Clinical trial NCT06217302: Sotagliflozin to Slow Kidney Function Decline in Persons With Type 1 Diabetes and Diabetic Kidney Disease
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Diabetic Nephropathies
Kidney Failure, Chronic
Diabetes Mellitus Type 1
Heart Failure
Keywords: Diabetic Nephropathies
Kidney Failure, Chronic
Type 1 diabetes
Heart failure
Cardiovascular disease
Glomerular filtration rate
SGLT2 inhibitors
Diabetic kidney disease
Lead sponsor: Joslin Diabetes Center
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: The Kidney Foundation of Canada
name: The Cleveland Clinic
name: University of Michigan
name: University of Colorado, Denver
name: Northwestern University
name: Washington University School of Medicine
name: State University of New York - Upstate Medical University
name: Providence Medical Research Center
name: Stanford University
name: Montefiore Medical Center
name: University of Toronto
name: University Health Network, Toronto
name: University of Calgary
name: University of Alberta
name: University of British Columbia
name: Institut de Recherches Cliniques de Montreal
name: LMC Diabetes & Endocrinology Ltd.
name: Joslin Diabetes Center
name: Lexicon Pharmaceuticals
name: DexCom, Inc.
name: University of Washington
name: Breakthrough T1D
First posted: 2024-01-22
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: Inclusion Criteria:

* 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 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 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.

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 dual medication RASB therapy (spironolactone, eplerenone, finerenone are allowed in combination with RASB therapy);
* 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 kidney 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.

Primary outcomes:
measure: eGFR at the end of the wash-out period following the treatment period
timeFrame: End of the 2-month wash-out period following the 3-year treatment period (weeks 162 and 164)
Secondary outcomes:
measure: Time to ≥40% eGFR decline from baseline, kidney failure , or death from renal causes
timeFrame: Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
Other outcomes:
measure: eGFR at the end of the 3-yr treatment period
timeFrame: End of the 3-year treatment period (week 156)
measure: Time to fatal or non-fatal cardiovascular disease (CVD) events
timeFrame: Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
measure: Time to hospitalization or urgent visit for heart failure or CV death
timeFrame: Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
measure: Time to hospitalization for heart failure
timeFrame: Up to the end of the 2-month wash-out period following the 3-year treatment period (week 0 to 164)
measure: B-type natriuretic peptide (NTproBNP) serum levels at the end of the drug washout
timeFrame: End of the 2-month wash-out period following the 3-year treatment period (week 164)
measure: High-sensitivity cardiac troponin (hs-cTnT) serum levels at the end of the drug washout
timeFrame: End of the 2-month wash-out period following the 3-year treatment period (week 164)
measure: NTproBNP serum levels at the end of the treatment period
timeFrame: End of the 3-year treatment period (week 156)
measure: hs-cTnT serum levels at the end of the treatment period
timeFrame: End of the 3-year treatment period (week 156)
measure: Mean blood HbA1c levels during the treatment period
timeFrame: Weeks 0, 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean blood glucose levels during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean GMI during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean time in range (TIR) during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean time below range 70 (TBR70) during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean time below range 54 (TBR54) during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean time above range 180 (TAR180) during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean time above range 250 (TAR250) during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean Glucose CV during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean MAGE during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean GRI during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Mean total daily insulin dose during the treatment period
timeFrame: Weeks 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
measure: Urinary albumin excretion rate change from baseline equal to or more negative than -30% at the end of treatment
timeFrame: End of treatment period (Week 156).
measure: Urinary albumin excretion rate change from baseline equal to or more negative than -30% at the end of the washout period
timeFrame: End of the 2-month wash-out period following the 3-year treatment period (week 164)
measure: eGFR slope during the treatment period
timeFrame: Weeks 0, 2, 8, 16, 28, 44, 60, 76, 92, 108, 124, 140 156 (from baseline to the end of the treatment period)
Locations:
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Aurora
country: United States
facility: Barbara Davis Center / University of Colorado Denver
state: Colorado
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Bronx
country: United States
facility: Albert Einstein College of Medicine / Montefiore Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center
state: Washington
city: Calgary
country: Canada
facility: Unversity of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Alberta Diabetes Institute
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: LMC Diabetes and Endocrinology
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Institut de Recherches Cliniques de Montréal
state: Quebec
Study officials:
affiliation: Joslin Diabetes Center
name: Alessandro Doria, MD PhD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Michael Mauer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Toronto
name: David Cherney, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
citation: Markham A, Keam SJ. Sotagliflozin: First Global Approval. Drugs. 2019 Jun;79(9):1023-1029. doi: 10.1007/s40265-019-01146-5.