Ambrisentan + Sotagliflozin for Type 1 Diabetes Kidney Protection

(ASPIRE Trial)

Recruiting at 6 trial locations

Overseen By Hiddo J Lambers Heerspink, Phd, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Medical Center Groningen

Must be taking: RAAS inhibitors

Must not be taking: Antihyperglycemics, SGLT2 inhibitors

Disqualifiers: Type 2 diabetes, Severe hypoglycemia, Ketoacidosis, Coronary syndrome, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

36 Participants Needed

Trial Summary

What is the purpose of this trial?

The aim of this study is to test the hypothesis that sotagliflozin (SGLT1/2 inhibitor) and ambrisentan (ERA) combination therapy augments nephroprotection and mitigates fluid retention and ketogenesis in people with T1D through complementary and synergistic mechanisms of actions.

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

The trial requires that you have been on stable RAAS inhibition medication for at least 4 weeks before screening. You should not have been treated with an SGLT2 inhibitor within 30 days of the first visit or with any antihyperglycaemic agents like metformin within 3 months.

What data supports the effectiveness of the drug Ambrisentan + Sotagliflozin for Type 1 Diabetes Kidney Protection?

Sotagliflozin, one of the drugs in the treatment, has been shown to improve blood sugar control and reduce body weight in people with type 1 diabetes when used alongside insulin. It also has potential benefits for kidney health, as it may decrease the risk of further kidney issues in patients with diabetes. ^{1 2 3 4 5}

Is the combination of Ambrisentan and Sotagliflozin safe for humans?

Sotagliflozin is generally well tolerated in humans, but it carries a risk of diabetic ketoacidosis (a serious diabetes complication where the body produces excess blood acids) when used with insulin in type 1 diabetes. There is no specific safety data available for the combination of Ambrisentan and Sotagliflozin. ^{1 3 4 5 6}

What makes the drug Ambrisentan + Sotagliflozin unique for type 1 diabetes kidney protection?

This drug combination is unique because it combines sotagliflozin, a dual inhibitor that targets both SGLT1 and SGLT2 to improve blood sugar control and reduce insulin needs, with ambrisentan, which may offer additional kidney protection. This approach is novel as it leverages different mechanisms to potentially enhance kidney protection in type 1 diabetes. ^{1 3 4 5 7}

Research Team

Hiddo J Lambers Heerspink, PhD, PharmD

Principal Investigator

University Medical Center Groningen

Eligibility Criteria

This trial is for adults aged 18-65 with Type 1 Diabetes and diabetic kidney disease, who are not pregnant or lactating, can use effective contraception, have a stable medication regimen, and understand their condition. They must have specific levels of albumin in urine and kidney function. Those with recent severe hypoglycemia, heart issues, edema or other conditions that could affect safety/outcomes cannot join.

Inclusion Criteria

You must have a body mass index of 21 or higher.

Your HbA1c level is between 6.5% and 10.5%.

I am willing and able to follow the study's required procedures.

Exclusion Criteria

I have been diagnosed with type 2 diabetes.

I have taken medication for high blood sugar in the last 3 months.

I often have low blood sugar without noticing.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

Participants undergo a 4-week run-in phase before randomization

4 weeks

Treatment Period 1

Participants receive either Ambrisentan, Sotagliflozin, or their combination for 4 weeks

4 weeks

2 visits (in-person)

Wash-out

Participants undergo a 4-week wash-out phase to study off-drug effects

4 weeks

Treatment Period 2

Participants receive a different treatment from period 1 for 4 weeks

4 weeks

2 visits (in-person)

Wash-out

Participants undergo a 4-week wash-out phase to study off-drug effects

4 weeks

Treatment Period 3

Participants receive the remaining treatment option for 4 weeks

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ambrisentan
• Sotagliflozin

Trial Overview The study tests if combining Sotagliflozin (a drug reducing sugar absorption) with Ambrisentan (which widens blood vessels) provides better protection against kidney damage in Type 1 Diabetics without causing fluid retention or increased ketone production compared to each drug alone.

Participant Groups

Group I: Treatment order 6 Experimental Treatment 3 Interventions

Subjects will start with 4 weeks of a combination of Ambrisentan and Sotagliflozin in period 1. In period 2 subjects will receive Sotagliflozin. In period 3 subjects will receive Ambrisentan. Between treatment periods there is a 4-week wash-out.

Group II: Treatment order 5 Experimental Treatment 3 Interventions

Subjects will start with 4 weeks of a combination of Ambrisentan and Sotagliflozin in period 1. In period 2 subjects will receive Ambrisentan. In period 3 subjects will receive Sotagliflozin. Between treatment periods there is a 4-week wash-out.

Group III: Treatment order 4 Experimental Treatment 3 Interventions

Subjects will start with 4 weeks of Sotagliflozine in treatment period 1. In period 2 subjects will receive Ambrisentan. In period 3 subjects will receive a combination of Ambrisentan and Sotagliflozin. Between treatment periods there is a 4-week wash-out.

Group IV: Treatment order 3 Experimental Treatment 3 Interventions

Subjects will start with 4 weeks of Sotagliflozine in treatment period 1. In period 2 subjects will receive a combination of Ambrisentan and Sotagliflozine. In period 3 subjects will receive Ambrisentan. Between treatment periods there is a 4-week wash-out.

Group V: Treatment order 2 Experimental Treatment 3 Interventions

Subjects will start with 4 weeks of Ambrisentan in treatment period 1. In period 2 subjects will receive a combination of Ambrisentan and Sotagliflozin. In period 3 subjects will receive Sotagliflozin. Between treatment periods there is a 4-week wash-out.

Group VI: Treatment order 1 Experimental Treatment 3 Interventions

Subjects will start with 4 weeks of Ambrisentan in treatment period 1. In period 2 subjects will receive Sotagliflozin. In period 3 subjects will receive a combination of Ambrisentan and Sotagliflozin. Between treatment periods there is a 4-week wash-out.

Who Is Running the Clinical Trial?

University Medical Center Groningen

Lead Sponsor

Trials

770

Recruited

1,101,000+

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

Findings from Research

Sotagliflozin, a new medication for diabetes, was found to be safe for renal function, showing no significant adverse effects on kidney health in a review of 14 studies involving 17,574 participants, including those with existing renal impairment.

The drug did not significantly change urinary albumin excretion or the risk of composite renal events, indicating that while it is safe, more research is needed to fully understand its effectiveness in preventing diabetic kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of the dual sodium-glucose co-transporter-1 and -2 inhibitor sotagliflozin on renal outcomes in type 1 diabetes and type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. Bantounou, MA., Sardellis, P., Thuemmler, R., et al.[2023]

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, 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, 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Effect of the dual sodium-glucose co-transporter-1 and -2 inhibitor sotagliflozin on renal outcomes in type 1 diabetes and type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. [2023]

2. 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]

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

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

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

Sotagliflozin: First Global Approval. [2020]

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

Sotagliflozin improves glycemic control in nonobese diabetes-prone mice with type 1 diabetes. [2020]

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

Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American inTandem1 Study. [2022]

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

Efficacy and safety of zibotentan and dapagliflozin in patients with chronic kidney disease: study design and baseline characteristics of the ZENITH-CKD trial. [2023]