Precision T1D Platform - New Therapies for Cardio-Renal Complications

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 (see section XX) 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, 30, 48, and 72. The total study duration of participation will be up to 78 weeks, inclusive of screening and follow-up visits. Participants will be enrolled in this study at Oregon Health and 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.

Inclusion criteria

• 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:

• presence of circulating T1D-associated autoantibodies, or
• history of hospitalization for diabetic ketoacidosis, or
• documented plasma C-peptide below the limit of detection with standard assay (with concurrent blood glucose >100 mg/dL)
• Aged 18-75 years, inclusive
• T1D duration >10 years
• HbA1c: 7-10%
• Meets one of the following, either

• 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
• Early (Stage B HF) defined as NT-proBNP > 125 pg/mL
• Willing and able to adhere to schedule of activities and protocol requirements, including written informed consent

Exclusion criteria

• Diagnosis of Type 2 diabetes or monogenic forms of diabetes or diabetes secondary to pancreatic disease
• Use of any active platform study therapies outside study assignment within 2 months prior to screening. See Appendix A for active therapy arms.:
• Use of GLP-1 receptor agonists if in use for less than 1 month and/or not on stable dose for at least 2 weeks at screening
• Use of aldosterone inhibitors within 2 months prior to screening
• Immunosuppressive medications within 3 months prior to screening
• Systolic BP>160 or diastolic BP >95 mmHg at screening
• History of ≥3 severe hypoglycemic events requiring third-party assistance for correction within 3 months prior to screening
• Evidence of either of the following:

• History of diabetic ketoacidosis (DKA) or non-ketotic hyperosmolar state within 3 months prior to screening, or
• >1 episode of DKA or non-ketotic hyperosmolar state within 12 months prior to screening
• Serum potassium > 5 mmol/L at screening
• Absolute neutrophil count < 2.0 × 109 per L at screening
• Platelet count < 120 × 109 per L at screening
• Known active tuberculosis, HIV, or hepatitis B or C at screening
• 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
• History of severe acquired immune deficiency syndrome or severely immunocompromised status in the opinion of the investigator
• History of biopsy-proven non-diabetic CKD
• History of any other cause of HF (viral, congenital, valvular)
• History of heart or renal transplant or currently on chronic dialysis
• 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
• Illicit drug abuse within 6 months prior to screening in the opinion of the investigator
• 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)
• Participation in another interventional clinical research study within 30 days prior to screening
• Breastfeeding, pregnancy, or unwillingness to be on contraception during the trial
• Presence of a clinically significant medical history, physical examination, laboratory finding or other investigator concern that may interfere with any aspect of study conduct or interpretation of results