Imaging Biomarkers of Pancreatic Function and Disease

Cincinnati Children's Hospital Medical Center

Status and phase: Invitation-only; Phase 4

Conditions: Diabetes Mellitus; Pancreatitis

Treatments: Diagnostic Test: Endoscopic pancreatic function tests (ePFTs); Other: Survey Completion; Diagnostic Test: Blood Tests; Diagnostic Test: Stool Tests; Genetic: Genetic Sequencing; Drug: Secretin; Diagnostic Test: Research MRI without administration of intravenous secretin; Diagnostic Test: Research MRI with administration of intravenous secretin

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05659147

R01DK132346 (U.S. NIH Grant/Contract)

2022-0779

Details and patient eligibility

About

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.

Full 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.

Enrollment: 195 estimated patients

Sex: All

Ages: 5 to 21 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Diagnostic

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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195 participants in 5 patient groups

Imaging markers of exocrine and endocrine insufficiency

Experimental group

Description:

We will prospectively enroll 85 participants; 40 with known or suspected EPI and 45 controls (no known organic gastrointestinal pathology and no history of pancreatic disease) in this aim. Participants will be undergoing clinically-indicated endoscopy and will have endoscopic pancreatic function tests (ePFTs) collected for research during the clinically-indicated endoscopy examination. A research blood draw and a research stool collection will also be collected from all participants. Participants will undergo a research MRI examination with administration of intravenous secretin within 2 weeks of their clinical endoscopy but no sooner than 2 hours before or after endoscopy.

Treatment:

Diagnostic Test: Research MRI with administration of intravenous secretin

Drug: Secretin

Diagnostic Test: Stool Tests

Diagnostic Test: Endoscopic pancreatic function tests (ePFTs)

Other: Survey Completion

Diagnostic Test: Blood Tests

Imaging markers of diabetes and prediction of progression to diabetes

Experimental group

Description:

We will prospectively enroll 30 participants; 10 with a single episode of acute pancreatitis, 10 with acute recurrent pancreatitis, and 10 with pancreatitis-related diabetes in this aim. Participants will undergo a research MRI examination. Participants will also undergo a research blood draw for laboratory analysis and 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.

Treatment:

Diagnostic Test: Research MRI without administration of intravenous secretin

Genetic: Genetic Sequencing

Other: Survey Completion

Diagnostic Test: Blood Tests

Imaging stratification of stages of pancreatitis

Experimental group

Description:

We will prospectively enroll 60 participants; 15 healthy controls, 15 participants with a single episode of acute pancreatitis, 15 participants with acute recurrent pancreatitis, and 15 participants with chronic pancreatitis. A research blood draw and a research stool collection will be collected from all participants. Participants will undergo a research MRI examination with administration of intravenous secretin.

Treatment:

Diagnostic Test: Research MRI with administration of intravenous secretin

Drug: Secretin

Diagnostic Test: Stool Tests

Other: Survey Completion

Diagnostic Test: Blood Tests

Imaging reproducibility

Experimental group

Description:

We will prospectively enroll up to 20 participants enrolled in Aims 1 or 3 (up to 5 controls and 15 patients with pancreatic disease) to undergo repeat research MRI imaging between 24 hours and 14 days after their first research MRI. Participants will undergo a research MRI examination with administration of intravenous secretin, identical to the research MRI performed under Aims 1 or 3. MRI images will be quantitatively analyzed and agreement between the two MRI examinations (1st and repeat MRI) will be assessed.

Treatment:

Diagnostic Test: Research MRI with administration of intravenous secretin

Drug: Secretin

Automated or semi-automated image analysis

No Intervention group

Description:

We will use images prospectively collected under Aims 1-3, as well as existing images that had been obtained for clinical care of children with pancreatitis at CCHMC to develop and optimize image processing pipelines for MRI images. Performance of these pipelines will be benchmarked against manual segmentation performed by multiple observers.