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| Name | Class |
|---|---|
| Juvenile Diabetes Research Foundation | OTHER |
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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 the investigators 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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Taurourodeoxycholic Acid (TUDCA) | Experimental | TUDCA 1750 mg/day x 12 months |
|
| Sugar pill (placebo) | Placebo Comparator | Placebo at same dose, frequency, and duration as experimental treatment |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tauroursodeoxycholic Acid (TUDCA) | Drug | TUDCA at 1750 mg/day x 12 months |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in C-peptide Measurement as Reflection of Insulin Secretion at 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. | Baseline and 6 months |
| Change in C-peptide Measurement as Reflection of Insulin Secretion at 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. | Baseline and 12 months |
| Change in C-peptide Measurement as Reflection of Insulin Secretion at 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 | Baseline and 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Liver Function Test Abnormalities | 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. | 18 months |
| Change in Insulin Use at 6 Months |
| 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. The investigators will measure markers of endoplasmic reticulum stress in beta cells taken from skin biopsies from subjects before treatment with TUDCA or placebo. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Robin Goland, MD | Columbia University | Principal Investigator |
| Rudolph Leibel, MD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Naomi Berrie Diabetes Center, Columbia University, 1150 St. Nicholas Ave. | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34547326 | Derived | 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. |
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primary data to be shared
2021
email rsg2@columbia.edu
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| ID | Title | Description |
|---|---|---|
| FG000 | Taurourodeoxycholic Acid (TUDCA) | TUDCA 1750 mg/day x 12 months Tauroursodeoxycholic Acid (TUDCA): TUDCA at 1750 mg/day x 12 months |
| FG001 | Sugar Pill (Placebo) | Placebo at same dose, frequency, and duration as experimental treatment Sugar Pill (placebo): Placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sugar Pill (Placebo) | Placebo at same dose, frequency, and duration as experimental treatment Sugar Pill (placebo): Placebo |
| BG001 | Taurourodeoxycholic Acid (TUDCA) | TUDCA 1750 mg/day x 12 months Tauroursodeoxycholic Acid (TUDCA): TUDCA at 1750 mg/day x 12 months |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in C-peptide Measurement as Reflection of Insulin Secretion at 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. | Posted | Mean | Standard Deviation | nmol/L*120 min | Baseline and 6 months |
|
18 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sugar Pill (Placebo) | Placebo at same dose, frequency, and duration as experimental treatment Sugar Pill (placebo): Placebo |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Robin Goland, MD | Columbia University Irving Medical Center | 212-851-5494 | rsg2@cumc.columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 9, 2021 | May 19, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| C536271 | Ichthyosis prematurity syndrome |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C031655 | ursodoxicoltaurine |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D002241 | Carbohydrates |
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| Sugar Pill (placebo) | Drug | Placebo |
|
|
Change in insulin use from baseline at 6 months |
| Baseline and 6 months |
| Change in Insulin Use at 12 Months | Change in insulin use from baseline at 12 months | Baseline and 12 months |
| Change in Insulin Use at 18 Months | Change in insulin use from baseline at 18 months | Baseline and 18 months |
| Change in HbA1c at 6 Months | Change in HbA1c from baseline at 6 months | Baseline and 6 months |
| Change in HbA1c at 12 Months | Change in HbA1c from baseline at 12 months | Baseline and 12 months |
| Change in HbA1c at 18 Months | Change in HbA1c from baseline at 18 months | Baseline and 18 Months |
| 1 week |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Glutamic acid decarboxylase (GAD) Result | Count of Participants | Participants |
|
| Islet cell antigen 2 (IA2) Result | Count of Participants | Participants |
|
| Insulin Autoantibodies (IAA) Result | Count of Participants | Participants |
|
| Pancreatic islet-cell antibodies (ICA) Result | Count of Participants | Participants |
|
| Zinc Transporter 8 Autoantibody (ZnT8A) Result | Count of Participants | Participants |
|
| Positive Autoantibodies | Mean | Standard Deviation | Positive Autoantibodies |
|
| Days from Diagnosis to Randomization | Mean | Standard Deviation | Days |
|
| Weight | Mean | Standard Deviation | Kilograms |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Area Under Curve (AUC) for C-Peptide | Mean | Standard Deviation | nmol/L*120 min |
|
| Hemoglobin A1C (HbA1C) | Mean | Standard Deviation | Percent |
|
| Total Daily Insulin Dose (Average 3 days before baseline visit) | Mean | Standard Deviation | units/kg |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Primary | Change in C-peptide Measurement as Reflection of Insulin Secretion at 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. | Posted | Mean | Standard Deviation | nmol/L*120 min | Baseline and 12 months |
|
|
|
| Primary | Change in C-peptide Measurement as Reflection of Insulin Secretion at 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 | Posted | Mean | Standard Deviation | nmol/L*120 min | Baseline and 18 months |
|
|
|
| Secondary | Number of Participants With Liver Function Test Abnormalities | 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. | Posted | Count of Participants | Participants | 18 months |
|
|
|
| Secondary | Change in Insulin Use at 6 Months | Change in insulin use from baseline at 6 months | Posted | Mean | Standard Deviation | units/kg | Baseline and 6 months |
|
|
|
| Secondary | Change in Insulin Use at 12 Months | Change in insulin use from baseline at 12 months | Posted | Mean | Standard Deviation | units/kg | Baseline and 12 months |
|
|
|
| Secondary | Change in Insulin Use at 18 Months | Change in insulin use from baseline at 18 months | Posted | Mean | Standard Deviation | units/kg | Baseline and 18 months |
|
|
|
| Secondary | Change in HbA1c at 6 Months | Change in HbA1c from baseline at 6 months | Posted | Mean | Standard Deviation | Percent | Baseline and 6 months |
|
|
|
| Secondary | Change in HbA1c at 12 Months | Change in HbA1c from baseline at 12 months | Posted | Mean | Standard Deviation | Percent | Baseline and 12 months |
|
|
|
| Secondary | Change in HbA1c at 18 Months | Change in HbA1c from baseline at 18 months | Posted | Mean | Standard Deviation | Percent | Baseline and 18 Months |
|
|
|
| Other Pre-specified | 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. The investigators will measure markers of endoplasmic reticulum stress in beta cells taken from skin biopsies from subjects before treatment with TUDCA or placebo. | Biopsy samples were collected, but not sent for pathological analysis due to trial futility. There are no results available to report. | Posted | 1 week |
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Taurourodeoxycholic Acid (TUDCA) | TUDCA 1750 mg/day x 12 months Tauroursodeoxycholic Acid (TUDCA): TUDCA at 1750 mg/day x 12 months | 0 | 10 | 0 | 10 | 0 | 10 |
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| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| Month 18 |
|