E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the superiority of sotagliflozin versus placebo on hemoglobin A1c (HbA1c) reduction in patients with type 2 diabetes (T2D) who have inadequate glycemic control on a Dipeptidyl Peptidase 4 Inhibitor (DPP4(i)) with or without metformin. |
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E.2.2 | Secondary objectives of the trial |
-To demonstrate non-inferiority of sotagliflozin versus empagliflozin on HbA1c reduction. -To demonstrate the superiority of sotagliflozin versus placebo on 2-hour postprandial glucose (PPG) reduction, fasting plasma glucose (FPG) reduction, body weight reduction, on the proportion of patients with HbA1c <6.5% and <7.0%, and on sitting systolic blood pressure (SBP) reduction. -To demonstrate the superiority of sotagliflozin versus empagliflozin on HbA1c reduction and sitting SBP reduction - To evaluate the safety of sotagliflozin versus empagliflozin, and placebo, throughout the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
To compare the effect of sotagliflozin, empagliflozin and placebo in a subset of patients based on: -24-hour average SBP and diastolic blood pressure (DBP). -Average adjusted awake time blood pressure (BP) as measured by SBP and DBP with adjustment based on actigraphy. - Average adjusted sleeping time BP as measured by SBP and DBP with adjustment based on actigraphy.
Title: Ambulatory blood pressure monitoring substudy Protocol version 1 dated 29 September 2017 |
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E.3 | Principal inclusion criteria |
-Patients with Type 2 Diabetes on Dipeptidyl peptidase-4 inhibitors(DPP4(i)) with or without metformin at a stable dose for at least 12 weeks prior to Screening Visit. Metformin dose will be ≥1500 mg per day (or maximum tolerated dose [documented]). DPP4(i) dose must be the appropriate dose as per local label. -Signed written informed consent. |
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E.4 | Principal exclusion criteria |
-Body mass index (BMI) ≤20 kg/m² or >45 kg/m² at Screening. -Use of any antidiabetic drug other than DPP4 inhibitors and metformin within 12 weeks preceding the Screening Visit. -Patients who have previously participated in any clinical trial of sotagliflozin/LX4211. -Use of a selective Sodium-glucose co-transporter type 2 (SGLT2) inhibitor (eg, canagliflozin, dapagliflozin, or empagliflozin) within 3 months prior to screening visit. -Patients with severe anemia, severe cardiovascular disease (including congestive heart failure New York Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active malignant tumor or other major systemic disease or patients with short life expectancy that, according to Investigator, will preclude their safe participation in this study, or will make implementation of the protocol or interpretation of the study results difficult. -Current diagnosis of chronic hepatitis and/or other clinically active liver disease requiring treatment. -Patients with contraindication to empagliflozin as per local labeling. -Patients with contraindication to metformin as per local labeling. -Hemoglobin A1c <7.0% or >11.0% at Screening (central laboratory). -Fasting plasma glucose >270 mg/dL (>15.0 mmol/L) measured by the central laboratory at Screening (Visit 1), and confirmed by a repeat test (>270 mg/dL [>15.0 mmol/L]) before Randomization. -Previous use of any types of insulin for >1 month (except for treatment of gestational diabetes). -Pregnant (confirmed by serum pregnancy test at Screening) or breast-feeding women. -Women of childbearing potential not willing to use highly effective method(s) of birth control during the study treatment period and follow-up period, or who are unwilling or unable to be tested for pregnancy during the study. -Mean of 3 separate blood pressure (BP) measurements >180 mmHg (systolic blood pressure |SBP|) or >100 mmHg (diastolic blood pressure |DBP|). -History of hypertensive crisis resulting in emergency medical care within 12 weeks prior to Screening Visit. -Lower extremity complications (such as skin ulcers, infection, osteomyelitis and gangrene) identified during the screening period, and still requiring treatment at randomization; -Laboratory findings with the central laboratory tests at Visit 1: -Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of the normal laboratory range (ULN); -Total bilirubin >1.5 times the ULN (except in case of Gilbert’s syndrome); -Neutrophils <1 500/mm3 (or according to ethnic group) and/or platelets <100 000/mm3; -Amylase and/or lipase >3 times the ULN; -Patients with renal impairment as defined by the estimated glomerular filtration rate (eGFR) criterion that precludes initiation of empagliflozin as per the approved local label (eg, <45 mL/min/1.73 m2 in US; <60 mL/min/1.73 m2 in EU). -Secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome). -If the patient is on hypertensive medications, the antihypertensive has been changed in the 8 weeks prior to Screening (new drug or new dose). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HbA1c: Absolute change from baseline to week 26 in Hemoglobin A1 (HbA1c) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Change in sitting SBP in patients with SBP ≥130 mmHg at Baseline : Absolute change from baseline to week 12 in sitting systolic blood pressure (SBP) 2. Change in 2-hour PPG following a MMTT: Absolute change in 2-hour post prandial glucose (PPG) following a mixed meal tolerance test (MMTT) from baseline to week 26 3. Change in FPG: Absolute change in fasting plasma glucose (FPG) from baseline to week 26 4. Change in body weight: Absolute change in body weight from baseline to week 26 5. Change in sitting SBP in all patients: Absolute change from baseline to week 12 in sitting systolic blood pressure (SBP) in all patients 6. Patients with HbA1c <6.5%: Proportion of patients with Hemoglobin A1c (HbA1c) <6.5% at week 26 7. Patients with HbA1c <7.0%: Proportion of patients with Hemoglobin A1c (HbA1c) <7.0% at week 26 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) and 5) Baseline to week 12 2), 3) and 4) Baseline to week 26 6) and 7) At week 26 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
placebo- and active-controlled, double-dummy |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 78 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Canada |
Czech Republic |
France |
Italy |
Latvia |
Mexico |
Russian Federation |
Slovakia |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last Subject Last Visist (LSLV) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |