Imaging Biomarkers of Pancreatic Function and Disease

Diabetes Mellitus Clinical Trial

Official title:

Imaging Biomarkers of Pancreatic Function and Disease

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05659147
• Other study ID #: 2022-0779
• Secondary ID: R01DK132346
• Status: Enrolling by invitation
• Phase: Phase 4
• Start date: January 18, 2023
• Est. completion date: December 2027

Study information

• Verified date: February 2024
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study seeks to understand the performance of MRI to characterize pancreatitis and predict chronic complications (endocrine and exocrine) of pancreatitis. Through multiple aims, the investigators will benchmark MRI against relevant reference standards (e.g. endoscopic pancreatic function tests, laboratory data). The investigators will also characterize repeatability of the imaging findings and will work to develop methods to simplify and automate analysis of the MRI images.

Research interventions depend on the Aim(s) participants enroll in but include: endoscopic pancreatic function testing (added on to clinically indicated upper GI endoscopy), blood tests, stool tests, gene sequencing, and survey completion. All participants will undergo research MRI examinations, a subset of which will include administration of intravenous secretin.

Description:

Pancreatitis can be acute [AP], acute recurrent [ARP] (defined as two discrete attacks with interval resolution), or chronic [CP]. Adult studies show that up to 40% of patients develop abnormal glucose metabolism after a single attack of AP, with a 2.5x increased risk of diabetes. CP is defined, in part, by the presence of established endocrine (diabetes) or exocrine pancreatic insufficiency [EPI]. Currently, it is not possible to non-invasively diagnose or predict development of pancreatitis-related endocrine or exocrine insufficiency.

The investigator's data has shown that CFTR gene variants play a significant role in progression to diabetes post first attack AP. Existing literature suggests that imaging findings such as decreased pancreas volume are associated with diabetes, but this has not been systematically studied in children.

EPI, defined as insufficient secretion of digestive enzymes and fluid by the pancreas, can have significant effects in childhood including malnutrition, osteoporosis, and growth failure. If diagnosed early, EPI can be treated with pancreatic enzyme replacement, improving nutrition and stabilizing growth. Unfortunately, diagnosing EPI early and accurately is a challenge in children and it is currently not possible to predict progression to CP or development of EPI.

Magnetic resonance imaging (MRI) is a powerful, non-invasive technique, capable of characterizing pancreatic disease. Quantitative non-contrast MRI techniques are attractive as potential markers of pancreatic disease but they have not been validated for diagnosis or prediction of diabetes or EPI in children and they have not been explored for staging of pediatric pancreatitis.

The overall goals of this study are to:

1. Define associations between non-invasive, quantitative MRI measures and established measures of pancreas health and function including diabetes and EPI in children

2. Identify clinical, genetic and imaging-related factors that predict progression to diabetes in children with pancreatitis.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 195
• Est. completion date: December 2027
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 5 Years to 21 Years

Eligibility

Aim 1-

Patient Group:

Inclusion Criteria:

• Age 5 to <21 years

• Scheduled for clinically-indicated gastrointestinal endoscopy

• Clinical diagnosis or suspicion of exocrine pancreatic insufficiency

Exclusion Criteria:

• Complete fatty replacement of pancreas on prior imaging

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Allergy to secretin

• Pregnancy

Control Group:

Inclusion Criteria:

• Age 5 to <21 years

• Scheduled for clinically-indicated gastrointestinal endoscopy

Exclusion Criteria:

• Sweat chloride >60 mmol/L

• Clinical diagnosis of gastrointestinal pathology

• Clinical diagnosis or history of pancreatic disease

• Complete fatty replacement of pancreas on prior imaging

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Allergy to secretin

• Pregnancy

Aim 2-

Acute Pancreatitis Group:

Inclusion Criteria:

• Age 5 to <21 years

• Clinically documented episode of acute pancreatitis

Exclusion Criteria:

• More than one episode of acute pancreatitis

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Pregnancy

Acute Recurrent Pancreatitis Group:

Inclusion Criteria:

• Age 5 to <21 years

• Clinical diagnosis of acute recurrent pancreatitis

Exclusion Criteria:

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Pregnancy

Pancreatitis-Related Diabetes Group:

Inclusion Criteria:

• Age 5 to <21 years

• Clinical diagnosis of pancreatitis-related diabetes

Exclusion Criteria:

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Pregnancy

Aim 3-

Control Group:

Inclusion Criteria:

• Age 5 to <21 years

Exclusion Criteria:

• Sweat chloride >60 mmol/L

• Clinical diagnosis of gastrointestinal pathology

• Clinical diagnosis or history of pancreatic disease, including acute pancreatitis

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Allergy to secretin

• Pregnancy

Acute Pancreatitis Group:

Inclusion Criteria:

• Age 5 to <21 years

• Clinically documented episode of acute pancreatitis

Exclusion Criteria:

• More than one episode of acute pancreatitis

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Allergy to secretin

• Pregnancy

Acute Recurrent Pancreatitis Group:

Inclusion Criteria:

• Age 5 to <21 years

• Clinical diagnosis of acute recurrent pancreatitis with no evidence of CP or EPI

Exclusion Criteria:

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Allergy to secretin

• Pregnancy

Chronic Pancreatitis Group:

Inclusion Criteria:

• Age 5 to <21 years

• Clinical diagnosis of chronic pancreatitis

Exclusion Criteria:

• Current acute pancreatitis or acute pancreatitis less than 30 days prior to research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Allergy to secretin

• Pregnancy

Aim 4-

Inclusion Criteria:

• Age 5 to <21 years

• Completed research MRI under Aims 1 or 3 of this study

Exclusion Criteria:

• Failed/unable to complete first research MRI under Aims 1 or 3

• Episode of acute pancreatitis since first research MRI

• Current acute pancreatitis

• Any gastrointestinal surgery or pancreas intervention (e.g. ERCP) since first research MRI

• Need for sedation for MRI

• Contraindication to MRI (implanted metal hardware)

• Allergy to secretin

• Pregnancy

Aim 5-

Inclusion Criteria:

• MRI performed at CCHMC

Exclusion Criteria:

• Severe image artifact compromising image quality (judgement of study team)

• Age >21 years

Related Conditions & MeSH terms

• Diabetes Mellitus
• Pancreatitis

Intervention

Diagnostic Test:
• Research MRI without administration of intravenous secretin
Participants will undergo a research MRI examination. MRI images will be quantitatively analyzed and will be compared to / used to predict diabetes.
• Research MRI with administration of intravenous secretin
Participants will undergo a research MRI examination with intravenous administration of secretin. MRI images will be quantitatively analyzed and will be compared to / used to predict exocrine and endocrine pancreatic insufficiency based on the reference standards of ePFTs or fecal elastase and blood hemoglobin A1c (HbA1c) and fasting glucose, respectively.

Genetic:
• Genetic Sequencing
Blood will be drawn to enable gene sequencing for gene mutations associated with heritable pancreatitis. We will assess the association between identified gene variants and the presence of diabetes and will construct models based on identified variants to predict progression to diabetes.

Diagnostic Test:
• Blood Tests
Research blood draw (for markers of pancreatic endocrine insufficiency)
• Stool Tests
Research stool collection (for fecal elastase as a marker of exocrine insufficiency)

Other:
• Survey Completion
Participants will be contacted to complete a survey and their charts will be reviewed annually after research MRI to identify any evidence of subsequent development of pancreatic endocrine insufficiency or progression of pancreatitis. Survey and chart review will occur within +/- 14 days of the anniversary date.

Diagnostic Test:
• Endoscopic pancreatic function tests (ePFTs)
At least two duodenal fluid aspirates will be collected over 15 minutes following secretin administration. Aspirates will be immediately pH tested and will be submitted for analysis of bicarbonate, enzyme (trypsin, amylase, lipase, chymotrypsin) activity, and total protein.

Drug:
• Secretin
Participants enrolled in Aim 1, Aim 3, and Aim 4 will receive intravenous secretin at a dose of 0.2 mcg/kg (maximum 16 mcg). Participants in Aim 1 will receive two doses (1 during endoscopy and 1 during MRI). Participants in Aim 3 will receive one dose during MRI. Participants in Aim 4 will receive two doses (1 during each MRI). Secretin for intravenous use is FDA-approved for stimulation of pancreatic secretions, including bicarbonate, to aid in the diagnosis of exocrine pancreas dysfunction. Safety and effectiveness of secretin in pediatrics have not been established. However, secretin is routinely used in children at CCHMC at the same dose at which it will be administered for this study.

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pancreas volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).	2 x 2 table analyses of pancreas volume (categorized as normal vs. abnormal) vs. exocrine function (categorized as normal vs. abnormal)	5 years
Primary	Pancreas volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).	2 x 2 table analyses of pancreas volume (categorized as normal vs. abnormal) vs. endocrine function (categorized as normal vs. abnormal)	5 years
Primary	Pancreas T1 signal as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).	2 x 2 table analyses of pancreas T1 signal (categorized as normal vs. abnormal) vs. exocrine function (categorized as normal vs. abnormal)	5 years
Primary	Pancreas T1 signal as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).	2 x 2 table analyses of pancreas T1 signal intensity (categorized as normal vs. abnormal) vs. endocrine function (categorized as normal vs. abnormal)	5 years
Primary	Pancreas secreted fluid volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).	2 x 2 table analyses of pancreas secreted fluid volume (categorized as normal vs. abnormal) vs. exocrine function (categorized as normal vs. abnormal)	5 years
Primary	Pancreas secreted fluid volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).	2 x 2 table analyses of pancreas secreted fluid volume (categorized as normal vs. abnormal) vs. endocrine function (categorized as normal vs. abnormal)	5 years
Primary	Frequency of genetic mutations in patients progressing to diabetes vs. those not	Frequency of genetic mutations in each study group will be compared using 2x2 tables to identify mutations associated with development of diabetes	5 years