Type 1 Diabetes Mellitus With Diabetic Nephropathy
Conditions
Keywords
Diabetic kidney disease, sodium glucose co-transporter 2 inhibitors, endothelin receptor antagonists, Type 1 Diabetes, combination therapy
Brief summary
The aim of this study is to test the hypothesis that dapagliflozin (SGLT2 inhibitor) and SC0062 (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/1.73 m2 and HbA1c \> 6.5 and \<10.5%. 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 SC0062, dapagliflozin, 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 SC0062 10mg twice daily (20mg/day); dapagliflozin 5mg once daily; combination of SC0062 10mg twice daily and dapagliflozin 5mg once daily.
Interventions
5 mg/day as a tablet
20 mg/day, twice daily, capsule
DRUGSC0062 and dapagliflozin
20 mg/day SC0062 10 mg twice daily as a capsule in combination with 5 mg/day dapagliflozin 5 mg as a tablet
Sponsors
Juvenile Diabetes Research Foundation
Biocity Biopharmaceutics Co., Ltd.
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Multicenter, open-label randomized cross-over trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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 ≥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, or other types of diabetes (e.g. LADA). * Treatment with an anti-hyperglycaemic 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. * NT-proBNP \> 600 pg/mL * Hemoglobin \< 90 g/L * Diagnosis of severe edema (per investigator judgment) within 3 months of screening * Diagnosis of heart failure (NYHC stage III or IV).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in Urine Albumin-Creatinine Ratio (UACR) | 4 weeks | Primary: change from baseline in Urine Albumin-Creatinine Ratio (UACR) when treated with SC0062 alone versus combination of dapagliflozin and SC0062. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Denmark, Finland, Netherlands
Contacts
Primary ContactHiddo J Lambers Heerspink, Phd, PharmD
Outcome results
None listed