Sotagliflozin + Volagidemab for Type 1 Diabetes

(SOTA Trial)

Overseen By Todd May

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of California, San Diego

Must be taking: Insulin

Must not be taking: GLP-1 RA, SGLT-2i

Disqualifiers: Pancreatitis, Liver disease, Anemia, others

Stay on Your Current Meds You can continue your current medications while participating

Compensation: Varies

Number of Visits: 1

24 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

Yes, you must stop using any diabetes medications other than insulin at least one month before the trial.

What data supports the effectiveness of the drug Sotagliflozin for Type 1 Diabetes?

Research shows that Sotagliflozin, when added to insulin therapy, helps improve blood sugar control and reduces body weight in adults with Type 1 Diabetes who struggle to manage their condition with insulin alone. However, it may increase the risk of diabetic ketoacidosis, a serious condition where the body produces high levels of blood acids. ^{1 2 3 4 5}

Is the combination of Sotagliflozin and Volagidemab safe for humans?

Sotagliflozin is generally well tolerated but carries a risk of diabetic ketoacidosis (a serious diabetes complication) when used with insulin in type 1 diabetes. Volagidemab did not increase hypoglycemia (low blood sugar) but was associated with increases in liver enzymes, LDL cholesterol, and blood pressure in a study for type 1 diabetes. ^{1 3 5 6 7}

How does the drug Sotagliflozin + Volagidemab differ from other treatments for type 1 diabetes?

Sotagliflozin is unique because it is a dual inhibitor of sodium-glucose co-transporters 1 and 2, which helps control blood sugar by affecting both the gut and kidneys. This drug is used alongside insulin to improve blood sugar control and reduce insulin needs, especially in patients who are overweight. However, it carries a risk of diabetic ketoacidosis, a serious condition that needs careful monitoring. ^{1 5 8 9 10}

What is the purpose of this trial?

This is a single site, double-blind, placebo-controlled, crossover trial to quantify the effects of combination adjunctive therapy on glycemic control, ketogenesis during insulinopenia, insulin resistance, and diabetes burden and quality of life.

Eligibility Criteria

Adults aged 18-70 with Type 1 diabetes, A1c levels between >7% and ≤10%, using insulin pumps or hybrid closed loop systems, and a CGM system can join. Women must use two contraception methods during the study and for three months after; men must also use contraception during the study and for six months after.

Inclusion Criteria

A1c > 7% and ≤ 10%

I have been diagnosed with Type 1 diabetes.

eGFR ≥ 60 mL/min/1.73m²

Exclusion Criteria

I have not donated more than 500 mL of blood in the last 8 weeks.

I am currently using or have used diabetes medication other than insulin in the last month.

History or evidence of clinically significant disorder or condition that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline data collection including A1c, CGM, ambulatory insulin dosing, ambulatory ketones, and psychosocial questionnaires. Participants complete an insulin withdrawal test and a hyperinsulinemic-euglycemic clamp with indirect calorimetry.

1 week

Treatment Period 1

Participants receive 12-week insulin-adjunctive treatment with SGLTi + Placebo or SGLTi + GRA in a random-order, cross-over design.

12 weeks

Weekly visits for medication dosing and data review

Washout Period

14-week washout period between treatment periods.

14 weeks

Treatment Period 2

Participants receive the alternate 12-week insulin-adjunctive treatment with SGLTi + Placebo or SGLTi + GRA.

12 weeks

Weekly visits for medication dosing and data review

Follow-up

Participants return for a safety follow-up visit 6 weeks after the final GRA or placebo dose.

6 weeks

1 visit (in-person)

Treatment Details

Interventions

• Sotagliflozin
• Volagidemab

Trial Overview The trial is testing Sotagliflozin and Volagidemab to see if they improve blood sugar control, reduce ketone production when insulin is low, decrease insulin resistance, and enhance life quality in Type 1 diabetes patients. It's a double-blind study where neither doctors nor participants know who gets real treatment or placebo.

Participant Groups

Group I: volagidemab 35 mg Active Control 1 Intervention

Each participant will receive 12-week insulin-adjunctive treatment with both: (1) SGLTi (sotagliflozin 200 mg PO each day) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods. Volagidemab is a human monoclonal antibody glucagon receptor antagonist (GRA).

Group II: sotagliflozin 200 mg Active Control 1 Intervention

Each participant will receive 12-week insulin-adjunctive treatment with both: (1) SGLTi (sotagliflozin 200 mg PO each day) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods. Sotagliflozin is a dual sodium-glucose co-transporter-1 and sodium-glucose co-transporter-2 (SGLT1/2) inhibitor.

Group III: Placebo Placebo Group 1 Intervention

Each participant will receive 12-week insulin-adjunctive treatment with both: (1) SGLTi (sotagliflozin 200 mg PO each day) + Placebo and (2) SGLTi + GRA (volagidemab 35 mg subcutaneously each week), in a random-order, cross-over design with a 14-week washout period between treatment periods.

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Juvenile Diabetes Research Foundation

Collaborator

Trials

237

Recruited

142,000+

Lexicon Pharmaceuticals

Industry Sponsor

Trials

67

Recruited

24,400+

Dr. Mike Exton

Lexicon Pharmaceuticals

Chief Executive Officer

PhD in Neuroscience from the University of Newcastle and PhD in Immunology from the University of Essen, Germany

Dr. Craig Granowitz

Lexicon Pharmaceuticals

Chief Medical Officer since 2021

MD

Breakthrough T1D

Collaborator

Trials

3

Recruited

190+

Breakthrough T1D

Collaborator

Findings from Research

Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, significantly improved glycemic control, reduced body weight, and lowered insulin requirements in adults with type 1 diabetes over 24 weeks, with benefits maintained for up to 52 weeks.

The drug is generally well tolerated and does not increase the risk of hypoglycemia, although it does carry a risk of diabetic ketoacidosis, making it a valuable adjunct to insulin therapy for overweight or obese patients with type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotagliflozin: A Review in Type 1 Diabetes. Deeks, ED.[2020]

Sotagliflozin effectively lowers HbA1c levels in patients with type 1 diabetes mellitus (T1DM) without significantly increasing the risk of hypoglycemia, making it a promising option for better glycemic control.

However, the risk of diabetic ketoacidosis is notably higher with sotagliflozin, which means it should only be used in carefully selected patients who are well-informed and closely monitored by their healthcare provider.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An up-to-date evaluation of sotagliflozin for the treatment of type 1 diabetes. Chatzopoulos, G., Tziomalos, K.[2022]

In a pooled analysis of 1575 adults with type 1 diabetes over 52 weeks, the addition of sotagliflozin to optimized insulin significantly improved glycemic control, with participants achieving a mean HbA1c reduction of -0.36% to -0.38% compared to placebo.

Sotagliflozin also enabled a higher proportion of patients to reach HbA1c levels below 7% without weight gain (21.8% for 200 mg and 26.1% for 400 mg) compared to only 9.1% for placebo, although there was an increased risk of diabetic ketoacidosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotagliflozin added to optimized insulin therapy leads to HbA1c reduction without weight gain in adults with type 1 diabetes: A pooled analysis of inTandem1 and inTandem2. Rodbard, HW., Giaccari, A., Lajara, R., et al.[2022]

In a meta-analysis of 9 randomized controlled trials involving 2389 patients, combining GLP-1 receptor agonists with basal insulin significantly reduced HbA1c levels, daily insulin doses, and body weight in individuals with type 1 diabetes mellitus.

While this combined treatment did not increase the risk of severe hypoglycaemia, it was associated with a higher occurrence of gastrointestinal side effects, indicating a trade-off between efficacy and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incretin-based therapies for patients with type 1 diabetes: a meta-analysis. Liu, L., Shao, Z., Xia, Y., et al.[2022]

Sotagliflozin, a dual SGLT 1 and 2 inhibitor, has been shown to significantly reduce HbA1c levels in patients with type 1 diabetes when used alongside optimized insulin therapy, indicating its efficacy as a treatment option.

Despite its benefits, sotagliflozin is associated with a higher risk of diabetic ketoacidosis compared to placebo, which raised safety concerns during the FDA review process, leading to its approval only in the EU for specific patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sotagliflozin: First Global Approval. Markham, A., Keam, SJ.[2020]

In a phase 2 study involving 79 adults with type 1 diabetes, the monoclonal antibody volagidemab showed a significant reduction in hemoglobin A1c (HbA1c) levels compared to placebo, indicating improved glycemic control.

Volagidemab also led to a decrease in daily insulin use without increasing the risk of hypoglycemia, although some side effects like increased serum transaminases and LDL-cholesterol were noted, suggesting a need for further studies on its long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial. Pettus, J., Boeder, SC., Christiansen, MP., et al.[2023]

In a post hoc analysis of pooled phase 3 trials, sotagliflozin (200 mg and 400 mg) significantly reduced glycated hemoglobin levels and body weight in adults with type 1 diabetes and a BMI ≥ 27 kg/m² over 24 weeks, while also increasing time in range for glucose levels compared to placebo.

Sotagliflozin was associated with fewer severe hypoglycemia events and a higher incidence of diabetic ketoacidosis compared to placebo, indicating it can help manage diabetes effectively without significantly increasing the risk of low blood sugar in overweight or obese patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of adding sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1 and SGLT2 inhibitor, to optimized insulin therapy in adults with type 1 diabetes and baseline body mass index ≥ 27 kg/m2. Danne, T., Edelman, S., Frias, JP., et al.[2022]

Sotagliflozin (SOTA) is being evaluated as a potential first oral antidiabetic drug for Type 1 Diabetes Mellitus (T1DM), which traditionally requires insulin treatment.

The systematic review will analyze randomized controlled trials to assess the efficacy and safety of SOTA, aiming to provide strong evidence for its clinical use in T1DM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of sotagliflozin adjuvant therapy for type 1 diabetes mellitus: A protocol for Systematic review and Meta-analysis. Chen, MB., Xu, RJ., Zheng, QH., et al.[2022]

Sotagliflozin (SOTA) significantly improves blood sugar control in type 1 diabetes mellitus (T1DM) patients, as evidenced by lower hemoglobin A1c levels, reduced insulin use, and better glucose management, based on a meta-analysis of 7 randomized controlled trials.

While SOTA is effective, it is associated with increased risks of genital mycotic infections and diabetic ketoacidosis, highlighting the need for careful monitoring of these side effects in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sotagliflozin adjuvant therapy for type 1 diabetes mellitus: A systematic review and meta-analysis. Chen, MB., Xu, RJ., Zheng, QH., et al.[2022]

In a phase 3 trial with 1402 patients, those taking sotagliflozin alongside insulin therapy had a significantly higher rate of achieving a glycated hemoglobin level below 7.0% compared to the placebo group (28.6% vs. 15.2%).

While sotagliflozin improved glycemic control and reduced weight and insulin dosage, it was associated with a higher rate of diabetic ketoacidosis (3.0% vs. 0.6% in the placebo group), indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. Garg, SK., Henry, RR., Banks, P., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Sotagliflozin: A Review in Type 1 Diabetes. [2020]

2. England pubmed.ncbi.nlm.nih.gov

An up-to-date evaluation of sotagliflozin for the treatment of type 1 diabetes. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Sotagliflozin added to optimized insulin therapy leads to HbA1c reduction without weight gain in adults with type 1 diabetes: A pooled analysis of inTandem1 and inTandem2. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Incretin-based therapies for patients with type 1 diabetes: a meta-analysis. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Sotagliflozin: First Global Approval. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of adding sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1 and SGLT2 inhibitor, to optimized insulin therapy in adults with type 1 diabetes and baseline body mass index ≥ 27 kg/m2. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of sotagliflozin adjuvant therapy for type 1 diabetes mellitus: A protocol for Systematic review and Meta-analysis. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sotagliflozin adjuvant therapy for type 1 diabetes mellitus: A systematic review and meta-analysis. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. [2022]