Investigation of Thermal Injury on Intestinal Permeability in Both Thermal Injury and Healthy Participants

A Prospective, Longitudinal Study to Investigate the Effect of Thermal Injury on Intestinal Permeability and Systemic Inflammation (HESTIA)

This longitudinal, prospective study aims to establish the magnitude and time course of changes in intestinal permeability; establish the optimal method for assessment of intestinal permeability in thermally injured participants: describe the participant population most likely to benefit from a new medicinal product which could prevent changes in intestinal permeability; and improve our understanding of the links between intestinal damage, changes in the gut microbiome and microbial translocation to the systemic circulation following thermal injury. The key factors of interest in this study are to understand the impact of thermal injury on intestinal permeability in thermally injured participants compared to healthy participants; and to understand the changes in intestinal permeability over time. Approximately 15 eligible healthy participants and 25 thermally injury participants will be included. The sugar test material (STM) comprises of Lactulose, Mannitol and Sucralose and will be intermittently administered enterally to all the participants. The full duration of the study for healthy participants will be approximately two weeks and 6 months for thermally injured participants. In order to enter this study thermally injured participants will be required to co-enroll in this study and an allied study entitled: A Multi-center, Prospective Study to Examine the Relationship between Neutrophil Function and Sepsis in Adults and Children with Severe Thermal Injury (SIFTI-2). (reference number IRAS ID: 200366).

Study Overview

• Status: Terminated
• Conditions: Burns
• Intervention / Treatment: Other: Lactulose and Mannitol solution; Other: Sucralose

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For Healthy participants:

• Males or females must be greater than or equal to 18 years of age at the time of signing informed consent.
• Participants who are healthy as determined by the investigator following medical evaluation including medical history, physical examination, and laboratory tests.
• A female participant is eligible to participate if she is not pregnant (negative pregnancy testing at screening or Day 1 as needed) and not breastfeeding.
• Capable of giving signed informed consent.

For Thermally injured participants:

• Participants must be greater than or equal to 18 years of age.
• Participants who have sustained a burn (thermal injury) with a Total Burn Surface Area (TBSA) greater than or equal to 15 percent.
• Admission to the burn center (study site) less than or equal to 24 hours following injury.
• Able to take enteral fluids either orally or via a nasogastric tube (depends on facial burn damage).
• A female participant is eligible to participate if she is not pregnant (negative pregnancy testing at study entry) and not breastfeeding.

Exclusion Criteria

For Healthy participants:

• Healthy participants are excluded from this study if they are receiving anti-coagulation therapy.
• Pregnancy or breastfeeding.
• A body mass index greater than 34 kilogram per meter square (kg/m^2).
• An active history of alcohol dependency.
• History of sensitivity to any of the STM, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator and/or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody and confirmatory Hepatitis C Polymerase Chain Reaction (PCR) result within 3 months of screening.
• A positive pre-study urine drug/alcohol screen.
• A positive test for Human Immuno-deficiency Virus (HIV) antibody.
• Participants unable to swallow large capsules (the capsules will be shown to participants at screening).
• Galactosaemia or severe lactose intolerance.
• Use of an antibiotic 2 weeks prior to study start (administration of the STM).
• Gastroenteritis in the 2 weeks prior to study start (administration of the STM).

For thermally injured participants:

• Chemical or electrical burn.
• Multiple traumatic injuries with an Injury Severity Score (ISS) more than or equal to 16.
• Participants received substantial undocumented management prior to arrival at the study site (burn center) e.g. from paramedics or in a local accident and emergency department.
• Systemic corticoidsteroid use.
• Intravenous (IV) Mannitol use.
• HIV infection.
• Viral Hepatitis B or C infection.
• Gastrointestinal disease (e.g. inflammatory bowel disease) which may affect intestinal permeability.
• Previous bowel resection (e.g. hemicolectomy, small bowel resection).
• Galactosaemia or severe lactose intolerance.
• Bowel obstruction.
• Renal dysfunction requiring renal replacement therapy (end-stage renal failure prior to thermal injury).
• Active autoimmune disease and receiving immunomodulatory therapy e.g. rheumatoid arthritis anti-Tumor Necrosis Factor (TNF).
• Active chemotherapy for cancers or immunoremittive therapies (prednisolone, Adalimumab) within 60 days of thermal injury.
• Premorbid conditions of malignancy currently under treatment.
• Previous bilateral lower extremity amputation.
• Decision not to treat the participant due to futility.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Healthy controls; Approximately 15 healthy participants of age 18 years or above will be included in the study and will receive STM intermittently via oral route. The total duration of study for healthy participants will be approximately 2 weeks.	Other: Lactulose and Mannitol solution; Participants will receive 100 milliliter (mL) oral solution of Lactulose [5 grams (g)]/ Mannitol (2g), a non-investigational medicinal product, by oral route to measure intestinal permeability.; Other: Sucralose; Participants will receive 3 capsules of Sucralose (2g), a non-investigational medicinal product, by oral route to measure intestinal permeability.
Other: Thermal injury participants; Approximately 25 thermally injured participants having TBSA more than or equal to 15 percent and who are co-consented to the SIFTI-2 and HESTIA studies will be included in the study and will receive STM intermittently via oral route. The total duration of study for thermal injury participants will be approximately 6 months.	Other: Lactulose and Mannitol solution; Participants will receive 100 milliliter (mL) oral solution of Lactulose [5 grams (g)]/ Mannitol (2g), a non-investigational medicinal product, by oral route to measure intestinal permeability.; Other: Sucralose; Participants will receive 3 capsules of Sucralose (2g), a non-investigational medicinal product, by oral route to measure intestinal permeability.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol on Day 1	Urine samples were collected at indicated time-points to determine the impact of thermal injury on the magnitude of small intestine permeability following the injury. As, L/M does not get metabolized, it gets filtered in the kidney and excreted in the urine. The impact of injury in thermal injury participants was compared with healthy participants using L/M ratio in urine.	0 to 5 hours and 0 to 24 hours on Day 1
Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Healthy Participants	Urine samples were collected at indicated time-points to determine the impact of thermal injury on the magnitude of small intestine permeability following the injury. As, L/M does not get metabolized, it gets filtered in the kidney and excreted in the urine. Baseline value was considered as Day 1 for both the groups. Change from Baseline is equal to post-Baseline visit value minus Baseline value.	0 to 5 hours and 0 to 24 hours on Day 8 and Day 15
Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants	Urine samples were collected at indicated time-points to determine the impact of thermal injury on the magnitude of small intestine permeability following the injury. As, L/M does not get metabolized, it gets filtered in the kidney and excreted in the urine. Baseline value was considered as Day 1 for both the groups. Change from Baseline is equal to post-Baseline visit value minus Baseline value.	0 to 5 hours on Days 3, 5, 7, 11, 13 and 0 to 24 hours on Days 3, 5, 7, 9, 11 and 13

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2018
• Primary Completion (Actual): March 26, 2018
• Study Completion (Actual): March 26, 2018

Study Registration Dates

• First Submitted: August 3, 2017
• First Submitted That Met QC Criteria: August 3, 2017
• First Posted (Actual): August 8, 2017

Study Record Updates

• Last Update Posted (Actual): August 19, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Intestinal permeability; Thermal injury; Lactulose; Mannitol; Sucralose; HESTIA
• Additional Relevant MeSH Terms: Wounds and Injuries; Burns; Physiological Effects of Drugs; Gastrointestinal Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Lactulose; Mannitol
• Other Study ID Numbers: 206243

Drug and device information, study documents

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