Burns
Conditions
Keywords
Mannitol, Intestinal permeability, Thermal injury, HESTIA, Sucralose, Lactulose
Brief summary
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).
Interventions
OTHERLactulose 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.
OTHERSucralose
Participants will receive 3 capsules of Sucralose (2g), a non-investigational medicinal product, by oral route to measure intestinal permeability.
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol on Day 1 | 0 to 5 hours and 0 to 24 hours 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. |
| Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Healthy Participants | 0 to 5 hours and 0 to 24 hours on Day 8 and Day 15 | 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. |
| Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | 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 | 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. |
Countries
United Kingdom
Participant flow
Recruitment details
This study was a longitudinal study which involved healthy participants and participants who had sustained a thermal injury. The study was conducted in United Kingdom. This study was terminated early prior to the full sample size being achieved as the development of the formulation was terminated.
Pre-assignment details
A total 23 participants were screened for study of which 5 participants were screen failure and 18 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Participants Healthy participants were invited to donate a blood sample for biomarker measurement on day one. They were also requested to undergo measurements of intestinal permeability by taking a 100 milliliter (mL) solution of lactulose (5 gram \[g\]) and mannitol (2g) along with 3 capsules (2g) of sucralose on days 1, 8 and 15 followed by a 24 hour urine collection. | 14 |
| Thermally Injured Participants Participants were invited to undergo measurements of intestinal permeability by taking a 100 mL solution of lactulose (5 g) and mannitol (2g) along with 3 capsules (2g) of sucralose on days 1,3,5,7,9,11 and 13. | 3 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
Baseline characteristics
| Characteristic | Healthy Participants | Thermally Injured Participants | Total |
|---|---|---|---|
| Age, Continuous | 41.4 Years STANDARD_DEVIATION 9.43 | 52.0 Years STANDARD_DEVIATION 21 | 43.3 Years STANDARD_DEVIATION 12.02 |
| Race/Ethnicity, Customized Black or African American | 1 Count of Participants | 0 Count of Participants | 1 Count of Participants |
| Race/Ethnicity, Customized Central/South Asian Heritage | 1 Count of Participants | 0 Count of Participants | 1 Count of Participants |
| Race/Ethnicity, Customized White | 13 Count of Participants | 2 Count of Participants | 15 Count of Participants |
| Sex: Female, Male Female | 8 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 2 / 3 |
| other Total, other adverse events | 5 / 15 | 0 / 3 |
| serious Total, serious adverse events | 0 / 15 | 0 / 3 |
Outcome results
Primary
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.
Time frame: 0 to 5 hours and 0 to 24 hours on Day 1
Population: Evaluable Population included of all participants in the safety population excluding any healthy volunteers that received any concomitant medication or food and drink containing Sugar Test Material (STM) as identified by review of the protocol deviation. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol on Day 1 | Day 1, 0 to 24 hours | 0.0093 Ratio | Standard Deviation 0.00409 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol on Day 1 | Day 1, 0 to 5 hours | 0.0078 Ratio | Standard Deviation 0.00102 |
| Thermally Injured Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol on Day 1 | Day 1, 0 to 5 hours | 0.0415 Ratio | Standard Deviation 0.06243 |
| Thermally Injured Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol on Day 1 | Day 1, 0 to 24 hours | 0.0296 Ratio | Standard Deviation 0.04031 |
Primary
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.
Time frame: 0 to 5 hours and 0 to 24 hours on Day 8 and Day 15
Population: Evaluable Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Healthy Participants | Day 8 (0-5 hours) | 0.0132 Ratio | Standard Deviation 0.0206 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Healthy Participants | Day 15 (0-5 hours) | 0.0016 Ratio | Standard Deviation 0.00548 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Healthy Participants | Day 15 (0-24 hours) | 0.0090 Ratio | Standard Deviation 0.00698 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Healthy Participants | Day 8 (0-24 hours) | 0.0092 Ratio | Standard Deviation 0.01304 |
Primary
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.
Time frame: 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
Population: Evaluable Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 3, (0-5 hours), n= 3 | -0.0037 Ratio | Standard Deviation 0.09936 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 5, (0-5 hours), n= 3 | -0.0213 Ratio | Standard Deviation 0.08213 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 11, (0-5 hours), n= 1 | -0.1044 Ratio | — |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 13, (0-5 hours), n= 1 | -0.0043 Ratio | — |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 3, (0-24 hours), n= 3 | 0.0111 Ratio | Standard Deviation 0.09085 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 5, (0-24 hours), n= 3 | -0.0046 Ratio | Standard Deviation 0.06456 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 7, (0-24 hours), n= 2 | 0.0178 Ratio | Standard Deviation 0.0264 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 9, (0-24 hours), n= 2 | -0.0327 Ratio | Standard Deviation 0.05953 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 11, (0-24 hours), n= 2 | -0.0218 Ratio | Standard Deviation 0.05846 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 7, (0-5 hours), n= 2 | 0.0566 Ratio | Standard Deviation 0.07509 |
| Healthy Participants | Change From 0 to 5 Hours, and 0 to 24 Hours in the Ratio of Lactulose/Mannitol Over Time for Thermal Injury Participants | Day 13, (0-24 hours), n= 1 | -0.0634 Ratio | — |