Conditions: Type 1 Diabetes
Keywords: type 1 diabetes (T1D) endoplasmic reticulum (ER) stress induced pluripotential stem (iPS) cells Tauroursodeoxycholic Acid (TUDCA)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

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.

Arms:
arm 1: TUDCA 1750 mg/day x 12 months arm 2: Placebo at same dose, frequency, and duration as experimental treatment

Interventions: intervention 1: Tauroursodeoxycholic Acid (TUDCA) intervention 2: Sugar Pill (placebo)
Intervention descriptions: intervention 1: TUDCA at 1750 mg/day x 12 months intervention 2: Placebo

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Investigation of Efficacy of Tauroursodeoxycholic Acid 
(TUDCA) to Enhance Pancreatic Beta Cell Survival In Type 1 
Diabetes by Reducing Endoplasmic Reticulum Stress 
 
 
National Clinical Trial Identifier: NCT02218619 
 
Document Date: March 9, 2021 


1. Study Purpose and Rationale 
Hypothesis: An agent (TUDCA) that reduces ER stress will protect against the 
deterioration of beta-cell function in new-onset T1D. 
Rationale: Abnormalities of ER stress responses contribute to the beta cell failure in 
early-onset T1D. Treatment of pre-diabetic NOD mice with TUDCA preserves beta 
cell mass and insulin secretion (see Background). In mice, TUDCA treatment also 
decreases lymphocytic infiltration of the islets and improves survival and 
morphology of beta- cells. Patients with newly- diagnosed T1D have a residual beta 
cell mass of 30-50% (c-peptide often >0.2 pmol/mL); beta cell destruction continues 
for at least 12-24 months after diagnosis until C-peptide is generally low or 
undetectable. 
In this pilot study in human subjects with T1D, we will enroll 20 new-onset (within 
100 days of diagnosis) subjects with measurable stimulated C-peptide (>0.2 pmol/mL). 
2. Study Design and Statistical Procedures Also see Trial Flow Diagram 
Visit -1 -Screening visit (+/- 3 days) Each participant must sign a consent form prior 
to screening. The screening visit consists of a medical history, physical exam, 
assessment of other medications that they may be taking and a review of their insulin 
usage and blood glucose values over the previous three days, blood tests including 
liver function tests, a urine test and a combination 2 hour Mixed Meal Tolerance Test 
(MMTT). 
For females only: A sample of their urine will be utilized for a urine pregnancy test during 
the screening. Only the participant will be told the results of this test. If the test is positive, 
then they will not be able to participate. Females who are lactating are also ineligible for this 
study. 
Visit 2- Screening visit Week 0 (+/- 14 days) This visit and all subsequent visits will 
only occur if participants have been found eligible to continue on the trial. It will 
include a 3 mm punch of skin; discussion about any medications they may be taking, 
a review of home blood glucose monitoring results, a review of adverse events and a 
review of insulin usage over 3 days prior to this visit. A urine sample will also be 
tested for pregnancy if the participant is female and of childbearing potential. The 
participants will be provided with a 3-month supply of the study drug/placebo. You 
will start TUDCA/placebo at a dose of 1750 mg orally daily. 
Visit 3- Interim Visit (Month 1) (+/- 14 days) This in-person visit will include 
discussion about any medications the particpant may be taking, review of home blood 
glucose monitoring results, a review of adverse events, and a review of insulin usage 
over 3 days prior to this visit. Blood tests will be done including liver function tests 
and a urine sample will also be tested for pregnancy if the participant is female and of 
childbearing potential. Participants will continue the study medication. 


Visit 4- Interim Visit (Month 2) (+/- 14 days) This phone visit will include 
discussion about any medications participants may be taking, review of home blood 
glucose monitoring results, a review of adverse events, and a review of insulin usage 
over 3 days prior to this visit. Participants will continue the study medication. 
Visit 5 - Interim Visit (Month 3) (+/- 14 days) This in-person visit will include a 
physical exam, a discussion about any medications the participant may be taking, 
review of home blood glucose monitoring results, a review of adverse events, and a 
review of insulin usage and blood glucose values over 3 days prior to this visit. The 
participant’s blood will be drawn for liver function tests and HbA1c. A urine sample 
will also be tested for pregnancy if the participant is female and of childbearing 
potential. Participants will be provided with a 3-month supply of the study 
drug/placebo. Participants will continue the study medication. 
Visit 6- Interim Visit (Month 6) (+/- 14 days) This in-person visit will include a 
physical exam, a discussion about any medications the participant may be taking, 
review of home blood glucose monitoring results, a review of adverse events, and a 
review of insulin usage, and blood glucose values over 3 days prior to this visit. The 
participant will complete a 2 hr Mixed Meal Tolerance Test and have blood drawn 
for a HbA1c and liver function tests. A urine sample will also be tested for 
pregnancy if the participant is female and of childbearing potential. Participants will 
be provided with a 3-month supply of the study medication. Participants will 
continue the study medication. 
Visit 7- Interim Visit (Month 9) (+/- 14 days) This in-person visit will include a 
discussion about any medications participants may be taking, review of home blood 
glucose monitoring results, a review of adverse events, and a review of insulin 
usage over 3 days prior to this visit. Participants will have blood drawn for a HbA1c 
and liver function tests. Participants will be provided with a 3-month supply of the 
study drug/ placebo. Participants will continue the study medication. 
Visit 8- Interim Visit (Month 12) (+/- 14 days) This visit will include a physical 
exam, a discussion about any medications participants may be taking, review of 
home blood glucose monitoring results, a review of adverse events, and a review of 
insulin usage and blood glucose values over 3 days prior to this visit. Participants 
will complete a 2 hr Mixed Meal Tolerance Test and have blood drawn for a HbA1c 
and liver function tests. Medication will be stopped at the end of 12 months. 
Visit 9- Interim Visit (Month 15) (+/- 1 month) This phone visit will include 
discussion about any medications participants may be taking, review of home blood 
glucose monitoring results, a review of adverse events, and a review of insulin usage 
over 3 days prior to this visit. 
This in-person visit will include a physical exam, a discussion about any medications 
participants may be taking, review of home blood glucose monitoring results, a 


review of adverse events, and a review of insulin usage and blood glucose values 
over 3 days prior to this visit. Participants will complete a 2 hr Mixed Meal 
Tolerance Test and have blood drawn for a HbA1c and liver function tests. 
i. Endpoints: The primary endpoints will be the area under the stimulated C-peptide 
curve of a 2- hour mixed meal tolerance test (MMTT) conducted at screening, and 
during the 12 months of drug treatment at 6 and 12 months and at 6 months after drug 
or placebo is stopped. 
The study will also examine as secondary endpoints the effect of the experimental 
treatment on diabetes-specific autoantibodies and metabolic parameters. Interim 
metabolic assessments will consist of periodic review of glucose records and reports 
of hypoglycemia, insulin dose and HbA1c. 
 
ii. Trial Design: This single-center double-masked, Phase II placebo-controlled study 
will examine the efficacy of TUDCA to arrest beta cell hypofunction/destruction in 20 
subjects with new- onset T1D (ages 18-45 years), randomized within 100 days of 
diagnosis). All subjects will receive standard intensive diabetes treatment with insulin 
and dietary management, consistent with American Diabetes Association Standards of 
Care. Diabetes management will be done by the primary diabetes care team at the 
Berrie Center. Subjects will be randomly assigned 1:1 to receive either daily TUDCA 
1750 mg/day or placebo for 12 months. All subjects will be followed for until study 
end and will be offered option for re-contact in the informed consent so that longer-
term study follow-up is a possibility. Enrollment is expected to occur over 18 months. 
The mean c-peptide responses to MMTT in the TUDCA treatment group will be 
compared to the placebo-treated group at 0, 6, 12 and 18 months. The study will also 
examine the effects of TUDCA treatment on other T1D- related metabolic and 
immunologic outcome measures. 
iii. Exploratory outcome: If a significant change in c-peptide responses are detected 
in both groups, we will compare the in vivo responses to ER stress relief to in-vitro 
responses to ER stress relief. In these subjects, we will compare the clinical response 
to an agent that reduce ER stress to the response of the iPS-derived beta cells, 
derived from the same subject, when treated with the same experimental agent to 
reduce ER stress.  
 
iv. Treatment and Dose: Subjects will be treated with either TUDCA at a dose of 
1750 mg/day or placebo for 12 months with an additional 6 months of follow-up. 
1750 mg is the most commonly used dose used to treat biliary disease and was used 
in a recent study of human obesity and insulin resistance (39). In this 4 week study, 
an effects on ER stress was not observed on adipose cells; however we plan a longer 
treatment time period and hypothesize that since TUDCA undergoes extensive 


hepatic metabolism, the exposure of pancreatic beta cells to drug at this dose may be 
sufficient to cause an effect on ER stress. In addition, in vitro studies will enable us 
to manipulate exposure of beta cells to a range of TUDCA concentrations, thus 
revealing extent of individual differences in sensitivity to the agent. 
v. Duration: All subjects will be followed for 1 year of treatment and at least 6 
months of follow-up. 
vi DSMB: The progress of the study will be monitored by the DSMB which will 
review safety data and make recommendations regarding continuation, termination, 
or modification of the study. Based on an 18 month enrollment period and an 
additional study period of at least 6 months, the DSMB will formally review the 
safety data, enrollment, and clinical outcome data at least twice yearly. 
vii The number of subjects who discontinue study treatment will also be included 
in the reports prepared for the DSMB. 
Statistical analysis: These studies are pilots in which we anticipate substantial inter-
individual differences in responses to the proposed in vivo intervention (TUDCA). 
We will compare the clinical endpoints between treated and control subjects using 
repeated measures ANOVA, treating (if indicated) age, gender and BMI as 
covariates. The endpoints of the in vitro studies will be analyzed for differences 
between individuals regardless of the experimental group to which they have been 
randomized. These analyses will inform us of the range of autonomous beta cell 
differences in response to ER stress, and to the mitigation conveyed by TUDCA. 
These data will then be related to clinical endpoints, probing for the ability of the in 
vitro studies to predict (correlate with) clinical course and response to TUDCA. We 
are experienced in all of the relevant analytic techniques and have the software on 
hand. If necessary, we have access to expert statistical consultations through the 
Columbia NIH CTSA. 
3. Study Procedures MMTT and skin biopsy 
Aim: To assess the performance of canonical ER stress response pathways, including 
the ability of TUDCA to meliorate such stress in vitro in beta cells of the subjects of 
this study. 
Rationale: As noted, there is growing recognition that ER stress plays an important 
role in beta cell responses to the immunologic and metabolic stresses that are the 
hallmarks of T1D. Pharmacological “relief” of ER stress is beneficial in rodent 
models of diabetes. Molecules that have these effects (e.g. TUDCA) are very well 
tolerated in children and adults to whom they have been administered for other 
indications. 
Hypothesis: In patients with very recent onset of clinical T1D, TUDCA 


administration will slow or prevent the advance of the disease. 
 
Anticipated outcome: Individuals treated with TUDCA will show a trend toward 
preservation of beta cell mass and function as reflected in stimulated C-peptide in 
MMTT at 6 and 12 months of treatment compared to placebo; it is possible that if 
observed, this effect will still be present 6 months after cessation of treatment or 
later. 
4. Name of investigational product: TUDCA 
 
i.Risks and Benefits: The known risks of drug treatment: In a summary of post-
marketing data of 37 trials involving 1283 subjects treated with TUDCA up to 1750 
mg/day for up to 1 year for severe liver disease, the most common side effect was 
diarrhea that occurred in .01% subjects. Less frequent adverse events were nausea, 
abdominal pain, pruritis, and headache. 
 
ii.Study drug and placebo are manufactured and supplied by Bruschettini (Genoa, Italy) 
and provided at no charge to study participants. The study drug is administered orally 
twice daily. 
iii. Population to be studied: New-onset T1D. We will recruit individuals between 
the ages of 18 and 45 with new- onset T1D (within 100 days of diagnosis). All 
patients will be in otherwise good health. Inclusion criteria will include: at least 
one diabetes- related autoantibody present (insulin autoantibody alone will not be 
sufficient in subjects treated with insulin for > 14 days) and a stimulated C-peptide 
levels > 0.2 pmol/ml measured during a  mixed meal tolerance test (MMTT) 
conducted at least 21 days   from diagnosis of diabetes and within one month (37 
days) of randomization to either TUDCA or placebo. Pregnant women will be 
excluded. Participants of childbearing potential and/or their partners must agree to 
use acceptable methods of birth control beginning at the pre-study visit and 
throughout the study. 
Examples of acceptable methods of birth control include abstinence, or 2 of the following: 
intrauterine device (IUD-with or without local hormone release), diaphragm, spermicides, 
cervical cap, contraceptive sponge, and /or condoms. 
iv. Drug handling/distribution/administration is conducted in accordance with 
the policies of the Research Pharmacy and Columbia University Medical 
Center 
5. Study Instruments (e.g., Questionnaires, Interview Outlines, Focus Group 
Guides): N/A 


 
6. Study Subjects 
 
I. Subject Inclusion Criteria 
 
1. Be between the ages of 18 and 45 years. 
2. Be within 3 months (100 days) of diagnosis of T1D based on ADA criteria. 
3. Must have at least one diabetes-related autoantibody present. 
4. Must have stimulated C-peptide levels > 0.2 pmol/ml measured during an 
MMTT conducted at least 21 days from diagnosis of diabetes and within one 
month (37 days) of randomization. 
5. If participant is female with reproductive potential, she must be willing to avoid 
pregnancy and have a negative pregnancy test during the 12 months of 
treatment and for an additional 3 months. 
6. Must be willing to comply with intensive diabetes management. 
7. Must be willing to undergo 3 mm skin biopsy at randomization. 
II. Subject Exclusion Criteria 
 
1. Be currently pregnant, lactating or anticipating getting pregnant. 
2. Ongoing use of medications known to influence glucose tolerance. 
3. Have serologic evidence of current or past HIV, hepatitis B, or C infection. 
4. Have any complicating medical issues or abnormal clinical laboratory results including 
abnormal liver function test (more than 1.5 x ULN) that interfere with study conduct 
or cause increased risk. 
5. Have a history of malignancy. 
6. Currently using non-insulin drugs that affect glucose control. 
7. Currently using drugs that may interfere with TUDCA absorption or effect such as bile 
acid sequestering agents (cholestyramine and colestipol), aluminum based antacids, 
estrogens, oral contraceptives and clofibrate. 
8. Currently participating in another T1D treatment trial or Sensitivity to TUDCA or other 
similar agent. 
iii. Subject withdrawal criteria: An intent–to-treat approach will be used. Subjects will 
not be replaced. All data acquired prior to termination for the reasons outlined 
below will be included in the primary analysis unless a participant withdraws 
consent. Every effort will be made to conduct a final study visit with the participant 
and participants will be followed clinically until, if applicable, all adverse events 
resolve. All subjects will be offered clinical follow-up at the Berrie Center for T1D. 
Reasons for withdrawal and stopping rules: The drug will be stopped by the 
investigator because of serious and unexpected adverse events, safety laboratory 
parameters and/or vital signs. Subject may be withdrawn by the investigator; the 
subject my withdraw from the study; there may be an Intercurrent illness or event 
that precludes further to the study site or ability to evaluate disease. 


Treatment of Subjects: Participants will be treated with either TUDCA at a dose of 
1750 mg/day or placebo for 12 months, with study visits every 3 months during 
treatment, and undergo at least 6 months of follow-up, depending upon time of 
randomization. The study will be stopped based on occurrence of serious and 
unexpected adverse events, safety laboratory parameters and/or abnormal vital signs. 
Subjects will agree to avoid the following drugs during the study: non-insulin drugs 
that affect glucose   control, bile acid sequestering agents (cholestyramine and 
colestipol), aluminum based antacids, estrogens, oral contraceptives and clofibrate. 
Subjects will be offered option of ongoing clinical care at Berrie Center for T1D as 
well as option for re-contact in informed consent, providing possibility for longer- term 
follow-up studies to be performed in the future on these subjects. 
Recruitment: Participants will be recruited from patients seen at the Berrie Center. 
Researchers will not directly approach a patient for recruitment until the patient has 
been informed by the study by their physician who has ascertained that the patient is 
willing to discuss the study with the investigators. 
 
7. Informed consent process: Consent will be obtained by study investigator, Dr. 
Robin Goland or by the study coordinator Ellen Greenberg. Consent will be obtained 
verbally in-person. 
v. Duration: All subjects will be followed for 1 year of treatment and at least 6 
months of follow-up. 
vi DSMB: The progress of the study will be monitored by the DSMB which will 
review safety data and make recommendations regarding continuation, termination, 
or modification of the study. Based on an 18 month enrollment period and an 
additional study period of at least 6 months, the DSMB will formally review the 
safety data, enrollment, and clinical outcome data at least twice yearly. 
vii The number of subjects who discontinue study treatment will also be included 
in the reports prepared for the DSMB. 
 
8. Confidentiality of Study Data: Subjects' medical and research records will be 
confidential to the extent permitted by law. Efforts will be made to keep subjects' 
personal information private. However, there is no guarantee for complete 
confidentiality. Subjects will be identified by a code, and personal information from 
your records will not be released without the subject's written permission. When 
information from this study is published, subjects will not be identified by name. All 
end-user devices will be encrypted and all data will be password protected. 
9. 
Privacy Protections: Study will be carried out in accordance with all HIPPA 
regulations. 


10. IND Holder Responsibilities 
a) Ensure proper monitoring: The Sponsor-Investigator will ensure that the study 
protocol is followed, the data is accurate and the research subjects are safe. Safety data 
will be reviewed by the Sponsor-Investigator or designee as soon as it is received. As 
per  the “AE Reporting” document that was submitted as part of the protocol, events 
that are considered to be serious and unexpected “Suspected Adverse Reactions” or 
SARs, will be submitted to the FDA as soon as possible, but no later than 15 calendar 
days from notification, and unexpected fatal or life-threatening SARs will be submitted 
no later than 7 calendar days from initial notification. Events that are considered to be 
“Unanticipated Problems” or UPs, will be submitted promptly, but no later than 7 
calendar days following the occurrence of the UP or knowledge of the UP. The 
S-I will also notify the IRB and FDA of any serious deviations from the protocol and any 
new information indicating added risks to subjects. 
The S-I will review 100% of all source documentation of data collected including all 
safety data. The regulatory binder, along with other essential study documents, will 
also be reviewed to ensure that it is complete and up to date. The first review will 
occur after the first patient is enrolled and will continue periodically with new 
enrollments. Any discrepancies will be discussed with relevant study personnel for 
clarification and/or correction. 
b) Ensuring the study is conducted in accordance with the protocol: The Sponsor-
Investigator will continually monitor the study to ensure that the study is conducted 
in compliance with the IRB approved study protocol. Research personnel will be 
trained on the protocol, and the S-I will provide oversight to staff to ensure 
compliance. Potential subjects, research subjects, and study progress will be 
discussed at the weekly Type 1 Diabetes Departmental meeting. The performance of 
all aspects of the study, including the methods used to obtain informed consent, will 
be conducted in accordance with all applicable state and federal guidelines as well as 
the principles for protection of research subjects as outlined in the declaration of 
Helsinki, ICH Guidelines for Good clinical practice, applicable local health authority 
regulations and US Title 21 of the Code of Federal Regulations. 
c) Review of ongoing investigations; evaluate safety and efficacy and report to the 
FDA and IRB: The progress of study will be monitored by the Data and Safety 
Monitoring Board (DSMB) which will review safety data and make recommendations 
regarding continuation, termination, or modification of the study. The DSMB will 
formally review the safety data, enrollment, and clinical outcome data at least twice 
yearly. In addition, safety data will be reviewed by the Sponsor-Investigator or 
designee as soon as it is received, and will report findings to the FDA and IRB as 
appropriate. 
 
d) Keep and retain records/documentation: Adequate and accurate case histories on 


all subjects’ participation in the trial will be kept. This includes source data, progress 
notes, concomitant medications, subject eligibility and documentation of consent as 
well as signature and date of staff obtaining data. A record will be maintained of all 
monitoring activities, findings, conclusions and actions taken to correct deficiencies. 
Submissions to the FDA and other FDA correspondence will also be filed. All data 
collected   from the study will be maintained in charts and password protected 
computers in a locked facility with limited access. Only the S-I and designee(s) will 
have access to the records. Confidentiality of data and protection of privacy of 
subjects will be ensured following the IRB policy and federal regulations 45 CRF 
46.111(a)(7) and 21 CRF 56.111(a)(7). 
 
e) Submit amendments, IND Safety Reports, and Annual reports to the FDA: 
Protocol and information amendments will be submitted to the FDA in accordance 
with 21 CFR 312.30 and 21 CFR 312.31, respectively. 
Safety reporting will be submitted to the FDA in accordance with 21 CFR 312.32 and 
as outlined in the “AE Reporting” document. Sponsor-Investigator will submit IND 
Safety Reports for any adverse experiences that are both serious and unexpected and 
associated with the use of the drug. Serious and unexpected suspected adverse 
reactions will be reported to FDA as soon as possible, but no later than 15 calendar 
days following the S-I’s initial receipt of the information. Unexpected fatal or life- 
threatening suspected adverse reactions will be reported to FDA as soon as possible, 
but no later than 7 calendar days following the S- I’s initial receipt of the information. 
Any relevant information not reported in the initial IND safety report will be submitted 
as a follow-up report no later than 15 calendar days after the S-I receives the 
information. 
Annual reports will be submitted to the FDA within 60 days of the anniversary date 
that the IND went into effect. Annual reports include information on the progress of 
the investigation, as well as a summary of all safety reports submitted.