Clinical trial NCT05480241: Exocrine Pancreatic Insufficiency After Acute Pancreatitis and Pancreatic Enzyme Replacement Therapy
Official title: Impact of Exocrine Pancreatic Insufficiency Associated With Acute Pancreatitis and Pancreatic Enzyme Replacement Therapy on Gut Microbiota, Immunological Changes and Quality of Life
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Acute Pancreatitis
Exocrine Pancreatic Insufficiency
Gut Microbiota
Immunology
Lead sponsor: Centro Hospitalar e Universitário de Coimbra, E.P.E.
Sponsor class: OTHER
Collaborators: name: University of Coimbra
First posted: 2022-07-29
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind randomized placebo-controlled trial for patients with EPI after acute pancreatitis for PERT and collection of stool and blood samples before and after PERT/placebo
Primary purpose: TREATMENT

Brief summary: Acute pancreatitis represents an acute inflammatory process of the pancreas, which undergoes local and systemic complications, associated with non-negligible morbidity and mortality, and significant economic and quality of life impact. Even after the recovery phase, the development and persistence of sequelae from the inflammatory/necrotic process, including exocrine and endocrine pancreatic insufficiencies, are frequent. Although well documented as consequence of other pancreatic conditions, exocrine pancreatic insufficiency (EPI) after acute pancreatitis is poorly studied and probably underdiagnosed. The prevalence, diagnosis, independent risk factors and therapeutic approaches for EPI after acute pancreatitis need further investigation. Recent evidence suggests the involvement of the pancreas-intestinal axis and immunological dysfunction in several pancreatic pathologies, although their role in the development of EPI after acute pancreatitis is still scarce. Pancreatic enzyme replacement therapy (PERT) is the only treatment currently available in EPI, but the timing for start and duration of this therapy in acute pancreatitis remain to be established. This study have the following objectives: to determine the prevalence, clinical, analytical and nutritional biomarkers and duration of EPI after acute pancreatitis, as well as changes in gut microbiota and immunologic response, and quality of life in EPI and response to PERT after acute pancreatitis; and to determine the prevalence and biomarkers associated with endocrine pancreatic insufficiency following acute pancreatitis and the presence of gut dysbiosis and immunologic changes in acute pancreatitis according to its severity.

Detailed description: Introduction: Acute pancreatitis represents an acute inflammatory process of the pancreas, which undergoes local and systemic complications, associated with non-negligible morbidity and mortality, and significant economic and quality of life impact. Even after the recovery phase, the development and persistence of sequelae from the inflammatory/necrotic process, including exocrine and endocrine pancreatic insufficiencies, are frequent. Although well documented as consequence of other pancreatic conditions, exocrine pancreatic insufficiency (EPI) after acute pancreatitis is poorly studied and probably underdiagnosed. The prevalence, diagnosis, independent risk factors and therapeutic approaches for EPI after acute pancreatitis need further investigation. Recent evidence suggests the involvement of the pancreas-intestinal axis and immunological dysfunction in several pancreatic pathologies, although their role in the development of EPI after acute pancreatitis is still scarce. Pancreatic enzyme replacement therapy (PERT) is the only treatment currently available in EPI, but the timing for start and duration of this therapy in acute pancreatitis remain to be established.

Objectives: Primary objectives: To determine the prevalence, clinical, analytical and nutritional biomarkers and duration of EPI after acute pancreatitis, as well as changes in gut microbiota and immunologic response, and quality of life in EPI and response to PERT after acute pancreatitis. Secondary objectives: To determine the prevalence and biomarkers associated with endocrine pancreatic insufficiency following acute pancreatitis and the presence of gut dysbiosis and immunologic changes in acute pancreatitis according to its severity.

Methods: Prospective longitudinal study of total of patients consecutively admitted to the Gastroenterology Department of Coimbra Hospital and University Centre with acute pancreatitis diagnosis and double-blind randomized placebo-controlled clinical trial of PERT in patients developing EPI after acute pancreatitis. This study will be conducted in 4 Phases: Phase 1 - Recruitment of patients with acute pancreatitis and stratification of them according to the severity of acute pancreatitis and development of EPI (12-month followup), diagnosed by fecal elastase-1, 13C-labeled mixed triglyceride breath test assessing exocrine pancreatic function and comparison of them with 72-hour fecal fat quantification, as gold standard; Phase 2 - Double-blind randomized placebo-controlled trial in patients with EPI after acute pancreatitis for PERT with assessment of efficacy and safety of this therapy at 1 and 6 months post-randomization; Phase 3 - Evaluation of richness, diversity and uniformity of gut microbiota by DNA sequencing using the hypervariable region of the 16S ribosomal RNA gene as a taxonomic identification marker and assessment of quality of life using SF-36 and QLC-C30-V.3 scales (validated versions for the Portuguese population) in EPI patients after acute pancreatitis, and the impact of PERT on clinical course, gut dysbiosis and quality of life of patients (at the diagnosis of acute pancreatitis, EPI and after PERT); and Phase 4 - Analysis of immunological changes through the study of cell populations by flow cytometry (CD4+, CD8+, B-cell, T-cell, natural killer cells, cells ratio) and cytokines, chemokines and growth factors by xMAP/Luminex, at the diagnosis of acute pancreatitis, EPI and after PERT.

Expected results, impact and scientific outputs: Data on the prevalence of EPI after acute pancreatitis in its different forms of severity and the role of gut dysbiosis and immunologic changes remains unclear. It's expected that an adequate and timely diagnosis of this clinical condition will allow an early start of therapy with positive impact on clinical course, immunologic and gut homeostasis, survival and quality of life. With this study we expect to obtain a prevalence of EPI at admission of 25-62%, which should decrease during followup. Alcoholic etiology, severity of acute pancreatitis and the presence of pancreatic necrosis should be positively associated with the presence of EPI after acute pancreatitis. The prevalence of endocrine pancreatic insufficiency (pre-diabetes or diabetes mellitus) should be up to 40%. Nutritional deficits (single or multiple), breath test assessing exocrine pancreatic function and fecal elastase-1 are also expected to be positively associated with the development of EPI. It's expected that patients with acute pancreatitis developing EPI will have significant changes on gut microbiota and immunologic response, and PERT and/or gut microbiota modulating therapy, including prebiotics, probiotics, symbiotics and fecal microbiota transplantation, and probably targeted immunotherapies may have a beneficial impact on all patients or groups at risk, such as EPI, severe or necrotizing acute pancreatitis by reverting gut and immunologic dysbiosis, and improving quality of life.

Eligibility criteria: Inclusion Criteria:

* Definitive diagnosis of acute pancreatitis, according to revised Atlanta criteria 2012.

Exclusion Criteria:

* Age \<18years
* History of allergy, hypersensitivity or contraindication to use of PERT
* Prior acute pancreatitis
* Other causes that may occur with EPI, including celiac disease, diabetic gastroparesis, chronic pancreatitis, cystic fibrosis, pancreatic neoplasia, ampulloma, somatostatinoma, somatostatin analog therapy, small bowel pathology, inflammatory bowel disease, and rare diseases associated with exocrine pancreatic insufficiency (Zollinger-Ellison syndrome, Shwachman-Diamond syndrome, Johanson-Blizzard syndrome)
* Prior gastrointestinal or pancreatic surgery or endoscopic/surgical therapy for obesity
* medication with orlistat or acarbose
* Respiratory pathology (severe chronic obstructive pulmonary disease), hepatic (Child-Pugh C cirrhosis) or biliary (obstructive jaundice) severe pathology
* Non-compliance for PERT (when indicated)
* Uncontrolled thyroid pathology
* Refusal/incapacity to give informed consent
* Follow-up period \<12months after acute pancreatitis diagnosis

Primary outcomes:
measure: When to start PERT assessed by the time, in days, between acute pancreatitis diagnosis and EPI diagnosis in patients with EPI following acute pancreatitis
timeFrame: Up to 12 months
measure: PERT efficacy assessed by % of successful treatments in patients with EPI following acute pancreatitis
timeFrame: At 6 months after starting PERT
measure: PERT safety assessed by adverse effects according to Medical Dictionary for Regulatory Activities in patients with EPI following acute pancreatitis
timeFrame: At 6 months after starting PERT
measure: PERT duration assessed by the time of starting PERT to normalization of exocrine pancreatic function in patients with EPI following acute pancreatitis
timeFrame: At 6 months after starting PERT
Secondary outcomes:
measure: Prevalence of exocrine pancreatic insufficiency (EPI) following acute pancreatitis assessed by the proportion and percentage of patients with EPI after acute pancreatitis diagnosis
timeFrame: Up to 12 months
measure: Prevalence of endocrine pancreatic insufficiency (EnPI) following acute pancreatitis assessed by the proportion and % of patients with EnPI after acute pancreatitis diagnosis
timeFrame: Up to 12 months
measure: Changes in gut microbiota profile using DNA sequencing of ribosomal 16S bacteria gene in acute pancreatitis, EPI following acute pancreatitis and after PERT assessed by the changes in composition and diversity of gut microbiota (OTU changes)
timeFrame: Change from Baseline at 6 months after starting PERT
measure: Changes in Immunological profile assessed by study of cell populations in acute pancreatitis, EPI following acute pancreatitis diagnosis and after PERT
timeFrame: Change from Baseline at 6 months after starting PERT
measure: Changes in quality of life in patients with EPI after acute pancreatitis, EPI following acute pancreatitis and after PERT assessed by quality of life scale appropriated to this condition - SF-36
timeFrame: Change from Baseline at 6 months after starting PERT
measure: Post-PERT changes assessed by cytokines, chemokines and growth factors in immunological profile
timeFrame: Change from Baseline at 6 months after starting PERT
measure: Changes in quality of life in patients with EPI after acute pancreatitis, EPI following acute pancreatitis and after PERT assessed by quality of life scale appropriated to this condition - QLC-C30-V.3.0
timeFrame: Change from Baseline at 6 months after starting PERT
Other outcomes:
Locations:
city: Coimbra
country: Portugal
facility: Centro Hospitalar e Universitário de Coimbra, E.P.E.
Study officials:
affiliation: Centro Hospitalar e Universitário de Coimbra, E.P.E.
name: Marta Gravito-Soares, MD
role: PRINCIPAL_INVESTIGATOR
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