dose 10mg; forced titration after 4 weeks 25mg dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycated Haemoglobin (HbA1c) (%) at 24 Weeks | Change from baseline in HbA1c (%) at 24 weeks is presented. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) model is used in the statistical analysis. | baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean 24-hour Ambulatory Systolic Blood Pressure (SBP) at Week 12 | Change from baseline in mean 24-hour ambulatory Systolic blood pressure SBP at Week 12 is presented. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. This is a key secondary endpoint | baseline and 12 weeks | 
| Changes From Baseline in Trough Mean Ambulatory SBP at Week 12 | Changes from baseline in trough mean ambulatory SBP at Week 12 is presented. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. This is a key secondary endpoint | baseline and 12 weeks | 
| Change From Baseline in Body Weight at Week 24 | Changes from baseline in body weight at Week 24 is presented. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. This is a key secondary endpoint | baseline and 24 weeks | 
| Change From Baseline in Trough Seated SBP at Week 12 | Change from baseline in trough seated SBP (mmHg) at Week 12 is presented. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. This is a key secondary endpoint | baseline and 12 weeks | 
| Change From Baseline in Mean 24-hour Ambulatory SBP (mmHg) at Week 24 | Change from baseline in mean 24-hour ambulatory SBP (mmHg) at Week 24 is secondary endpoint. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. | baseline and 24 weeks | 
| Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (DBP) at Week 12 | Change from baseline in mean 24-hour ambulatory DBP (mmHg) at Week 12. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. | baseline and 12 weeks | 
| Change From Baseline in Mean 24-hour Ambulatory DBP (mmHg) at Week 24 | Change from baseline in mean 24-hour ambulatory DBP (mmHg) at Week 24 is secondary endpoint. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. | baseline and 24 weeks | 
| Change From Baseline in Trough Seated SBP (mmHg) at Week 24 | Change from baseline in trough seated SBP (mmHg) at Week 24 is secondary endpoint. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. | baseline and 24 weeks | 
| Change From Baseline in Trough Seated DBP (mmHg) at Week 12 | Change from baseline in trough seated DBP (mmHg) at Week 12 is secondary endpoint. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. | baseline and 12 weeks | 
| Change From Baseline in Trough Seated DBP (mmHg) at Week 24 | Change from baseline in trough seated DBP (mmHg) at Week 24 is secondary endpoint. The term baseline refers to the last observation prior to randomisation of the patient. Means presented are the adjusted means. | baseline and 24 weeks |