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

• ClinicalTrials.gov Identifier: NCT02218619
• Recruitment Status: Unknown
• First Posted: August 18, 2014
• Last Update Posted: December 4, 2018
• Sponsor: Robin Goland, MD
• Collaborator: Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): Robin Goland, MD, Columbia University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes	Drug: Tauroursodeoxycholic Acid (TUDCA); Drug: Sugar Pill (placebo)	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Clinical Investigation of Efficacy of Tauroursodeoxycholic Acid (TUDCA) to Enhance Pancreatic Beta Cell Survival In Type 1 Diabetes by Reducing Endoplasmic Reticulum Stress
• Study Start Date: August 2015
• Estimated Primary Completion Date: October 1, 2019
• Estimated Study Completion Date: October 1, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Taurourodeoxycholic Acid (TUDCA); TUDCA 1750 mg/day x 12 months	Drug: Tauroursodeoxycholic Acid (TUDCA); TUDCA at 1750 mg/day x 12 months; Other Names: TUDCA; Taurolite
Placebo Comparator: Sugar pill (placebo); Placebo at same dose, frequency, and duration as experimental treatment	Drug: Sugar Pill (placebo); Placebo; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. C-peptide measurement as reflection of insulin secretion [ Time Frame: 18 months ]
   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.

Secondary Outcome Measures :

1. Endoplasmic reticulum stress [ Time Frame: 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. We will measure markers of endoplasmic reticulum stress in beta cells taken from skin biopsies taken from subjects before treatment with TUDCA or placebo.
2. liver function tests [ Time Frame: 18 months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, New York

Naomi Berrie Diabetes Center, Columbia University, 1150 St. Nicholas Ave.

New York, New York, United States, 10032

Sponsors and Collaborators

Robin Goland, MD

Juvenile Diabetes Research Foundation

Investigators

• Principal Investigator: Robin Goland, MD; Columbia University
• Principal Investigator: Rudolph Leibel, MD; Columbia University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Robin Goland, MD, J. Merrill Eastman Professor of Clinical Diabetes, Co-Director, Berrie Center, Columbia University
• ClinicalTrials.gov Identifier: NCT02218619
• Other Study ID Numbers: AAAN2402
• First Posted: August 18, 2014
• Last Update Posted: December 4, 2018
• Last Verified: December 2018

Keywords provided by Robin Goland, MD, Columbia University:

type 1 diabetes (T1D); endoplasmic reticulum (ER) stress; induced pluripotential stem (iPS) cells; Tauroursodeoxycholic Acid (TUDCA)

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Ursodoxicoltaurine; Antiviral Agents; Anti-Infective Agents; Cholagogues and Choleretics; Gastrointestinal Agents