Ambrisentan + Sotagliflozin for Type 1 Diabetes Kidney Protection

(ASPIRE-1 Trial)

Recruiting at 10 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two medications, ambrisentan and sotagliflozin, to determine if they can jointly protect kidney health in people with Type 1 Diabetes. Researchers aim to discover if these drugs can reduce kidney damage and other complications. The trial seeks participants who have had Type 1 Diabetes for at least six months and manage their condition with regular insulin and blood sugar monitoring. Participants will try different combinations of the medications over several weeks. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ambrisentan and sotagliflozin are generally safe for use. Studies on ambrisentan have demonstrated its ability to protect kidneys with few side effects, though some individuals might experience swelling or a stuffy nose.

Sotagliflozin has also undergone safety testing. Research on individuals with type 1 diabetes found it to be safe, with most participants tolerating it well. However, like any medication, it can cause side effects such as diarrhea or urinary tract infections, which are usually mild.

Both treatments have been tested alone and in various combinations, indicating their safety for further research. This trial will examine how they work together to enhance kidney protection while monitoring for any new side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Ambrisentan and Sotagliflozin for kidney protection in Type 1 Diabetes because these treatments offer a fresh approach to managing the condition. Unlike current treatments that primarily focus on controlling blood sugar levels, Sotagliflozin, an SGLT1 and SGLT2 inhibitor, has the potential to improve kidney function by reducing glucose reabsorption and promoting glucose excretion. Ambrisentan, on the other hand, is an endothelin receptor antagonist, which may help in reducing kidney damage by improving blood flow and reducing inflammation. This dual approach not only aims to manage blood sugar but also directly targets kidney health, offering hope for better outcomes in diabetic kidney disease.

What evidence suggests that this trial's treatments could be effective for Type 1 Diabetes?

Research has shown that ambrisentan, a type of medication, may help protect the kidneys. It reduced kidney damage in animal studies. Other studies have found that sotagliflozin can slow kidney function decline in people with type 1 diabetes. It also stabilizes blood pressure and lowers the risk of heart problems. This trial will examine the combined effects of these two treatments to determine if they offer better protection against kidney issues in type 1 diabetes by working in different ways in the body. ^{2 4 5 6 7}

Who Is on the Research Team?

Hiddo J Lambers Heerspink, PhD, PharmD

Principal Investigator

University Medical Center Groningen

Are You a Good Fit for This Trial?

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

Your HbA1c level is between 6.5% and 10.5%.

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Treatment order 6 Experimental Treatment 3 Interventions

Subjects will start with 4 weeks of a combination of SC0062 and dapagliflozin in period 1. In period 2 subjects will receive dapagliflozin. In period 3 subjects will receive SC0062. 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 SC0062 and dapagliflozin in period 1. In period 2 subjects will receive SC0062. In period 3 subjects will receive dapagliflozin. 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 dapagliflozin in treatment period 1. In period 2 subjects will receive SC0062. In period 3 subjects will receive a combination of SC0062 and dapagliflozin. 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 dapagliflozin in treatment period 1. In period 2 subjects will receive a combination of SC0062 and dapagliflozin. In period 3 subjects will receive SC0062. 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 SC0062 in treatment period 1. In period 2 subjects will receive a combination of SC0062 and dapagliflozin. In period 3 subjects will receive dapagliflozin. 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 SC0062 in treatment period 1. In period 2 subjects will receive dapagliflozin. In period 3 subjects will receive a combination of SC0062 and dapagliflozin. 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+

Biocity Biopharmaceutics Co., Ltd.

Industry Sponsor

Trials

9

Recruited

1,100+

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

Published Research Related to This Trial

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]

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 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]

Citations

1. mdpi.com mdpi.com/1422-0067/24/4/3427

Endothelin Receptor Antagonists in Kidney Disease Ambrisentan (an ETA receptor antagonist, Table 2) and bosentan showed similar kidney protective effects in an ischemia-reperfusion rat model in terms of ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10100079/

Endothelin receptor antagonists in kidney protection for ... This review will provide an detailed review of the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety ...

3. researchgate.net researchgate.net/figure/Outcomes-of-clinical-studies-on-the-efficacy-of-ambrisentan-in-patients-with-PAH-overall_tbl2_280241044

Outcomes of clinical studies on the efficacy of ambrisentan ... ... improvements in 6MWD were observed after 2 and 3 years of treatment with both approved dosages of ambrisentan in ARIES-E, the large (N ¼ 383) ...

4. withpower.com withpower.com/clinical-trials/for-diabetic-kidney-disease

Top Diabetic Kidney Disease Clinical Trials | Power The estimated lifetime risk of kidney disease in persons with type 1 diabetes (T1D) has been reported to be as high as 50-70%, although risk may be lower in ...

5. researchgate.net researchgate.net/figure/Outcomes-of-clinical-studies-on-the-efficacy-of-ambrisentan-as-part-of-combination_tbl3_280241044

Outcomes of clinical studies on the efficacy of ambrisentan ... An ongoing clinical trial (NCT06072326) aims to investigate whether combining ambrisentan with sotagliflozin (an SGLT1/2 inhibitor) enhances renal protection ...

6. breakthrought1d.org breakthrought1d.org/grants/netherlands/groningen/ambrisentan-and-sotagliflozin-for-prevention-of-renal-injury-a-randomized-evaluation-aspireaspire/

Ambrisentan and Sotagliflozin for Prevention of renal Injury The goals of this research are first, to find out if sotagliflozin and ambrisentan slow the progression of kidney disease in people with type 1 diabetes, and ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11272963/

Prevalence of Chronic Kidney Disease in Type 1 Diabetes ... Based on data between 2015 and 2018, type 1 diabetes was identified in 47 out of 19,225 adults with evaluable kidney function data. CKD was present in 20 ...