Clinical trial NCT06072326: Ambrisentan Sotagliflozin and Prevention of Renal Injury; a Randomized Evaluation
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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus With Diabetic Nephropathy
Keywords: Diabetic kidney disease
sodium glucose co-transporter 2 inhibitors
endothelin receptor antagonists
Type 1 Diabetes
combination therapy
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
name: Lexicon Pharmaceuticals
First posted: 2023-10-10
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Multicenter, open-label randomized cross-over trial
Primary purpose: TREATMENT

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.

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

Eligibility criteria: 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)

Primary outcomes:
measure: change from baseline in Urine Albumin-Creatinine Ratio (UACR)
timeFrame: 4 weeks
Secondary outcomes:
measure: change from baseline in mGFR
timeFrame: 4 weeks
measure: Change in biomarkers of fluid retention
timeFrame: 4 weeks
measure: Change in biomarkers of fluid retention
timeFrame: 4 weeks
measure: Change in biomarkers of fluid retention
timeFrame: 4 weeks
measure: Change in biomarkers of fluid retention
timeFrame: 4 weeks
measure: Change from baseline Extracellular Volume (ECV)
timeFrame: 4 weeks
measure: Change from baseline blood pressure
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado, Anschutz Medical Center
state: Colorado
city: Montréal
country: Canada
facility: Institute de Recherches Cliniques de Montreal
state: Quebec
city: Toronto
country: Canada
facility: University of Toronto
city: Copenhagen
country: Denmark
facility: Steno Diabetes Center Copenhagen
city: Helsinki
country: Finland
facility: University of Helsinki
state: Uusimaa
city: Amsterdam
country: Netherlands
facility: Amsterdam University Academic Center
state: Noord Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: University Medical Center Groningen
name: Hiddo J Lambers Heerspink, PhD, PharmD
role: PRINCIPAL_INVESTIGATOR
References: