Investigating the effects of intravenous fluids and imatinib in human volunteers with a sepsis-like state
| ISRCTN | ISRCTN16409847 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16409847 |
| IRAS number | 1006559 |
| Secondary identifying numbers | 22064JS-AS, IRAS 1006559 |
- Submission date
- 12/04/2023
- Registration date
- 02/04/2024
- Last edited
- 01/08/2025
- Recruitment status
- Not yet recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Sepsis is a common, out-of-control immune response to infection, resulting in abnormal blood flow so that some areas may not receive enough blood and oxygen. Sepsis also causes damage to special cells in blood vessels called endothelial cells. The vessels become “leaky”, allowing fluid to move into surrounding areas. This leaked fluid makes it hard for oxygen to reach the cells where it is needed. A key treatment for sepsis is to give fluids intravenously in order to improve blood flow. However, fluid may cause more damage to blood vessels, thereby making swelling worse which makes it even more difficult for oxygen to be delivered where it is required. It is important to establish the effects of fluid on blood vessels and blood flow in sepsis, as it may be either helping or causing harm. It is also important to find out if any drugs can protect blood vessels from damage or control the immune response.
Who can participate?
Adult healthy volunteers
What does the study involve?
Volunteers will receive intravenous lipopolysaccharide (LPS). LPS causes a very mild sepsis-like state for a few hours, similar to mild flu. This will be carried out in a medical research centre. After giving LPS, some volunteers will be given intravenous fluids, and some not. We will perform blood tests to measure the immune response and to assess for blood vessel damage. We will use ultrasound technology to assess for fluid leakage and fluid accumulation.
What are the possible benefits and risks of participating?
1. Complications of LPS therapy: Intravenous LPS will be administered to volunteers whilst they are monitored in the Northern Ireland Clinical Research facility at the Belfast City Hospital. Participants will be observed for 10 hours following LPS administration. Expected symptoms include chills, headache, photophobia (aversion to bright lights), myalgia (muscle aches), arthralgia (joint pains), nausea (feeling sick), and rarely, vomiting. Peak symptom intensity occurs around 1 - 2 hours post-injection, abating to baseline by 6 - 8 hours. Rarely, a volunteer may find the degree of symptoms unacceptable during the height of the response. The symptoms can be ameliorated with the administration of paracetamol. Other adverse signs include fever, increase or decrease in heart rate and decrease in blood pressure. Medications required to treat adverse effects will be readily available. There are sporadic case reports of participants experiencing bradycardic episodes related to LPS administration. If a participant’s heart rate falls below 50 beats per minute or there is concern on the part of the supervising doctor, an appropriate dose of atropine or glycopyrrolate will be administered. Vital signs will be measured at baseline, then every 30 minutes until six hours following LPS administration and then hourly thereafter until participants are allowed home. Participants will be provided with a discharge summary which provides contact details in case of an emergency.
2. Complications of imatinib therapy: Extensive follow-up data of patients with chronic myeloid leukaemia who received imatinib therapy demonstrated that only 4% of patients discontinued imatinib because of adverse events, the overwhelming majority of which were mild. Commonly reported adverse events with chronic use include superficial oedema, muscle cramps, gastrointestinal upset, fatigue and headache. The main adverse events seen with short-term use are gastrointestinal upset: nausea, vomiting and diarrhoea. The single-dosing strategy utilised in this study is extremely unlikely to be problematic.
3. Complications of intravenous fluid therapy: Some participants will receive a total of 30ml/kg Compound Sodium Lactate solution, up to a maximum volume of 2500 ml. This dosing regimen is recommended by the internationally recognised Surviving Sepsis Guidelines for the management of patients with septic shock. There are risks of fluid overload and electrolyte disturbances in participants with impaired renal function, however, in this cohort of healthy volunteers, these risks are minimal. Moreover, previous volunteer studies have verified that this volume of fluid is well tolerated in healthy participants.
4. Complications of cannula insertion and blood sampling: A venous cannula will be inserted into each arm by a trained member of the research team. Intravenous injection of 2ng/kg LPS will be administered via one cannula, whereas the other cannula will facilitate intravenous fluid therapy and blood sampling. Blood sampling can be accompanied by discomfort or by vasovagal symptoms. Risks are minimised through all samples being taken in a fully supported medical facility. Blood will be drawn whilst the volunteer is positioned on a bed or in a self-reclining chair. Volunteers feeling syncopal will be positioned supine and cannulation or venepuncture will be temporarily discontinued. Cannulation and blood sampling will be undertaken by experienced members of the research team. All study personnel will be trained in aseptic techniques for handling peripheral venous lines.
5. Complications of sublingual microscopy: Sublingual microscopy provides a minimally invasive method for monitoring sublingual microcirculation. The microscope probe is placed under the surface of the tongue. There are theoretical risks of soft tissue injury and dental damage, however, the microscopy will be performed by clinicians who have undergone formal sublingual microscopy training. In addition, disposable probe covers will be used for each patient and the equipment will be adequately decontaminated as per the manufacturer's instructions.
6. Complications of ultrasound imaging: Ultrasonography is a non-invasive method for assessing for the development of fluid leakage in the lungs and the accumulation of fluid in major veins within the body. Ultrasound assessment will be performed by clinicians who have undergone formal training. Disposable probe covers will be used for each patient and the equipment will be adequately decontaminated as per the manufacturer's instructions. Steps will be taken to ensure participant dignity is maintained throughout the imaging process. Moreover, a chaperone will be present throughout.
Where is the study run from?
Queen's University Belfast Wellcome-Wolfson Institute for Experimental Medicine (Northern Ireland)
When is the study starting and how long is it expected to run for?
August 2022 to July 2026
Who is funding the study?
1. Medical Research Council (UK)
2. British Journal of Anaesthesia (UK)
3. Royal College of Anaesthetists (UK)
Who is the main contact?
Dr Ross McMullan, rmcmullan07@qub.ac.uk
Contact information
Scientific
QUB Wellcome-Wolfson Institute for Experimental Medicine
97 Lisburn Road
Belfast
BT9 7AB
United Kingdom
| Phone | +44 (0)2895 041096 |
|---|---|
| rmcmullan07@qub.ac.uk |
Principal Investigator
97 Lisburn Road
Belfast
BT97BL
United Kingdom
| Phone | (+44) 28 9097 1643 |
|---|---|
| j.silversides@qub.ac.uk |
Study information
| Study design | Randomized controlled double-blind parallel group study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Pharmaceutical testing facility |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Investigation of novel and established therapies in a human intravenous lipopolysaccharide model of sepsis |
| Study acronym | INITIALISE |
| Study objectives | The main objective of this trial is to assess the effects of intravenous fluid therapy and Imatinib therapy on small blood vessel function in participants with a sepsis like state. We aim to understand the effects of intravenous fluid therapy and Imatinib therapy on the immune response and on fluid leakage and fluid accumulation in participants with a sepsis like state. We also aim to investigate the effects of intravenous fluid therapy alone on small blood vessel function, the immune response and on fluid leakage and fluid accumulation. |
| Ethics approval(s) |
1. Approved 09/01/2024, London - Westminster Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)2071048000; westminster.rec@hra.nhs.uk), ref: 23/LO/0394 2. Approved 09/01/2024, MHRA (10 South Colonnade, Canary Wharf, London, E14 4PU, United Kingdom; +44 (0)20 3080 6000; info@mhra.gov.uk), ref: 32485/0042/001-0001 |
| Health condition(s) or problem(s) studied | Sepsis |
| Intervention | Current Interventions as of 12/08/2024: This study will assess the biological effects of two interventions on participants receiving intravenous lipopolysaccharide (LPS). Intervention 1: Start dose of 600mg imatinib administered orally. The administration is to commence 1 hour prior to intravenous LPS. Intervention 2: 30mls/kg of Compound Sodium Lactate solution (maximum volume of 2500mls) administered in two divided doses (15mls/kg) intravenously. Each bolus will be administered at a fixed rate of 999mls/hr. The administration is to commence 90 minutes following intravenous LPS. Participants will be randomised into 1 of 4 groups using a Sealed Envelope: 1. LPS only 2. LPS + Compound Sodium Lactate solution 3. LPS + Imatinib 4. LPS + Compound Sodium Lactate solution + Imatinib Previous interventions: This study will assess the biological effects of two interventions on participants receiving intravenous lipopolysaccharide (LPS). Intervention 1: Start dose of 800mg imatinib administered orally. The administration is to commence 1 hour prior to intravenous LPS. Intervention 2: 30mls/kg of Compound Sodium Lactate solution (maximum volume of 2500mls) administered in two divided doses intravenously over 90 minutes. The administration is to commence 90 minutes following intravenous LPS. Participants will be randomised into 1 of 4 groups using a Sealed Envelope: 1. LPS only 2. LPS + Compound Sodium Lactate solution 3. LPS + Imatinib 4. LPS + Compound Sodium Lactate solution + Imatinib |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Imatinib, intravenous lipopolysaccharide (LPS) |
| Primary outcome measure | Current primary outcome measures as of 01/10/2024: 1. Inflammation is assessed by measuring circulating levels of white blood cells, C- reactive protein, IL-6 and TNF-α at baseline, 1 hour, 3 hours, 5 hours and 7 hours post intravenous LPS administration 2. Vascular injury is assessed by measuring circulating levels of Hyaluronan, Heparan Sulphate and Angiopoietin-2 at baseline, 1 hour, 3 hours, 5 hours and 7 hours post intravenous LPS administration Previous primary outcome measures: Microvascular flow index (MFI) measured using a CytoCam sublingual microscope at baseline, 90 minutes post-LPS, 2 hours post-LPS, 3 hours post-LPS, 4 hours post-LPS and 8 hours post-LPS. |
| Secondary outcome measures | Current secondary outcome measures as of 01/10/2024: 1. Biological network alteration is assessed by measuring differential mRNA expression at baseline, 1 hour and 5 hours post intravenous LPS administration 2. Pulmonary oedema is assessed by measuring an ultrasound-based B-line score at baseline, 1 hour, 3 hours and 5 hours post intravenous LPS administration 3. Venous congestion is assessed by measuring an ultrasound-based Venous Excess Ultrasound (VExUS) Score at baseline, 1 hour, 3 hours and 5 hours post intravenous LPS administration Previous secondary outcome measures: 1. Perfused vessel density measured using a CytoCam sublingual microscope at baseline, 90 minutes post-LPS, 2 hours post-LPS, 3 hours post-LPS, 4 hours post-LPS and 8 hours post-LPS 2. Pulmonary oedema (B line score) measured using an ultrasound device at baseline, 2 hours post-LPS, 3 hours post-LPS and 4 hours post-LPS 3. Systemic venous congestion (VExUS score) measured using an ultrasound device at baseline, 2 hours post-LPS, 3 hours post-LPS and 4 hours post-LPS |
| Overall study start date | 03/08/2022 |
| Completion date | 01/07/2026 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 40 Years |
| Sex | Both |
| Target number of participants | 65 |
| Total final enrolment | 65 |
| Key inclusion criteria | 1. Healthy adult volunteers aged between 18 and 40 years of age 2. Informed consent to participate |
| Key exclusion criteria | 1. Current participation in a clinical trial 2. Pregnant or breastfeeding 3. Current history of smoking 4. Alcohol intake > 21 units per week 5. Intake of any prescription and over-the-counter medication (except paracetamol, hormonal contraceptives and hormonal replacement therapy) within 7 days prior to the first dose of IMP 6. Oxygen saturation <95% breathing room air 7. Abnormal findings on history, examination or laboratory tests suggestive of underlying illness (in the opinion of the clinician undertaking screening) 8. History of recurrent vaso-vagal episodes 9. Known history of allergy to imatinib |
| Date of first enrolment | 01/10/2025 |
| Date of final enrolment | 30/05/2026 |
Locations
Countries of recruitment
- United Kingdom
Study participating centre
Lisburn Road
Belfast
BT9 7AB
United Kingdom
Sponsor information
Hospital/treatment centre
Research & Development Office
King Edward Building
Royal Victoria Hospital
Belfast
BT12 6AB
Northern Ireland
United Kingdom
| Phone | +44 (0)2896 156057 |
|---|---|
| alison.murphy@belfasttrust.hscni.net | |
| Website | http://www.belfasttrust.hscni.net/ |
"ROR" |
https://ror.org/02tdmfk69 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- British Journal of Anaesthesia Ltd, BJA
- Location
- United Kingdom
Private sector organisation / Associations and societies (private and public)
- Alternative name(s)
- RCoA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 05/08/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on a website 5. Other publication The findings will be presented at conferences with abstracts available online and in accordance with open-access policies. Moreover, the outcomes will be published in peer-reviewed open-access journals. We will communicate the data generated and analysed in this project to potential academic beneficiaries through the conventional routes of journal publications and conference presentations. We will aim to publish in the highest impact journals achievable and will attend the most relevant conferences in order to disseminate the important findings of our work. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date. The data we propose to collect will be suitable for sharing as it will be of relevance to other researchers in the fields of sepsis, fluid management and microcirculatory dysfunction. After the publication of our results all data and appropriate metadata will be deposited in the Open Access QUB Research Information Management System, PURE. This can be accessed through the QUB Research Portal. Our paper(s) will contain a clear statement outlining how the primary data can be accessed. |
Editorial Notes
01/08/2025: The date of first enrolment was changed from 06/08/2025 to 01/10/2025.
06/03/2025: The following changes were made to the trial record:
1. The recruitment start date was changed from 03/03/2025 to 06/08/2025.
2. The recruitment end date was changed from 30/05/2025 to 30/05/2026.
04/02/2025: The recruitment start date was changed from 01/02/2025 to 03/03/2025.
10/01/2025: The recruitment start date was changed from 01/12/2024 to 01/02/2025.
01/10/2024: The following changes have been made:
1. The recruitment start date was changed from 04/06/2023 to 01/12/2024.
2. The primary and secondary outcome measures were updated.
12/08/2024: The following changes were made:
1. Ethics approval added.
2. The overall study start date was changed from 06/04/2023 to 03/08/2022.
3. The overall study end date was changed from 05/08/2025 to 04/08/2026.
4. The interventions were updated.
5. The lower and upper age limits and units were added.
6. Total final enrolment added.
7. The recruitment end date was changed from 04/08/2026 to 01/07/2026.
8. Northern Ireland Clinical Research Facility added as a study participating centre.
12/04/2023: Trial's existence confirmed by Health Research Authority (HRA) (UK).
