Type 1 Diabetes
Conditions
Keywords
type 1 diabetes (T1D), endoplasmic reticulum (ER) stress, induced pluripotential stem (iPS) cells, Tauroursodeoxycholic Acid (TUDCA)
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 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.
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 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.
Interventions
TUDCA at 1750 mg/day x 12 months
Placebo
Sponsors
Juvenile Diabetes Research Foundation
Robin Goland, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 |
| Change in HbA1c at 6 Months | Baseline and 6 months | Change in HbA1c from baseline at 6 months |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sugar Pill (Placebo) Placebo at same dose, frequency, and duration as experimental treatment
Sugar Pill (placebo): Placebo | 10 |
| Taurourodeoxycholic Acid (TUDCA) TUDCA 1750 mg/day x 12 months
Tauroursodeoxycholic Acid (TUDCA): TUDCA at 1750 mg/day x 12 months | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Sugar Pill (Placebo) | Taurourodeoxycholic Acid (TUDCA) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 20 Participants |
| Area Under Curve (AUC) for C-Peptide | 0.53 nmol/L*120 min STANDARD_DEVIATION 0.2 | 0.54 nmol/L*120 min STANDARD_DEVIATION 0.27 | 0.53 nmol/L*120 min STANDARD_DEVIATION 0.23 |
| Body Mass Index | 24.91 kg/m^2 STANDARD_DEVIATION 2.85 | 23.26 kg/m^2 STANDARD_DEVIATION 2.86 | 24.09 kg/m^2 STANDARD_DEVIATION 2.91 |
| Days from Diagnosis to Randomization | 87.50 Days STANDARD_DEVIATION 47.44 | 67.70 Days STANDARD_DEVIATION 21.41 | 77.60 Days STANDARD_DEVIATION 37.24 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 9 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Glutamic acid decarboxylase (GAD) Result GAD Negative | 0 Participants | 1 Participants | 1 Participants |
| Glutamic acid decarboxylase (GAD) Result GAD Positive | 10 Participants | 9 Participants | 19 Participants |
| Hemoglobin A1C (HbA1C) | 7.10 Percent STANDARD_DEVIATION 0.95 | 8.65 Percent STANDARD_DEVIATION 2.19 | 7.88 Percent STANDARD_DEVIATION 1.83 |
| Insulin Autoantibodies (IAA) Result IAA Negative | 5 Participants | 5 Participants | 10 Participants |
| Insulin Autoantibodies (IAA) Result IAA Positive | 5 Participants | 5 Participants | 10 Participants |
| Islet cell antigen 2 (IA2) Result IA2 Negative | 7 Participants | 3 Participants | 10 Participants |
| Islet cell antigen 2 (IA2) Result IA2 Positive | 3 Participants | 7 Participants | 10 Participants |
| Pancreatic islet-cell antibodies (ICA) Result ICA Negative | 4 Participants | 1 Participants | 5 Participants |
| Pancreatic islet-cell antibodies (ICA) Result ICA Positive | 6 Participants | 9 Participants | 15 Participants |
| Positive Autoantibodies | 3 Positive Autoantibodies STANDARD_DEVIATION 1.49 | 3.6 Positive Autoantibodies STANDARD_DEVIATION 1.17 | 3.3 Positive Autoantibodies STANDARD_DEVIATION 1.34 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 10 Participants | 20 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
| Total Daily Insulin Dose (Average 3 days before baseline visit) | 0.22 units/kg STANDARD_DEVIATION 0.12 | 0.40 units/kg STANDARD_DEVIATION 0.16 | 0.31 units/kg STANDARD_DEVIATION 0.17 |
| Weight | 72.50 Kilograms STANDARD_DEVIATION 10.18 | 69.05 Kilograms STANDARD_DEVIATION 9.17 | 70.78 Kilograms STANDARD_DEVIATION 9.59 |
| Zinc Transporter 8 Autoantibody (ZnT8A) Result ZnT8A Negative | 4 Participants | 4 Participants | 8 Participants |
| Zinc Transporter 8 Autoantibody (ZnT8A) Result ZnT8A Positive | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
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.
Time frame: Baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in C-peptide Measurement as Reflection of Insulin Secretion at 12 Months | -0.10 nmol/L*120 min | Standard Deviation 0.18 |
| Taurourodeoxycholic Acid (TUDCA) | Change in C-peptide Measurement as Reflection of Insulin Secretion at 12 Months | -0.12 nmol/L*120 min | Standard Deviation 0.17 |
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
Time frame: Baseline and 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in C-peptide Measurement as Reflection of Insulin Secretion at 18 Months | -0.11 nmol/L*120 min | Standard Deviation 0.21 |
| Taurourodeoxycholic Acid (TUDCA) | Change in C-peptide Measurement as Reflection of Insulin Secretion at 18 Months | -0.14 nmol/L*120 min | Standard Deviation 0.16 |
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.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in C-peptide Measurement as Reflection of Insulin Secretion at 6 Months | -0.07 nmol/L*120 min | Standard Deviation 0.11 |
| Taurourodeoxycholic Acid (TUDCA) | Change in C-peptide Measurement as Reflection of Insulin Secretion at 6 Months | -0.07 nmol/L*120 min | Standard Deviation 0.1 |
Secondary
Change in HbA1c at 12 Months
Change in HbA1c from baseline at 12 months
Time frame: Baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in HbA1c at 12 Months | -0.02 Percent | Standard Deviation 3.31 |
| Taurourodeoxycholic Acid (TUDCA) | Change in HbA1c at 12 Months | -2.25 Percent | Standard Deviation 2.13 |
Secondary
Change in HbA1c at 18 Months
Change in HbA1c from baseline at 18 months
Time frame: Baseline and 18 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in HbA1c at 18 Months | -0.48 Percent | Standard Deviation 2.22 |
| Taurourodeoxycholic Acid (TUDCA) | Change in HbA1c at 18 Months | -1.89 Percent | Standard Deviation 2.14 |
Secondary
Change in HbA1c at 6 Months
Change in HbA1c from baseline at 6 months
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in HbA1c at 6 Months | -0.98 Percent | Standard Deviation 1.57 |
| Taurourodeoxycholic Acid (TUDCA) | Change in HbA1c at 6 Months | -2.27 Percent | Standard Deviation 2.13 |
Secondary
Change in Insulin Use at 12 Months
Change in insulin use from baseline at 12 months
Time frame: Baseline and 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in Insulin Use at 12 Months | -0.10 units/kg | Standard Deviation 0.14 |
| Taurourodeoxycholic Acid (TUDCA) | Change in Insulin Use at 12 Months | 0.09 units/kg | Standard Deviation 0.16 |
Secondary
Change in Insulin Use at 18 Months
Change in insulin use from baseline at 18 months
Time frame: Baseline and 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in Insulin Use at 18 Months | -0.17 units/kg | Standard Deviation 0.18 |
| Taurourodeoxycholic Acid (TUDCA) | Change in Insulin Use at 18 Months | 0.02 units/kg | Standard Deviation 0.21 |
Secondary
Change in Insulin Use at 6 Months
Change in insulin use from baseline at 6 months
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Pill (Placebo) | Change in Insulin Use at 6 Months | -0.10 units/kg | Standard Deviation 0.18 |
| Taurourodeoxycholic Acid (TUDCA) | Change in Insulin Use at 6 Months | 0.09 units/kg | Standard Deviation 0.23 |
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.
Time frame: 18 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sugar Pill (Placebo) | Number of Participants With Liver Function Test Abnormalities | Month 12 | 0 Participants |
| Sugar Pill (Placebo) | Number of Participants With Liver Function Test Abnormalities | Month 18 | 0 Participants |
| Sugar Pill (Placebo) | Number of Participants With Liver Function Test Abnormalities | Month 6 | 0 Participants |
| Taurourodeoxycholic Acid (TUDCA) | Number of Participants With Liver Function Test Abnormalities | Month 6 | 0 Participants |
| Taurourodeoxycholic Acid (TUDCA) | Number of Participants With Liver Function Test Abnormalities | Month 12 | 0 Participants |
| Taurourodeoxycholic Acid (TUDCA) | Number of Participants With Liver Function Test Abnormalities | Month 18 | 0 Participants |
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.
Time frame: 1 week
Population: Biopsy samples were collected, but not sent for pathological analysis due to trial futility. There are no results available to report.