Ambrisentan Sotagliflozin and Prevention of Renal Injury; a Randomized Evaluation

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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

Conditions
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Type 1 Diabetes Mellitus With Diabetic Nephropathy

Intervention / Treatment
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* Drug: Sotagliflozin
* Drug: Ambrisentan
* Drug: Ambrisentan and Sotagliflozin


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Multicenter, open-label randomized cross-over trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment order 1<br>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<br>* 200 mg/day as a tablet<br>Drug: Ambrisentan<br>* 2.5 mg/day as a tablet<br>Drug: Ambrisentan and Sotagliflozin<br>* 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet<br>|
| Experimental: Treatment order 2<br>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<br>* 200 mg/day as a tablet<br>Drug: Ambrisentan<br>* 2.5 mg/day as a tablet<br>Drug: Ambrisentan and Sotagliflozin<br>* 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet<br>|
| Experimental: Treatment order 3<br>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<br>* 200 mg/day as a tablet<br>Drug: Ambrisentan<br>* 2.5 mg/day as a tablet<br>Drug: Ambrisentan and Sotagliflozin<br>* 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet<br>|
| Experimental: Treatment order 4<br>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<br>* 200 mg/day as a tablet<br>Drug: Ambrisentan<br>* 2.5 mg/day as a tablet<br>Drug: Ambrisentan and Sotagliflozin<br>* 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet<br>|
| Experimental: Treatment order 5<br>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<br>* 200 mg/day as a tablet<br>Drug: Ambrisentan<br>* 2.5 mg/day as a tablet<br>Drug: Ambrisentan and Sotagliflozin<br>* 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet<br>|
| Experimental: Treatment order 6<br>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<br>* 200 mg/day as a tablet<br>Drug: Ambrisentan<br>* 2.5 mg/day as a tablet<br>Drug: Ambrisentan and Sotagliflozin<br>* 2.5 mg/day Ambrisentan as a tablet in combination with 200 mg/day Sotagliflozin as a tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change from baseline in mGFR | Glomerular Filtration Rate (GFR) using iohexol clearance techniques. | 4 weeks | 
| 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 | 
| Change in biomarkers of fluid retention | Change from baseline biomarkers of fluid retention (Body Weight) | 4 weeks | 
| Change in biomarkers of fluid retention | Change from baseline biomarkers of fluid retention (hemoglobin) | 4 weeks | 
| Change in biomarkers of fluid retention | Change from baseline biomarkers of fluid retention (N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP)) | 4 weeks | 
| Change from baseline Extracellular Volume (ECV) | Extracellular volume (ECV) using iohexol clearance techniques and bioimpedance spectroscopy. | 4 weeks | 
| Change from baseline blood pressure | Change in blood pressure as measure in mmHg | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic kidney disease, sodium glucose co-transporter 2 inhibitors, endothelin receptor antagonists, Type 1 Diabetes, combination therapy