Prophylactic Tributyrin Supplementation in Acute Pancreatitis (PARROT)

Prophylactic Tributyrin Supplementation in Acute Pancreatitis; a Phase IIa (Proof of Concept) Double-blind Randomized Placebo-controlled Food Supplement Trial

The goal of this clinical trial is to investigate the possible effects of tributyrin supplementation in patients with a first episode of acute pancreatitis. The main question it aims to answer is:

• The effect of oral tributyrin supplementation on the plasma endotoxin level

Participants will be randomized between two groups: intervention and control group. They will receive:

- three times daily 4grams of micro-encapsulated granules of tributyrin, and the control group three times daily 4 grams of micro-encapsulated sunflower oil (i.e. placebo), for a total of 14 days

In total 92 adult patients with a first episode of acute pancreatitis will be included.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Pancreatitis
• Intervention / Treatment: Dietary supplement: Micro-encapsulated granules of tributyrin (intervention); Dietary supplement: Micro-encapsulated granules of sunflower oil (placebo)

Detailed Description

Rationale: Acute pancreatitis (AP) is a common gastrointestinal disorder requiring acute hospitalization. Around 20% of patients that present with acute pancreatitis eventually develop severe complications such as (multiple) organ failure, (peri-) pancreatic necrosis, and secondary infections (i.e. infected necrosis, bacteraemia, pneumonia). The gut, especially the gut microbiome, is likely to play a role in development of infectious complications. Short-chain fatty acids (SCFAs) produced by the gut microbiota, such as butyrate, are known immunomodulators of the host response and exert local beneficial effects on the gut barrier and microbiota. Currently, there are no safe and effective therapies to mitigate disease severity that can be administered in the early phase of pancreatitis. We hypothesize that orally administered tributyrin, a pro-drug of butyrate, might beneficially influence disease progression in acute pancreatitis and may be useful as prophylaxis.

Objective: The main objective is to investigate the effect of oral tributyrin on plasma endotoxin in patients with acute pancreatitis after 3 days of treatment.

Study design: Phase IIa (Proof of concept) double-blind randomized placebo-controlled food supplement trial.

Study population: 92 adult patients with a first episode of acute pancreatitis.

Intervention: The intervention group receives three times daily 4g micro-encapsulated granules of tributyrin and the control group receives three times daily an equivalent volume of micro-encapsulated vegetable oil (i.e. placebo), for a total of maximum 14 days.

Main study parameters/endpoints: The primary endpoint is plasma endotoxin concentration after 3 days of tributyrin treatment. Secondary endpoints include toxicity, clinical outcomes, intestinal permeability, fecal SCFA concentrations, intestinal microbiota composition and systemic inflammatory response parameters (pulse, respiratory rate, temperature and white blood cell count).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The blood sampling at inclusion, and day 3 and 7 of treatment are preferably combined with regular blood sampling. Participants may experience minor discomfort from rectal swabs. Phase 1 studies with oral tributyrin conducted in patients with solid tumors did not report serious adverse events. However, there is a risk of unanticipated adverse events in our target population. An independent data safety and monitoring board (DSMB) will discuss all reported serious adverse events (SAE's).

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hannah Pauw, MD; Phone Number: +31 0883207051; Email: ha.pauw@antoniusziekenhuis.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• First episode of acute pancreatitis (AP)
• Able to read and/or understand the study procedures
• Able to give informed consent (or their legal representatives)
• <24 hours after diagnosis of AP
• <72 hours after onset of symptoms of AP

Exclusion Criteria:

• Pancreatitis due to endoscopic retrograde cholangiopancreatography (ERCP), malignancy or trauma
• Post-operative pancreatitis
• Intra-operative diagnosis
• Immunocompromised patients (history or current immunosuppressive treatment such as chemotherapy, radiotherapy, longer use of immunosuppressive medication or recent high doses, immunocompromised illness' such as AIDS, leukemia, lymphoma)
• Pregnancy and/or lactation
• Age <18 years old
• History of recurrent or chronic (MANNHEIM criteria25) pancreatitis (see Appendix 15.1 for definition)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; Micro-encapsulated tributyrin granules, 4 grams three times daily, for a maximum of 14 days	Dietary supplement: Micro-encapsulated granules of tributyrin (intervention); Three times daily 4 grams of micro-encapsulated granules of tributyrin, for a maximum of 14 days
Placebo Comparator: Control group; Micro-encapsulated sunflower oil granules, 4 grams three times daily, for a maximum of 14 days	Dietary supplement: Micro-encapsulated granules of sunflower oil (placebo); Three times daily 4 grams of micro-encapsulated granules of sunflower oil, for a maximum of 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma endotoxin levels	Plasma endotoxin levels	Measured 3 days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Occurence of death	During the whole study period including follow-up of 90 days
Infectious complications	The occurence of infected pancreatic necrosis, bacteremia, pneumonia, urosepsis, and/or infected ascites	During the whole study period including follow-up of 90 days
(New onset) transient/persistant (multiple) organ failure	The occurence of (new onset) transient/persistant (multiple) organ failure	During the whole study period including follow-up of 90 days
Disease severity according to the revised Atlanta Classification	Disease severity according to the revised Atlanta Classification	During the whole study period including follow-up of 90 days
(Peri-)pancreatic necrosis	The occurence of (peri)pancreatic necrosis	During the whole study period including follow-up of 90 days
Length of hospital and/or ICU stay	Measured in days	During the whole study period including follow-up of 90 days
The need (and number of) for surgical, endoscopic or radiologic interventions	The need (and number of) for surgical, endoscopic or radiologic interventions	During the whole study period including follow-up of 90 days
Fecal and saliva microbiota and fecal metabolomics (i.e., SCFAs) analysis	Fecal and saliva microbiota and fecal metabolomics (i.e., SCFAs) analysis	During the whole study period including follow-up of 90 days
Readmissions	The occurrence and number of readmissions	During the whole study period including follow-up of 90 days
Systemic inflammatory response parameters (SIRS): pulse	Pulse measured in beats per minute	During the initial admission
Systemic inflammatory response parameters (SIRS): respiratory rate	Respiratory rate measured in breaths per minute	During the initial admission
Systemic inflammatory response parameters (SIRS): temperature	Temperature measured in degrees celsius	During the initial admission
Systemic inflammatory response parameters (SIRS): white blood cell count	White blood cell count	During the initial admission
Exocrine insufficiency	Exocrine insufficiency	During the whole study period including follow-up of 90 days
Endocrine insufficiency	Endocrine insufficiency	During the whole study period including follow-up of 90 days

Collaborators and Investigators

• Sponsor: St. Antonius Hospital
• Investigators: Principal Investigator: H. C. van Santvoort, dr. prof., St. Antonius Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2023
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: July 10, 2023
• First Submitted That Met QC Criteria: November 24, 2023
• First Posted (Actual): November 27, 2023

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pancreatic Diseases; Pancreatitis
• Other Study ID Numbers: NL81496.100.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No