Clinical trial NCT05266963
Conditions: Type 1 Diabetes
Sponsor: Vanderbilt University Medical Center
Start date: 2022-09-02; Completion date: 2024-03-22
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Recent studies have demonstrated reduced pancreatic volume is present within months of T1D diagnosis in children, adolescents, and adults. As the pancreatic beta cells constitute only 1-2% of the pancreas, the degree of reduction in pancreas volume at disease onset suggests exocrine involvement, challenging the established paradigm of T1D being solely a disease of the endocrine pancreas.

To date there has not been an investigation of the potential for pancreatic enzyme replacement therapy in the management of T1D. In individuals with cystic fibrosis-related diabetes, enzyme replacement has been shown to reduce post-prandial glycemia excursions, which are reflected in improved GLP-1 responses to mixed meal tolerance testing. As post-prandial excursions and glucose variability are a significant challenge in T1D, how enzyme replacement may impact these parameters is an important question.

The investigators hypothesize that patients with T1DM who have reduced pancreatic volume will have improved glycemic responsiveness, reduced hypoglycemia, and improved symptoms of pancreatic exocrine insufficiency when treated with pancreatic enzyme replacement (CREON).

Detailed description:

Arms: arm 1: CREON is a pancreatic enzyme replacement arm 2: Placebo
Interventions: intervention 1: CREON intervention 2: Placebo
Intervention descriptions: intervention 1: The study will enroll 6-10 adult subjects with T1D who will receive both pancreatic enzyme replacement (CREON) or placebo each for 7 days in a random order. The effect of the intervention will be monitored by continuous glucose monitoring, diet recording, capsule counts, a mixed-meal tolerance test, and a survey to assess symptoms of PEI. This study design will allow for estimation of the effect of pancreatic enzyme replacement on the measured parameters. intervention 2: Placebo

Protocol documents:
ICF_002.pdf: 
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes 
NCT05266963 
Informed Consent Document 
3/14/2024 
 
 
 


2
VUMCInstitutional Review Board
Informed Consent Document for Research
Study Title:
Version Date:
PI:
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes
31JAN2022
Daniel J. Moore, MD, PhD
Date of IRB Approval: 03/14/2024 
Date of Expiration: 03/13/2025
Name of participant:
Age:
The followingisgivento you to tell you about this researchstudy. Please read this form withcare and 
ask any questions you may have about this study. Your questions will be answered. Also, you will be 
given a copy of this consent form.
Key informationabout this study:
This study explores how reduced pancreas size may affect blood sugars in type 1diabetes. Persons with 
type 1 diabetes have a smaller than normal pancreas size. In addition to making insulin, the pancreas 
also makes other enzymes and hormones. This study explores whether replacement of these pancreatic 
enzymes may help persons with type 1 diabetes achieve better blood sugar control, change any 
symptoms they may have, and improve how their body responds to meals.
This study will ask you to take pancreatic enzyme supplementation (CREON) and a placebo for a week 
each in a random order; you will receive both treatments, but you will not know which one you have 
while you are taking it. You will be instructed to take 2 capsules with all meals and 1 capsule with snacks 
during both of the weeks. Creon is not approved by the Food and Drug Administration (FDA) for use in 
type 1 diabetes.
You will also be asked to come in for a mixed meal tolerance test (MMTT) three times to assess your 
body’s response to food; you will have this test in the morning and will be asked to fast overnight the 
night before. You will be asked to continue wearing your continuous glucose monitor and to share the 
data with us; you will be asked to record what you eat.
You are being asked to take part in this research study because you have type 1 diabetes and have 
previously been found to have reduced pancreas volume.
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services, or other rights. You can stop being in this study 
at any time. If we learn something new that may affect the risks or benefits of this study, you will be told 
so that you can decide whether or not you still want to be in this study. Your medical record will contain 
a note saying you are in a research study and may contain some research information about you.
Anyone you authorize to receive your medical record will also get this information.
Key Information:
The first section of this document contains some key points that the research team thought you 
would find important. The study is described in more detail after this section. If you do not 
understand something, please ask someone.


3
VUMCInstitutional Review Board
Informed Consent Document for Research
Study Title:
Version Date:
PI:
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes
31JAN2022
Daniel J. Moore, MD, PhD
Date of IRB Approval: 03/14/2024 
Date of Expiration: 03/13/2025
Side effects and risks that you can expectif you take part in this study:
There are possible risks of taking Creon. The risks and precautions include:
•
Fibrosing colonopathy, a rare, serious adverse reaction has been described in association with 
high-dose use of pancreatic enzyme replacement in the treatment of cystic fibrosis patients. 
Caution should be exercised when doses of CREON exceed 2,500 lipase units/kg of body weight 
per meal (or greater than 10,000 lipase units/kg of body weight per day).
•
Care should be taken to ensure that CREON is not chewed or retained in the mouth to avoid 
irritation of oral mucosa.
•
Caution should be exercised when prescribing CREON to patients with gout, renal impairment, 
or hyperuricemia.
•
There is theoretical risk of viral transmission with all pancreatic enzyme products including 
CREON.
•
Caution should be exercised when administering CREON to a patient with a known allergy to 
proteins of porcine origin.
•
Treatment-emergent adverse events occurring in at least 2 patients (greater than or equal to 
6%) receiving CREON or placebo are abdominal pain, abdominal pain upper, abnormal feces, 
cough, dizziness, flatulence, headache, and weight decreased.
•
There is no post-marketing experience.
•
There are no known drug interactions.
Additionally, there are some things that could cause temporary discomfort. Here are the things you 
should know about:
•
Blood draw: drawing blood can possibly cause bruising, bleeding, discomfort, and infection. 
Sometimes people may feel sick to their stomach, be lightheaded, or even faint during this 
procedure. We will attempt to minimize these possibilities by cleaning the skin and having you 
lie down or sit during this procedure.
There are several other potential risks to changing the way you eat that you should know about:
•
Low blood sugar. All persons with diabetes experience low blood sugar some of the time. It is 
possible that the frequency of low blood sugar could increase during this study. We will ask you 
to consistently wear your continuous glucose monitor to detect these low blood sugars. If you 
have a low blood sugar, we will ask you to follow standard treatment recommendations 
including eating 15grams of glucose and reassessing in 15 minutes if you are able. If you are 
unresponsive or unable to eat, you should receive glucagon.


4
VUMCInstitutional Review Board
Informed Consent Document for Research
Study Title:
Version Date:
PI:
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes
31JAN2022
Daniel J. Moore, MD, PhD
Date of IRB Approval: 03/14/2024 
Date of Expiration: 03/13/2025
It is possible that you will not directly benefit from this study.
Risks that are not known:
Because this treatment is investigational, meaning non-FDA approved for use in type 1 diabetes, there 
may be risks that we do not know about at this time.
Good effects that might result from this study:
The benefits to science and humankind that might result from this study: This study may show that persons 
with type 1 diabetes who have a small pancreas need additional treatments to improve their blood sugar 
control. This study may improve our understandi ng of blood sugar regulation in type 1 diabetes.
Proceduresto be followed:
During this study you will be asked to do the following:
1)
Complete a screening visit and sign a copy of this informed consent document.
2)
Have a baseline visit where we will obtain your physical measurements and perform an initial 
MMTT. You will be provided with instructions for the MMTT.
3)
Record your daily food intake for the month of the study.
4)
Wear your continuous glucose monitor (CGM) during the study.
5)
Upload your CGM and pump data, if applicable, and share the data with us.
6)
Take CREON capsules or placebo during each of two weeks as instructed.
7)
Complete a brief survey and obtain aMMTT at the end of the treatment and placebo weeks.
8)
Report any adverse events to us.
Payments for your time spenttaking part in this study or expenses:
You will receive$200 for each of the 3 study visits requiring a MMTT to be performed.
We will ask you for your Social Security number and address before you are compensated for taking part 
in this study.
You may receive up to $600 for taking part in this study. This amount may be taxable and will be 
reported to the Internal Revenue Service (IRS).
You are not allowed to accept any money for taking part in this study if you are not eligible to receive 
money from a U.S. person or company or the U.S. government because of U.S. national security and/or 
foreign policy laws. You can still take part in the study, however, you will not be paid if you are a 
resident of a country restricted by the U.S. government‘s comprehensive territorial sanctions or if you 
are listed on the U.S. Treasury Department’s Office of Foreign Assets Control’s Specially Designated 
Nationals (SDN) list of prohibited individuals. You do not have to say why you choose not to be paid.


5
VUMCInstitutional Review Board
Informed Consent Document for Research
Study Title:
Version Date:
PI:
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes
31JAN2022
Daniel J. Moore, MD, PhD
Date of IRB Approval: 03/14/2024 
Date of Expiration: 03/13/2025
Costs to you if you take part inthis study:
If you agree to take part in this research study, you and/or your insurance will not have to pay for the 
tests and treatments that are being done only for research. However, you are still responsible for 
paying for the usual care you would normally receive for the treatment of your illness. This includes 
treatments and tests you would need even if you were not in this study. These costs will be billed to you 
and/or your insurance.
You have the right to ask what it may cost you to take part in this study. If you would like assistance, 
financial counseling is available through the Vanderbilt Financial Assistance Program. The study staff 
can help you contact this program. You have the right to contact your insurance company to discuss the 
costs of your routine care (non-research) further before choosing to be in the study. You may choose 
not to be in this study if your insurance does not pay for your routine care (non-research) costs and your 
doctor will discuss other treatment plans with you.
Payment incase you are injuredbecause of this research study:
If it is determined by Vanderbilt and the Investigator that an injury occurred, then you and/or your 
insurance may be billed for the cost of medical care provided at Vanderbilt to treat the injury. You will 
be responsible for any copayments or deductibles associated with treatment of that injury.
There are no plans for Vanderbilt to pay for the costs of any additional care. There are no plans for 
Vanderbilt [or the Sponsor] to give you money for the injury.
Whoto call for any questions or in case you are injured:
If you should have any questions about this research study or if you feel you have been hurt by being a 
part of this study, please feel free to contact Dr. Daniel Moore at 615-948-6721 If you cannot reach the 
research staff, please page the study doctor at 615-831-4060.
For additional information about giving consent or your rights as a person in this study, to discuss 
problems, concerns, and questions, or to offer input, please feel free to call the VUMC Institutional 
Review Board Office at (615) 322-2918 or toll free at (866) 224-8273.
Reasons why the study doctor may take you out of this study:
•
You become pregnant.
•
There is concern that continuing the study may be harmful to you.
•
You no longer meet the requirements for this study.
What will happen if you decide to stop being in this study?
If you decide to stop being part of the study, you should tell your study doctor. Deciding to not be part 
of the study will not change your regular medical care in any way.


6
VUMCInstitutional Review Board
Informed Consent Document for Research
Study Title:
Version Date:
PI:
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes
31JAN2022
Daniel J. Moore, MD, PhD
Date of IRB Approval: 03/14/2024 
Date of Expiration: 03/13/2025
Clinical Trials Registry:
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law. This 
website will not include information that can identify you. At most, the website will include a summary 
of the results. You can search this Web site at any time.
Confidentiality:
Only research associates in our laboratory or individuals directly involved in the study will have access to 
data or protected health information. Research records and data with personal identifiers will be stored 
in our locked offices or on a secure data collection program (REDCap). Only the study doctor and key 
personnel on the research team will be able to access study patients’ names or other identifying data.
Data from the study will be maintained in HIPAA-compliant, password-protected databases.
Vanderbilt may share your information, without identifiers, to others or use it for o ther research 
projects not listed in this form. Vanderbilt, Dr. Moore, and his staff will comply with any and all laws 
regarding the privacy of such information. There are no plans to pay you for the use or transferof this 
de-identifiedinformation.
This study may have some support from the National Institutes of Health (NIH). If so, your study 
information is protected by a Certificate of Confidentiality. This Certificateallows us, in some cases, to 
refuse to give out your information even if requested using legal means.
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases. The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help.
Disclosures that you consent to in this document are not protected. This includes putting research data 
in the medical record or sharing research data for this study or future research. Disclosures that you 
make yourself are also not protected.
Privacy:
Any samples and information about you may be made available to others to use for research. To protect 
your privacy, we will not release your name. You will not receive any benefit because of the tests done on 
your samples. These tests may help us or other researchers learn more about the causes, risks, treatments, 
or how to prevent this and other health problems.
Study Results:
A summary of the study results will be made availablevia https://clinicaltrials.gov/ once the project is 
complete.


7
VUMCInstitutional Review Board
Informed Consent Document for Research
Study Title:
Version Date:
PI:
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes
31JAN2022
Daniel J. Moore, MD, PhD
Date of IRB Approval: 03/14/2024 
Date of Expiration: 03/13/2025
Authorization to Use/Disclose Protected Health Information 
What information is being collected, used, or shared?
To do this research, we will need to collect, use, and share your private health information. By signing 
this document, you agree that your health care providers (including both Vanderbilt UniversityMedical 
Centerand others) may release your private health information to us, and that we may use any and all 
of your information that the study team believes it needs to conduct the study. Your private information 
may include things learned from the procedures described in this consent form, as well as information 
from your medical record (which may include information such as HIV status, drug, alcohol or STD 
treatment, genetic test results, or mental health treatment).
Whowill see, use or share the information?
The people who may request, receive, or use your private health information include the researchers 
and their staff. Additionally, we may share your information with other people at Vanderbilt, for 
example if needed for your clinical care or study oversight. By signing this form, you give permission to 
the research team to share your information with others outside of Vanderbilt University Medical 
Center. This may include the sponsor of the study and its agents or contractors, outside providers, study 
safety monitors, government agencies, other sites in the study, data managers and other agents and 
contractors used by the study team. We try to make sure that everyone who sees your information 
keeps it confidential, but we cannot guarantee that your information will not be shared with others. If 
your information is disclosed by your health care providers or the research team to others, federal and 
state confidentiality laws may no longer protect it.
Do you have to signthis Authorization?
You do not have to sign this Authorization, but if you do not, you may not join the study.
How long will your information be usedor shared?
Your Authorization for the collection, use, and sharing of your information does not expire. Additionally, 
you agree that your information may be used for similar or related future research studies.
What if you change your mind?
You may change your mind and cancel this Authorization at any time. If you cancel, you must contact the 
Principal Investigator in writing to let them knowby using the contact information providedin this consent 
form. Your cancellation will not affect information already collected in the study, or information that has 
already been shared with others before you cancelled your authorization.


8
VUMCInstitutional Review Board
Informed Consent Document for Research
Study Title:
Version Date:
PI:
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes
31JAN2022
Daniel J. Moore, MD, PhD
Date of IRB Approval: 03/14/2024 
Date of Expiration: 03/13/2025
If you decide not to take part in this research study, it will not affect your treatment, payment or 
enrollmentin any health plans or affectyour ability to get benefits. You will geta copy of this form 
after it is signed.
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY
I have read this consent form and the research study has been explained to me verbally. All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.
Date
Signature of patient/volunteer 
Consent obtained by:
Date
Study Staff Signature
Printed Name and Title

Prot_000.pdf: 
Protocol Version #: 6 
 
1 
Protocol Date: 04DEC2023 
 
 
 
 
 
 
 
 
Pancreatic enzyme replacement and glucose regulation in Type 1 diabetes 
NCT05266963 
Protocol 
12/4/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Version #: 6 
 
2 
Protocol Date: 04DEC2023 
 
 
 
 
Impact of Pancreatic Enzyme Replacement in T1D Subjects with Low Pancreas Volume 
 
 
Daniel J. Moore, M.D., PhD 
Assistant Professor of Pediatrics 
Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics 
Vanderbilt University Medical Center 
 
Alvin C. Powers, MD 
Professor of Medicine  
Division of Diabetes, Endocrinology, and Metabolism  
Vanderbilt University Medical Center 
 
Jordan Wright, M.D., PhD 
Assistant Professor of Medicine 
Division of Diabetes, Endocrinology, and Metabolism  
Vanderbilt University Medical Center 
 
Jon M. Williams, PhD 
Study Coordinator 
Division of Diabetes, Endocrinology, and Metabolism  
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Version #: 6 
 
3 
Protocol Date: 04DEC2023 
 Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or 
Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 


Protocol Version #: 6
4
Protocol Date: 04DEC2023
1.0
Background
Total pancreas volume is decreased in T1D. Recent studies have demonstrated reduced pancreatic 
volume is present within months of T1D diagnosis in children, adolescents, and adults [1-4]. As the pancreatic 
beta cells constitute only 1-2% of the pancreas, the degree of reduction in pancreas volume at disease onset 
suggests exocrine involvement, challenging the established paradigm of T1D being solely a disease of the 
endocrine pancreas. These unexpected findings raise fundamental questions that challenge our understanding 
of T1D pathogenesis and point to new questions about management. Especially relevant to the proposed 
studies, these changes in pancreatic volume and size could reflect deficiency in the exocrine pancreas which 
could alter food absorption and effect clinical management of glycemia, but this hypothesis has not been 
investigated. 
Our group has developed advanced, standardized approaches to image the pancreas and has applied this 
approach to understanding the role of whole pancreas pathology in T1D, a disease traditionally thought to only 
involve the pancreatic islet. An example image of the pancreas of a control participant and participant with 
recent-onset T1D is shown in Figures 1B and 1C, respectively, with the pancreas outlined in white. Within 100 
days of diabetes onset, individuals with T1D (n = 51) had a smaller pancreas (median volume = 29.6 ml) than 
controls (n = 58, median volume = 47.8 ml, p < 0.001), including when normalized by individual weight 
(p<0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than the 
T1D cohort (p=0.014), but smaller than the control cohort (p=0.019). To account for normal adolescent growth, 
we compared pancreas volume and weight in control study participants. In the control cohort, pancreas volume 
correlated with participant weight (Figure 1D, R = 0.76, p < 0.001). Thus, to account for changes in pancreatic 
volume during normal adolescent growth, pancreas volume was normalized by participant weight yielding what 
has been termed the pancreas volume index. Normalization by body surface area and BMI were also explored 
but were inferior to normalizing by weight. At the first study time point, the pancreas volume index was smaller 
in participants with recent-onset T1D than controls (Figure 1E; median 0.931ml/kg in controls and 0.615 ml/kg 
in T1D, p < 0.001). Pancreas volume index was smaller in participants with T1D when adjusted for age, sex, 
and BMI (mean difference -0.279 ml/kg with 95% CI -0.352 to -0.205, p < 0.001 from linear regression). Key 
data from these early studies are highlighted in Figure 1 and in our published work. As highlighted in Figure 1, 
pancreas volume declines over the first year after diagnosis (Figure 1F, G). This finding demonstrates the small 
Figure 1. A) Schematic of study design employed to study recent-onset T1D. B) An axial MRI slice through the abdomen
of a control participant shows the pancreas (outlined in white). C) An axial MRI slice through the abdomen of a participant
with recent-onset T1D shows a smaller, thinner pancreas than seen in the control (outlined in white). D) In the control
cohort, pancreas volume correlated with participant weight over the course of adolescent growth. E) Pancreas volume
normalized by participant weight, yielding a pancreas volume index in units of [ml/kg], is smaller in participants with T1D
than controls. F) Pancreas volume index is unchanged in the control pancreas over a one-year period but declines in 
participants with T1D over the year after diagnosis. G) When normalized to the baseline measurement for each study
participant, pancreas volume increases in the control population but declines in participants with T1D. 


Protocol Version #: 6 
 
5 
Protocol Date: 04DEC2023 
pancreas in T1D and the presence of an underlying process resulting in ongoing changes in the pancreas after 
diagnosis with T1D; the physiologic consequences of these changes are not known.  
 
Alterations in exocrine biochemical values in T1D. The significant reduction in pancreas size raises 
questions as to whether there is also a reduction in exocrine pancreas function. Several studies to date have 
now demonstrated reductions in key markers of exocrine enzymatic activity. These reductions include 
abnormalities in fecal elastase and reduced measured in the blood of amylase, lipase, and trypsinogen. The 
degree of these reductions range from slight deviations from normal to more profound losses of 60% or more. 
To date there has not been a detailed study of clinical symptoms in patients with T1D to determine whether 
persons living with T1D have symptoms of pancreatic exocrine insufficiency. 
 
Role of Enzyme Replacement in Diabetes Management. To date there has not been an investigation of 
the potential for pancreatic enzyme replacement therapy in the management of T1D. Related information can 
be gleaned from treatment of cystic-fibrosis related diabetes (CFRD) which is characterized by a strong 
component of exocrine insufficiency related to the CFTR mutation. In individuals with CFRD, enzyme replacement 
has been shown to reduce post-prandial glycemia excursions, which are reflected in improved GLP-1 responses 
to mixed meal tolerance testing. As post-prandial excursions and glucose variability are a significant challenge 
in T1D, how enzyme replacement may impact these parameters is an important question. 
 
2.0 
Rationale and Specific Aims 
 
We hypothesize that patients with T1DM who have reduced pancreatic volume will have improved 
glycemic responsiveness, reduced hypoglycemia, and improved symptoms of pancreatic exocrine 
insufficiency (PEI) when treated with pancreatic enzyme replacement. To test our hypotheses, we will 
employ a double-blinded crossover study. This study will be a pilot study to gather preliminary information on 
potential effect size in preparation for a larger study if supported by these results. The study will enroll 
approximately 15 adult subjects with T1D who will receive both pancreatic enzyme replacement (Creon) or 
placebo each for 7 days in a random order. The effect of the intervention will be monitored by continuous 
glucose monitoring, diet recording, capsule counts, a mixed-meal tolerance test, and a survey to assess 
symptoms of PEI. This study design will allow for estimation of the effect of pancreatic enzyme replacement on 
the measured parameters. 
 
Aim 1 will provide preliminary estimates of the effect of enzyme replacement on glucose 
responsiveness, variability, and hypoglycemia. We will download and analyze CGM data to determine 
changes occurring in measures of glycemic variability and in the duration and severity of hypoglycemia. Data 
will be divided into 4 7-day blocks including a run-in period, treatment A, a wash out period, and treatment B. 
Participants will track their meal composition, report daily exercise duration, and a capsule count will be obtained. 
At the end of treatment A and treatment B, participants will undergo a mixed meal tolerance test (MMTT) in 
which glucose, C-peptide, GLP-1, GIP, and glucagon will be measured at defined timepoints. 
 
Aim 2 will provide an initial assessment of the effect of enzyme replacement on symptoms of 
pancreatic exocrine insufficiency in T1D.  We will use the PEI-Q to quantitate symptoms of PEI and their 
relative change during enzyme replacement at each of the 4 intervals. The frequency and degree of PEI 
symptoms has not been objectively measured in T1D patients previously. 
 
We will obtain information on the adherence to the intervention and will obtain initial information on median and 
standard deviation for measured variables that will inform future studies. We will perform a paired t-test to 
provide an initial assessment of outcomes between groups.  
 
This proposed research will be the first study to determine the effect of enzyme replacement therapy on glycemic 
variability and patient-reported symptoms or PEI in T1D.  
 


Protocol Version #: 6 
 
6 
Protocol Date: 04DEC2023 
 
3.0 
Animal Studies and Previous Human Studies 
There have been no previous animal or human studies of the effects of pancreatic enzyme replacement on 
glucose regulation in T1D. The reported studies to date, as discussed in the background, strongly support that 
there is pancreatic volume loss and resultant reduction in exocrine enzymes in T1D. However, the clinical 
impact of this change is not known; an impact of pancreatic enzyme deficiency and enzyme replacement on 
glucose tolerance/responsiveness in CFRD has been described. 
 
4.0 
Inclusion/Exclusion Criteria 
 
Table 1: Inclusion and Exclusion Criteria  
Inclusion Criteria 
Exclusion Criteria  
• 
Diagnosed with T1DM for at least 12 months 
• 
Age over 18  
• 
Total daily dose of insulin greater than 
0.6u/kg/day 
• 
Current use of a CGM 
• 
Current use of smart phone 
• 
Able to read and speak English  
• 
Willingness and ability to download and 
provide CGM and pump (if applicable) data 
• 
Reduction of pancreas volume (<0.6mL/kg 
BW) 
• 
History of celiac disease or inflammatory 
bowel disease 
• 
Unwilling to temporarily discontinue use of 
medication or supplements other than insulin 
to control blood glucose  
• 
Pregnant or breast feeding 
• 
Following a restrictive diet (such as very low 
carb diet) 
• 
History of major bowel or bariatric surgery 
 
 
5.0 
Enrollment/Randomization 
 
5.1 
Recruitment 
5.1.1 Recruitment Resources 
We have previously completed a study of over 70 patients with T1D in which they have 
received one or more MRI studies. This study group allows us to identify patients with 
significantly reduced pancreas volume for enrollment in this study.   
 
5.1.2 Initial Contact with Potential Participants 
Participants will be contacted by telephone. The initial discussion will provide information 
about the study and assess whether the subject might be eligible to participate in the 
study.  Study personnel will ask the potential subject to confirm his or her: 
- 
Diagnosis of T1DM  
- 
Age 
- 
Weight 
- 
Height 
- 
Diabetes duration  
- 
Medications 
- 
Food preferences and restrictions 
-  
Use of CGM  
-  
Ability to read and speak English 
 
Inclusion and exclusion criteria are listed in table 1. We will invite eligible subjects to 
participate in the initial screening visit. The initial screening visit will occur at Vanderbilt 
University Medical Center. The participant will receive an electronic or paper copy of the 
informed consent document to review prior to the initial screening visit.  
 


Protocol Version #: 6 
 
7 
Protocol Date: 04DEC2023 
 
5.2 
Enrollment 
A member of the study team (i.e. key study personnel, KSP) will obtain written, informed 
consent at the beginning of the screening visit as detailed in section 6.1.1.1. Once consent is 
obtained, the participant will be enrolled in the study.  
 
5.3 
Randomization  
Patients will be randomized for order to receive pancreas enzyme replacement or placebo. The 
Vanderbilt Investigational Drug Services (IDS) pharmacy will do the randomization. They will 
dispense the randomized capsule bottles for weeks A and B to the study team to be given to 
the study participants. 
 
5.4 
Participant Compensation 
Participants will receive $200 for each completed MMTT for a total of up to $600 for 
participation in the study. 
 
6.0 
Study Procedures 
 
6.1 
Research visits 
 
6.1.1 Study Visit 1, Initial Screening Visit  
Screening visits will take place in a room designated for research in the Eskind Diabetes Center 
or in the CRC.  
 
The purpose of the screening visit is to:   
- 
obtain informed, written consent,  
- 
confirm each participant is able to properly upload their continuous glucose monitor (CGM) 
and pump (if applicable),  
- 
provide participants with blinded treatments (pancreatic enzyme replacement and placebo)  
- 
show participants how to log their food intake on their digital device. 
 
The screening visit will consist of the following:  
6.1.1.1 
Consent 
The PI or designated KSP will obtain consent from all participants. Consent will 
be obtained in a private room in the Eskind Diabetes Center prior to beginning 
study procedures. The consent form will be provided to the subject for review 
prior to the visit. The PI or designated Key Study Personnel will review the 
consent forms with the participant in detail and provide time for discussing any 
questions. The study team will provide a copy of the consent form to the 
participant if applicable.  
 
6.1.1.2 
History and Initial Measurements 
The PI or designee will review each subject’s clinical history and take 
anthropometric measurements (Height/Weight). 
 
 
 
6.1.1.3 
Nutritional Tracking App Instructions 
The study team will use a nutritional tracking smartphone application, such as 
Nutrihand, MyFitnessPal, or FatSecret, on which participants will log their daily 
caloric intake using the software’s web-based or Smartphone app interfaces.  


Protocol Version #: 6 
 
8 
Protocol Date: 04DEC2023 
Participants will be asked to track intake using this smartphone app throughout 
the study. 
 
Participants may be asked to use their personal email to send a CSV file 
containing data files from the smartphone app to the study team.  This CSV 
file does not contain any PHI.  The file will be directly uploaded into REDCap, 
then the email will be deleted. 
 
6.1.1.4 
Continuous Glucose Monitor Instructions  
The study team will instruct participants in the use of a continuous glucose 
monitor (CGM) such as Dexcom G6 or Medtronic Guardian or Freestyle Libre 
for the monitoring of glycemia during the study. The team will then show T1DM 
participants how to upload CGM data into a HIPAA and FDA-compliant cloud-
based, data-integration platform such as Dexcom Clarity or Tidepool.   
 
6.1.1.5 
Insulin Instructions 
For participants using insulin pumps, the study team will instruct T1DM 
participants in the transmittal of data derived from an insulin pump such as 
Medtronic Minimed 670G, Tandem T-Slim, or Omnipod Insulim Management 
System.  Participants will be encouraged to administer all insulin via insulin 
pump and enter all carbohydrates consumed into the insulin pump. The team 
will then show T1DM participants how to upload insulin pump data into a HIPAA 
and FDA-compliant cloud-based, data-integration platform such as Medtronic 
Careline or Tidepool.  Participants not using an insulin pump wil be asked to 
record their insulin doses given throughout the day. 
 
 
6.1.1.6 
Randomization and Treatment Plan 
Participants will be randomized for order in which enzyme replacement or placebo is 
received. An equal number of participants will receive either order (A/B or B/A). 
Participants will receive a range of 50,000-100,000 lipase units per meal (approx. 2 Creon 
36,000 capsules) and 25,000-50,000 per snack (1 capsule). The participant will be 
instructed to take same number of capsules of placebo. Participant and provider will be 
blinded to capsule assignment. 
 
 
6.1.2 Study visit (baseline)  
6.1.2.1 
Demographic and history information will be obtained. 
6.1.2.2 
Participant will be counseled on using and uploading devices and information. 
6.1.2.3 
Participant will complete a baseline Mixed Meal Tolerance Test (MMTT). The 
test will be administered according to the well established practices used in the 
TrialNet clinical T1D research program and described in the included appendix. 
This baseline visit will take place in the Adult Clinical Research Center (CRC). 
 
6.1.3 Study Visit (end of week A) 
6.1.3.1 
On last day of week A, subject will have an MMTT at the Adult CRC. 
 
6.1.4 Study Visit (end of week B/end of study) 
This visit will include an MMTT at the Adult CRC and will be scheduled on the last day of 
week B. 
 
6.1.4.1 
History and measurements 


Protocol Version #: 6 
 
9 
Protocol Date: 04DEC2023 
The PI or designee will review each subject’s clinical history and take anthropometric 
measurements.  
 
6.1.4.2 
Continuous glucose monitor and insulin pump data collection 
Continuous glucose monitor and insulin pump will be downloaded into a HIPAA and FDA-
compliant cloud-based, data-integration platform such as Dexcom Clarity, Medtronic 
Carelink, or Tidepool.  
 
Information that will be collected from the continuous glucose monitor download will 
include (but not be limited to):  
- 
Percent of time spent above the glycemic target of 140 mg/dL 
- 
Percent of time spent in the glycemic target of 70 – 140 mg/dL 
- 
Percent of time spent below the glycemic target of 70 mg/dL 
- 
Percent of time spent in hypoglycemia below 50 mg/dL 
- 
Average blood glucose 
- 
Blood glucose standard variation 
- 
All blood glucose values during the study interval  
 
Information that will be collected from the insulin pump download will include (but not be 
limited to): 
- 
Average total daily dose of insulin 
- 
Average bolus amount of insulin per day 
- 
Average basal amount of insulin per day 
 
6.1.4.3 
Nutritional tracking smartphone application data collection  
 
Information that will be collected from the smartphone app will include (but not be limited 
to):  
 
- 
Total number of calories consumed  
- 
Average grams of carbohydrates consumed per day 
- 
Average grams of fat consumed per day 
- 
Average grams of protein consumed per day 
- 
Additional macronutrient data 
 
6.1.4.4 
Pancreatic Exocrine Insufficiency Questionnaire 
Participants will complete the PEI-Q, a validated measure of PEI symptoms at baseline 
and at end of Week A and Week B. All surveys will be scored by a member of the research 
team. 
 
6.1.4.5 
Diet Instructions 
Patients will be instructed to follow their routine diet. 
6.1.4.6 
Quality Assurance of Interventions 
A capsule count will be performed at end of study to assess adherence to treatment 
assignment. 
 
6.1.4.7 
Mixed Meal Tolerance Test 
Subjects will participate in an MMTT at baseline and at end of Week A and Week B. The 
protocol for the MMTT is described in the Appendix; as a slight modification of the 
Appendix, an additional 8.5 ml tube of blood will be drawn at each time point. 


Protocol Version #: 6 
 
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Protocol Date: 04DEC2023 
 
7.0 
Risks 
 
7.1 
The following risks associated with participation are considered: 
7.1.1 Hypoglycemia 
Hypoglycemia is encountered intermittently by all patients with T1DM as part of the natural 
consequence of diabetes management with exogenous insulin administration, and we do not 
anticipate that this risk will be increased by utilizing enzyme replacement treatment. 
 
We will use the following safety provisions to minimize risk of hypoglycemia: participants will 
monitor their blood sugar via continuous glucose monitor. Participants will be reminded that if 
hypoglycemia occurs, the patient should treat hypoglycemia with oral intake (administer 15 
grams of carbohydrates in liquid form or with glucose tablets) if the patient is responsive and 
able to consume the treatment orally.  If the patient is unresponsive, the study team would 
instruct the participant’s caretaker to administer intramuscular glucagon.  The study team will 
ensure that the participants have an up-to-date glucagon kit at time of enrollment.  
 
 
7.2 
Discussion of Risks as Part of the Consent Process  
The study team will discuss all procedures, risks, and benefits with potential study participants, 
as part of the consent process. An IRB approved written informed consent document will be 
required for participation in this study. It is understood that consent is a process and not a 
discrete event.  A participant’s decision to withdraw consent will be respected throughout the 
duration of each subject’s participation in this study. It is also understood that there may be as-
yet unknown or unanticipated adverse effects of this study. The study team will continually 
monitor for these effects and consider altering the protocol as needed to ensure patient safety.  
Changes in the procedures of the study, as well as any change(s) in the risks and/or benefits 
will be presented to and discussed with the subjects upon approval from the IRB for 
implementation of such revision(s), and any IRB revised written consent will be signed, as 
appropriate.   
 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or 
Others 
 
8.1 
Serious Adverse Events 
8.1.1 Defining Serious Adverse Events 
Consistent with FDA guidelines, serious adverse events (SAEs) will be defined as any 
untoward medical occurrence that: 
- 
requires inpatient hospitalization 
- 
results in persistent or significant disability 
- 
is suspected to cause a congenital anomaly or birth defect in a subject's unborn child 
- 
is life-threatening 
- 
results in death 
- 
is considered to be an important medical event based on appropriate medical 
judgement (e.g. bronchospasms requiring emergency department referral, seizures 
that might not result in hospitalization). 
 
8.2 
Assessing relationship between a SAE and relationship to study procedures 
An SAE's relationship to the study procedures will be assessed and graded as either: not 
related, unlikely, possible, probable, or definite. 
 


Protocol Version #: 6 
 
11 
Protocol Date: 04DEC2023 
8.3 
Assessing whether an AE is an anticipated problem 
Any AE will be assessed for whether or not it was an anticipated problem. In accordance with 
Department of Health and Human Services guidance and consistent with 45 CFR part 46, an 
"unanticipated problem" will include any incident, experience, or outcome that meets all of the 
following criteria: 
1. unexpected (in terms of nature, severity, or frequency) given  
a. the research procedures that are described in the protocol-related documents, 
including the IRB-approved research protocol and informed consent document; and  
b. the characteristics of the subject population being studied; related or possibly 
related to participation in the research; and 
2. suggests that the research places subjects or others at a greater risk of harm. 
3. related or possibly related to participation in the research; 
4. suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
 
8.4 
Hypoglycemia 
Hypoglycemia Instances of significant impairment consistent with hypoglycemia and requiring 
assistance (ie, often referred to as “severe” hypoglycemia), even in the absence of a blood 
glucose reading, are classified as “Level 3 Hypoglycemia” (IHSG 2017). Level 3 hypoglycemia 
may include cognitive impartment, altered/loss of consciousness, confusion, seizure, 
syncope/fainting, or coma, and support may be general assistance, glucagon, or oral 
carbohydrate (ie, fruit juice or glucose tablets). Such episodes may or may not require medical 
attention or hospitalization. This study will consider clinically significant hypoglycemia to be 
Grade 3 or greater hypoglycemia as defined below. Grade 1 and Grade 2 hypoglycemia are 
expected normal consequences of T1D and will not be recorded as AEs for this protocol. For AE 
reporting purposes, the severity of a hypoglycemia event should be identified by the 
Investigator and classified according to CTCAE v5.0 as follows:  
• 
Grade 3 hypoglycemia: 30-39 mg/dL (1.7–2.1 mmol/L). This is considered severe or 
medically significant but not immediately life-threatening. Hospitalization or prolongation 
of hospitalization may be indicated. It is likely to be disabling and to limit self-care. 
• 
Grade 4 hypoglycemia: ≤29 mg/dL (1.6 mmol/L). This is considered life threatening (eg, 
seizures) with urgent intervention indicated.  
• 
Grade 5 hypoglycemia: Hypoglycemia resulting in death. 
 
8.5 
Unanticipated, non-serious AEs 
All unanticipated, non-serious AEs and the study team’s response to the non-serious AE will be 
included in a report at the time of annual continuing review.  The PI will review the AEs and 
notify the IRB of any changes needed to the protocol. If needed, appropriate changes will be 
made to the consent form.   
 
8.6 
Unanticipated SAEs 
In accordance with IRB policy, any unanticipated SAE that is considered possibly related to 
participation in the study will be reported within 7 calendar days of the PI's notification of the 
event to the IRB. The study team will continue to follow or obtain documentation of the 
resolution of any SAE.   
 
8.7 
Adverse Event Reporting 
The annual summary of all unanticipated adverse events and any audit reports will be sent to 
the IRB at the time of continuing review.  
 


Protocol Version #: 6 
 
12 
Protocol Date: 04DEC2023 
This protocol will be reviewed annually (at a minimum) by the Vanderbilt IRB.  The goal of this 
process is to determine the risks and benefits of the study in the actual experience of subjects 
and that measures taken to minimize risks are adequate 
 
9.0 
Study Withdrawal/Discontinuation 
 
Subjects will be free to withdraw from the study at any time, which will be made clear at enrollment. Subjects 
will be withdrawn from the study if:  
- 
Pregnancy is detected 
- 
The PI’s (or designated MD, NP, or PA KSP) medical judgement is that participation places the subject 
at risk for harm. 
 
10.0 Statistical Considerations 
 
10.1 
Recruitment  
We have targeted an accrual of 15 participants in this pilot study. We will estimate the effect 
size and variance of the intervention on glycemic variability and symptoms. We will also 
ascertain the intra-individual variation from comparison between our two non-treatment 
intervals (run-in and wash-out periods) which will set a lower bound on measurable effects. To 
estimate the pilot study’s optimum accrual, we utilized the method of Whitehead et al. which 
proposes stepped increases in sample size based on the anticipated standard difference, d, 
between interventions1,2.  We defined the minimum important difference (MID) in low blood 
glucose index, a measure of low blood glucose from CGM data) between enzyme replacement 
and placebo interventions as 1 (difference in values of 3 for more variable and 2 for less 
variable as reflected in clinical experience) and estimated a pooled SD of 1.29 based on our 
review of CGM data from other studies.  If d=MID/SDpooled=1/1.29=0.77, a sample size of 15 
participants per arm will optimize future sample size calculations for a definitive study. 
 
10.2 
Statistical Analysis  
Statistical analysis will be performed using a paired samples t-test to compare differences 
between the two groups.   
 
11.0 Privacy/Confidentiality Issues 
 
A database will be designed for this study using REDCap (Research Electronic Data Capture) tools. REDCap is 
a secure, web-based application designed to support data capture for research studies, providing validated 
data entry, audit trails, seamless data downloads to common statistical packages, and mechanisms for 
importing data from external sources. It will reside on a secure server with access provided exclusively to the 
research personnel. Subjects will be identified with a study identification number. A key to the subject 
identification number will be kept in a separate locked file drawer to which only the Principal Investigator and 
research coordinators have access. Reports will thereby be generated without Protected Health Information 
(PHI) data, and access will be restricted so that statisticians, etc. don't have access to all data. 
 
Risk of leakage of PHI is minimized by keeping paper records in a locked cabinet and maintaining 
computerized records in the password protected REDCap data base. The principal investigator and the 
research staff are trained in HIPAA privacy regulations. The participant's identification is concealed, and a 
number is used as the identifier instead of the subject's name.  Only the principal investigator or members of 
the research team will have the list of study patient's names as the correlate with the study number. 
 
12.0 Follow-up and Record Retention 
 


Protocol Version #: 6 
 
13 
Protocol Date: 04DEC2023 
The study is anticipated to last for up to eighteen months.  The study results will be maintained indefinitely for 
research purposes. 
 
REFERENCES 
1. 
Bell ML, Whitehead AL, Julious SA. Guidance for using pilot studies to inform the design of intervention 
trials with continuous outcomes. Clinical epidemiology 2018;10:153-7. 
2. 
Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised 
trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome 
variable. Statistical methods in medical research 2016;25:1057-73. 
 

SAP_001.pdf: 
Pancreatic enzyme replacement and glucose regulation in Type 1 
diabetes 
 
NCT05266963 
 
Statistical Analysis Plan 
 
12/4/2023 


Statistical Analysis Plan 
NCT05266963 - Pancreatic Enzyme Replacement and Glucose Regulation in Type 1 
Diabetes (CREON) 
 
 
Background 
In T1D, there is significant reduction in pancreas volume. The biological impact of this is not 
known. Because islet cells make up a small fraction of pancreas size, the major reduction in 
volume is due to loss of exocrine tissue. Since patient with T1D have substantial loss of exocrine 
tissue and pancreatic enzymes support glucoe regulation and pancreas function, this study tests 
the hypothesis that pancreatic enzyme replacement will improve C-peptide secretion to regulate 
glucose excursions and/or will improve symptoms of pancreatic exocrine insufficiency. This 
document provides additional description of the analysis plan and complements the protocol 
document where study details are provided. 
 
 
Primary objective 
Aim 1: To assess impact of pancreas enzyme replacement on C-peptide auc in subjects with T1D 
and reduced pancreas volume 
Aim 2: To assess the impact of pancreas enzyme replacement on symptoms of pancreatic 
exocrine insufficiency (PEI) in T1D. 
Secondary Objectives 
Secondary assessments will be made to explore mechanisms of effect if the primary outcome is 
met. These could include analysis of CGM data, measure of circulating hormones and cytokines, 
assessment of dietary intake. 
Trial Design 
The study is a single center, double-blinded randomized cross over design in which subjects 
receive Creon or placebo each for 1 week with a 1 week washout period between. 
Eligibility 
 
Inclusion Criteria 
Exclusion Criteria 
• Diagnosed with T1DM for at least 
12 months 
• Age over 18 
• Total daily dose of insulin greater 
than 0.6u/kg/day 
• History 
of 
celiac 
disease 
or 
inflammatory bowel disease 
• Unwilling to temporarily discontinue 
use of medication or supplements 


• Current use of a CGM 
• Current use of smart phone 
• Able to read and speak English 
• Willingness and ability to download 
and provide CGM and pump (if 
applicable) data 
• Reduction of pancreas volume 
(<0.6mL/kg BW) 
other than insulin to control blood 
glucose 
• Pregnant or breast feeding 
• Following a restrictive diet (such as 
very low carb diet) 
• History of major bowel or bariatric 
surgery 
 
Treatment 
Participants will continue their standard care for diabetes with calculation and adjustment of 
doses per their primary endocrinologists. 
Participants will receive a range of 50,000-100,000 lipase units per meal (approx. 2 Creon 
36,000 capsules) and 25,000-50,000 per snack (1 capsule). The participant will be instructed to 
take same number of capsules of placebo. Participant and provider will be blinded to capsule 
assignment. 
Assessment of Outcomes 
Outcomes will be assessed at baseline and at completion of each treatment week. 
Hypothesis 
The null hypothesis to be tested is that there will be no difference between the treatment groups. 
Blinding 
Subjects and investigators will be blinded to treatment assignment. Blinded drug or placebo is 
provided by the VUMC Investigational Pharmacy. 
Analysis 
Only subjects completing both arms will be included in the final analysis. 
Data collection 
Demographics: Participants age, sex, weight will be obtained. 
Diabetes Management: Participants estimated or actual insulin dosing, CGM download, diet 
history, pancreas volume index will be obtained. 
Study results: Participants will complete MMTT and PEI questionnaires. 
Adherence 


Pill counts will be obtained. Participants with significant discrepancy between pill count and diet 
history may be excluded from analysis. 
Primary Outcome Analysis 
C-peptide AUC will be calculated from MMTT data. Data from creon and placebo intervals will 
be compared for each individual in a matched analysis. Comparison will be made by Wilcoxon 
matched-pairs assessment. 
Severity score will be calculatd from the PEI-Q survey. Data from creon and placebo intervals 
will be compared for each individual in a matched analysis. Comparison will be made by t-test 
Statistical Software 
Analysis will be performed on Prism Ver 10 or on current version of Microsoft excel. 
Exploratory Analysis 
Additional analyses may be performed if primary endpoint is met to provide mechanistic insight 
or if requested by journal or editorial review.