INSPPIRE 2: Pediatric Longitudinal Cohort Study of Chronic Pancreatitis

Sponsor

Aliye Uc (Other)

Overall Status

Completed

CT.gov ID

NCT03672422

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Cancer Institute (NCI) (NIH)

623

Enrollment

Locations

Actual Duration (Months)

28.3

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators will enroll a total of 628 patients under 18 years of age with ARP or CP. Included in the total are the 357patients in the INSPPIRE 1 database who are planned to be reenrolled under this protocol over the next 4 years. Patient questionnaires and physician surveys will be applied at the time of enrollment and annually thereafter as long as possible. At the first study visit after turning 18 years of age, the patient will sign the informed consent to continue in the study. Specifically, the investigators will define the demographics of the pediatric ARP and CP cohort, describe risk factors, presence of family history of acute and chronic pancreatitis, diabetes and pancreatic cancer and assess disease burden and sequelae.

Condition or Disease	Intervention/Treatment	Phase
Pancreatitis, Chronic Pancreatitis, Acute	Diagnostic Test: Blood sample Behavioral: Patient questionnaires Diagnostic Test: Saliva sample Diagnostic Test: Urine sample

Detailed Description

Disease Burden Pain. The pattern of the pain (constant versus episodic), its frequency, duration, visits to the emergency room or hospitalizations for pain, impact of pain on quality of life will be recorded in questionnaires. The intensity of the pain will be measured at enrollment, during an attack and annually using FACES Pain Scale-Revised, a self-report questionnaire validated for children >4 y/o. The names, dosing and frequency of medications taken for pain will also be queried.

Health-Related Quality of Life (HRQOL). An age-specific instrument validated for United States children will be used to measure HRQOL at enrollment and annually thereafter. Parents of children 5-18 years old will complete Child Health Questionnaire Parent Form 50 questions (CHQ PF-50). Children >10 years old will answer Child Health Questionnaire Child Form 87 questions (CHQ-87). Adults >18 years old will not complete a health-related questionnaire. These questionnaires capture physical functioning, social, emotional, physical and behavioral limitations, bodily pain, general behavior, mental health, self-esteem, general health perceptions, change in health and parental emotional impact.

Depression and anxiety. Depression and anxiety are strong predictors of chronic pain and pain-related disability in children, but it is not known whether this applies to children with ARP or CP. The investigators will assess for depression and anxiety in the INSPPIRE cohort at the time of enrollment and annually thereafter. The investigators will utilize the Child Behavioral Checklist (CBCL), one of the most widely-used standardized measures in child psychology for evaluating maladaptive behavioral and emotional problems in preschool subjects aged 1½ to 5 years and in school-age subjects between the ages of 6 and 18. For preschool-age children, the CBCL/1½-5 (completed by parents or surrogates) will be used. For school-age children 6-18 y/o, the investigators will utilize CBCL/6-18 y/o (completed by parents or surrogates). Children who are 11-18 y/o will answer a self-report questionnaire (Youth-Self Report Form or YSR/11-18). CBCL assesses internalizing (i.e., anxious, depressive, and over controlled) and externalizing (i.e., aggressive, hyperactive, noncompliant, and undercontrolled) behaviors. Adults >18 years old will not complete a behavioral checklist.

Patients/parents will spend approximately 2 hours answering questionnaires; their time will be compensated at $50 per visit. Patients will be enrolled during clinic visit as outpatient or as an inpatient. Alternatively, questionnaires can be applied over the phone or completed at home and returned via mail if the patient is unable to travel. Self-addressed stamped envelopes will be given to the patient/parent as needed for returning the questionnaires.

Disease Sequelae

The presence of exocrine pancreatic insufficiency and glucose intolerance/diabetes will be monitored at the time of enrollment and annually thereafter. Monitoring will include specifically:

Exocrine pancreatic insufficiency: defined as the presence of abnormal fecal elastase (< 100 ug/ g stool on 2 separate samples ≥ 1 month apart) or abnormal serum trypsin or serum trypsinogen.
Diabetes or prediabetes: Monitoring for diabetes in our cohort will include once yearly assessments with fasting glucose (diabetes range if ≥ 126 mg/dL), HbA1c (abnormal if >6; diabetic if >6.5%) and oral glucose tolerance test (OGTT). For OGTT, 1.75 grams/kg of standard glucose beverage (glucola, maximum 75 grams) will be consumed within 10 minutes at time 0. Glucose will be drawn prior to the beverage and at time 120 minutes. From this test, glycemic status will be defined as: (1) normal glucose tolerance (NGT, fasting glucose <100 mg/dL, 2 hour <140 mg/dL); (2) pre-diabetic based on impaired fasting glucose (IFG, fasting glucose 100-125 mg/dL) and/or impaired glucose tolerance (IGT, 2 hour glucose 140-199 mg/dL); or (3) diabetic (DM, fasting glucose >126 mg/dL or 2 hour glucose >200 mg/dL).
Nutritional status including micronutrient deficiency: To determine the nutritional sequelae of ARP or CP in children, the investigators will assess for malnutrition/obesity (weight, height, BMI, z scores; body fat mass and lean mass as measured by DXA scan), fat soluble vitamin deficiencies (serum vitamin levels for A, D, and E and bone density (DXA scan) in children with ARP or CP at the time of enrollment and annually thereafter.

The investigators will identify subjects within our cohort that presented with acute recurrent pancreatitis episodes, normal exocrine and endocrine pancreas function and normal pancreas imaging without any signs of chronicity (ARP cohort). The investigators will identify the development of CP on an annual basis as long as possible, as well as development of sequelae and disease burden as listed above.

Prospective Registry

The investigators will develop a database of children with ARP and CP. This will provide a cohort of well-phenotyped subjects for future studies targeting pathogenesis and novel therapies. The investigators will establish a process by which investigators outside of the consortium may have access to the data and biospecimens.

At enrollment, via the informed consent, subjects will choose whether or not to allow use of their biological samples for this study, future research, genetic analysis, genetic analysis for future research, and any type of future research. They will also choose whether or not we may keep their name and personal information in a registry to allow us to contact them for other future research.

BIOSPECIMEN COLLECTION

Sample collection for deoxyribonucleic acid (DNA): The subject will be able to give either blood or saliva. Six ml of blood will be collected from subjects in an ethylenediaminetetraacetic acid tube or 2 ml saliva samples in Oragene DNA collection kits then labeled with the barcoded specimen labels provided by the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) Coordinating Center. The specimen labels provided by CPDPC include a specimen identification (ID) number and barcode. Subject identifiers (for example names or initials) are not included on the labels. Before shipping the specimens to the central repository the specimen ID number from the label will be connected to the patient information in the CPDPC's secure IIMS Specimen Manager system. After the specimen ID number is linked to the subject in the CPDPC system the samples will be submitted to the central repository for the study via overnight courier. The central repository for DNA will be at the University of Iowa. The central repository at Iowa will not have access to the link that connects to the patient's personal identifiers in the Integrated Information Management System (IIMS). The central repository will log receipt of the specimens into the CPDPC IIMS Specimen Manager system using the specimen ID from the labeled vials. The central repository will process the specimens into aliquots for the extraction of genomic DNA following the CPDPC specimen processing described in the appendices. The aliquots will be labeled with CPDPC supplied labels and stored in a freezer at -80 degree Centigrade. The CPDPC aliquots labels contain barcodes and specimen ID numbers that do not link the aliquots to each other. The only link to the subject information resides in the secured database at the CPDPC coordinating and data management center. The central repository laboratory staff and the study researchers do not have access to this link. At the end of the study the specimens stored in the central repository at Iowa will be transferred to a central repository at National Institute of Diabetes and Digestive and Kidney Diseases.

Urine collection for bio-markers: To be completed only at sites identified by the lead site to collect urine samples. Not all sites will be collecting urine. See Appendix 14.27 for collection and processing instructions. The subject will be instructed to collect a minimum of 50 mL clean-catch urine sample. A dipstick urine analysis will be performed immediately after urine collection. Urine samples will then be kept on wet ice or refrigerated until processed. Samples will be processed within 4 hours of collection. Samples will be labeled with the barcoded specimen labels provided by the CPDPC Coordinating Center. The specimen labels provided by CPDPC include a specimen ID number and barcode. Subject identifiers (for example names or initials) are not included on the labels. Before shipping the specimens to the central repository the specimen ID number from the label will be connected to the subject information in the CPDPC's secure IIMS Specimen Manager system. After processing, samples will be frozen at -80ºC. The urine processing log sheet will be completed. Samples will be stored and batch shipped to the Central repository at University of Iowa annually. The central repository will log receipt of the specimens into the CPDPC IIMs Specimen Manager system using the specimen ID from the labeled vials. The central repository at University of Iowa will not have access to the link that connects the subject's personal identifiers in the IIMS system. The central repository will log receipt of the specimens into the CPDPC IIMS Specimen Manager system using the specimen ID from the labeled vials. The CPDPC aliquots labels contain barcodes and specimen ID numbers that do not link the aliquots to each other. The only link to the subject information resides in the secured database at the CPDPC coordinating and data management center. The central repository laboratory staff and the study researchers do not have access to this link. At the end of the study the specimens stored in the central repository at Iowa will be transferred to a central repository at NIDDK.

Study Design

Study Type:

Observational [Patient Registry]

Actual Enrollment :

623 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) CPDPC16-03 Pediatric Longitudinal Cohort Study of Chronic Pancreatitis

Actual Study Start Date :

Jun 30, 2017

Actual Primary Completion Date :

Aug 31, 2020

Actual Study Completion Date :

Aug 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Acute Recurrent Pancreatitis At least 2 episodes of acute pancreatitis with complete resolution of pain and a >1 month pain-free interval between episodes.	Diagnostic Test: Blood sample Six ml of blood will be collected from patients in an EDTA tube. 2 ml saliva samples in Oragene DNA collection kits Behavioral: Patient questionnaires Questionnaires will be completed at the baseline and annual follow-up visits to collect data that will define the demographics of the pediatric ARP and CP cohort, describe risk factors, presence of family history of acute and chronic pancreatitis, diabetes and pancreatic cancer and assess disease burden and sequelae. Diagnostic Test: Saliva sample 2 ml saliva samples in Oragene DNA collection kits collected if no blood sample being collected. Diagnostic Test: Urine sample 50 ml of urine in collection container.
Chronic Pancreatitis Children with at least: 1) One irreversible structural change* in the pancreas with or without abdominal pain +/- exocrine pancreatic insufficiency +/- diabetes. *irreversible structural changes: Ductal calculi, dilated side branches, parenchymal calcifications found in any imaging (abdominal ultrasound (abd US), magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP), computerized tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), endoscopic US (EUS). Ductal obstruction or stricture/dilatation/irregularities that are persistent (for >2 months) on any imaging. Parenchymal atrophy, irregular contour, accentuated lobular architecture, cavities alone are not diagnostic findings for CP. Surgical or pancreatic biopsy specimen demonstrating histopathologic features compatible with CP (acinar atrophy, fibrosis, protein plugs, infiltration with lymphocytes, plasma cells, macrophages).	Diagnostic Test: Blood sample Six ml of blood will be collected from patients in an EDTA tube. 2 ml saliva samples in Oragene DNA collection kits Behavioral: Patient questionnaires Questionnaires will be completed at the baseline and annual follow-up visits to collect data that will define the demographics of the pediatric ARP and CP cohort, describe risk factors, presence of family history of acute and chronic pancreatitis, diabetes and pancreatic cancer and assess disease burden and sequelae. Diagnostic Test: Saliva sample 2 ml saliva samples in Oragene DNA collection kits collected if no blood sample being collected. Diagnostic Test: Urine sample 50 ml of urine in collection container.

Arm

Intervention/Treatment

Acute Recurrent Pancreatitis

At least 2 episodes of acute pancreatitis with complete resolution of pain and a >1 month pain-free interval between episodes.

Diagnostic Test: Blood sample

Six ml of blood will be collected from patients in an EDTA tube. 2 ml saliva samples in Oragene DNA collection kits

Behavioral: Patient questionnaires

Questionnaires will be completed at the baseline and annual follow-up visits to collect data that will define the demographics of the pediatric ARP and CP cohort, describe risk factors, presence of family history of acute and chronic pancreatitis, diabetes and pancreatic cancer and assess disease burden and sequelae.

Diagnostic Test: Saliva sample

2 ml saliva samples in Oragene DNA collection kits collected if no blood sample being collected.

Diagnostic Test: Urine sample

50 ml of urine in collection container.

Chronic Pancreatitis

Children with at least: 1) One irreversible structural change* in the pancreas with or without abdominal pain +/- exocrine pancreatic insufficiency +/- diabetes. *irreversible structural changes: Ductal calculi, dilated side branches, parenchymal calcifications found in any imaging (abdominal ultrasound (abd US), magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP), computerized tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), endoscopic US (EUS). Ductal obstruction or stricture/dilatation/irregularities that are persistent (for >2 months) on any imaging. Parenchymal atrophy, irregular contour, accentuated lobular architecture, cavities alone are not diagnostic findings for CP. Surgical or pancreatic biopsy specimen demonstrating histopathologic features compatible with CP (acinar atrophy, fibrosis, protein plugs, infiltration with lymphocytes, plasma cells, macrophages).

Diagnostic Test: Blood sample

Six ml of blood will be collected from patients in an EDTA tube. 2 ml saliva samples in Oragene DNA collection kits

Behavioral: Patient questionnaires

Diagnostic Test: Saliva sample

2 ml saliva samples in Oragene DNA collection kits collected if no blood sample being collected.

Diagnostic Test: Urine sample

50 ml of urine in collection container.

Outcome Measures

Primary Outcome Measures

Length of time from progression from Acute Recurrent Pancreatitis to Chronic Pancreatitis [3 years]
Date of diagnosis of first acute pancreatitis to date of diagnosis of chronic pancreatitis presented as minimum, maximum, median number of days and no progression to chronic pancreatitis.

Secondary Outcome Measures

Number of subjects with abdominal pain [1 year]
Presence of abdominal pain in the past year presented as number with "Yes", "No", "I don't know" and missing responses.
Number of subjects with constant abdominal pain [1 year]
Presence of constant abdominal pain described as number of subjects with "Yes", "No", "I don't know" and missing responses.
Number of subjects with episodic abdominal pain [1 year]
Number of subjects who are usually pain free with episodes of abdominal pain described as number with "Yes", "No", "I don't know" and missing responses..
Number of emergency room visits subject had in the past 12 months [1 year]
Number of emergency room visits subjects experienced in the past 12 months presented as minimum, maximum, and median number of emergency room visits and number of missing responses.
Number of emergency room visits subject had in whole life [18 years]
Number of emergency room visits the subject experienced in their whole life presented as minimum, maximum, and median number of visits and number of missing responses..
Number of hospitalizations subject had in past 12 months [1 year]
Number of hospitalizations subject experienced in the past 12 months presented as minimum, maximum, and median number and number of missing responses..
Number of hospitalizations subject had in whole life [18 years]
Number of hospitalizations subject had in their whole life presented as minimum, maximum, and median number and number of missing responses..
Number of school days subject missed in the last month [30 days]
Number of school days subject missed in the last month presented as minimum, maximum, and median number and number of missing responses..
Number of subjects with Exocrine Pancreatic Insufficiency [3 years]
Number of subjects with abnormal fecal elastase (< 100 micrograms/ gram of stool on 2 separate samples ≥ 1 month apart) presented as number of subjects with abnormal and normal lab values and number of subjects who did not have test done.
Number of subjects with abnormal fasting glucose [3 years]
Number of subjects with fasting glucose ≥126 milligrams per deciliter presented as number of subjects with abnormal and normal lab value and number of subjects who did not have test done.
Number of subjects with abnormal hemoglobin A1c (HbA1c) [3 years]
Number of subjects with HbA1c (abnormal if >6; diabetic if >6.5%) results that were normal, abnormal, and diabetic and number who did not have test done.
Number of subjects with abnormal oral glucose tolerance test (OGTT) [3 years]
Number of subjects with abnormal OGTT test results. OGTT performed with 1.75 grams/kilogram of standard glucose beverage (glucola, maximum 75 grams) consumed within 10 minutes at time 0. Glucose drawn prior to the beverage and at time 120 minutes. Glycemic status will be defined as: (1) normal glucose tolerance (NGT, fasting glucose <100 mg/dL, 2 hour <140 mg/dL); (2) pre-diabetic based on impaired fasting glucose (IFG, fasting glucose 100-125 mg/dL) and/or impaired glucose tolerance (IGT, 2 hour glucose 140-199 mg/dL); or (3) diabetic (DM, fasting glucose >126 mg/dL or 2 hour glucose >200 mg/dL). Findings presented as number of subjects with normal, pre-diabetic, impaired, and diabetic results and number that did not have test done.

Eligibility Criteria

Criteria

Ages Eligible for Study:

0 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All patients/parents must sign an informed consent and/or assent indicating that they are aware of the investigational nature of this study.

2 Patients/parents must have signed an authorization for the release of their or their child's protected health information.

3 All children providing samples should fit the ARP or CP inclusion criteria defined below.

4 All children must be under 18 years of age at the time of enrollment.

Acute pancreatitis (AP): AP is defined as requiring 2 of the following:

Abdominal pain compatible with AP,
Serum amylase and/or lipase values ≥3 times upper limits of normal,
Imaging findings of AP, such as gland enlargement, acute inflammatory changes, and fluid collections.

ARP is defined as:

At least 2 episodes of acute pancreatitis with complete resolution of pain and a >1 month pain-free interval between episodes.

Chronic Pancreatitis:

Children with at least:

One irreversible structural change* in the pancreas with or without abdominal pain +/- exocrine pancreatic insufficiency +/- diabetes.

*irreversible structural changes:

Ductal calculi, dilated side branches, parenchymal calcifications found in any imaging (abdominal ultrasound (abd US), magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP), computerized tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), endoscopic US (EUS).
Ductal obstruction or stricture/dilatation/irregularities that are persistent (for >2 months) on any imaging.
Parenchymal atrophy, irregular contour, accentuated lobular architecture, cavities alone are not diagnostic findings for CP.
Surgical or pancreatic biopsy specimen demonstrating histopathologic features compatible with CP (acinar atrophy, fibrosis, protein plugs, infiltration with lymphocytes, plasma cells, macrophages).

Exclusion Criteria:

Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate study interventions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Beverly Hills	California	United States	90211
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	University of California San Francisco	San Francisco	California	United States	94158
4	Stanford University	Stanford	California	United States	94305
5	Riley Hospital for Children Indiana University	Indianapolis	Indiana	United States	46202
6	University of Iowa Stead Family Children's Hospital	Iowa City	Iowa	United States	52242
7	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
8	University of Minnesota Medical Center	Minneapolis	Minnesota	United States	55455
9	Washington University	Saint Louis	Missouri	United States	63112
10	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
11	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
12	Children's Hospital of Philadelphia	Philipsburg	Pennsylvania	United States	19104
13	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15224
14	Children's Health University of Texas Southwestern Medical Center	Dallas	Texas	United States	75235
15	Texas Children's Hospital	Houston	Texas	United States	77030
16	Primary Children's Hospital	Salt Lake City	Utah	United States	84108
17	Seattle Children's Hospital	Seattle	Washington	United States	98105
18	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
19	Sydney Children's Hospital Randwick	Randwick	New South Wales	Australia	2031
20	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
21	Montreal Children's Hospital	Montréal	Quebec	Canada	H4A 3J1
22	Hadassah University Hospital Mt. Scopus	Jerusalem		Israel	91240