Prophylactic Tributyrin Supplementation in Acute Pancreatitis

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Acute Pancreatitis

Intervention / Treatment
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* Dietary Supplement: Micro-encapsulated granules of tributyrin (intervention)
* Dietary Supplement: Micro-encapsulated granules of sunflower oil (placebo)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 |