Inulin for Infections in the Intensive Care Unit

Prebiotic Inulin to Limit Antimicrobial-Resistant Infections During Critical Illness: A Phase II Clinical Trial

Normal gut bacteria prevent colonization and subsequent infection with MDR organisms (MDROs) through competition for resources and other mechanisms. During critical illness, this function of the microbiome is lost and there are no current treatments to restore it. Preliminary data indicates that the prebiotic fiber inulin is safe and may alter the gastrointestinal microbiome to improve gut barrier function, decrease colonization with MDROs, and reduce downstream risk for intensive care unit (ICU)-acquired MDR infections. However, the impact of inulin during critical illness is unknown. This double-blind, randomized clinical trial will test inulin for the prevention of antibiotic resistant infections in the ICU.

The trial's specific aims are to determine (1) the feasibility, tolerability, and safety of inulin in the intensive care unit; (2) the impact of inulin on gut colonization with antibiotic-resistant pathogens; and (2A/exploratory) the impact of inulin on ICU-acquired antibiotic-resistant infections.

Study Overview

• Status: Active, not recruiting
• Conditions: Sepsis; Critical Illness; Nutrition Disorders; Antibiotic Resistant Infection; Nosocomial Infection; Pathogen Transmission
• Intervention / Treatment: Drug: Inulin Oral Suspension; Drug: Broad-spectrum antibiotics; Drug: Placebo Oral Suspension

Detailed Description

The proposed trial hypothesizes that inulin maintains short-chain fatty acid (SCFA)-producing colonic anaerobes and that these bacteria are protective against multi-drug resistant organism (MDRO) colonization and subsequent MDR infection. Inulin, a vegetable-derived non-digestible polysaccharide is well established as the key nutrient source for SCFA-producing bacteria. Previous human studies have shown that (1) inulin increases levels of SCFA producers and SCFAs and (2) that this increase correlates with improved colonic mucosal integrity and resistance to MDR pathogens. In animal studies, inulin improves survival after pathogen challenge or injection with lipopolysaccharide. The overall aim of this clinical trial is to determine whether inulin improves gut colonization resistance against antibiotic-resistant pathogens and therefore prevents antibiotic-resistant infections in the setting of critical illness. To accomplish this, 90 critically ill adults who are receiving broad-spectrum antibiotics will be blindly randomized 1:1:1 to receive placebo, inulin 8 g twice daily, or inulin 16 g twice daily for a minimum of 7 days, with bedside follow-up extending to 30 days or hospital discharge.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daniel E Freedberg, MD, MS; Phone Number: 8579989370; Email: def2004@cumc.columbia.edu
• Study Contact Backup: Name: Elissa Lynch; Email: el2888@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10023
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Hospitalized in an eligible medical ICU
2. Age ≥ 18 years old at the time of hospitalization
3. With sepsis as defined by the Sepsis-3 (2016) consensus as a known or suspected infection with a SOFA score of ≥2 points above baseline
4. Received broad-spectrum antibiotics within the last 24 hours or ordered and pending administration
5. Able to complete enrollment within 4 hours of ICU admission for administration of the intervention within 6 hours of ICU admission

Exclusion Criteria:

1. Inability to receive oral or enteric fluids
2. Inulin allergy
3. Hyponatremia (serum sodium ≤128 mEq/L)
4. Immunosuppression, defined as history of solid organ transplant or as receipt of ablative chemotherapy, steroids at the equivalent of ≥5 mg/day prednisone, antimetabolites, anti-TNFα agents, calcineurin inhibitors, or mycophenolate
5. Surgery involving the intestinal lumen within 30 days or known intestinal strictures
6. Do Not Resuscitate (DNR) or Do Not Intubate (DNI) status, or "no escalation of care" orders
7. Lack capacity for consent and no appropriate Legally Authorized Representative (LAR)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inulin 32 g/day; Critically ill adults who are receiving broad-spectrum antibiotics will also receive inulin oral suspension (16g twice daily) for a minimum of 7 days.	Drug: Inulin Oral Suspension; Inulin powder, derived from chicory root and re-suspended in 250cc water Dosage will be either 8g twice a day or 16g twice a day - dissolved in 250cc sterile water, given oral or via enteric tube; Other Names: Inulin; Drug: Broad-spectrum antibiotics; Standard of care treatment for infections; Other Names: Antibiotics
Experimental: Inulin 16 g/day; Critically ill adults who are receiving broad-spectrum antibiotics will also receive inulin oral suspension (8g twice daily) for a minimum of 7 days.	Drug: Inulin Oral Suspension; Inulin powder, derived from chicory root and re-suspended in 250cc water Dosage will be either 8g twice a day or 16g twice a day - dissolved in 250cc sterile water, given oral or via enteric tube; Other Names: Inulin; Drug: Broad-spectrum antibiotics; Standard of care treatment for infections; Other Names: Antibiotics
Placebo Comparator: Placebo; Critically ill adults who are receiving broad-spectrum antibiotics will also receive placebo oral suspension for a minimum of 7 days.	Drug: Broad-spectrum antibiotics; Standard of care treatment for infections; Other Names: Antibiotics; Drug: Placebo Oral Suspension; 250cc sterile water alone, given twice daily a sweetener is added to the water to create identical flavor; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Within-individual change in SCFA producer level	relative abundance (i.e., proportion) of SCFA producing bacteria within each treatment group, will be assessed via 16S sequencing of rectal swabs	modified intent-to-treat, comparing baseline vs Day 3 levels of SCFAs among those who receive one or more doses of the intervention and complete both assessments
MDRO colonization status	proportion of patients who are MDRO colonized within each treatment group, with MDRO colonization status classified categorically based on the presence or absence of MRSA, VRE, or Gram negative bacteria with CFTX non-susceptibility	ICU Day 3, calculated in a similar manner as outcome 1
MDR infections	proportion of patients with culture-proven infections within each treatment group, with culture-proven infections defined as those that have (1) an organism meeting MDRO criteria from a clinical culture, (2) signs and symptoms of infection by CDC/NHSN guideline definitions, and (3) receive appropriate antibiotics from the treating team	through 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nutritional intake	proportion of goal calories consumed within each treatment group, after adjusting for death	through Day 3 and through Day 7
ICU length of stay (LOS)	compared between groups, after adjusting for death as a competing risk	through ICU Day 30
Multi-omic approach to changes related to inulin	overall goal is to understand effects of inulin: will compare SCFA level in whole stools, overall taxonomy, functional metagenomics, metabolomics, and sepsis biomarkers between groups	outcomes focus on Day 3 and re-analyzed based on Day 7

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Daniel E Freedberg, MD, MS, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2019
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: March 4, 2019
• First Submitted That Met QC Criteria: March 4, 2019
• First Posted (Actual): March 7, 2019

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Microbiome; Nutrition; Intensive care unit; Sepsis; Antibiotic resistance; Pathogen colonization
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Iatrogenic Disease; Infections; Communicable Diseases; Critical Illness; Nutrition Disorders; Cross Infection; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: AAAS2576; PR181960 (Other Grant/Funding Number: Department of Defense)

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