Autoimmune Diseases, Combination Therapy, Diabetes Melletus, Type 1, Endocrine System Diseases, Glucose Metabolism Disorders, Immune System Diseases, Metabolic Diseases, Nutritional and Metabolic Diseases, Type 1 Diabetes (T1D)
Conditions
Brief summary
The study is a randomized, double-blind, parallel-group clinical trial to examine the effects of 24 weeks of oral AMX0035 (sodium phenylbutyrate + taurursodiol) versus placebo in 60 adults with Type 1 Diabetes (T1D) (n=30 per arm). Enrollment will be distributed equally between the University of Washington and Amsterdam University Medical Center/Diabetes Center Amsterdam. Participants will be recruited through diabetes research registries, local T1D clinics, and community outreach.
Detailed description
This is a randomized, double-blind, parallel-group clinical trial to evaluate the effects of 24 weeks of oral AMX0035 (sodium phenylbutyrate + taurursodiol) versus placebo in 60 adults with type 1 diabetes (T1D) (n=30 per arm). Following screening and baseline assessments, eligible participants will be randomized 1:1 to receive either AMX0035 or placebo, with stratification by sex and body mass index (≥30 vs. \<30 kg/m2). Participants will undergo comprehensive metabolic phenotyping at baseline and 24 weeks, including hyperinsulinemic-euglycemic clamp studies, body composition imaging, continuous glucose monitoring, and tissue biopsies (skeletal muscle and adipose) for assessment of mitochondrial function and biological markers. Participants, clinicians administering the intervention, and laboratory personnel analyzing the samples will remain blinded to treatment assignments throughout the study.
Interventions
DRUGAMX0035
AMX0035 sachets
DRUGPlacebo
Placebo sachets
Sponsors
University of Washington
Breakthrough T1D
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
1. Adults ≥18 years to \<70 years of age with established T1D (duration ≥1 year) 2. Currently on insulin therapy (multiple daily injections or insulin pump) 3. HbA1c \<9.5% 4. BMI 18.5-40 kg/m2 5. On stable dose of RASB or statin, if indicated 6. Willing and able to comply with all study procedures
Exclusion criteria
1. History of pancreatic disease (including pancreatitis) or pancreatic surgery 2. History of cardiovascular disease or stroke within the past 6 months 3. History of heart failure per New York Heart Association criteria 4. History of severe edema or salt restriction requirement 5. Biliary disease or pathologies that may alter enterohepatic circulation of bile acids 6. Estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73m² 7. Liver disease (ALT/AST \>3x upper limit of normal \[ULN\]) 8. Pregnancy, breastfeeding, or planning pregnancy during the study period 9. Known hypersensitivity to study drug components 10. Abnormal baseline ECG 11. Use of off label medications that affect insulin sensitivity within the past 1 month (e.g., metformin, GLP-1RA, SGLT2i, pioglitazone) 12. Chronic use of anticoagulants 13. Use of bile acid sequestering agents, inhibitors of bile acid transporters, bile acid derivatives, aluminum-based antacids, probenecid, pan-HDAC inhibitors, phase 2 metabolizing enzymes (e.g., uridine diphosphate glucuronosyl transferases), phase 1 metabolizing enzymes other than cytochrome P450 enzymes (CYPs), and OATP1B3 14. Use of substrates of CYP1A2, CYP2C8, CYP2B6, CYP3A4, Organic Anion transporter 1, P-glycoprotein, and Breast Cancer Resistance Protein 15. History of severe hypoglycemia requiring assistance within the past 3 months 16. History of diabetic ketoacidosis (DKA) within the past 3 months 17. Personal or family history of breast cancer or ovarian cancer 18. Current participation in another clinical trial 19. Any condition(s) found by the study team and confirmed with the Investigator that make it unsafe to participate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in whole-body insulin sensitivity (M-value) measured by hyperinsulinemic-euglycemic clamp | Baseline, 24 weeks | Evaluate the effect of 24 weeks of AMX0035 versus placebo on whole-body insulin sensitivity in T1D as assessed by gold-standard two-stage hyperinsulinemic-euglycemic clamp. * Two-stage hyperinsulinemic-euglycemic clamp studies will occur at baseline and 24 weeks. * Insulin sensitivity will be quantified using the M-value (glucose infusion rate), normalized to lean body mass measured by dual-energy X-ray absorptiometry (DXA) and insulin concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in glycemic control | Baseline, 24 weeks | Glycemic control will be evaluated via continuous glucose monitoring (CGM) and HbA1c. |
| Changes in body composition | Baseline, 24 weeks | Body composition, including total, regional, visceral, and hepatic fat, will be quantified using DXA and multiparametric MRI. |
| Changes in immune and metabolic biomarkers | Baseline, 24 weeks | * Circulating and peripheral blood mononuclear cell (PBMC)-based biomarkers of inflammation and oxidative stress will be measured. * Associations between these biological markers and insulin sensitivity or glycemic metrics will be examined using multivariable models. |
| Changes in mitochondrial function | Baseline, 24 weeks | Skeletal muscle and adipose tissue biopsies will be analyzed for ER stress, inflammation, and insulin signaling. Skeletal muscle tissue will also undergo assessment of mitochondrial function by ex vivo respiration. |
| Establish the safety and tolerability of AMX0035 in adults with T1D | Duration of study | * Adverse events including hypoglycemia, DKA, and changes in hepatic and renal function will be closely monitored throughout the study. * Tolerability will be assessed through participant-reported symptoms, including gastrointestinal side effects and study discontinuations. * An independent Data Safety Monitoring Board (DSMB) will periodically review unblinded safety data and provide guidance. |
Countries
Netherlands, United States
Contacts
CONTACTAmanda Bard, MMS, MS, CCRC
PRINCIPAL_INVESTIGATORPetter M Bjornstad, MD
University of Washington
Outcome results
None listed