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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Type 1 Diabetes Mellitus With Diabetic Nephropathy
• Intervention / Treatment: Drug: Sotagliflozin; Drug: Ambrisentan; Drug: Ambrisentan and Sotagliflozin

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 Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hiddo J Lambers Heerspink, Phd, PharmD; Phone Number: +31-50-3617859; Email: h.j.lambers.heerspink@umcg.nl

Study Locations

• Canada
  • Toronto, Canada, M5G 2N2
    • University of Toronto
    • Contact: David Cherney, MDCM, PhD
  • Quebec
    • Montréal, Quebec, Canada, H2W IR7
      • Institute de Recherches Cliniques de Montreal
• Denmark
  • Copenhagen, Denmark, 2730 Herlev
    • Steno Diabetes Center Copenhagen
    • Contact: Frederik Persson, MD DMSc
• Finland
  • Uusimaa
    • Helsinki, Uusimaa, Finland, 00029 HUS
      • University of Helsinki
      • Contact: Daniel Gordin, MD DMSc
• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen
    • Contact: Peter R van Dijk, MD, PhD
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1081 HV
      • Amsterdam University Academic Center
      • Contact: Daniel van Raalte, MD
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado, Anschutz Medical Center
      • Contact: Petter Bjornstad, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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

What is the study measuring?

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 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
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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Juvenile Diabetes Research Foundation; Lexicon Pharmaceuticals
• Investigators: Principal Investigator: Hiddo J Lambers Heerspink, PhD, PharmD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: October 2, 2023
• First Submitted That Met QC Criteria: October 2, 2023
• First Posted (Actual): October 10, 2023

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 20, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: combination therapy; Type 1 Diabetes; Diabetic kidney disease; endothelin receptor antagonists; sodium glucose co-transporter 2 inhibitors
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Sodium-Glucose Transporter 2 Inhibitors; (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol; Ambrisentan
• Other Study ID Numbers: 17042

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No