Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04907266 |
| Other study ID # |
IEC/2018/426 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2018 |
| Est. completion date |
December 31, 2019 |
Study information
| Verified date |
May 2021 |
| Source |
Postgraduate Institute of Medical Education and Research |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Clinical course of chronic pancreatitis is still unpredictable, due to the lack of clinical
classification. There is no model to assess disease severity or progression or predict
patient outcomes. So we need to validate an objective predictive model - Chronic Pancreatitis
Prognosis Score (COPPS) for classification, prognostication and management in Chronic
Pancreatitis (CP)
Description:
INTRODUCTION Chronic pancreatitis is an inflammatory disease of the pancreas characterized by
abdominal pain, repeated episodes of acute pancreatitis, and fibrotic destruction of the
organ, resulting in exocrine and endocrine insufficiency. During the last decade, several
reports have provided evidence that repeated attacks of acute pancreatitis may progress to
chronic pancreatitis [1].
The disease may present clinically either with an individual symptom or a combination of
symptoms associated with loss of pancreatic function. The natural history of chronic
pancreatitis is usually characterized by progression of tissue damage and various degrees of
exocrine and endocrine pancreatic insufficiency, which will become apparent over time,
independent of the underlying etiology, chronic pancreatitis evolves toward the same end
stage, i.e., pancreatic fibrosis [2].
The prevalence of CP has been approximated at ~50/100,000 population [3]. The underlying
etiologies are multifactorial and among many involve excessive alcohol consumption, smoking,
genetic predisposition and autoimmune pancreatitis.
It is general knowledge that the terminal stage of chronic pancreatitis results in a loss of
organ function, with the clinical manifestations of maldigestion and diabetes mellitus.
However, there is little knowledge of the early structural and functional abnormalities
because the current diagnostic imaging procedures are not sensitive enough to visualize them
and histology is normally not available in these early stages [4].
Abdominal pain is the most frequent symptom of CP. However, the severity, temporal nature,
and natural history of pain is highly variable [5].
Chronic pancreatitis encompasses a number of disease entities and can be broadly classified
into three forms: chronic calcifying pancreatitis, chronic obstructive pancreatitis, and
steroid-responsive pancreatitis (chronic auto immune pancreatitis) [6].
The presentation of multiple clinical symptoms and the frequent occurance of various
complications require a well-differentiated therapeutic approach. Current therapies in the
management of chronic pancreatitis include conservative measures (analgesics,
anti-inflammatory agents, enzyme replacement), endoscopic interventions as well as surgical
procedures [7-10] The main reason for the lack of guided strategies in the therapeutic
management of chronic pancreatitis is the absence of clearity in the clinically applicable
classifications of chronic pancreatitis developed so far, which needs to be developed for
guiding management and predicting disease outcome [11].
REVIEW OF LITERATURE For many years, pancreatologists have struggled to achieve a workable
classification of chronic pancreatitis. A uniformly accepted and clinically relevant
classification is essential to allow for a valid comparison of information among
institutions, to improve patient care, and to ensure that patients entered into randomized
trials have similar characteristics. Such a classification is also required for staging the
disease severity, to plan the management accordingly and to predict disease outcome in both
short and long term.
The first classification of chronic pancreatitis was developed at a symposium in Marseilles
in 1963, it was based on morphological changes and etiology underlying the disease [12].It
correlated clinical features with histology. Pancreatitis was classified as the following
four subgroups: acute pancreatitis, relapsing acute pancreatitis, chronic relapsing
pancreatitis, and chronic (primarily painless) pancreatitis. The term acute pancreatitis
referred to an episode of acute inflammation of the pancreas that resolved completely both
clinically and histologically. Relapsing acute pancreatitis referred to recurring episodes of
acute pancreatitis that also resolved completely both clinically and histology. The term
chronic pancreatitis indicated that histologic changes persisted even after the etiologic
agent had been removed. The distinction between chronic relapsing and chronic (primarily
painless) pancreatitis was clinical. It was thought that almost all diseases that caused
chronic pancreatitis were associated with recurring episodes of pain, and they were therefore
termed chronic relapsing pancreatitis, including both chronic pancreatitis caused by alcohol
and hereditary pancreatitis. It was recognized that some patients with chronic pancreatitis
never experienced pain and that others might experience fewer episodes of pain in time. In
summary, at the Marseille Classification Symposium, acute pancreatitis was thought to be
associated with complete structural and functional recovery, and it was thought to rarely
evolve into chronic pancreatitis. On the other hand, in chronic pancreatitis, structural and
functional damage was thought to persist even if the primary cause was eliminated. The major
focus of the Marseille Classification of 1963 was pathological anatomy and etiology, and no
correlation between anatomical and functional changes was discussed.
It was then generally recognized that reclassification of pancreatitis was required because
of the development of new imaging procedures and function tests. At an international workshop
in Cambridge in 1983 [13], a revised classification simplified matters by considering
pancreatitis as either acute or chronic. Acute pancreatitis was defined as an acute
inflammation of the pancreas, usually presenting with abdominal pain and usually associated
with increased pancreatic enzymes in the blood or urine. Acute pancreatitis was subdivided
into mild and severe cases, and it was recognized that acute pancreatitis could recur.
Chronic pancreatitis was defined as an ongoing inflammatory disease typically associated with
abdominal pain and characterized by irreversible structural changes and permanent loss of
function. It was acknowledged that chronic pancreatitis could recur and was occasionally
painless. The Cambridge classification, which was the first clinical grading system for
chronic pancreatitis, was based on changes in ductal morphology on endoscopic retrograde
pancreatography (ERP) [Table 1] and to some extent had equivalent findings on ultrasound or
computed tomography (CT) [14].
Moreover, it was acknowledged that additional studies would be required to provide a grading
system of functional impairment. Subsequently, such a grading system of exocrine pancreatic
insufficiency has been developed (Table 3) and published [15].
The Cambridge criteria remain the standard for grading of chronic pancreatitis on imaging,
but already when it was first introduced, experts stated that morphological changes in
chronic pancreatitis might not reflect the functional or histological state of the pancreas
and early stages of the disease might be missed [15].
In the revised version of Marseille Classification, published in 1985 [16], the morphological
changes that were specified earlier, were linked to a potential loss of endocrine and
exocrine organ function. In acute pancreatitis there is a gradation of severity of histologic
lesions from mild peripancreatic fat necrosis and interstitial edema to a severe form
involving extensive peripancreatic and intrapancreatic fat necrosis, parenchymal necrosis,
and bleeding. The process can be localized or diffuse . It was also noted that clinical
severity need not correlate with morphological severity. Morphologic characterization of
chronic pancreatitis was that of destruction and of permanent loss of exocrine parenchyma in
either a focal, segmental, or diffuse pattern, progressive or permanent loss of exocrine or
endocrine function, irregular scarring, varying degrees of pancreatic duct dilatation, and
preservation of islets of Langerhans. A distinctive form of chronic pancreatitis, obstructive
chronic pancreatitis, was also delineated in this re-classification. Descriptive terms that
were applied included chronic pancreatitis with focal necrosis, chronic pancreatitis with
segmental or diffuse fibrosis, and chronic pancreatitis with or without calculi.
Further modifications in the Marseilles Classification were finally introduced in the
consecutively published Marseilles-Rome classification [6]. Two additional forms were
introduced- Chronic calcifying pancreatitis and Chronic inflammatory pancreatitis. Chronic
inflammatory pancreatitis was characterized by loss of exocrine parenchyma with replacement
by diffuse fibrosis with infiltration by mononuclear cells. Chronic calcifying pancreatitis
was subdivided into a variety of forms, including hereditary pancreatitis, nutritional
pancreatitis (including tropical pancreatitis), and hypercalcemic pancreatitis. They also
emphasized on the need for the development of a clinical classification of chronic
pancreatitis.
Ammann introduced the concept of stage wise progression in chronic alcoholic pancreatitis.
Two stages in the evolution of CP were distinguished: (1) early-stage CP, i.e., no
calcification and only minor or no exocrine insufficiency; and (2) late-stage CP, i.e., with
calcification and/or persistent exocrine insufficiency. [17] In 2002, Ramesh et al [18]
proposed ABC classification which graded chronic pancreatitis based on the presence or
absence of clinical pain syndrome and complications like bile duct/ duodenal
obstruction/bleeding complications, but it does not clearly differentiate between different
degrees of disease severity within a given category, nor does it allow categorization of all
possible clinical presentations of chronic pancreatitis.
In 2006, Manchester classification [19] graded chronic pancreatitis into mild, moderate and
severe categories. In mild chronic pancreatitis, there was no regular opiate intake (with
regular being defined as weekly) and that there be no clinical evidence of impaired
pancreatic exocrine or endocrine function or extra-pancreatic complications (duodenal
stenosis, portal vein thrombosis and/or distal bile duct stricture). Moderate category has
regular abdominal pain requiring opiod use with clinical evidence of impairment of either
endocrine or exocrine function without extra-pancreatic complications. End stage chronic
pancreatitis has a range of extra-pancreatic complications plus one or more clinical factors
to suggest end-stage pancreatic function: either steatorrhoea or diabetes mellitus. [Table 4]
Table 4. MANCHESTER CLASSIFICATION
In 2007, based on the previous chronic pancreatitis classifications, Schneider J et al
proposed the MANNHEIM classification [20], grading the disease on the basis of clinical
symptoms, imaging findings based on Cambridge classification and pancreatic function
insufficiency. It had the following diagnostic criteria-
Definite chronic pancreatitis is established by one or more of the following additional
criteria:
1. Pancreatic calcifications
2. Moderate or marked ductal lesions (according to the Cambridge classification)
3. Marked and persistent exocrine insufficiency defined as pancreatic steatorrhea markedly
reduced by enzyme supplementation
4. Typical histology of an adequate histological specimen
Probable chronic pancreatitis is established by one or more of the following additional
criteria:
1. Mild ductal alterations (according to the Cambridge classification)
2. Recurrent or persistent pseudocysts
3. Pathological test of pancreatic exocrine function (such as fecal elastase-1 test,
secretin test, secretin-pancreozymin test)
4. Endocrine insufficiency (i.e., abnormal glucose tolerance test) Borderline chronic
pancreatitis is already established and is defined by a typical clinical history of the
disease but without any of the additional criteria required for definite or probable
chronic pancreatitis. This form is also established as a first episode of acute
pancreatitis with or without (1) a family history of pancreatic disease (i.e., other
family members with acute pancreatitis or pancreatic cancer) or (2) the presence of risk
factors.
They also proposed a clinical staging system, subcategorizing into an asymptomatic phase
(stage 0) and a symptomatic phase (stages I, II, III, IV) of chronic pancreatitis [table
5]. The poorly defined asymptomatic and early phase of chronic pancreatitis, during
which clinically recognized symptoms are not present (stage 0 a), was estimated only
retrospectively, for example, during surgical intervention or by autopsy. First episode
of acute pancreatitis (stage 0 b) was also included since it has been hypothesized that
any episode of acute pancreatitis in individuals at risk may cause the later development
of chronic pancreatitis. Table 5 . M-ANNHEIM clinical staging of chronic pancreatitis
This classification also includes a scoring system to determine the severity of the
disease to guide clinical treatment decisions and to predict the prognosis of the
disease [table 6]. But it is rather a very complex score was not correlated against any
valid outcome criteria when first developed [20].
Table 6. M-ANNHEIM scoring system for the grading of clinical features of chronic
pancreatitis In 2009, came the Heidelberg classification [11]which again classified the
disease based on clinical features, imaging findings, presence or absence of local
complications and end stage disease in the form of exocrine or endocrine insufficiency.
Stage A disease was defined as pain of any type and degree and/or attacks of acute
pancreatitis, without any complications ; nor steatorrhea, nor insulin-dependent
diabetes mellitus. Stage B is the intermediate stage where chronic pancreatitis has led
to complications like bile duct obstruction with cholestasis or jaundice ,duodenal
obstruction, vascular obstruction , portal/splenic vein hypertension, pancreatic
pseudocysts , pancreatic fistula (internal or external), pancreatogenic ascites but
clinical exocrine and endocrine function is still preserved. Stage C is the end stage of
chronic pancreatitis, where pancreatic fibrosis has led to clinical exocrine and/or
endocrine pancreatic function loss (steatorrhea and/or diabetes mellitus). Complications
of chronic pancreatitis might or might not be present.
All these classifications described earlier help to describe the natural progression of
the disease by grading the severity on the basis of imaging, clinical symptoms, need for
intervention and loss of function, but are neither suited to assess the current severity
nor to evaluate short- to mid-term outcomes of the disease [21]. Furthermore, none of
the published severity scoring systems have been developed in a prospective cohort of
patients nor have they been evaluated for predicting relevant clinical outcome
parameters, so in future we need to develop an objective scoring system for
classification of chronic pancreatitis which is simple to use on day to day basis yet
effective in predicting disease outcome.
In 2016, Olsen et al did a prospective study in Denmark [22] on their cohort of chronic
pancreatitis outpatients and studied various risk factors for the hospitalization rate.
On multivariate analysis they demonstrated that high dose opioid treatment (>100 mg per
day) and hypoalbuminemia were identified as independent risk factors for
hospitalisation.
Recently in 2017 Bayer et al [21]have developed a simple and dynamic scoring
system-Chronic Pancreatitis Prognostic score (COPPS), in a prospective study, comparable
to the Turcotte-Child-Pugh-score for liver cirrhosis based on routine laboratory
parameters (serum platelet counts, CRP, HbA1c), pain symptoms, body mass index (BMI).
They have also validated the same in an independent cohort and found positive
co-relation with hospital re-admission rates and duration of hospital stay in the follow
up. On this basis they propose that it can be used by general physicians in the
outpatient setting and hospitalists alike to reliably predict the risk of hospital
(re)admission as a measure of disease severity. This is a new score which need to be
further validated in other patient cohort of chronic pancreatitis to prove its utility
in predicting disease outcome.
AIM OF THE STUDY
- Clinical course of chronic pancreatitis is still unpredictable, due to the lack of
clinical classification
- There is no model to assess disease severity or progression or predict patient
outcomes
- So we need to validate an objective predictive model - Chronic Pancreatitis
Prognosis Score (COPPS) for classification, prognostication and management in
Chronic Pancreatitis (CP)
DEFINITION OF CHRONIC PANCREATITIS Diagnosis of chronic pancreatitis was made if one or
more met -
• recurrent bouts of pancreatic pain with documented rise in amylase or lipase activity
for a duration of more than one year and radiological evidence (CECT ABDOMEN) supporting
the diagnosis
- pancreatic calcifications and/or MPD dilatation
- histological proof of chronic pancreatitis
- unequivocal changes in pancreatic duct morphology
- Severely abnormal pancreatic function tests with maldigestion [23]
INCLUSION CRITERIA
- MEETS THE DEFINITION OF CP
- Not underwent pancreas related endoscopy/surgery earlier
- Follow up/index visit in our OPD/ward
- GIVES INFORMED WRITTEN CONSENT
EXCLUSION CRITERIA • Pancreatic carcinoma
OUTCOMES OF THE STUDY PRIMARY OUTCOME
- Total number of hospitalizations (all reasons)
- Total number of days spent in hospital within 12 months from inclusion SECONDARY
OUTCOME
- pancreatitis related no of readmissions (episodes of acute pancreatitis, pain
episodes , complications, pancreatic endoscopy/sx, infections related to
pancreatitis)
- pancreatitis related complications
- need for endoscopic or surgical interventions (no. and nature of procedure done)
MATERIALS AND METHODS
• Study area: School of Digestive & Liver Diseases, IPGMER and SSKM Hospital, Kolkata.
- Study population: Patient diagnosed with Chronic Pancreatitis visiting our
OPD/Indoors
- Study Period: June 2018 to December 2019
- Sample Size: As many patients satisfying inclusion criteria
- Study Design: Prospective non-randomised Cohort Study.
- Study area: School of Digestive & Liver Diseases, IPGMER and SSKM Hospital,
Kolkata.
- Study population: Patient diagnosed with Chronic Pancreatitis visiting our
OPD/Indoors
- Study Plan:
- Enrollment process for 1st 6 months; follow up for 1 year from ENROLLMENT DATE
- Detailed records will be taken and clinical examination will be carried out as
per Proforma designed in each visit
- All patients will undergo routine blood investigations prospectively from the
institute only
- All the patients will be followed up every 3 monthy - in Pancreatic Clinic or
indoor visit or Telephonic
- Study tool - Structured Questionnaire - Analysis of Previous Medical and
Interventional records
- Blood investigations
- Statistical Analysis - All continuous variables expressed as MEAN +/- SD - All
Categorical data expressed as Proportion/Ratio - Non-parametric statistics,
Chi-square test for categorical variables and Kruskal-Wallis test and Dunn´s
multiple comparison test for continuous variables.
- Data entered will be done in MS EXCEL Spread Sheet, Data analysis will be
carried out by SPSS version 16.0
- All P value <0.05 will be considered as statistical significant
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