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

Heart Failure Clinical Trial

— SUGARNSALT  

Official title:

Effectiveness and Safety of Sotagliflozin in Slowing Kidney Function Decline in Persons With Type 1 Diabetes and Moderate to Severe Diabetic Kidney Disease

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06217302
• Other study ID #: STUDY00000249
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: May 2024
• Est. completion date: December 2028

Study information

• Verified date: January 2024
• Source: Joslin Diabetes Center
• Contact: Christine Mendonca
• Phone: 617-309-2735
• Email: christine.mendonca[@]joslin.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Powerful new drugs that can prevent or delay end stage kidney disease (ESKD) - so called sodium-glucose cotransporter-2 inhibitors (SGLT2i) - are now available for patients with type 2 diabetes. Whether these drugs have similar effects in patients with type 1 diabetes (T1D) remains unknown because of the few studies in this population, due to concerns about the increase in risk of diabetic ketoacidosis (DKA, a serious, potentially fatal acute complication of diabetes due to the accumulation of substances called ketone bodies) observed with SGLT2i therapy in T1D. One of the few T1D studies conducted to date showed that implementing an enhanced DKA prevention plan can reduce the risk of DKA associated with the SGLT2i sotagliflozin (SOTA) to very low levels. In the present study, a similar DKA prevention program will be used to carry-out a 3-year trial to test the kidney benefit of SOTA in 150 persons with T1D and moderate to advanced DKD. After a 2-month period, during which diabetes care will be standardized and education on monitoring and minimizing DKA implemented, eligible study subjects will be randomly assigned (50/50) to take one tablet of SOTA (200 mg) or a similarly looking inactive tablet (placebo) every day for 3 years followed by 2-months without treatment. Neither the participants nor the study staff will know whether a person was assigned to taking SOTA or the inactive tablet. Kidney function at the end of the study will be compared between the two treatment groups to see whether SOTA prevented kidney function loss in those treated with this drug as compared to those who took the inactive tablet. The DKA prevention program will include participant education, close follow-up with study staff, continuous glucose monitoring, and systematic ketone body self-monitoring with a meter provided by the study. If successful, this study will provide efficacy and safety data that could be used to seek FDA approval of SOTA for the prevention of kidney function decline in patients with T1D and DKD.

Description:

Despite improvements in glycemia management and the use of renin-angiotensin system blockade (RASB), the overall incidence of ESKD incidence in the US T1D population is not decreasing. For patients with type 2 diabetes (T2D), powerful new drugs that can prevent or delay ESKD, sodium-glucose cotransporter-2 inhibitors (SGLT2i), are now available. Whether similar results can be achieved in T1D remains unknown because of the paucity of studies in this population, due to concerns about the 2- to 3-fold increase in risk of diabetic ketoacidosis (DKA) associated with SGLT2i therapy in T1D. One of the few T1D studies conducted to date (inTandem, a sotagliflozin [SOTA] trial), showed that implementation of an enhanced DKA risk monitoring and mitigation strategy can reduce DKA incidence to <1%/year in subjects on 200 mg/day of this dual SGLT1 and SGLT2 inhibitor. The goals of the present study are to evaluate the renal effectiveness of SGLT2i in T1D and to better understand the benefit/risk ratio of SOTA in T1D persons with moderate to advanced diabetic kidney disease (DKD) - two goals that are warranted and critical given the high risk of death and ESKD in this population. The study, carried out by the Preventing Early Renal Loss (PERL) and the Canadian Institute of Health Research (CIHR)-funded SUGARNSALT (S&S) consortia, is a multi-center, double-blind, placebo-controlled, parallel-group randomized clinical trial in 150 patients with T1D and moderate to advanced diabetic kidney disease (estimated glomerular filtration rate [eGFR] 20-60 ml/min/1.73 m2 and ACR>200 mg/g). After a 2-month run-in period, during which diabetes care is standardized and education on monitoring and minimizing DKA implemented, eligible study subjects are randomized in a 1:1 ratio to receive placebo or once daily 200 mg SOTA for 3 years followed by a 2-month wash-out period. The eGFR at the end of the wash-out adjusted by its baseline value will be used as the primary outcome on which SOTA efficacy on DKD progression will be evaluated. An intensive DKA risk mitigation plan will be implemented based on the inTandem enhanced protocol as well as on the STICH (Stop SGLT2i, Insulin administration, Carbohydrate intake, Hydration) and STOP-DKA protocols. Cornerstones of this plan will be enhanced participant education, close follow-up with study staff, continuous glucose monitoring, and systematic ketone body (beta-hydroxybutyrate [BHB]) self-monitoring. If successful, the present study will provide efficacy and safety data that could be used to seek FDA and Health Canada approval of SOTA for a T1D DKD indication. Based on the available data in T1D, it can be conservatively postulated that SOTA may reduce eGFR loss by 2 ml/min/1.73 m2 per year. Depending on the baseline eGFR, this would translate to a 5-10 year delay of ESKD. The reduction in morbidity and mortality resulting from the prevention or delay of ESKD due to the use of SOTA would have a major impact on the lives of T1D patients with significant DKD as well as on society at large, substantially reducing the human and financial costs associated with this condition.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 150
• Est. completion date: December 2028
• Est. primary completion date: August 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Type1 diabetes (T1D) continuously treated with insulin within one year from diagnosis.
• Duration of T1D = 8 years;
• eGFR based on serum creatinine between 20 and 60 ml/min/1.73 m2 at screening;
• First morning void urinary albumin/creatinine ratio (UACR) =200 mg/g at screening;
• HbA1c <10% at screening;
• Receiving standard of care, including renin angiotensin system blockade (RASB), 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.

Exclusion Criteria:

• Type 2 diabetes or monogenic forms of diabetes or diabetes secondary to pancreatic disease;
• Use of non-FDA approved automated insulin delivery devices;
• Use of any SGLT inhibitor in the previous 2 months;
• Use of glucagon-like peptide (GLP-1) receptor agonists and other non-insulin glucose lowering agents if in use for less than 3 months and/or not on stable dose at screening;
• Use of anti tumor necrosis factor (TNF) alpha biologic medications at screening;
• 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;
• Blood beta-hydroxybutyrate (BHB) >0.6 mmol/L for >2 hours on >2 occasions during the Run-in period;
• Inadequate beta hydroxybutyrate (BHB) testing (<50% of the prescribed measurements) during Run-in;
• History of primary renal glycosuria;
• History of biopsy-proven non-diabetic chronic kidney disease (CKD);
• History of renal transplant or currently on chronic dialysis;
• 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).
• 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.
• Illicit drug abuse within 6 months of screening;
• 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;
• Systolic blood pressure >155 mmHg or diastolic blood pressure >95 mmHg at screening;
• 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;
• Any condition that may render the patient unable to comply with study requirements and/or complete the study.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus Type 1
• Diabetes Mellitus, Type 1
• Diabetic Nephropathies
• Heart Failure
• Kidney Diseases
• Kidney Failure, Chronic
• Renal Insufficiency

Intervention

Drug:
• Sotagliflozin
Oral sotagliflozin (200 mg per day)
• Placebo
Inactive tablets identical to sotagliflozin tablets

Locations

Country	Name	City	State
Canada	Unversity of Calgary	Calgary	Alberta
Canada	Alberta Diabetes Institute	Edmonton	Alberta
Canada	Institut de Recherches Cliniques de Montréal	Montreal	Quebec
Canada	LMC Diabetes and Endocrinology	Toronto	Ontario
Canada	Mount Sinai Hospital / University of Toronto	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
United States	Brehm Center for Diabetes Research / University of Michigan	Ann Arbor	Michigan
United States	Barbara Davis Center / University of Colorado Denver	Aurora	Colorado
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Albert Einstein College of Medicine / Montefiore Medical Center	Bronx	New York
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	University of Texas Southwestern	Dallas	Texas
United States	Washington University	Saint Louis	Missouri
United States	University of Washington	Seattle	Washington
United States	Providence Sacred Heart Medical Center	Spokane	Washington
United States	Stanford University Medical Center	Stanford	California
United States	SUNY Upstate Medical University	Syracuse	New York

Sponsors (25)

Lead Sponsor

Collaborator

Alessandro Doria

Canadian Institutes of Health Research (CIHR), DexCom, Inc., Institut de Recherches Cliniques de Montreal, Joslin Diabetes Center, Juvenile Diabetes Research Foundation, Lexicon Pharmaceuticals, LMC Diabetes & Endocrinology Ltd., Montefiore Medical Center, Northwestern University, Providence Medical Research Center, Stanford University, State University of New York - Upstate Medical University, The Cleveland Clinic, The Kidney Foundation of Canada, University Health Network, Toronto, University of Alberta, University of British Columbia, University of Calgary, University of Colorado, Denver, University of Michigan, University of Minnesota, University of Toronto, University of Washington, Washington University School of Medicine

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (4)

Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, Cherney DZI, Dwyer JP, Scirica BM, Bailey CJ, Diaz R, Ray KK, Udell JA, Lopes RD, Lapuerta P, Steg PG; SCORED Investigators. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021 Jan 14;384(2):129-139. doi: 10.1056/NEJMoa2030186. Epub 2020 Nov 16. — View Citation

Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B; SOLOIST-WHF Trial Investigators. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021 Jan 14;384(2):117-128. doi: 10.1056/NEJMoa2030183. Epub 2020 Nov 16. — View Citation

Markham A, Keam SJ. Sotagliflozin: First Global Approval. Drugs. 2019 Jun;79(9):1023-1029. doi: 10.1007/s40265-019-01146-5. — View Citation

van Raalte DH, Bjornstad P, Persson F, Powell DR, de Cassia Castro R, Wang PS, Liu M, Heerspink HJL, Cherney D. The Impact of Sotagliflozin on Renal Function, Albuminuria, Blood Pressure, and Hematocrit in Adults With Type 1 Diabetes. Diabetes Care. 2019 Oct;42(10):1921-1929. doi: 10.2337/dc19-0937. Epub 2019 Aug 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Urinary albumin excretion rate change from baseline equal to or more negative than -30% at the end of treatment	Urinary albumin excretion rate (UAER, timed overnight collection) change from baseline equal to or more negatvive than -30% at the end of treatment (determined from the geometric mean of two UAER measurements in timed overnight urine collections during the last 3 months of the treatment period [Visits 16 and 17])	Last three months of treatment period (Weeks 142 and 156).
Other	Urinary albumin excretion rate change from baseline equal to or more negative than -30% at the end of the washout period	UAER change from baseline equal to or more negative than -30% at the end of the 8-week washout period following the 3-year treatment period (determined from the geometric mean of two UAER measurements in timed overnight urine collections brought by the participant at visit 19).	End of the 2-month wash-out period following the 3-year treatment period (week 164)
Other	eGFR slope during the treatment period	eGFR slope from baseline to the end of the 3-yr treatment period (before the washout period), ESKD, death, or study discontinuation, whichever occurs first	Weeks 0, 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	eGFR at the end of the 3-yr treatment period	eGFR at the end of the 3-yr treatment period (before the washout period) adjusted for the baseline value	End of the 3-year treatment period (week 156)
Other	Time to fatal or non-fatal cardiovascular disease (CVD) events	Time to fatal or non-fatal CVD events (CV death, non-fatal myocardial infarction, non-fatal stroke, or coronary, carotid, or peripheral revascularization procedures)	Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
Other	Time to hospitalization or urgent visit for heart failure or CV death	Time to hospitalization or urgent visit for heart failure or death for cardiovascular causes	Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
Other	Time to hospitalization for heart failure	Time to hospitalization for heart failure	Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
Other	B-type natriuretic peptide (NTproBNP) serum levels at the end of the drug washout	Serum levels of NTproBNP at the end of the 8-week drug washout, adjusted for its baseline value	End of the 2-month wash-out period following the 3-year treatment period (week 164)
Other	High-sensitivity cardiac troponin (hs-cTnT) serum levels at the end of the drug washout	Serum levels of hs-cTnT at the end of the 8-week drug washout, adjusted for its baseline value	End of the 2-month wash-out period following the 3-year treatment period (week 164)
Other	NTproBNP serum levels at the end of the treatment period	Serum levels of B-type natriuretic peptide (NTproBNP) at the end of the 3-year treatment period, adjusted for its baseline value	End of the 3-year treatment period (week 156)
Other	hs-cTnT serum levels at the end of the treatment period	Serum levels of high-sensitivity cardiac troponin (hs-cTnT ) at the end of the 3-year treatment period, adjusted for its baseline value	End of the 3-year treatment period (week 156)
Other	Mean blood HbA1c levels during the treatment period	Mean HbA1c during the 3-year treatment period	Weeks 0, 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean blood glucose levels during the treatment period	Mean blood glucose from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean GMI during the treatment period	Mean glucose management indicator (GMI) from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean time in range (TIR) during the treatment period	Mean time with blood glucose in the 70 to 180 mg /dl range from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean time below range 70 (TBR70) during the treatment period	Mean time with blood glucose below 70 mg/dl from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean time below range 54 (TBR54) during the treatment period	Mean time with blood glucose below 54 mg/dl from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean time above range 180 (TAR180) during the treatment period	Mean time with blood glucose above 180 mg/dl from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean time above range 250 (TAR250) during the treatment period	Mean time with blood glucose above 250 mg/dl from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean Glucose CV during the treatment period	Mean blood glucose coefficient of variation (CV) from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean MAGE during the treatment period	Mean amplitude of glycemic excursions (MAGE) from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean GRI during the treatment period	Mean glycemic risk index (GRI) from continuous glucose monitoring during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Other	Mean total daily insulin dose during the treatment period	Mean total daily insulin dose (TDD, units/kg) during the 3-year treatment period	Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Primary	eGFR at the end of the wash-out period following the treatment period	eGFR at the end of the 8-week drug washout period following the 3-year treatment period, estimated from Central Lab serum creatinine and cystatin C using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and adjusted by its baseline value. Baseline and end-of-washout eGFRs will be considered as the average of two eGFR values taken on two separate days before randomization (V2 and V4) and after the washout (V18 and V19), respectively.	End of the 2-month wash-out period following the 3-year treatment period (weeks 162 and 164)
Secondary	Time to =40% eGFR decline from baseline, end-stage kidney disease, renal replacement therapy, or death from renal causes	Time from randomization to =40% eGFR decline (based on eGFR estimated from serum creatinine and cystatin C using the 2021 CKD-EPI equation) confirmed after 30 days, ESKD defined by eGFR =10ml/min/ 1.73m2 confirmed after 30 days, renal replacement therapy, or death from renal causes.	Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)