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Imaging Biomarkers of Pancreatic Function and Disease

Primary Purpose

Pancreatitis, Diabetes Mellitus

Status

Enrolling by invitation

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Research MRI without administration of intravenous secretin

Research MRI with administration of intravenous secretin

Genetic Sequencing

Blood Tests

Stool Tests

Survey Completion

Endoscopic pancreatic function tests (ePFTs)

Secretin

About this trial

This is an interventional diagnostic trial for Pancreatitis focused on measuring MRI

Eligibility Criteria

5 Years - 21 Years (Child, Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Cincinnati Children's Hospital Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

No Intervention

Arm Label

Imaging markers of exocrine and endocrine insufficiency

Imaging markers of diabetes and prediction of progression to diabetes

Imaging stratification of stages of pancreatitis

Imaging reproducibility

Automated or semi-automated image analysis

Arm 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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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)

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)

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)

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)

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)

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)

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

Secondary Outcome Measures

Full Information

NCT ID

NCT05659147

First Posted

November 22, 2022

Last Updated

January 19, 2023

Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT05659147

Brief Title

Imaging Biomarkers of Pancreatic Function and Disease

Official Title

Imaging Biomarkers of Pancreatic Function and Disease

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Enrolling by invitation

Study Start Date

January 18, 2023 (Actual)

Primary Completion Date

December 2025 (Anticipated)

Study Completion Date

December 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Children's Hospital Medical Center, Cincinnati

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Device Product Not Approved or Cleared by U.S. FDA

Yes

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief 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.

Detailed 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: Define associations between non-invasive, quantitative MRI measures and established measures of pancreas health and function including diabetes and EPI in children Identify clinical, genetic and imaging-related factors that predict progression to diabetes in children with pancreatitis.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pancreatitis, Diabetes Mellitus

Keywords

MRI

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

Participants will be prospectively recruited to one or more of four prospective imaging aims (Aims 1-4). All participants who enroll in any imaging Aim will have their images used for Aim 5 (image analysis aim) which will also include a retrospective component.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

195 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Imaging markers of exocrine and endocrine insufficiency

Arm Type

Experimental

Arm Description

Arm Title

Imaging markers of diabetes and prediction of progression to diabetes

Arm Type

Experimental

Arm Description

Arm Title

Imaging stratification of stages of pancreatitis

Arm Type

Experimental

Arm Description

Arm Title

Imaging reproducibility

Arm Type

Experimental

Arm Description

Arm Title

Automated or semi-automated image analysis

Arm Type

No Intervention

Arm Description

Intervention Type

Diagnostic Test

Intervention Name(s)

Research MRI without administration of intravenous secretin

Intervention Description

Participants will undergo a research MRI examination. MRI images will be quantitatively analyzed and will be compared to / used to predict diabetes.

Intervention Type

Diagnostic Test

Intervention Name(s)

Research MRI with administration of intravenous secretin

Intervention Description

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.

Intervention Type

Genetic

Intervention Name(s)

Genetic Sequencing

Intervention Description

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.

Intervention Type

Diagnostic Test

Intervention Name(s)

Blood Tests

Intervention Description

Research blood draw (for markers of pancreatic endocrine insufficiency)

Intervention Type

Diagnostic Test

Intervention Name(s)

Stool Tests

Intervention Description

Research stool collection (for fecal elastase as a marker of exocrine insufficiency)

Intervention Type

Other

Intervention Name(s)

Survey Completion

Intervention Description

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.

Intervention Type

Diagnostic Test

Intervention Name(s)

Endoscopic pancreatic function tests (ePFTs)

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Secretin

Intervention Description

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.

Primary Outcome Measure Information:

Title

Pancreas volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).

Description

2 x 2 table analyses of pancreas volume (categorized as normal vs. abnormal) vs. exocrine function (categorized as normal vs. abnormal)

Time Frame

5 years

Title

Pancreas volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).

Description

2 x 2 table analyses of pancreas volume (categorized as normal vs. abnormal) vs. endocrine function (categorized as normal vs. abnormal)

Time Frame

5 years

Title

Pancreas T1 signal as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).

Description

2 x 2 table analyses of pancreas T1 signal (categorized as normal vs. abnormal) vs. exocrine function (categorized as normal vs. abnormal)

Time Frame

5 years

Title

Pancreas T1 signal as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).

Description

2 x 2 table analyses of pancreas T1 signal intensity (categorized as normal vs. abnormal) vs. endocrine function (categorized as normal vs. abnormal)

Time Frame

5 years

Title

Pancreas secreted fluid volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).

Description

2 x 2 table analyses of pancreas secreted fluid volume (categorized as normal vs. abnormal) vs. exocrine function (categorized as normal vs. abnormal)

Time Frame

5 years

Title

Pancreas secreted fluid volume as a predictor of pancreas health and function (including endocrine and exocrine pancreatic insufficiency).

Description

2 x 2 table analyses of pancreas secreted fluid volume (categorized as normal vs. abnormal) vs. endocrine function (categorized as normal vs. abnormal)

Time Frame

5 years

Title

Frequency of genetic mutations in patients progressing to diabetes vs. those not

Description

Frequency of genetic mutations in each study group will be compared using 2x2 tables to identify mutations associated with development of diabetes

Time Frame

5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

5 Years

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Andrew Trout, MD

Organizational Affiliation

Children's Hospital Medical Center, Cincinnati

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cincinnati Children's Hospital Medical Center

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Imaging Biomarkers of Pancreatic Function and Disease

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