Ambrisentan Sotagliflozin and Prevention of Renal Injury; a Randomized Evaluation

Type 1 Diabetes Mellitus With Diabetic Nephropathy Clinical Trial

— ASPIRE  

Official title:

Individual and Combined Endothelin Receptor and SGLT1/2 Antagonism in Adults With Type 1 Diabetes Mellitus and Chronic Kidney Disease: a Phase 2, Multicenter, Open-label Randomized Cross-over Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06072326
• Other study ID #: 17042
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: March 2024
• Est. completion date: March 2025

Study information

• Verified date: October 2023
• Source: University Medical Center Groningen
• Contact: Hiddo J Lambers Heerspink, Phd, PharmD
• Phone: +31-50-3617859
• Email: h.j.lambers.heerspink[@]umcg.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

A phase 2, multicenter, randomized, open-label, cross-over trial will be conducted in male or female individuals (N=36) diagnosed with type 1 diabetes at least 6 months prior to informed consent aged between 18 and 65 years, Body Mass Index (BMI) ≥ 21 kg/m2, urinary albumin:creatinine ratio ≥ 50 mg/g and < 3000 mg/g, eGFR > 30 and <90 ml/min/1.73m2 and HbA1c between 6.5 and 10.0%. Patients have to be on stable RAAS inhibition for at least 4 weeks prior to screening.

The study will consist of a screening visit, a 4-week run-in phase. After the run-in phase, the participant will be randomized to treatment of ambrisentan, sotagliflozin or their combination in random order. The duration of each treatment period is 4 weeks with study visits scheduled at 2 and 4 weeks in each treatment period. At the end of each treatment period patients proceed to a 4 weeks wash-out phase to study off drug effects. The total duration of the study for each participant after randomization is thus 24 weeks

Interventions Ambrisentan 2.5 mg once daily; sotagliflozin 200mg once daily; combination of ambrisentan 2.5mg once daily and sotagliflozin 200mg once daily

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 36
• Est. completion date: March 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Willing and able to sign informed consent

• Male or female individuals diagnosed with type 1 diabetes at least 6 months prior to informed consent

• WOCBP must have a negative pregnancy test at screening and must not be lactating.

• Male individuals must use highly effective method of contraception for the duration of the study (from the time they sign consent) and for 4 weeks after the last dose of study medication, or be able to provide proof of vasectomy.

• Female individuals must use highly effective method of contraception for the duration of the study (from the time they sign consent) and for 4 weeks after the last dose of study medication, provide proof of hysterectomy or sterilization, or be deemed menopausal based on a FSH-test.

• Age =18 and <65years, at the time of signing consent.

• Body Mass Index = 21 kg/m2

• Urinary albumin:creatinine ratio = 50 mg/g and <3000 mg/g

• eGFR > 30 and <90 ml/min/1.73m2

• Stable RAAS inhibition medication for at least 4 weeks prior to screening

• HbA1c between 6.5 and 10.5%

• Based on the Investigator's judgment participant must have a good understanding of his/her disease and how to manage it, and be willing and capable of performing the following study assessments (assessed before randomization):

• patient-led management and adjustment of insulin therapy

• reliable approach to insulin dose adjustment for meals, such as carbohydrate counting

• reliable and regular home-based blood glucose monitoring

• established "sick day" management regimen

Exclusion Criteria:

• Diagnosis of type 2 diabetes

• Treatment with an antihyperglycaemic agent (e.g., metformin, alpha-glucosidase inhibitors, pramlintide, glucagon-like peptide receptor agonist, etc.) within 3 months

• Occurrence of severe hypoglycaemia involving coma/unconsciousness and/or seizure that required hospitalisation or hypoglycaemia-related treatment by an emergency physician or paramedic within 3 months

• Hypoglycaemia unawareness based on Investigator judgement or frequent episodes of unexplained hypoglycaemia (2 or more unexplained episodes within 3 months)

• Occurrence of diabetic ketoacidosis within 6 months prior to study enrolment

• Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or transient ischemic attack within 6 months

• Any other clinical condition that, based on Investigator's judgement, would jeopardize patient safety during trial participation or would affect the study outcome (e.g., immunocompromised patients, patients who might be at higher risk of developing urinary, genital or mycotic infections, patients with chronic viral infections, etc.)

• Treatment with an SGLT2i within 30 days of Visit 1

• Diagnosis of severe edema (per investigator judgment) or heart failure (NYHC stage III or IV)

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Diabetic Nephropathies
• Type 1 Diabetes Mellitus With Diabetic Nephropathy

Intervention

Drug:
• Sotagliflozin
200 mg/day as a tablet
• Ambrisentan
2.5 mg/day as a tablet
• Ambrisentan and Sotagliflozin
2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet

Locations

Country	Name	City	State
Canada	Institute de Recherches Cliniques de Montreal	Montréal	Quebec
Canada	University of Toronto	Toronto
Denmark	Steno Diabetes Center Copenhagen	Copenhagen
Finland	University of Helsinki	Helsinki	Uusimaa
Netherlands	Amsterdam University Academic Center	Amsterdam	Noord Holland
Netherlands	University Medical Center Groningen	Groningen
United States	University of Colorado, Anschutz Medical Center	Aurora	Colorado

Sponsors (3)

Lead Sponsor	Collaborator
University Medical Center Groningen	Juvenile Diabetes Research Foundation, Lexicon Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  Finland,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	change from baseline in Urine Albumin-Creatinine Ratio (UACR)	change from baseline in Urine Albumin-Creatinine Ratio (UACR) when treated with ambrisentan alone versus combination of sotagliflozin and ambrisentan.	4 weeks
Secondary	change from baseline in mGFR	Glomerular Filtration Rate (GFR) using iohexol clearance techniques.	4 weeks
Secondary	Change in biomarkers of fluid retention	Change from baseline biomarkers of fluid retention (body weight, hemoglobin, N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP))	4 weeks
Secondary	Change in biomarkers of fluid retention	Change from baseline biomarkers of fluid retention (Body Weight)	4 weeks
Secondary	Change in biomarkers of fluid retention	Change from baseline biomarkers of fluid retention (hemoglobin)	4 weeks
Secondary	Change in biomarkers of fluid retention	Change from baseline biomarkers of fluid retention (N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP))	4 weeks
Secondary	Change from baseline Extracellular Volume (ECV)	Extracellular volume (ECV) using iohexol clearance techniques and bioimpedance spectroscopy.	4 weeks
Secondary	Change from baseline blood pressure	Change in blood pressure as measure in mmHg	4 weeks