Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To compare the metabolic and gastrointestinal pharmacodynamic (PD) effects of an 8 weeks treatment with sotagliflozin once daily (QD) to an 8 weeks treatment to empagliflozin QD in mild or moderate hypertensive T2DM patients on a stable treatment regimen with metformin and an angiotensin converting enzyme (ACE) inhibitor or Angiotensin Receptor Blocker (ARB) under standardized diet conditions. Secondary Objectives: * To compare the renal and cardiovascular PD effects of an 8 weeks treatment with sotagliflozin QD to an 8 weeks treatment to empagliflozin QD in mild or moderate hypertensive T2DM patients on a stable treatment regimen with metformin and an ACE inhibitor or ARB. * To evaluate the safety and tolerability of an 8 weeks QD treatment with sotagliflozin or empagliflozin in mild to moderate hypertensive T2DM patients on a stable treatment with metformin and an ACE inhibitor or ARB. * To evaluate the pharmacokinetic (PK) profile of sotagliflozin in steady state conditions.
Detailed description
The total study duration per patient is 70-105 days (for patients without drug washout/switch period), and up to 175 days (for patients with drug washout/switch period), including 2-30 days of screening, 5 days of run-in period, 56 days of treatment period, and a 7-14 days of follow-up period.
Interventions
Pharmaceutical form: tablet Route of administration: oral
DRUGPlacebo
Pharmaceutical form: tablet Route of administration: oral
DRUGEmpagliflozin
Pharmaceutical form: capsule Route of administration: oral
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
: * Male or female patients with Type 2 Diabetes Mellitus (T2DM) (diagnosed at least 1 year before screening visit), between 18 and 74 years of age, inclusive, with: * Hypertension grades 1 or 2 as defined by the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) at screening; systolic blood pressure (SBP) has to be in the range of 140-179 mmHg (after 10 minutes resting in supine position, measurement in triplicate with each measurement to be within this range at screening). If the blood pressure (BP) range is not met at screening, one repeat measurement at another occasion is allowed prior to inclusion into the study. * Glycated Haemoglobin A1c (HbA1c) at screening between 6.5% and 11%. * On a stable treatment with metformin, i.e., no change in dose regimen or in dose levels in the last 3 months prior to screening and throughout the study. * On a stable treatment with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker, i.e., no change in dose regimen or in dose levels in the last 4 weeks prior to screening and until randomization. * On a stable treatment with an ACE inhibitor or an angiotensin receptor blocker after switching from beta-blockers and/or thiazides for eligible patients after screening, i.e., no change in dose regimen and in dose levels in the last 4 weeks prior to run-in phase and until randomization * Body weight between 50.0 kg and 130 kg, inclusive, if male, and between 40.0 kg and 110 kg, inclusive, if female, body mass index between 18.0 and 38.0 kg/m2, inclusive. * Kidney function: Estimated glomerular filtration rate at screening must be 60 mL/min/1.73m2 or higher.
Exclusion criteria
* Patients with severe anemia, severe cardiovascular, gastrointestinal, respiratory, neurological, osteomuscular, psychiatric, or active malignant tumor or other major systemic disease or patients with infectious disease, signs of acute illness, or short life expectancy making implementation of the protocol or interpretation of the study results difficult (as evaluated by detailed medical history and complete physical and laboratory examination). * Heart failure New York Heart Association (NYHA) Classification III/IV. * Any clinically significant abnormality in echocardiography performed at screening as judged by the investigator based on age, gender and medical history of the individual patient. * History of myocardial infarction within the last 12 months prior to screening. * Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol (e.g., long-term systemic glucocorticoids) and refusing or unable to take alternative treatment. * Type 1 diabetes mellitus. * Secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome). * Clinically significant pulmonary hypertension, in particular World Health Organisation (WHO) Classes IV (Pulmonary hypertension due to chronic thrombotic and/or embolic disease \[CTEPH\]) and V (miscellaneous). * Diabetic retinopathy. * History of diabetic ketoacidosis or non-ketotic hyperosmolar coma within 12 weeks prior to the Screening Visit. * History of severe hypoglycemia resulting in hospitalization or unconsciousness/seizures within 6 months prior to the Screening visit. * History of prior gastric or intestinal surgical procedure including gastric banding within 3 years before the Screening Visit. Any gastrointestinal surgery with removal of part of the bowels or the stomach * History of unexplained pancreatitis, chronic pancreatitis, stomach/gastric surgery, inflammatory bowel disease. * Known hypersensitivity to sotagliflozin, empagliflozin or any excipient of the drug products. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of pharmacodynamic (PD) parameters in feces | Baseline and on Day 55 and 56 (over 48 hours) | Change from baseline in fecal sodium excretion |
| Assessment of PD parameters in urine | Baseline and on Day 56 (over 24 hours) | Change from baseline in 24-hour urinary glucose excretion |
| Assessment of PD parameters in blood | Baseline and on Day 56 | 14 hour plasma glucose profile after standardized meals |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pulse wave velocity | Baseline and on Day 55 | Change from baseline in carotid-femoral pulse wave velocity |
| Continuous Glucose Monitoring (CGM) | Baseline, last 3 days of treatment | Change from baseline in average diurnal glucose |
| Echocardiography | Baseline and on Day 54 | Change from baseline in left ventricular ejection fraction (LVEF) |
| Plasma Volume Measurement | Baseline and on Day 54 | Change from baseline in plasma volume |
| Fasting metabolic laboratory panel | Baseline and on Day 56 | Change from baseline in fasting plasma glucose |
| Assessment of pharmacokinetic (PK) parameters: Cmax | 24 hours after last investigational medicinal product (IMP) administration | Sotagliflozin: maximum plasma concentration observed (Cmax) |
| Assessment of pharmacokinetic (PK) parameters: Ctrough | 24 hours after last IMP administration | Sotagliflozin: plasma concentration observed before administration during repeated dosing (Ctrough) |
| Assessment of pharmacokinetic (PK) parameters: AUCtau | 24 hours after last IMP administration | Sotagliflozin: Area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (AUCtau) |
| Assessment of pharmacokinetic (PK) parameters: tmax | 24 hours after last IMP administration | Sotagliflozin: First time to reach Cmax (tmax) |
| Adverse events | Over 15 weeks | Number of patients with reported adverse events |
| Ambulatory Blood Pressure Measurement (ABPM) | Baseline and on days 54 until Day 56 | Change from baseline in average 24h systolic arterial pressure |
| Cardiovascular parameters | Baseline and on Day 56 | Change from baseline in plasma aldosterone |
Countries
Germany
Outcome results
None listed