Acute PancreatitisNCT05480241
Exocrine Pancreatic Insufficiency After Acute Pancreatitis and Pancreatic Enzyme Replacement Therapy
A study testing Pancreatic Enzyme Replacement Therapy in people with Acute Pancreatitis and Exocrine Pancreatic Insufficiency, run by Unidade Local de Saúde de Coimbra, EPE at 1 site in Portugal.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Pancreatitis, Exocrine Pancreatic Insufficiency, Gut Microbiota
- What is being tested?
- Pancreatic Enzyme Replacement Therapy
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 84 participants
- Where
- 1 sitePortugal
- Study dates
- 1 May 2022to 31 Dec 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Definitive diagnosis of acute pancreatitis, according to revised Atlanta criteria 2012.
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Portugal1 site, 1 recruiting
- Recruiting
Centro Hospitalar e Universitário de Coimbra, E.P.E.
Coimbra, 3000-075
Marta Gravito-Soares, MD, (+351)239400483, ms18498@gmail.com
Pedro Figueiredo, PhD, (+351)239400483, pnf11@sapo.pt
About this study
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
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.
Read the 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.
- Being tested
- Pancreatic Enzyme Replacement Therapy, Placebo
- Medical subject headings
- Pancreatitis, Exocrine Pancreatic Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Pancreatic Enzyme Replacement TherapyDrug
Also called kreon
Pancreatic Enzyme Replacement Therapy (PERT) 50000 Ph.U./meal + 25000 Ph.U./snack + Omeprazole 20mg once daily on fasting
PlaceboDrug
Placebo + Omeprazole 20mg once daily on fasting
| Study group | Role | What they receive |
|---|---|---|
| Pancreatic Enzyme Replacement Therapy | Experimental | Pancreatic Enzyme Replacement Therapy (PERT) 50000 Ph.U./meal + 25000 Ph.U./snack + Omeprazole 20mg once daily on fasting Receives: Drug: Pancreatic Enzyme Replacement Therapy |
| Placebo | Placebo comparator | Placebo + Omeprazole 20mg once daily on fasting Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
When to start PERT assessed by the time, in days, between acute pancreatitis diagnosis and EPI diagnosis in patients with EPI following acute pancreatitis
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo).
To evaluate when to start PERT we will determine the time between acute pancreatitis diagnosis and EPI diagnosis, in days. Searching for EPI will take place up to 12 months after acute pancreatitis diagnosis.
Measured: Up to 12 months
PERT efficacy assessed by % of successful treatments in patients with EPI following acute pancreatitis
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo). The PERT dose will be the one agreed for EPI for benign pancreatic pathologies associated with proton pump inhibitor (PPI).
PERT efficacy will be assessed by the % of successful treatments in patients with EPI diagnosis after acute pancreatitis, using the test that was positive for EPI diagnosis (fecal elastase-1, 13 C Mixed Triglyceride Breath Test or Fecal Fat Quantitative Test). Efficacy corresponds to the normalization of exocrine pancreatic function test and will be assessed by at 6 months post-randomization. The compliance of PERT will be checked in all follow-up visits.
Measured: At 6 months after starting PERT
PERT safety assessed by adverse effects according to Medical Dictionary for Regulatory Activities in patients with EPI following acute pancreatitis
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo). The PERT dose will be the one agreed for EPI for benign pancreatic pathologies associated with proton pump inhibitor (PPI).
PERT safety will be evaluated with the determination of adverse effects according to Medical Dictionary for Regulatory Activities (MedDRa will be evaluated in terms of visual analogic intolerance scale (0-10) for abdominal pain and other adverse events severity in relation to the influence on activities of daily life. PERT safety will be assessed at 6 months post-randomization. The compliance of PERT will be checked in all follow-up visits.
Measured: At 6 months after starting PERT
PERT duration assessed by the time of starting PERT to normalization of exocrine pancreatic function in patients with EPI following acute pancreatitis
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo). The PERT dose will be the one agreed for EPI for benign pancreatic pathologies associated with proton pump inhibitor (PPI).
The duration of PERT will be evaluated determining the time, in months, between EPI diagnosis after acute pancreatitis diagnosis and the normalization of exocrine pancreatic function, determined by the normalization of positive test diagnosing EPI (fecal elastase-1, 13 C Mixed Triglyceride Breath Test or Fecal Fat Quantitative Test), using the test that was positive for EPI diagnosis.
Measured: At 6 months after starting PERT
Secondary outcomes (7)
Prevalence of exocrine pancreatic insufficiency (EPI) following acute pancreatitis assessed by the proportion and percentage of patients with EPI after acute pancreatitis diagnosis
After the recruitment of eligible patients with the first episode of acute pancreatitis, they will be stratified according to acute pancreatitis severity and EPI development. Acute pancreatitis severity will be classified into mild, moderately severe and severe cases according to the revised criteria of Atlanta 2012. The EPI diagnosis will be performed by noninvasive 13C-labeled mixed triglyceride breath test and by the non-invasive fecal elastase-1 test. At diagnosis, 72-hour fecal fat quantification will also be used as a validated indirect gold standard test.
The prevalence of EPI will be determined by the proportion and percentage of patients with each of these complications to the total of patients with acute pancreatitis during 12-month follow-up after acute pancreatitis diagnosis. Searching for EPI will take place up to 12 months after acute pancreatitis diagnosis.
Measured: Up to 12 months
Prevalence of endocrine pancreatic insufficiency (EnPI) following acute pancreatitis assessed by the proportion and % of patients with EnPI after acute pancreatitis diagnosis
After the recruitment of eligible patients with the first episode of acute pancreatitis, they will be stratified according to acute pancreatitis severity and EPI development. Acute pancreatitis severity will be classified into mild, moderately severe and severe cases according to the revised criteria of Atlanta 2012. Assessment of EnPI (secondary endpoint) will be defined by the development of new-onset pre-diabetes and/or diabetes mellitus - type 3 diabetes mellitus according to the diagnostic criteria of the American Diabetes Association 2019.
The prevalence of EnPI will be determined by the proportion and percentage of patients with each of these complications to the total of patients with acute pancreatitis during 12-month follow-up after acute pancreatitis diagnosis.
Measured: Up to 12 months
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)
Analysis of gut microbiota by DNA sequencing using the hypervariable region of the ribosomal 16S bacteria gene as a taxonomic identification marker and quality of life assessment: Gut microbiota will be assessed for a number of species present (richness) and qualitative composition (diversity and uniformity) using next-generation genome sequencing techniques by an independent operator who will not know the status and therapy of EPI (PERT vs placebo). After extraction of the bacterial DNA, the sequencing of the gut microbiota by bioinformatic analysis will be performed for taxonomic identification and determination of the relative abundance of each Operational Taxonomy Units (OTU). Gut microbiota will be evaluated at baseline (acute pancreatitis diagnosis), at EPI diagnosis and 6 months after starting PERT.
Measured: Change from Baseline at 6 months after starting PERT
Changes in Immunological profile assessed by study of cell populations in acute pancreatitis, EPI following acute pancreatitis diagnosis and after PERT
To evaluate the role of immunological response in EPI post-acute pancreatitis and PERT response, fresh peripheral blood samples will be collected and processed until obtain serum by centrifugation at 4ºC and stored at -20°C and then analyzed after the diagnosis of acute pancreatitis, after diagnosis of EPI and 6months after PERT. A standard protocol with be followed. Analysis of immunological changes: Immunological profile will be analyzed through the study of cell populations (CD4+, CD8+, B-cell, T-cell, natural killer cells, cells ratio) by multiparametric flow cytometry at acute pancreatitis diagnosis, immediately after EPI diagnosis and 6 months after PERT. This analysis will be performed by an independent operator who will not know the status and therapy of EPI (PERT vs placebo).
Measured: Change from Baseline at 6 months after starting PERT
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
The quality of life will be measured through the scale SF-36, validated for the Portuguese population and applicable to this pathology, that will take place after the diagnosis of acute pancreatitis, after diagnosis of EPI and 6 months after PERT. It is a 36-item questionnaire. All ofthe scales and single item scales range in score from 0 to 100. A high score for global health status/QoL represents high/healthy level of functioning and QoL.
Measured: Change from Baseline at 6 months after starting PERT
Post-PERT changes assessed by cytokines, chemokines and growth factors in immunological profile
Fresh peripheral blood samples will be collected and processed until obtain serum by centrifugation at 4ºC and stored at -20°C and then analyzed after the diagnosis of acute pancreatitis, after diagnosis of EPI and 6months after PERT. A standard protocol with the conditions of collection, storage and transport of the different collected samples will be used. Changes from Baseline in immunological profile on cytokines, chemokines and growth factors by xMAP/Luminex at 6 months post-PERT. This analysis will be performed by an independent operator who will not know the status and therapy of EPI (PERT vs placebo).
Measured: Change from Baseline at 6 months after starting PERT
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
The quality of life will be measured through the scale QLC-C30-V.3.0, validated for the Portuguese population and applicable to this pathology, that will take place after the diagnosis of acute pancreatitis, after diagnosis of EPI and 6 months after PERT. It is a 30-item questionnaire. All ofthe scales and single item scales range in score from 0 to 100. A high score for functional scales and global health status/QoL represents high/healthy level of functioning and QoL. A high score for a symptom scale/item represents a high level of symptomatology or problems.
Measured: Change from Baseline at 6 months after starting PERT
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jul 2022
- Study start1 May 2022
- Primary completion31 Dec 2023 (estimated)
- Study completion31 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (29)Papers the sponsor has linked to this study.
- Other trials for Acute PancreatitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 84 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Unidade Local de Saúde de Coimbra, EPE
- Sponsor type
- University, hospital or other
- Collaborators
- University of Coimbra
- Responsible party
- Principal investigator, Marta Isabel da Fonseca Gravito Soares, Unidade Local de Saúde de Coimbra, EPE
- Investigators
- Marta Gravito-Soares, MD, Principal investigator, Unidade Local de Saúde de Coimbra, EPE
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05480241
- Sponsor's protocol ID
- EPInAP
- Status last verified
- Jul 2022
- First submitted
- 22 May 2022
- Last updated
- 29 Jul 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Lee PJ, Papachristou GI. New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol. 2019 Aug;16(8):479-496. doi: 10.1038/s41575-019-0158-2.
PubMed 31138897Roberts SE, Morrison-Rees S, John A, Williams JG, Brown TH, Samuel DG. The incidence and aetiology of acute pancreatitis across Europe. Pancreatology. 2017 Mar-Apr;17(2):155-165. doi: 10.1016/j.pan.2017.01.005. Epub 2017 Jan 19.
PubMed 28159463Xiao AY, Tan ML, Wu LM, Asrani VM, Windsor JA, Yadav D, Petrov MS. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol. 2016 Sep;1(1):45-55. doi: 10.1016/S2468-1253(16)30004-8. Epub 2016 Jun 28.
PubMed 28404111Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. doi: 10.1136/gutjnl-2012-302779. Epub 2012 Oct 25.
PubMed 23100216Hollemans RA, Hallensleben NDL, Mager DJ, Kelder JC, Besselink MG, Bruno MJ, Verdonk RC, van Santvoort HC; Dutch Pancreatitis Study Group. Pancreatic exocrine insufficiency following acute pancreatitis: Systematic review and study level meta-analysis. Pancreatology. 2018 Apr;18(3):253-262. doi: 10.1016/j.pan.2018.02.009. Epub 2018 Feb 20.
PubMed 29482892Huang W, de la Iglesia-Garcia D, Baston-Rey I, Calvino-Suarez C, Larino-Noia J, Iglesias-Garcia J, Shi N, Zhang X, Cai W, Deng L, Moore D, Singh VK, Xia Q, Windsor JA, Dominguez-Munoz JE, Sutton R. Exocrine Pancreatic Insufficiency Following Acute Pancreatitis: Systematic Review and Meta-Analysis. Dig Dis Sci. 2019 Jul;64(7):1985-2005. doi: 10.1007/s10620-019-05568-9. Epub 2019 Jun 4.
PubMed 31161524Gravito-Soares M, Gravito-Soares E, Gomes D, Almeida N, Tome L. Red cell distribution width and red cell distribution width to total serum calcium ratio as major predictors of severity and mortality in acute pancreatitis. BMC Gastroenterol. 2018 Jul 5;18(1):108. doi: 10.1186/s12876-018-0834-7.
PubMed 29976140Das SL, Singh PP, Phillips AR, Murphy R, Windsor JA, Petrov MS. Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis. Gut. 2014 May;63(5):818-31. doi: 10.1136/gutjnl-2013-305062. Epub 2013 Aug 8.
PubMed 23929695Ahmed Ali U, Issa Y, Hagenaars JC, Bakker OJ, van Goor H, Nieuwenhuijs VB, Bollen TL, van Ramshorst B, Witteman BJ, Brink MA, Schaapherder AF, Dejong CH, Spanier BW, Heisterkamp J, van der Harst E, van Eijck CH, Besselink MG, Gooszen HG, van Santvoort HC, Boermeester MA; Dutch Pancreatitis Study Group. Risk of Recurrent Pancreatitis and Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis. Clin Gastroenterol Hepatol. 2016 May;14(5):738-46. doi: 10.1016/j.cgh.2015.12.040. Epub 2016 Jan 6.
PubMed 26772149Pendharkar SA, Salt K, Plank LD, Windsor JA, Petrov MS. Quality of life after acute pancreatitis: a systematic review and meta-analysis. Pancreas. 2014 Nov;43(8):1194-200. doi: 10.1097/MPA.0000000000000189.
PubMed 25333403Sankaran SJ, Xiao AY, Wu LM, Windsor JA, Forsmark CE, Petrov MS. Frequency of progression from acute to chronic pancreatitis and risk factors: a meta-analysis. Gastroenterology. 2015 Nov;149(6):1490-1500.e1. doi: 10.1053/j.gastro.2015.07.066. Epub 2015 Aug 20.
PubMed 26299411Vanga RR, Tansel A, Sidiq S, El-Serag HB, Othman MO. Diagnostic Performance of Measurement of Fecal Elastase-1 in Detection of Exocrine Pancreatic Insufficiency: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018 Aug;16(8):1220-1228.e4. doi: 10.1016/j.cgh.2018.01.027. Epub 2018 Jan 31.
PubMed 29374614Loser C, Brauer C, Aygen S, Hennemann O, Folsch UR. Comparative clinical evaluation of the 13C-mixed triglyceride breath test as an indirect pancreatic function test. Scand J Gastroenterol. 1998 Mar;33(3):327-34. doi: 10.1080/00365529850170946.
PubMed 9548629Adolph TE, Mayr L, Grabherr F, Schwarzler J, Tilg H. Pancreas-Microbiota Cross Talk in Health and Disease. Annu Rev Nutr. 2019 Aug 21;39:249-266. doi: 10.1146/annurev-nutr-082018-124306.
PubMed 31433743Zhu Y, He C, Li X, Cai Y, Hu J, Liao Y, Zhao J, Xia L, He W, Liu L, Luo C, Shu X, Cai Q, Chen Y, Lu N. Gut microbiota dysbiosis worsens the severity of acute pancreatitis in patients and mice. J Gastroenterol. 2019 Apr;54(4):347-358. doi: 10.1007/s00535-018-1529-0. Epub 2018 Dec 5.
PubMed 30519748
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05480241
- Acronym / sponsor ID
- EPInAP
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 84 participants (estimated)
- Lead sponsor
- Unidade Local de Saúde de Coimbra, EPEUniversity, hospital or other
- Collaborators
- University of Coimbra
- Study start
- 1 May 2022 (actual)
- Primary completion
- 31 Dec 2023 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 29 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- 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
| Arm | Type | Receives |
|---|---|---|
| Pancreatic Enzyme Replacement Therapy | Experimental | Drug: Pancreatic Enzyme Replacement TherapyPancreatic Enzyme Replacement Therapy (PERT) 50000 Ph.U./meal + 25000 Ph.U./snack + Omeprazole 20mg once daily on fasting |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo + Omeprazole 20mg once daily on fasting |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Definitive diagnosis of acute pancreatitis, according to revised Atlanta criteria 2012.
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Pancreatic Enzyme Replacement TherapyAlso: kreonPancreatic Enzyme Replacement Therapy (PERT) 50000 Ph.U./meal + 25000 Ph.U./snack + Omeprazole 20mg once daily on fasting | Drug | Pancreatic Enzyme Replacement Therapy |
| PlaceboPlacebo + Omeprazole 20mg once daily on fasting | Drug | Placebo |
Primary outcome
When to start PERT assessed by the time, in days, between acute pancreatitis diagnosis and EPI diagnosis in patients with EPI following acute pancreatitis
Time frame: Up to 12 months
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo). To evaluate when to start PERT we will determine the time between acute pancreatitis diagnosis and EPI diagnosis, in days. Searching for EPI will take place up to 12 months after acute pancreatitis diagnosis.
PERT efficacy assessed by % of successful treatments in patients with EPI following acute pancreatitis
Time frame: At 6 months after starting PERT
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo). The PERT dose will be the one agreed for EPI for benign pancreatic pathologies associated with proton pump inhibitor (PPI). PERT efficacy will be assessed by the % of successful treatments in patients with EPI diagnosis after acute pancreatitis, using the test that was positive for EPI diagnosis (fecal elastase-1, 13 C Mixed Triglyceride Breath Test or Fecal Fat Quantitative Test). Efficacy corresponds to the normalization of exocrine pancreatic function test and will be assessed by at 6 months post-randomization. The compliance of PERT will be checked in all follow-up visits.
PERT safety assessed by adverse effects according to Medical Dictionary for Regulatory Activities in patients with EPI following acute pancreatitis
Time frame: At 6 months after starting PERT
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo). The PERT dose will be the one agreed for EPI for benign pancreatic pathologies associated with proton pump inhibitor (PPI). PERT safety will be evaluated with the determination of adverse effects according to Medical Dictionary for Regulatory Activities (MedDRa will be evaluated in terms of visual analogic intolerance scale (0-10) for abdominal pain and other adverse events severity in relation to the influence on activities of daily life. PERT safety will be assessed at 6 months post-randomization. The compliance of PERT will be checked in all follow-up visits.
PERT duration assessed by the time of starting PERT to normalization of exocrine pancreatic function in patients with EPI following acute pancreatitis
Time frame: At 6 months after starting PERT
A standardized protocol will be applied for both groups differing only in drug used (PERT or placebo). The PERT dose will be the one agreed for EPI for benign pancreatic pathologies associated with proton pump inhibitor (PPI). The duration of PERT will be evaluated determining the time, in months, between EPI diagnosis after acute pancreatitis diagnosis and the normalization of exocrine pancreatic function, determined by the normalization of positive test diagnosing EPI (fecal elastase-1, 13 C Mixed Triglyceride Breath Test or Fecal Fat Quantitative Test), using the test that was positive for EPI diagnosis.
7 secondary outcomes
Prevalence of exocrine pancreatic insufficiency (EPI) following acute pancreatitis assessed by the proportion and percentage of patients with EPI after acute pancreatitis diagnosis
Time frame: Up to 12 months
Prevalence of endocrine pancreatic insufficiency (EnPI) following acute pancreatitis assessed by the proportion and % of patients with EnPI after acute pancreatitis diagnosis
Time frame: Up to 12 months
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)
Time frame: Change from Baseline at 6 months after starting PERT
Changes in Immunological profile assessed by study of cell populations in acute pancreatitis, EPI following acute pancreatitis diagnosis and after PERT
Time frame: Change from Baseline at 6 months after starting PERT
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
Time frame: Change from Baseline at 6 months after starting PERT
Post-PERT changes assessed by cytokines, chemokines and growth factors in immunological profile
Time frame: Change from Baseline at 6 months after starting PERT
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
Time frame: Change from Baseline at 6 months after starting PERT
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2022.
- Results publication: PubMed 31138897Lee PJ, Papachristou GI. New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol. 2019 Aug;16(8):479-496. doi: 10.1038/s41575-019-0158-2.
- Results publication: PubMed 28159463Roberts SE, Morrison-Rees S, John A, Williams JG, Brown TH, Samuel DG. The incidence and aetiology of acute pancreatitis across Europe. Pancreatology. 2017 Mar-Apr;17(2):155-165. doi: 10.1016/j.pan.2017.01.005. Epub 2017 Jan 19.
- Results publication: PubMed 28404111Xiao AY, Tan ML, Wu LM, Asrani VM, Windsor JA, Yadav D, Petrov MS. Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol. 2016 Sep;1(1):45-55. doi: 10.1016/S2468-1253(16)30004-8. Epub 2016 Jun 28.
- Results publication: PubMed 23100216Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege SS; Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62(1):102-11. doi: 10.1136/gutjnl-2012-302779. Epub 2012 Oct 25.
- Results publication: PubMed 29482892Hollemans RA, Hallensleben NDL, Mager DJ, Kelder JC, Besselink MG, Bruno MJ, Verdonk RC, van Santvoort HC; Dutch Pancreatitis Study Group. Pancreatic exocrine insufficiency following acute pancreatitis: Systematic review and study level meta-analysis. Pancreatology. 2018 Apr;18(3):253-262. doi: 10.1016/j.pan.2018.02.009. Epub 2018 Feb 20.
- Results publication: PubMed 31161524Huang W, de la Iglesia-Garcia D, Baston-Rey I, Calvino-Suarez C, Larino-Noia J, Iglesias-Garcia J, Shi N, Zhang X, Cai W, Deng L, Moore D, Singh VK, Xia Q, Windsor JA, Dominguez-Munoz JE, Sutton R. Exocrine Pancreatic Insufficiency Following Acute Pancreatitis: Systematic Review and Meta-Analysis. Dig Dis Sci. 2019 Jul;64(7):1985-2005. doi: 10.1007/s10620-019-05568-9. Epub 2019 Jun 4.
- Results publication: PubMed 29976140Gravito-Soares M, Gravito-Soares E, Gomes D, Almeida N, Tome L. Red cell distribution width and red cell distribution width to total serum calcium ratio as major predictors of severity and mortality in acute pancreatitis. BMC Gastroenterol. 2018 Jul 5;18(1):108. doi: 10.1186/s12876-018-0834-7.
- Results publication: PubMed 23929695Das SL, Singh PP, Phillips AR, Murphy R, Windsor JA, Petrov MS. Newly diagnosed diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis. Gut. 2014 May;63(5):818-31. doi: 10.1136/gutjnl-2013-305062. Epub 2013 Aug 8.
- Results publication: PubMed 26772149Ahmed Ali U, Issa Y, Hagenaars JC, Bakker OJ, van Goor H, Nieuwenhuijs VB, Bollen TL, van Ramshorst B, Witteman BJ, Brink MA, Schaapherder AF, Dejong CH, Spanier BW, Heisterkamp J, van der Harst E, van Eijck CH, Besselink MG, Gooszen HG, van Santvoort HC, Boermeester MA; Dutch Pancreatitis Study Group. Risk of Recurrent Pancreatitis and Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis. Clin Gastroenterol Hepatol. 2016 May;14(5):738-46. doi: 10.1016/j.cgh.2015.12.040. Epub 2016 Jan 6.
- Results publication: PubMed 25333403Pendharkar SA, Salt K, Plank LD, Windsor JA, Petrov MS. Quality of life after acute pancreatitis: a systematic review and meta-analysis. Pancreas. 2014 Nov;43(8):1194-200. doi: 10.1097/MPA.0000000000000189.
- Results publication: PubMed 26299411Sankaran SJ, Xiao AY, Wu LM, Windsor JA, Forsmark CE, Petrov MS. Frequency of progression from acute to chronic pancreatitis and risk factors: a meta-analysis. Gastroenterology. 2015 Nov;149(6):1490-1500.e1. doi: 10.1053/j.gastro.2015.07.066. Epub 2015 Aug 20.
- Results publication: PubMed 29374614Vanga RR, Tansel A, Sidiq S, El-Serag HB, Othman MO. Diagnostic Performance of Measurement of Fecal Elastase-1 in Detection of Exocrine Pancreatic Insufficiency: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018 Aug;16(8):1220-1228.e4. doi: 10.1016/j.cgh.2018.01.027. Epub 2018 Jan 31.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marta Gravito-Soares, MD principal investigator
Unidade Local de Saúde de Coimbra, EPE
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Pancreatic Enzyme Replacement Therapy in people with Acute Pancreatitis and Exocrine Pancreatic Insufficiency, run by Unidade Local de Saúde de Coimbra, EPE at 1 site in Portugal.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Portugal. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Marta Gravito-Soares, MD ((+351)239400483, ms18498@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: Up to 12 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05480241, which also lists 29 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2022.