Prophylactic Tributyrin Supplementation in Acute Pancreatitis

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).

• Mortality [Time frame: During the whole study period including follow-up of 90 days]
• Infectious complications [Time frame: During the whole study period including follow-up of 90 days]
• (New onset) transient/persistant (multiple) organ failure [Time frame: During the whole study period including follow-up of 90 days]
• Disease severity according to the revised Atlanta Classification [Time frame: During the whole study period including follow-up of 90 days]
• (Peri-)pancreatic necrosis [Time frame: During the whole study period including follow-up of 90 days]
• Length of hospital and/or ICU stay [Time frame: During the whole study period including follow-up of 90 days]
• The need (and number of) for surgical, endoscopic or radiologic interventions [Time frame: During the whole study period including follow-up of 90 days]
• Fecal and saliva microbiota and fecal metabolomics (i.e., SCFAs) analysis [Time frame: During the whole study period including follow-up of 90 days]
• Readmissions [Time frame: During the whole study period including follow-up of 90 days]
• Systemic inflammatory response parameters (SIRS): pulse [Time frame: During the initial admission]
• Systemic inflammatory response parameters (SIRS): respiratory rate [Time frame: During the initial admission]
• Systemic inflammatory response parameters (SIRS): temperature [Time frame: During the initial admission]