Sotagliflozin to Slow Kidney Function Decline in Persons With Type 1 Diabetes and Diabetic Kidney Disease

Prior treatment

• Use of any SGLT inhibitor in the previous 2 months;
• Use of dual medication RASB therapy (spironolactone, eplerenone, finerenone are allowed in combination with RASB therapy);
• Use of anti tumor necrosis factor (TNF) alpha biologic medications at screening;
• History of kidney transplant or currently on chronic dialysis;
• Illicit drug abuse within 6 months of screening;

Other illness

• Type 2 diabetes or monogenic forms of diabetes or diabetes secondary to pancreatic disease;
• Known allergies, hypersensitivity, or intolerance to SOTA;
• History of ≥3 severe hypoglycemic events (requiring third-party assistance for correction) within 3 months of screening;
• History of diabetic ketoacidosis (DKA) or non-ketotic hyperosmolar state within 3 months of screening OR \>1 episode of DKA or non-ketotic hyperosmolar state within 12 months of screening;
• History of primary renal glycosuria;
• History of biopsy-proven non-diabetic chronic kidney disease (CKD);
• History of severe acquired immune deficiency syndrome or human immunodeficiency virus (HIV) infection or severely immunocompromised status;
• Cancer treatment (excluding non-melanoma skin cancer treated by excision, carcinoma in situ of the cervix or uterus, ductal breast cancer in situ, resected non-metastatic breast or prostate cancer) within one year of screening.
• Any condition that may render the patient unable to comply with study requirements and/or complete the study.

Lab values

• Use of GLP-1 receptor agonists and other non-insulin glucose-lowering agents if not on stable dose for \> 2 months at screening (patients can be rescreened after being on stable dose for \> 2 months);
• Blood beta-hydroxybutyrate (BHB) \>0.6 mmol/L for \>2 hours on \>2 occasions during the Run-in period;
• Current or past history of decompensated cirrhosis (defined as variceal bleeding, ascites or hepatic encephalopathy), and/or known diagnosis of cirrhosis based on liver biopsy, imaging, or elastography, and/or aspartate aminotransferase (AST) or alanine transaminase (ALT) at screening \>2 times upper limit of normal, and/or total bilirubin at screening \>1.3 times upper limit of normal).
• Presence of a clinically significant medical history, physical examination, or laboratory finding that may interfere with any aspect of study conduct or interpretation of results;

Other

• Use of automated insulin delivery devices that are not approved by health regulatory agencies, or used in ways that do not align with manufacturer recommendations;
• Inadequate beta hydroxybutyrate (BHB) testing (\<50% of the prescribed measurements) during Run-in;
• Heavy alcohol use (for men, 5 drinks or more on any day or 15 drinks or more per week; for women, 4 drinks or more on any day or 8 drinks or more per week);
• Participation in another interventional clinical research study within 30 days of screening;
• Breastfeeding, pregnancy, or unwillingness to be on contraception during the trial;

• Type1 diabetes (T1D) continuously treated with insulin within one year from diagnosis.
• Duration of T1D ≥ 8 years;
• eGFR based on serum creatinine and cystatin c (2021 serum creatinine-cystatin C CKD-EPI equation) between 20 and 60 ml/min/1.73 m2 at screening (with the option of a second eGFR measurement within 4 weeks from the first one if the eGFR was in the range of \>60 to ≤65 or ≥16 to \<20 ml/min/1.73 m2);
• a. First morning void urinary albumin creatinine ratio (UACR) ≥200 mg/g at Screening or on repeat measurement within 4 weeks from the first one, or b. First morning void urinary UACR ≥100 mg/g at Screening or on repeat measurement within 4 weeks and at least one uACR \>=30 in the previous 2 years while treated with RASB at a stable dose;
• HbA1c at screening \<10% (with the option of a second HbA1c measurement within 4 weeks from the first one if the HbA1c was ≤10.2%);
• Receiving standard of care, including renin angiotensin system blockers (RASB) at a clinically appropriate dose, unless contraindicated or not tolerated.
• Willing and able to comply with schedule of events and protocol requirements, including written informed consent, and willing to wear a continuous glucose monitoring (CGM) device for the entire duration of the study.
• a. Blood pressure ≤155/95 mmHg at screening, or b. BP ≤155/95 mmHg at the end of the run-in period, or c. consistent BP ≤155/95 mmHg on home monitoring during the run-in period, as determined by study site investigator, despite BP values \>155/95 mmHg in clinic.