Clinical trial NCT06147635: Prophylactic Tributyrin Supplementation in Acute Pancreatitis
Official title: Prophylactic Tributyrin Supplementation in Acute Pancreatitis; a Phase IIa (Proof of Concept) Double-blind Randomized Placebo-controlled Food Supplement Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Pancreatitis
Lead sponsor: St. Antonius Hospital
Sponsor class: OTHER
First posted: 2023-11-27
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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)

Primary outcomes:
measure: Plasma endotoxin levels
timeFrame: Measured 3 days after randomisation
Secondary outcomes:
measure: Mortality
timeFrame: During the whole study period including follow-up of 90 days
measure: Infectious complications
timeFrame: During the whole study period including follow-up of 90 days
measure: (New onset) transient/persistant (multiple) organ failure
timeFrame: During the whole study period including follow-up of 90 days
measure: Disease severity according to the revised Atlanta Classification
timeFrame: During the whole study period including follow-up of 90 days
measure: (Peri-)pancreatic necrosis
timeFrame: During the whole study period including follow-up of 90 days
measure: Length of hospital and/or ICU stay
timeFrame: During the whole study period including follow-up of 90 days
measure: The need (and number of) for surgical, endoscopic or radiologic interventions
timeFrame: During the whole study period including follow-up of 90 days
measure: Fecal and saliva microbiota and fecal metabolomics (i.e., SCFAs) analysis
timeFrame: During the whole study period including follow-up of 90 days
measure: Readmissions
timeFrame: During the whole study period including follow-up of 90 days
measure: Systemic inflammatory response parameters (SIRS): pulse
timeFrame: During the initial admission
measure: Systemic inflammatory response parameters (SIRS): respiratory rate
timeFrame: During the initial admission
measure: Systemic inflammatory response parameters (SIRS): temperature
timeFrame: During the initial admission
measure: Systemic inflammatory response parameters (SIRS): white blood cell count
timeFrame: During the initial admission
measure: Exocrine insufficiency
timeFrame: During the whole study period including follow-up of 90 days
measure: Endocrine insufficiency
timeFrame: During the whole study period including follow-up of 90 days
Other outcomes:
Locations:
city: Nieuwegein
country: Netherlands
facility: St. Antonius Hospital
state: Utrecht
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
state: Zuid-Holland
Study officials:
affiliation: St. Antonius Hospital
name: H. C. van Santvoort, dr. prof.
role: PRINCIPAL_INVESTIGATOR
References: