Type 2 Diabetes, Cardiovascular Risk Factors and Moderately Impaired Renal Function

Primary Objectives: To compare the effect of sotagliflozin to placebo on total occurrences of cardiovascular (CV) death, hospitalization for heart failure [HHF], and urgent visit for heart failure [HF] in patients with type 2 diabetes, cardiovascular risk factors, and moderate to severely impaired renal function.

Sotagliflozin

Sotagliflozin

Tablet

200

Primary efficacy endpoints:
x Time to the first occurrence of any of the following clinical events:
- Cardiovascular death
- Non-fatal MI
- Non-fatal stroke
x Time to the first occurrence of any of the following clinical events:
- Cardiovascular death
- Hospitalization for heart failure
Secondary efficacy endpoints:
x Time to the first occurrence of any of the following clinical events in patients with
Baseline eGFR •30 mL/min/1.73 m2:
- Sustained •50% decrease in eGFR from Baseline (for •30 days)
- Chronic dialysis
- Renal transplant
- Sustained eGFR <15 mL/min/1.73 m2 (for •30 days)
x Time to the first occurrence of any of the following clinical events in patients with
Baseline eGFR •30 mL/min/1.73 m2 and Baseline UACR •300 mg/g
(34 mg/mmol):
- Sustained •50% decrease in eGFR from Baseline (for •30 days)
- Chronic dialysis
- Renal transplant
- Sustained eGFR <15 mL/min/1.73 m2 (for •30 days)
x Total number (ie, including recurrent events) of the following clinical events:
- Cardiovascular death
- Hospitalization for heart failure
- Urgent HF visit (defined in Appendix E)
x Time to CV death
x Time to all-cause mortality

Inclusion criteria:
Mandatory Inclusion Criteria (all 4 criteria are necessary)
I 01. Signed written informed consent
I 02. Type 2 diabetes with HbA1c •7% (53 mmol/mol) at Screening (central laboratory)
I 03. Estimated glomerular filtration rate •25 and 60 mL/min/1.73 m2 by the
4 variable Modification of Diet in Renal Disease (MDRD) equation (at Screening,
based on central laboratory)
I 04. Patients either:
- Age •18 years with at least 1 (one) of the major CV risk factors listed below
OR
- In the absence of a major CV risk factor, age •55 years with at least 2 (two)
of the minor CV risk factors listed below
In order to be considered eligible to participate in the study, patients must meet all 4 (four)
of the mandatory criteria. Patients can be eligible if they have both major and minor CV
risk factors, as long as 1 of the 2 conditions in Inclusion Criterion Number 4 is met. Major
and minor CV risk factors are listed below.
Major CV risk factors (at least 1 criterion to fulfill Inclusion Criterion
Number 4)
A) Hospitalization for HF during previous 2 years
B) Ejection fraction (EF) 40%
Documented within the past year by previous imaging modality (such as
echocardiogram, MUltiple Gated Acquisition (MUGA) scan, Magnetic
Resonance Imaging (MRI), positron emission tomography (PET), single-photon
emission computed tomography (SPECT), left ventricular (LV) angiography)
Note: An echocardiogram to assess EF at the time of Screening MUST be
performed in all patients if an assessment of EF has not been documented
within 1 year prior to Screening
C) Diagnosis of left ventricular hypertrophy
By either electrocardiogram (ECG) or echocardiogram
D) Coronary artery calcium (CAC) score •300 Agatston Units
Documented by coronary artery CT scan
Note: a coronary artery CT scan MAY be performed to measure the CAC score
if required for eligibility if not previously documented
E) N-terminal pro-B-type natriuretic peptide •400 pg/mL (47 pmol/L)
At Screening, based on central laboratory
F) High-sensitivity troponin T >15.0 pg/mL (0.015 μg/L) for men and >10.0 pg/mL
(0.010 μg/L) for women
During Screening period, based on central laboratory
G) High-sensitivity C-reactive protein >3 mg/L (28.6 nmol/L)
At Screening, based on central laboratory, if the Investigator does not consider
the elevation to be due to an acute inflammatory condition (eg, acute infection)
H) Urinary albumin-to-creatinine ratio •300 mg/g (34 mg/mmol)
At Screening, based on central laboratory
Minor CV risk factors (if no major CV risk factors, at least 2 criteria to
fulfill Inclusion Criterion Number 4)
I) Body mass index •35 kg/m2 at Screening
J) Dyslipidemia despite maximally-tolerated statin therapy:
- Low-density lipoprotein cholesterol >130 mg/dL (>3.36 mmol/L)
Or
- High-density lipoprotein cholesterol <40 mg/dL (<1.03 mmol/L) for men or
<50 mg/dL (<1.29 mmol/L) for women
Based on the last measured and documented laboratory measurement in the
previous 6 months
K) Currently smoking tobacco
Consumes an average of at least 1 cigarette, pipe, or cigar per day, at
Screening
L) Coronary artery calcium score >100 and <300 Agatston Units
Documented by coronary artery CT scan
Note: a coronary artery CT scan MAY be performed to measure the CAC score
if required for eligibility if not previously documented
M) Urinary albumin-to-creatinine ratio •30 mg/g and <300 mg/g (3 and 34 mg/mmol)
During Screening period, based on central laboratory
N) Systolic blood pressure >140 mmHg and diastolic blood pressure >90 mmHg
despite antihypertensive therapy at the Screening Visit
O) Family history of premature coronary heart disease (defined as MI or coronary
revascularization procedure) in a first degree relative
In a male relative <55 years or in a female relative <65 years

Exclusion criteria:
E 01. History of diabetic ketoacidosis or nonketotic hyperosmolar coma within
3 months prior to the Screening Visit or between Screening and Randomization
E 02. Antihyperglycemic treatment (if applicable) has not been stable in the
12 weeks prior to Screening or between Screening and Randomization, in the opinion of the Investigator
E 03. Patients who are planning to start a sodium-glucose linked transporter-2
(SGLT2) inhibitor (other than study drug) during the study. This includes
patients who, in the opinion of the Investigator, based on their comorbid
profile, are likely to receive an SGLT2 inhibitor (other than study drug) during the study
E 04. Any SGLT2 inhibitor <1 month prior to the Screening Visit, or between
Screening and Randomization
E 05. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and gangrene) identified during the Screening period, and still requiring treatment at Randomization
E 06. Any allergic reaction to any SGLT2 inhibitor or sotagliflozin
E 07. Blood pressure •180 mmHg (systolic) or •110 mmHg (diastolic) at both the
Screening and Randomization Visits
E 08. Hospitalization for hypertensive emergency within 3 months prior to Randomization
E 09. End-stage HF: requiring LV assist device, intra-aortic balloon pump (IABP), or
any type of mechanical support at the time of Screening
E 10. Planned coronary revascularization procedures, electrophysiologic device
implantation, cardiac mechanical support implantation, or other cardiac surgery after Randomization
E 11. History of dialysis within 1 year prior to Randomization
E 12. History of solid organ transplant
E 13. Serum creatinine altering drugs 30 days before Screening, or between
Screening and Randomization (trimethoprim, cimetidine, cephalosporins,
probenecid, aminoglycosides, ketoconazole). Please note that diuretics are
allowed within 30 days of Screening
E 14. Clofibrate, fenofibrate, dronedarone, or ranolazine treatment that has not
been at a stable dose in the 30 days prior to Screening or between Screening
and Randomization or a dose adjustment is expected during the study based
on the judgement of the Investigator
E 15. Use of systemic glucocorticoids (excluding topical application or inhaled
forms) for more than 10 consecutive days within 3 months prior to Screening
Visit or for more than 10 consecutive days between Screening and randomization
E 16. Digoxin plasma level >1.2 ng/mL (in a patient treated with digoxin at Screening,
based on local laboratory*)
E 17. Use of any investigational drug(s) within 5 half-lives prior to the Screening
Visit or between Screening and Randomization
E 18. Severe disease or short life expectancy making implementation of the
protocol or interpretation of the study results difficult (CV disease [including
congestive HF New York Heart Association IV], respiratory, hepatic,
neurological [including stroke in 3 months prior to Screening], psychiatric, or
active malignant tumor (except for non-melanoma skin cancers, which are not
exclusionary) or other major systemic disease [including any diseases with
evidence of malabsorption or severe anemia])
E 19. Presence of any other conditions (eg, geographic, social) actual or
anticipated, that the Investigator feels would restrict or limit the patient’s
participation for the duration of the study
E 20. Patient is the Investigator or any Sub-investigator, research assistant,
pharmacist, study coordinator, other staff or relative thereof directly involved
in the conduct of the protocol
E 21. Any country-related specific regulation that would prevent the patient from
entering the study (eg, individuals committed to an institution by virtue of an
order issued either by the judicial or the administrative authorities)
E 22. Pregnant (demonstrated by serum pregnancy test at Screening) or
breastfeeding women
E 23. Women of childbearing potential not willing to use a highly-effective
method(s) of birth control during the study treatment period and the follow-up
period, or who are unwilling or unable to be tested for pregnancy (see contraceptive guidance in Appendix A), during the study
E 24. Laboratory findings at the Screening Visit:
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
>3 times the upper limit of the normal laboratory range (ULN) (1 repeat is allowed)*
- Total bilirubin >1.5 times the ULN (except in case of Gilbert’s syndrome)
One time rescreening is allowed at the Investigator’s medical judgment for any
manageable reasons that caused the Screening failure and if the patient is likely to be
eligible before the enrollment completion.