Condition category
Infections and Infestations
Date applied
18/11/2009
Date assigned
19/11/2009
Last edited
20/04/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Each year in the UK, about 31,000 people are admitted to critical care with severe sepsis, a syndrome where the body has an uncontrolled inflammatory response to infection which leads to damage to and subsequently failure of organs such as the lungs, heart and kidneys. Around one third of these patients die before discharge from hospital. Identifying these patients early and applying a strict protocol to control the amount of fluids, blood and drugs given may reduce the number of deaths and also the amount of time patients spend in hospital. However, we do not know whether this approach would be as successful if applied across all hospitals in the NHS. We aim to compare this protocol to the usual care delivered in NHS emergency departments and medical/surgical admissions units to establish the best approach to managing these patients.

Who can participate?
Patients aged 18 or over with the early signs of severe sepsis

What does the study involve?
Participants are randomly allocated either to be treated according to the new protocol or to receive the usual care. We assess the number of deaths within 90 days and the costs of each approach to determine whether the protocols offer good value for money to the NHS.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
Intensive Care National Audit and Research Centre (ICNARC) (UK)

When is the study starting and how long is it expected to run for?
February 2011 to December 2013

Who is funding the study?
NIHR Health Technology Assessment Programme - HTA (UK)

Who is the main contact?
Prof Kathryn Rowan
kathy.rowan@icnarc.org

Trial website

Contact information

Type

Scientific

Primary contact

Prof Kathryn Rowan

ORCID ID

Contact details

Intensive Care National Audit and Research Centre (ICNARC)
Napier House
24 High Holborn
London
WC1V 6AZ
United Kingdom
-
kathy.rowan@icnarc.org

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

HTA 07/37/47; ICNARC/01/01/09

Study information

Scientific title

A multicentre, randomised controlled trial of the clinical and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock

Acronym

ProMISe

Study hypothesis

Current hypothesis as of 04/01/2013:
To evaluate a resuscitation protocol, with pre-determined haemodynamic goals, compared with usual resuscitation

Previous hypothesis until 04/01/2013:
To evaluate a resuscitation strategy with pre-determined haemodynamic endpoints compared to usual care for patients with severe sepsis or septic shock.

More details can be found at: http://www.nets.nihr.ac.uk/projects/hta/073747
Protocol can be found at: http://www.nets.nihr.ac.uk/__data/assets/pdf_file/0014/51800/PRO-07-37-47.pdf

Ethics approval

Not provided at time of registration

Study design

Prospective multicentre randomised controlled trial

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 below to request a patient information sheet

Condition

Severe sepsis/septic shock

Intervention

Intervention arm: Early goal-directed protocolised resuscitation; targeting of specific haemodynamic goals including central venous pressure, mean arterial pressure and central venous oxygen saturation.
Control arm: Usual care

Patients admitted to Emergency Departments with severe sepsis or septic shock will undergo 6 hours of the intervention arm post-randomisation. For the control arm patients will be treated via usual care for these 6 hours. After this patients will be treated with standard care.

Patients will be followed up for a year post-admission to hospital. This will include assessments at 28 days, 90 days and 1 year. This trial is not classed as a CTIMP.

Intervention type

Other

Phase

Not Applicable

Drug names

Primary outcome measures

1. Mortality at 90 days
2. Incremental cost-effectiveness at one year

Secondary outcome measures

Current secondary outcome measures as of 04/01/2013:
1. To compare:
1.1. Mortality at one year
1.2. Health-related quality of life at 90 days and one year
1.3. Resource use and costs at 90 days and one year
1.4. Requirement for, and duration of, critical care unit organ support
1.5. Length of stay in the ED, critical care unit and acute hospital
2. To estimate:
2.1. Lifetime incremental cost-effectiveness

Previous secondary outcome measures until 04/01/2013:
1. Duration of survival
2. Mortality at 28 days
3. Mortality at discharge from critical care and discharge from hospital
4. Mortality at one year
5. Sequential Organ Failure Assessment (SOFA) score at 6 hours and 72 hours (adjusted for baseline)
6. Requirement for, and duration of, monitoring and support of specific organ systems (CCMDS)
7. Duration of ED, critical care unit and hospital stay
8. Health-related quality of life (EQ-5D) at 90 days and one year
9. Resource use and costs at 90 days and one year
10. Lifetime incremental cost-effectiveness

Overall trial start date

15/02/2011

Overall trial end date

31/12/2013

Reason abandoned

Eligibility

Participant inclusion criteria

1. Greater than or equal to 18 years of age, either sex
2. Known or presumed infection
3. Two or more systemic inflammatory response syndrome (SIRS) criteria:
3.1. Core temperature less than or equal to 36°C or greater than or equal to 38°C
3.2. Heart rate greater than or equal to 90 beats/min
3.3. Respiratory rate greater than or equal to 20 breaths/min (or hyperventilation indicated by partial pressure of carbon dioxide in arterial blood [PaCO2] 4.3 kPa or mechanical ventilation for an acute process)
3.4. White blood cell count less than or equal to 4 x 10^9 l or greater than or equal to 12 x 10^9 l (or the presence of greater than 10% immature neutrophils "bands")
4. Refractory hypotension or hypoperfusion:
4.1. Hypotension is confirmed by the presence of systolic blood pressure less than 90 mmHg despite an intravenous (IV) fluid challenge of at least 20 ml/kg within 30 minutes of Emergency Department (ED) arrival (including IV fluids administered by pre-hospital/Emergency Medical Services [EMS] personnel)
4.2. Hypoperfusion is confirmed by a blood lactate concentration greater than or equal to 4 mmol/L)
5. First dose of IV antimicrobial therapy commenced prior to randomisation

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

1260

Participant exclusion criteria

Current exclusion criteria as of 04/01/2013:
1. Age less than 18 years
2. Known pregnancy
3. Primary diagnosis of:
3.1. an acute cerebral vascular event
3.2. acute coronary syndrome
3.3. acute pulmonary oedema
3.4. status asthmaticus
3.5. major cardiac arrhythmia (as part of primary diagnosis)
3.6. seizure
3.7. drug overdose
3.8. injury from burn or trauma
4. Haemodynamic instability due to active gastrointestinal haemorrhage
5. Requirement for immediate surgery
6. Known history of AIDS
7. Do-Not-Attempt-Resuscitation (DNAR) status
8. Advanced directives restricting implementation of the resuscitation protocol
9. Contraindication to central venous catheterization
10. Contraindication to blood transfusion
11. Attending clinician deems aggressive resuscitation unsuitable
12. Transferred from another in-hospital setting
13. Not able to commence resuscitation protocol within one hour of randomisation or complete six hours of protocol treatment from commencement

Previous exclusion criteria until 04/01/2013:
1. Aged less than 18 years
2. Known pregnancy
3. Primary diagnosis of acute cerebral vascular event, acute coronary syndrome, acute pulmonary oedema, status asthmaticus, major cardiac arrhythmia (as part of primary diagnosis), seizure, drug overdose, injury from burn or trauma
4. Haemodynamic instability due to active gastrointestinal (GI) haemorrhage
5. Immunosuppressive agents including chemotherapy for uncured cancer, immunosuppression for organ transplantation or from systematic disease
6. Requirement for immediate surgery
7. Do not resuscitate status
8. Advanced directives restricting implementation of the protocol
9. Contraindications to central venous catheterisation
10. Contradiction to blood transfusion (i.e. Jehovah's Witness)
11. Attending physician deems aggressive care unsuitable
12. Participation in another interventional study
13. Transferred from another in-hospital setting
14. Not able to start within 1 hour of randomisation or finish within 6 hours

Recruitment start date

15/02/2011

Recruitment end date

31/12/2013

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Intensive Care National Audit and Research Centre (ICNARC)
London
WC1V 6AZ
United Kingdom

Sponsor information

Organisation

Intensive Care National Audit and Research Centre (ICNARC) (UK)

Sponsor details

c/o Keryn Vella
Napier House
24 High Holborn
London
WC1V 6AZ
United Kingdom

Sponsor type

Government

Website

https://www.icnarc.org/

Funders

Funder type

Government

Funder name

NIHR Health Technology Assessment Programme - HTA (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2013 statistical analysis plan in: http://www.ncbi.nlm.nih.gov/pubmed/24289513
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/25776532
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/26597979

Publication citations

  1. Statistical analysis plan

    Power GS, Harrison DA, Mouncey PR, Osborn TM, Harvey SE, Rowan KM, The Protocolised Management in Sepsis (ProMISe) trial statistical analysis plan., Crit Care Resusc, 2013, 15, 4, 311-317.

  2. Results

    Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM; ProMISe Trial Investigators, Trial of Early, Goal-Directed Resuscitation for Septic Shock, N Engl J Med., 2015 , doi: 10.1056/NEJMoa1500896.

  3. Results

    Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Tan JC, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM, Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock, Health Technol Assess, 2015, 19, 97, 1-150, doi: 10.3310/hta19970.

Additional files

Editorial Notes

20/04/2016: Plain English summary added. On 04/01/2013 the following changes were made to the trial record: 1. The overall trial start date was changed from 01/06/2010 to 15/02/2011. 2. The overall trial end date was changed from 31/07/2012 to 31/12/2013.