Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies, the PROCEED Study
Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies, the PROCEED Study
This study gathers information on patients at different stages of chronic pancreatitis to
 better understand the natural course and risk factors associated with pancreatitis. Chronic
 pancreatitis is a disease that occurs when the pancreas is inflamed (swollen and irritated)
 all of the time. It is important for doctors to diagnose chronic pancreatitis in the
 beginning stages of the disease. Over time, as chronic pancreatitis gets worse, the pancreas
 may stop working correctly. Since treatment options for advanced (end-stage) chronic
 pancreatitis are limited, patients with early-stage chronic pancreatitis or those at high
 risk of developing chronic pancreatitis are ideally suited for interventions to prevent the
 development of end-stage chronic pancreatitis and its associated complications. Information
 from this study may help researchers to develop lab tests for early diagnosis and prediction
 of disease progression, to understand disease mechanisms, and to discover genetic factors
 affecting susceptibility and progression.
PRIMARY OBJECTIVES:

 I. To establish a model longitudinal research cohort of adult patients for the study of
 chronic pancreatitis (CP) and its complications.

 II. To estimate the risk of progression from suspected to definite CP, and the risk of
 new-onset diabetes or exocrine insufficiency in definite CP, and study how the risks are
 influenced by patient characteristics and conditions.

 III. To test the predictive capability of candidate biomarkers for diagnosis and prognosis of
 CP.

 IV. To develop a framework for conducting biomarker, genetic, and mechanistic studies using
 clinical information and the biorepository developed as part of the longitudinal research
 cohort.

 SECONDARY OBJECTIVES:

 I. In patients with suspected and definite CP, to study:

 Ia. The risk of pancreatic cancer. (Clinical) Ib. The natural history of pain and its
 predictors (demographic, environmental, clinical, and morphological). (Clinical) Ic.
 Quantitative changes in quality of life and disability and their predictors (demographic,
 environmental, clinical, and morphological). (Clinical) Id. Composite and quantitative
 measures of morphological progression of CP. (Clinical) Ie. Frequency of single or composite
 patient-centered outcomes over time and their relationship with demographic, environmental,
 clinical and, morphological factors. (Clinical) If. The risk and predictors of metabolic bone
 disease. (Clinical) Ig. Long-term survival. (Clinical) II. To identify and validate a panel
 of biomarkers that discriminate patients with suspected or definite CP from the normal
 population and controls with unexplained upper abdominal pain but no morphological evidence
 of pancreatic disease. (Biomarkers and Mechanism of Disease) III. To identify and validate
 biomarkers that predict future development of important clinical outcomes for patients with
 indeterminate presentations, including progression to definite CP, occurrence of disease
 complications, cumulative disability, and quality of life over time. (Biomarkers and
 Mechanism of Disease) IV. To develop biomarkers that can define specific aspects of CP
 pathophysiology (including inflammation, fibrosis, acinar loss, ischemia and neuropathy) and
 to correlate these with disease stage and mechanisms. (Biomarkers and Mechanism of Disease)
 V. To develop and validate biomarkers suitable as intermediate outcome measures in
 therapeutic trials. (Biomarkers and Mechanism of Disease)

 OUTLINE: Participants are assigned to 1 of 4 groups.

 GROUP I (NO PANCREATIC DISEASE): Participants undergo collection of blood, urine, saliva, and
 stool samples at baseline.

 GROUP II (CHRONIC UPPER ABDOMINAL PAIN): Patients undergo collection of blood, urine, saliva,
 and stool samples, and intravenous (IV) contrast-enhanced magnetic resonance imaging (MRI)
 over 1.5-2 hours and computed tomography (CT) at baseline. Patients also undergo endoscopic
 ultrasound (EUS) or esophagogastroduodenoscopy (EGD) with collection of pancreatic fluid
 samples at baseline and year 2 (in a subset of patients). Patients may also undergo
 collection of blood and urine samples at year 2.

 GROUP III (ACUTE PANCREATITIS, RECURRENT ACUTE PANCREATITIS, OR INDETERMINE CP): Patients
 undergo collection of saliva and stool samples at baseline, and collection of blood and urine
 at baseline and yearly for years 1-4. Patient also undergo contrast-enhanced MRI over 1.5-2
 hours at baseline, and years 1 and 3, and IV contrast-enhanced CT at baseline, and years 2
 and 4. Patients also undergo EUS or EGD with collection of pancreatic fluid samples at
 baseline and year 2 (in a subset of patients).

 GROUP IV (DEFINITE CP): Patients undergo collection of saliva and stool samples at baseline,
 and collection of blood and urine at baseline and yearly for years 1-4. Patients also undergo
 EUS or EGD with collection of pancreatic fluid samples at baseline. Patients also undergo IV
 contrast-enhanced CT and MRI over 1.5-2 hours at baseline and years 1 and 3, and bone mineral
 density scan over 15 minutes at baseline and years 2 and 4.

 Patients in Groups II to IV are followed up yearly for 20 years.
Inclusion Criteria:

 -  ALL GROUPS: All participants must sign an informed consent indicating that they are
 aware of the investigational nature of this study and willing to undergo study
 interventions, and authorizing the use of their protected health information for
 research purposes

 -  ALL GROUPS: Meet one set of group-specific inclusion criteria listed below

 -  ALL GROUPS: All participants must be >= 18 years old and =< 75 years at the time of
 enrollment

 -  NO PANCREATIC DISEASE: No personal history or symptoms of pancreatic disease

 -  NO PANCREATIC DISEASE: No upper abdominal symptoms

 -  NO PANCREATIC DISEASE: No family history of pancreatic disorders, celiac disease,
 cystic fibrosis

 -  NO PANCREATIC DISEASE: No history of acute infectious or inflammatory conditions
 requiring medical treatment or evaluation in the preceding 6 months (per provider
 clinical judgment)

 -  NO PANCREATIC DISEASE: No history of cancer, except for non-melanoma skin cancers

 -  NO PANCREATIC DISEASE: No known pregnancy at the time of enrollment

 -  NO PANCREATIC DISEASE: No solid organ transplant or history of human immunodeficiency
 virus/acquired immunodeficiency syndrome (HIV/AIDS)

 -  NO PANCREATIC DISEASE: Able to provide an informed consent

 -  NO PANCREATIC DISEASE: Not currently incarcerated

 -  NO PANCREATIC DISEASE: American Society of Anesthesiologists (ASA) 1-2

 -  CHRONIC UPPER ABDOMINAL PAIN: Referred to a pancreas or gastrointestinal (GI) clinic
 or admitted to the hospital for evaluation of unexplained upper abdominal pain of at
 least 3 months in duration for which a pancreatic origin is clinically considered in
 the differential diagnosis

 -  Pancreatic type pain is defined as epigastric pain that is often constant, often
 worsens postprandially, and may radiate to the back. This can often be associated
 with lipase/amylase elevations that do not meet the threshold for diagnosis of
 acute pancreatitis (AP) (i.e. < 3-fold upper limit of normal)

 -  CHRONIC UPPER ABDOMINAL PAIN: No history of AP or CP

 -  CHRONIC UPPER ABDOMINAL PAIN: No prior endoscopic sphincterotomy or pancreatic surgery

 -  CHRONIC UPPER ABDOMINAL PAIN: Normal cross-sectional abdominal imaging (CT and
 MRI/Magnetic resonance cholangiopancreatography [MRCP])

 -  CT and MRI/MRCP must be performed =< 24 months prior to enrollment OR within 6
 months after study enrollment. CT and MRI scans must be intravenous
 contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without
 secretin prior to enrollment is acceptable at baseline to be used for
 enrollment). If the patient has had only one imaging study, the patient is
 eligible for enrollment as "Chronic Abdominal Pain - Undifferentiated". The
 second imaging study can be performed in this situation after the enrollment and
 the final assignment into the appropriate subgroup can be done after review of
 the imaging results. If the second study was planned within 6 months after
 enrollment but could not be completed, it will not be considered as eligibility
 violation and attempts will be made to complete this during follow- up as
 feasible. If the second study could not be performed, the subject will be
 assigned to chronic upper abdominal pain group if the available study was normal
 or as indeterminate CP if the available study shows Cambridge 1-2 findings

 -  INDETERMINATE CP: Referred to a pancreas or GI clinic or admitted to the hospital for
 evaluation of unexplained upper abdominal pain of at least 3 months in duration for
 which a pancreatic origin is clinically considered in the differential diagnosis

 -  Pancreatic type pain is defined as epigastric pain that is often constant, often
 worsens postprandially, and may radiate to the back. This can often be associated
 with lipase/amylase elevations that do not meet the threshold for diagnosis of AP
 (i.e. < 3-fold upper limit of normal)

 -  INDETERMINATE CP: No history of AP or CP

 -  AP is defined as compatible symptoms (upper abdominal pain) together with A) >=
 3-fold elevation of serum amylase and/or lipase above upper limit of normal,
 AND/OR B) features of AP on cross-sectional imaging (CT and/or MR)

 -  INDETERMINATE CP: Cambridge grade I-II changes of CP on cross-sectional imaging (CT or
 MRI/MRCP)

 -  CT and MRI/MRCP must be performed =< 24 months prior to enrollment OR within 6
 months after study enrollment. CT and MRI scans must be intravenous
 contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without
 secretin prior to enrollment is acceptable at baseline to be used for
 enrollment). If the patient has had only one imaging study, the patient is
 eligible for enrollment as "Chronic Abdominal Pain - Undifferentiated". The
 second imaging study can be performed in this situation after the enrollment and
 the final assignment into the appropriate subgroup can be done after review of
 the imaging results. If the second study was planned within 6 months after
 enrollment but could not be completed, it will not be considered as eligibility
 violation and attempts will be made to complete this during follow- up as
 feasible. If the second study could not be performed by month 6 after enrollment,
 the subject will be assigned to chronic upper abdominal pain group if the
 available study was normal or as indeterminate CP if the available study shows
 Cambridge 1-2 findings

 -  INDETERMINATE CP: No prior endoscopic sphincterotomy or pancreatic surgery

 -  AP: History of one documented attack of AP in the preceding 18 months

 -  AP is defined as compatible symptoms (upper abdominal pain) together with A) >=
 3-fold elevation of serum amylase and/or lipase above upper limit of normal,
 AND/OR B) features of AP on cross-sectional imaging (CT and/or MR). Patient
 should not have had an attack of AP in the month prior to enrollment.

 -  Patients should not have had an endoscopic retrograde
 cholangiopancreatography (ERCP) prior to the episode of AP

 -  AP: Pancreatitis episode is not attributable to gallstones (i.e. suspected or definite
 biliary etiology), medications, trauma or autoimmune pancreatitis

 -  AP: Pancreatic necrosis, if present, is < 50% (to be verified by a Chronic
 Pancreatitis, Diabetes and Pancreatic Cancer [CPDPC] site radiologist)

 -  AP: Cambridge grade < III changes of CP on cross-sectional imaging (CT or MRI/MRCP)

 -  CT and MRI/MRCP must be performed =< 24 months prior to enrollment OR within 6
 months after study enrollment. CT and MRI scans must be intravenous
 contrast-enhanced and MRCP with secretin (a non contrast MRI and MRCP without
 secretin prior to enrollment is acceptable at baseline to be used for
 enrollment). If the patient has had only one imaging study, the patient is
 eligible for enrollment. The second study can be performed in this situation
 after the enrollment. If the second study was planned within 6 months after
 enrollment but could not be completed, it will not be considered as eligibility
 violation. Final group assignment in this situation will be based on the
 available study

 -  AP: No prior pancreatic surgery

 -  RECURRENT AP: Two or more documented attacks of AP separated by at least 1 month, with
 complete symptom resolution between the attacks.

 -  AP is defined as compatible symptoms (epigastric pain with nausea or vomiting)
 together with A) >= 3-fold elevation of serum amylase and/or lipase above upper
 limit of normal, AND/OR B) features of AP on cross-sectional imaging (CT and/or
 MR).

 -  Patient should not have had an ERCP prior to having first documented attack
 of pancreatitis

 -  RECURRENT AP: Cambridge grade < III changes of CP on cross-sectional imaging (CT or
 MRI/MRCP)

 -  CT and MRI/MRCP must be performed =< 24 months prior to enrollment OR within 6
 months after study enrollment. CT and MRI scans must be intravenous
 contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without
 secretin prior to enrollment is acceptable at baseline to be used for
 enrollment). If the patient has had only one imaging study, the patient is
 eligible for enrollment. The second study can be performed in this situation
 after the enrollment. If the second study was planned within 6 months after
 enrollment but could not be completed, it will not be considered as eligibility
 violation. Final assignment in this situation will be based on the available
 study. In a rare circumstance, the last imaging patient had was > 24 months prior
 to enrollment. In this circumstance, the patient is still eligible for
 enrollment, and can undergo CT scan first, and if there is no evidence of
 Cambridge 3-4 findings, undergo an MRI/MRCP to fulfill entry criteria. If the
 planned studies could not be completed within 6 months after enrollment, the
 final group assignment will be in this situation will be based on the available
 study

 -  RECURRENT AP: Pancreatitis episodes are not attributable to gallstones, medications,
 trauma or autoimmune pancreatitis

 -  RECURRENT AP: No prior pancreatic surgery

 -  DEFINITE CP: Presence of unequivocal CP (i.e. Cambridge grade >= 3) and/or parenchymal
 and/or ductal calcifications by cross-sectional imaging (IV contrast-enhanced MRI/MRCP
 or CT) verified by the CPDPC site radiologist

 -  Must exclude the possibility that calcifications are vascular. Calcifications
 noted by EUS only (and not correlated with CT) are not included as definite CP. A
 non-contrast CT scan or MRI/MRCP documenting definite CP as per criteria is
 acceptable for enrollment

 -  DEFINITE CP: Pancreatic histology diagnostic of CP (including findings of fibrosis
 [Ammann's >= 6], chronic inflammation, and acinar loss) as verified by a CPDPC site
 pathologist, if pathology slides are available for review

 Exclusion Criteria:

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: History of autoimmune or traumatic
 pancreatitis, or sentinel attack of acute necrotizing pancreatitis which results in
 suspected disconnected duct syndrome

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Primary pancreatic tumors - pancreatic ductal
 adenocarcinoma, suspected cystic neoplasm (> 1 cms in size or main duct involvement),
 neuroendocrine tumors, and other uncommon tumors

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Pancreatic metastasis from other malignancies

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: History of solid organ transplant, HIV/AIDS

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Known isolated pancreatic exocrine
 insufficiency (e.g. in the absence of any eligible inclusion criteria)

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Participants must not have medical or
 psychiatric illnesses or ongoing substance abuse that in the investigator's opinion
 would compromise their ability to tolerate study interventions or participate in
 longitudinal follow up

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Patients with known abnormal creatinine
 (glomerular filtration rate [GFR] < 30) or renal failure (applies to patients with
 chronic upper abdominal pain of suspected pancreatic origin and suspected CP [yellow]
 subgroups)

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Failure to agree for longitudinal follow-up

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Known pregnancy. All participants of
 childbearing potential, except if post-menopausal [i.e. no menses for >= 2 years] or
 had a hysterectomy, bilateral tubal ligation/clip (surgical sterilization) or surgical
 removal of both the ovaries), must have a negative urine or serum human chorionic
 gonadotropin (B-HCG) pregnancy test documented within 2 days prior to any endoscopic
 or radiologic procedures done for research purposes. Any standard of care tests will
 follow institutional policies regarding pregnancy test

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Currently incarcerated

 -  ALL GROUPS EXCEPT NO PANCREATIC DISEASE: Inability to get MRI/MRCP in patients with
 chronic abdominal pain of suspected pancreatic origin (Green II) or suspected
 CP(Yellow groups) at baseline (e.g. metal object in the body which precludes
 performance of MRI)