Cardio-renal Vascular Function and Failure, Diabetic Chronic Kidney Disease, T1D Heart Failure, Type 1 Diabetes
Conditions
Keywords
Type 1 Diabetes, T1D, DKD, Heart Failure, Platform Trial
Brief summary
Breakthrough T1D has awarded support for a joint University of Michigan-Oregon Health & Science University Center of Excellence (CoE) to address cardio-renal complications in T1D. The overarching hypothesis of the CoE is that individuals with T1D have unique endophenotypes determining their progression towards cardio-renal end organ damage. Defining the underlying molecular programs in T1D endophenotypes provides the rationale for testing existing or new drug candidates in mechanistic trials targeting T1D cardio-renal complications by matching endophenotypes to targeted therapies.
Detailed description
This is a multicenter, open label pilot platform study to evaluate the impact of allocating patients with T1D and early signs of HF/DKD to targeted therapies based on their disease pathway activation signatures. The hypothesis is that stratifying T1D patients by molecularly-defined endophenotypes enables the use of targeted therapies that can more effectively prevent or slow cardio-renal complications. There is no randomized allocation to treatment arms; rather, the eligible participant's clinical and biomarker data will be reviewed by the Molecular T1D Board which will adjudicate each participant to a treatment arm based on their based on their disease pathway activation signatures. Activation of different treatment arms may be initiated at different time points during the study. The following sections describe the master protocol, outlining the requirements across all treatment arms, including the study-wide inclusion and exclusion criteria and study-wide procedures. Appendix A outlines any treatment arm/investigational agent specific information, including defining additional treatment-specific eligibility criteria and required study procedures. The study schema can be found in Section 1.2 and the Schedule of Activities (SoA) in Section 1.3. Potential participants will undergo a two-part consent and screening process. The initial consent and screening visit will be limited to activities necessary for assessment by the Molecular T1D Board. Following review by the Molecular T1D Board, participants will be adjudicated to one treatment arm. At this time, participants will undergo the second consent and screening step, which will include information about specific requirements for their assigned investigational arm and, if in agreement, a complete eligibility assessment via a full screening visit. If the participant is deemed eligible, they will be notified and investigational product will be mailed to them directly. The screening visit results will also serve as the baseline results provided the first dose of study drug is taken within 14 (target) to 21 (limit) days of the screening visit. If more than 21 days, a retest of all laboratory measures will be performed. Participants will receive open label treatment for 26 weeks, with planned study visits at weeks 2, 6, 12, 26, and 30. The total study duration of participation will be up to 36 weeks, inclusive of the screening period. Active study participation will conclude at Week 30 visit. Following completion of active study participation, participants will enter a passive follow-up period during which the study team may collect information on vital status, survival, hospitalizations, and other relevant clinical outcomes through review of medical records and other authorized data sources for up to 12 months after study participation ended. No additional protocol-required visits, procedures, or interventions will be conducted during the passive follow-up period. Participants will be enrolled in this study at Oregon Health & Science University and the University of Michigan. The currently planned number of study arms is three, with 15-19 participants enrolled in each arm. The study sponsors will have the option to increase the number of study arms and potential targeted therapies, which would be documented in the appendices and this master protocol.
Interventions
DRUGFinerenone
Each treatment arm will be a different unique drug. There will be no crossing over of participants between arms. Each participant that is adjudicated to their treatment arm will remain on that arm for the duration of the study through study completion.
DRUGSotagliflozin
Each treatment arm will be a different unique drug. There will be no crossing over of participants between arms. Each participant that is adjudicated to their treatment arm will remain on that arm for the duration of the study through study completion.
Sponsors
Oregon Health and Science University
University of Michigan
Breakthrough T1D
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A platform for personalized medicine where study participants will be assigned to specific treatment arms matched by their unique biomarker profiles.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of T1D, defined as hyperglycemia requiring treatment with insulin within one year from diagnosis or, if the onset was after age 35 years, documentation of the presence of hyperglycemia and one or more of the following: 1. presence of circulating T1D-associated autoantibodies, or 2. history of hospitalization for diabetic ketoacidosis, or 3. documented plasma C-peptide below the limit of detection with standard assay (with concurrent blood glucose \>100 mg/dL) 2. Aged 18-75 years, inclusive 3. T1D duration \>10 years 4. HbA1c: 7-10% 5. Meets one of the following, either 1. UACR \> 30 mg/dl with eGFR ≥ 60mL/min/1.73 m2 and receiving standard of care therapy for early DKD Stage 2, including renin angiotensin system blockade (RASB), unless contraindicated or not tolerated, or 2. Early (Stage B HF) defined as NT-proBNP ≥125 pg/mL 6. Willing and able to adhere to schedule of activities and protocol requirements, including written informed consent
Exclusion criteria
1. Diagnosis of Type 2 diabetes or monogenic forms of diabetes or diabetes secondary to pancreatic disease 2. Use of any active platform treatment arms outside study assignment within 2 months prior to screening. See Appendix A for active treatment arms 3. Current use of GLP-1 receptor agonists or other non-glucose lowering agent 4. Use of aldosterone inhibitors within 2 months prior to screening 5. Immunosuppressive medications within 3 months prior to screening 6. Systolic BP\>160 or diastolic BP \>95 mmHg at screening 7. History of ≥3 severe hypoglycemic events requiring third-party assistance for correction within 3 months prior to screening 8. Evidence of any episode of DKA or non-ketotic hyperosmolar state within 12 months prior to screening 9. Serum potassium \> 5.0 mmol/L at screening 10. Absolute neutrophil count \< 2.0 × 109 per L at screening 11. Platelet count \< 120 × 109 per L at screening 12. Known active tuberculosis, hepatitis B or C at screening, or history of HIV 13. Current or past history of decompensated cirrhosis (defined as variceal bleeding, ascites or hepatic encephalopathy), and/or known diagnosis of cirrhosis based on liver biopsy, imaging, or elastography, and/or AST or ALT \>2 times upper limit of normal, and/or total bilirubin \>1.3 times upper limit of normal at screening 14. History of severe acquired immune deficiency syndrome or severely immunocompromised status in the opinion of the study site investigator 15. History of biopsy-proven non-diabetic CKD 16. History of any other cause of HF (viral, congenital, valvular) 17. History of heart or renal transplant or currently on chronic dialysis 18. Cancer treatment, excluding non-melanoma skin cancer treated by excision, carcinoma in situ of the cervix or uterus, ductal breast cancer in situ, resected non-metastatic breast or prostate cancer, within one year prior to screening 19. Illicit drug abuse within 6 months prior to screening in the opinion of the study site investigator 20. Current heavy alcohol use (for men, ≥5 drinks on any day or ≥15 drinks per week; for women, ≥4 drinks on any day or ≥8 drinks per week) 21. Participation in another interventional clinical research study within 30 days prior to screening 22. Breastfeeding, pregnancy, or unwillingness to be on contraception during the trial 23. Presence of a clinically significant medical history, physical examination, laboratory finding or other identified study site investigator concern that may interfere with any aspect of study conduct or interpretation of results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Markers of Renal Health [Safety and Tolerability] | 26 weeks | The primary efficacy endpoints are measures of early (week 26) outcomes on markers of renal health, defined as the percent change from baseline to week 26 in UACR. |
| Markes of Cardio Health [Safety and Tolerability] | 26 weeks | The primary efficacy endpoints are measures of early (week 26) outcomes on markers of cardio health as defined by the percent change from baseline to week 26 in NT-proBNP. |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | 26 weeks | The primary safety endpoints are defined as incidence of serious adverse events, adverse events and clinically significant abnormal laboratory tests. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immediate Outcomes of Renal Health (week 6) | 20 weeks | The secondary endpoints are measures of immediate outcomes on markers of renal health as defined by changes from baseline to week 6 in UACR. |
| Immediate Outcomes of Cardio Health (week 6) | 20 weeks | The secondary endpoints are measures of immediate outcomes on markers of cardio health as defined by changes from baseline to week 6 in NT-proBNP. |
| Immediate (week 6) and Early (week 26) Outcomes of Nephron Function Failure | 26 weeks | The secondary endpoints are measures of immediate outcomes on markers of renal function failure as defined by changes from baseline to week 6 and from baseline to week 26 in eGFR. |
Countries
United States
Contacts
CONTACTLaura Nguyen
CONTACTAly Carlson
STUDY_CHAIRRodica Busui, MD, PhD
Oregon Health and Science University
Outcome results
None listed