Tauroursodeoxycholic Acid (TUDCA) in New-Onset Type 1 Diabetes

Reducing endoplasmic reticulum stress will promote beta cell survival in new-onset type 1 diabetes.

The primary aim is to test the clinical efficacy of an already approved agent, TUDCA, re-purposed to reduce endoplasmic reticulum stress and improve beta cell survival in patients with new onset type 1 diabetes. The primary endpoint of this proposed double-blinded randomized placebo-controlled pilot study is c-peptide measured after mixed meal stimulation test at randomization and then at 6 and 12 months of treatment with TUDCA compared to treatment with placebo and at 6 months following treatment.

TUDCA is an oral medication with a safety profile that is approved for use in Europe for gall stones and liver disease. The drug and similar compounds has been used in children, as young as newborns, and in adults. TUDCA's ability to lower endoplasmic reticulum stress has only recently been recognized and will be applied to new-onset type 1 diabetes in this proposal. If this pilot trial is successful, future studies could include broadening the recipients to antibody-positive pre-type 1 diabetes patients and/or combining TUDCA with other agents shown to have a beneficial effect on insulin secretion in new-onset type 1 diabetes.

• Tauroursodeoxycholic Acid (TUDCA) (Drug), also known as TUDCA, Taurolite: TUDCA at 1750 mg/day x 12 months
• Sugar Pill (placebo) (Drug), also known as Placebo: Placebo

Primary outcomes

• Change in C-peptide Measurement as Reflection of Insulin Secretion at 6 Months [Baseline and 6 months]: The primary endpoint will be the change from baseline in area under the stimulated C-peptide curve over the first 2 hours of a 4- hour mixed meal tolerance test conducted at 6 months.
• Change in C-peptide Measurement as Reflection of Insulin Secretion at 12 Months [Baseline and 12 months]: The primary endpoint will be the change from baseline in area under the stimulated C-peptide curve over the first 2 hours of a 4- hour mixed meal tolerance test conducted at 12 months.
• Change in C-peptide Measurement as Reflection of Insulin Secretion at 18 Months [Baseline and 18 months]: The primary endpoint will be the change from baseline in area under the stimulated C-peptide curve over the first 2 hours of a 4- hour mixed meal tolerance test conducted at 18 months

Secondary outcomes

• Number of Participants With Liver Function Test Abnormalities [18 months]: Measure liver function tests at 6 and 12 months and at 6 months after drug or placebo is stopped to ensure that no abnormalities (liver function blood tests outside of normal reference range) of liver function occur with the drug.
• Change in Insulin Use at 6 Months [Baseline and 6 months]: Change in insulin use from baseline at 6 months
• Change in Insulin Use at 12 Months [Baseline and 12 months]: Change in insulin use from baseline at 12 months
• Change in Insulin Use at 18 Months [Baseline and 18 months]: Change in insulin use from baseline at 18 months
• Change in HbA1c at 6 Months [Baseline and 6 months]: Change in HbA1c from baseline at 6 months
• Change in HbA1c at 12 Months [Baseline and 12 months]: Change in HbA1c from baseline at 12 months
• Change in HbA1c at 18 Months [Baseline and 18 Months]: Change in HbA1c from baseline at 18 months

Other outcomes

• Endoplasmic Reticulum Stress [1 week]: It is believed that the autoimmune assault of new onset type 1 diabetes leads to stress to the part of the beta cell that folds proteins; referred to as endoplasmic reticulum stress. When endoplasmic reticulum stress increases, changes in protein levels in beta cells occur. The investigators will measure markers of endoplasmic reticulum stress in beta cells taken from skin biopsies from subjects before treatment with TUDCA or placebo.

Sex: All, ages: 18 Years to 45 Years

Inclusion Criteria:

* Type 1 diabetes according to American Diabetes Association criteria
* Diagnosis of type 1 diabetes within 100 days of randomization
* One positive diabetes-related autoantibody
* Ages 18-45 years

Exclusion Criteria:

* Drugs known to affect glucose other than insulin
* Stimulated C-peptide levels < 0.2 pmol/ml measured during a mixed meal tolerance test conducted at least 21 days from diagnosis of diabetes and within one month (37 days) of randomization to either TUDCA or placebo.
* Women during pregnancy

Participant flow

Outcome results

• Change in C-peptide Measurement as Reflection of Insulin Secretion at 6 Months (Primary), Mean, nmol/L*120 min: Sugar Pill (Placebo) -0.07 +/- 0.11; Taurourodeoxycholic Acid (TUDCA) -0.07 +/- 0.10
• Change in C-peptide Measurement as Reflection of Insulin Secretion at 12 Months (Primary), Mean, nmol/L*120 min: Sugar Pill (Placebo) -0.10 +/- 0.18; Taurourodeoxycholic Acid (TUDCA) -0.12 +/- 0.17
• Change in C-peptide Measurement as Reflection of Insulin Secretion at 18 Months (Primary), Mean, nmol/L*120 min: Sugar Pill (Placebo) -0.11 +/- 0.21; Taurourodeoxycholic Acid (TUDCA) -0.14 +/- 0.16
• Number of Participants With Liver Function Test Abnormalities (Secondary), Count of participants, Participants: Sugar Pill (Placebo) 0; Taurourodeoxycholic Acid (TUDCA) 0
• Change in Insulin Use at 6 Months (Secondary), Mean, units/kg: Sugar Pill (Placebo) -0.10 +/- 0.18; Taurourodeoxycholic Acid (TUDCA) 0.09 +/- 0.23
• Change in Insulin Use at 12 Months (Secondary), Mean, units/kg: Sugar Pill (Placebo) -0.10 +/- 0.14; Taurourodeoxycholic Acid (TUDCA) 0.09 +/- 0.16
• Change in Insulin Use at 18 Months (Secondary), Mean, units/kg: Sugar Pill (Placebo) -0.17 +/- 0.18; Taurourodeoxycholic Acid (TUDCA) 0.02 +/- 0.21
• Change in HbA1c at 6 Months (Secondary), Mean, Percent: Sugar Pill (Placebo) -0.98 +/- 1.57; Taurourodeoxycholic Acid (TUDCA) -2.27 +/- 2.13
• Change in HbA1c at 12 Months (Secondary), Mean, Percent: Sugar Pill (Placebo) -0.02 +/- 3.31; Taurourodeoxycholic Acid (TUDCA) -2.25 +/- 2.13
• Change in HbA1c at 18 Months (Secondary), Mean, Percent: Sugar Pill (Placebo) -0.48 +/- 2.22; Taurourodeoxycholic Acid (TUDCA) -1.89 +/- 2.14
• Endoplasmic Reticulum Stress (Other pre specified)

Adverse events

Time frame: 18 months

• Results publication: Rosa LRO, Vettorazzi JF, Zangerolamo L, Carneiro EM, Barbosa HCL. TUDCA receptors and their role on pancreatic beta cells. Prog Biophys Mol Biol. 2021 Dec;167:26-31. doi: 10.1016/j.pbiomolbio.2021.09.003. Epub 2021 Sep 20. PMID 34547326

• Study Protocol and Statistical Analysis Plan (PDF, 2021-03-09)

• Robin Goland, MD, Principal investigator, Columbia University
• Rudolph Leibel, MD, Principal investigator, Columbia University