Condition category
Infections and Infestations
Date applied
04/12/2017
Date assigned
18/12/2017
Last edited
11/01/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Septic shock (blood poisoning) is a life-threatening condition caused by severe infection. For reasons still poorly understood, in some patients, their immune system remains excessively activated. Instead of fighting the infection, an ongoing inflammatory state results in widespread injury and failure of normal functioning of the body’s vital organs, such as the lungs, heart, brain and kidneys. A hallmark of septic shock is a very low blood pressure that does not improve with an intravenous fluid drip. Despite huge research efforts over the last 20-30 years the survival rate has remained stubbornly unchanged. Outcomes have improved for sepsis in general through earlier recognition and intervention with antibiotics, however once septic shock takes hold, the risk of dying remains very high. This research project wants to see if infusing a very short-acting beta-blocker in addition to standard treatment improves organ failure in patients with septic shock. Beta-blockers are widely used to counteract the stressful long-term actions of the hormones adrenaline and noradrenaline, for example in high blood pressure, chronic heart failure, abnormally fast heart rates and cardiac rhythms, and tremor. Recently, an Italian group gave a beta-blocker to reduce, and then maintain, heart rates of patients with septic shock at between 80-95 beats per minute. They found this treatment strategy to be safe and associated with improvements in survival and reduced time in intensive care. However, their study was relatively small and recruitment occurred at a single centre so did not provide enough information to make the use of beta-blockers a mainstream recommendation. This trial aims to repeat the Rome study in approximately 35 ICUs in the UK to see if the safety and benefits that were seen can be confirmed and will also investigate the way in which beta blockers act in septic shock patients.

Who can participate?
Adults aged 18 and older who are have septic shock.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive the usual care. Those in the second group receive the usual care with the addition of landiolol. For participants in the landiolol group, the rate of the drug is adjusted until their heart rate is controlled at 80-95 beats per minute and the infusion is stopped when they are able to control their heart rate themselves. Landiolol is given intravenously (IV) as an infusion whilst a participant’s heart rate is too high. This drug may be used for up to 2 weeks within the ICU where the treating team are able to monitor the participant closely. After discharge from ICU, or if the heart rate remains high after 14 days, ongoing treatment will be the decision of the treating doctor. One of the aims of this study is to better understand the biological mechanisms that are altered by beta-blockade in septic shock. As part of standard clinical care blood will be taken from a cannula (a thin tube inserted into a vein or body cavity to administer medication). Additional blood samples will be taken at study entry, on days 1, 2, 4 and 6 and at the end of noradrenaline treatment (if not a sampling day). Routinely collected clinical data will be recorded for the trial. However the progress of participants will be followed at day 28 and day 90 after trial entry, at these time points the local research team will call the participant and their GP to find out how they are. The trial will not follow participants beyond 90 days.

What are the possible benefits and risks of participating?
As landiolol is an exceptionally short-acting drug, switching off the infusion is expected to reverse any possible side effects. Beta blockers are not confirmed to be useful in septic shock and it is possible that landiolol has the potential for toxicity. Full information on the possible side effects are available on request from local treating teams. The main risks are the heart could go too slowly or blood pressure could lower if a participant is sensitive to the drug. Trial participants will be closely monitored within the ICU and should they experience any side effects from the study drug, the hospital staff will take measures to stop the infusion as with any other inpatient treatment.

Where is the study run from?
This study is being run by Warwick Clinical Trials Unit (University of Warwick) and takes place in hospitals in the UK.

When is the study starting and how long is it expected to run for?
June 2017 to August 2021

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Miss Nafisa Boota
STRESS-L@warwick.ac.uk

Trial website

http://www2.warwick.ac.uk/fac/med/research/hscience/ctu/trials/stressl

Contact information

Type

Scientific

Primary contact

Miss Nafisa Boota

ORCID ID

Contact details

Warwick Clinical Trials Unit
The University of Warwick
Gibbet Hill Road
Coventry
CV4 7AL
United Kingdom
+44 (0)2476572905
STRESS-L@warwick.ac.uk

Additional identifiers

EudraCT number

2017-001785-14

ClinicalTrials.gov number

Protocol/serial number

35229

Study information

Scientific title

STudy into the REversal of Septic Shock with Landiolol (Beta Blockade)

Acronym

STRESS-L

Study hypothesis

A reduction in heart rate using landiolol infusion in patients with septic shock and tachycardia improves organ failure during the 14 days after the patient is started in the trial. This study is investigate whether the changes are through a reduction in cardiac and immune dysfunction.

Ethics approval

East of England – Essex Research Ethics Committee, 09/11/2017, ref: 17/EE/0368

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet STRESS-L@warwick.ac.uk

Condition

Specialty: Critical care, Primary sub-specialty: Critical Care; UKCRC code/ Disease: Infection/ Other infectious diseases, Inflammatory and Immune System/ Certain disorders involving the immune mechanism

Intervention

Participants are randomised to receive standard treatment with the addition of a beta blocker infusion (landiolol) or standard treatment alone.

For those in the landiolol group, the rate of drug are adjusted until the heart rate is controlled between 80-94 beats per minute. Landiolol may be used for up to 14 days within the ICU. Follow up continues for up to 90 days following randomisation.

One of the aims of this study is to better understand the biological mechanisms that are altered by beta-blockade in septic shock. As part of standard clinical care blood will be taken from a cannula (a thin tube inserted into a vein or body cavity to administer medication). Additional blood samples will be taken at study entry, on days 1, 2, 4 and 6 and at the end of noradrenaline treatment (if not a sampling day). These samples will be sent to University Hospitals Birmingham NHS Foundation Trust and will be used in laboratory research to help define the mechanisms involved in treating sepsis with beta blockade. These samples will be destroyed once analysis has been completed.

Routinely collected clinical data will be recorded for the trial. However the progress of participants will be followed at day 28 and day 90 after trial entry, at these time points the local research team will call the participant and their GP to find out how they are. The trial will not follow participants beyond 90 days.

Intervention type

Drug

Phase

Not Applicable

Drug names

Landiolol

Primary outcome measure

Organ failure is measured using the mean SOFA score over the first 14 days from entry to the trial and whilst in ICU. Measurement of the SOFA score will cease if the patient dies or is discharged from the ICU.

Secondary outcome measures

1. Mortality is measured using patient records and telephone visits at day 28 and day 90
2. Length of ICU and hospital stay are measured using patient notes up to 90 days
3. Individual organ failure-days in 28 day survivors is measured using medical tests (recording SOFA score parameters - oxygenation, renal, hepatic and coagulation function) at day 28
4. Reduction in dose and duration of vasopressor treatment (total doses of adrenaline, dobutamine, phosphodiesterase inhibitors) is measured using patient notes for up to 14 days following randomisation
5. Cardiovascular safety outcomes are measured using hospital notes for the first 14 days

Exploratory Outcome Measures:
Myocardial dysfunction and inflammation are measured using assays on blood samples taken on days 0, 1, 2, 4, 6 and the End of Noradrenaline Treatment Visit.

Overall trial start date

01/06/2017

Overall trial end date

31/08/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Male or female aged 18 years or above
2. Being treated on an ICU
3. Septic shock according to internationally accepted definitions*
4. Heart rate ≥95 bpm (24 hours after start of vasopressor therapy)
5. Receiving vasopressor support with noradrenaline to maintain a target blood pressure for ≥24 hours
6. Are being treated with noradrenaline at a rate ≥ 0.1mcg/kg/min

*Sepsis -3 definitions:
1. Confirmed or suspected infection requiring antibiotic therapy
2. New organ dysfunction, as evidenced by an increase in SOFA score ≥2
3. A blood lactate >2 mmol/l at any point during shock resuscitation
4. Vasopressor therapy to maintain mean arterial pressure (MAP) ≥65 mmHg
In particular the presence of a blood lactate > 2 mmol/l is only necessary for the diagnosis of septic shock and is NOT necessary for randomisation 24 hours later.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 340; UK Sample Size: 340

Participant exclusion criteria

1. Noradrenaline infusion < 0.1mcg/kg/min
2. > 48 hours after start of vasopressor therapy
3. Having pre-existing severe cardiac dysfunction (NYHA grade 4 or more)
4. Having pre-existing severe pulmonary hypertension (mean PA pressures > 55mmHg)
5. Acute severe bronchospasm (due to asthma or COPD)
6. Untreated second or third degree heart block
7. Untreated pheochromocytoma
8. Prinzmetal's angina
9. A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated severe carotid stenosis.
10. Advanced liver disease
11. Having been treated with any beta-blocker drug in the seventy two hours prior to screening.
12. Known sensitivity to beta-blockers
13. Patient / legal representative unwilling to provide written informed consent
14. Known to be pregnant
15. Terminal illness other than septic shock with a life expectancy < 28 days
16. Participants who have participated in another research trial involving an investigational medicinal product in the past 30 days.
17. Patients in whom the clinical team feel are about to finish their noradrenaline therapy

Recruitment start date

10/01/2018

Recruitment end date

09/01/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Queen Elizabeth Hospital
University Hospitals Birmingham NHS Foundation Trust Trust HQ, PO Box 9551
Birmingham
B15 2TH
United Kingdom

Sponsor information

Organisation

University Hospitals Birmingham NHS Foundation Trust

Sponsor details

Trust Headquaters
Po Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal. The Warwick Clinical Trials Unit will publish the results of the trial on their website when these are available.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

05/01/2018: Internal review.