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

Study Overview
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Brief Summary
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Clinically, the ability to slow or prevent beta cell demise can prevent or improve the course of type 1 diabetes. The immune-mediated destruction of beta cells that is an apparent major pathological basis for the disease, has led to efforts to prevent or suppress this immune assault. Here we propose to buttress the beta cell's capacity to withstand this assault by improving the function of the endoplasmic reticulum stress resolving mechanisms within these cells. The ability to do so could have a major impact on preventive and therapeutic strategies for type 1 diabetes (and possibly other types of diabetes). The type of endoplasmic reticulum stress relieving agent (TUDCA) proposed here could ultimately be applied on an anticipatory basis to individuals at high risk for type 1 diabetes.

Detailed Description
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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 an excellent 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.

Official Title
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Clinical Investigation of Efficacy of Tauroursodeoxycholic Acid (TUDCA) to Enhance Pancreatic Beta Cell Survival In Type 1 Diabetes by Reducing Endoplasmic Reticulum Stress

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Tauroursodeoxycholic Acid (TUDCA)
* Drug: Sugar Pill (placebo)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Taurourodeoxycholic Acid (TUDCA)<br>TUDCA 1750 mg/day x 12 months | Drug: Tauroursodeoxycholic Acid (TUDCA)<br>* TUDCA at 1750 mg/day x 12 months<br>* Other names: Taurolite;|
| Placebo Comparator: Sugar pill (placebo)<br>Placebo at same dose, frequency, and duration as experimental treatment | Drug: Sugar Pill (placebo)<br>* Placebo<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-peptide measurement as reflection of insulin secretion | The primary endpoint will be the area under the stimulated C-peptide curve over the first 2 hours of a 4- hour mixed meal tolerance test conducted at screening, and during the 12 months of drug treatment at 6 and12 months and at 6 months after drug or placebo is stopped. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoplasmic reticulum stress | 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. We will measure markers of endoplasmic reticulum stress in beta cells taken from skin biopsies taken from subjects before treatment with TUDCA or placebo. | 1 week | 
| liver function tests | We will measure liver function tests at 6 and 12 months and at 6 months after drug or placebo is stopped to ensure that no abnormalities of liver function occur with the drug. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 1 diabetes (T1D), endoplasmic reticulum (ER) stress, induced pluripotential stem (iPS) cells, Tauroursodeoxycholic Acid (TUDCA)