ASPIRE: Ambrisentan Sotagliflozin and Prevention of Renal Injury; a Randomized Evaluation

Sponsor

University Medical Center Groningen (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06072326

Collaborator

Juvenile Diabetes Research Foundation (Other), Lexicon Pharmaceuticals (Industry)

Enrollment

Locations

Arms

Anticipated Duration (Months)

5.1

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus With Diabetic Nephropathy	Drug: Sotagliflozin Drug: Ambrisentan Drug: Ambrisentan and Sotagliflozin	Phase 2

Detailed 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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Multicenter, open-label randomized cross-over trialMulticenter, open-label randomized cross-over trial

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Mar 1, 2024

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment order 1 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.	Drug: Sotagliflozin 200 mg/day as a tablet Drug: Ambrisentan 2.5 mg/day as a tablet Drug: Ambrisentan and Sotagliflozin 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet
Experimental: Treatment order 2 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.	Drug: Sotagliflozin 200 mg/day as a tablet Drug: Ambrisentan 2.5 mg/day as a tablet Drug: Ambrisentan and Sotagliflozin 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet
Experimental: Treatment order 3 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.	Drug: Sotagliflozin 200 mg/day as a tablet Drug: Ambrisentan 2.5 mg/day as a tablet Drug: Ambrisentan and Sotagliflozin 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet
Experimental: Treatment order 4 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.	Drug: Sotagliflozin 200 mg/day as a tablet Drug: Ambrisentan 2.5 mg/day as a tablet Drug: Ambrisentan and Sotagliflozin 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet
Experimental: Treatment order 5 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.	Drug: Sotagliflozin 200 mg/day as a tablet Drug: Ambrisentan 2.5 mg/day as a tablet Drug: Ambrisentan and Sotagliflozin 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet
Experimental: Treatment order 6 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.	Drug: Sotagliflozin 200 mg/day as a tablet Drug: Ambrisentan 2.5 mg/day as a tablet Drug: Ambrisentan and Sotagliflozin 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet

Outcome Measures

Primary Outcome Measures

change from baseline in Urine Albumin-Creatinine Ratio (UACR) [4 weeks]
change from baseline in Urine Albumin-Creatinine Ratio (UACR) when treated with ambrisentan alone versus combination of sotagliflozin and ambrisentan.

Secondary Outcome Measures

change from baseline in mGFR [4 weeks]
Glomerular Filtration Rate (GFR) using iohexol clearance techniques.
Change in biomarkers of fluid retention [4 weeks]
Change from baseline biomarkers of fluid retention (body weight, hemoglobin, N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP))
Change from baseline Extracellular Volume (ECV) [4 weeks]
Extracellular volume (ECV) using iohexol clearance techniques and bioimpedance spectroscopy.
Change from baseline blood pressure [4 weeks]
Change in blood pressure as measure in mmHg

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado, Anschutz Medical Center	Aurora	Colorado	United States	80045
2	Institute de Recherches Cliniques de Montreal	Montréal	Quebec	Canada	H2W IR7
3	University of Toronto	Toronto		Canada	M5G 2N2
4	Steno Diabetes Center Copenhagen	Copenhagen		Denmark	2730 Herlev
5	University of Helsinki	Helsinki	Uusimaa	Finland	00029 HUS
6	Amsterdam University Academic Center	Amsterdam	Noord Holland	Netherlands	1081 HV
7	University Medical Center Groningen	Groningen		Netherlands	9700 RB