ADjunctive coRticosteroid trEatment iN criticAlly ilL Patients With Septic Shock

Condition(s) targeted: Septic Shock

Intervention: Hydrocortisone (Drug); Sterile air filled vial (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: The George Institute

Official(s) and/or principal investigator(s):
Balasubramanian Venkatesh, Study Chair, Affiliation: The George Institute

Overall contact:
Dorrilyn Rajbhandari, Phone: +61 410 442 828, Email: drajbhandari@georgeinstitute.org.au

The purpose of this study is to find out whether adult patients admitted to the Intensive Care Unit with septic shock who are given hydrocortisone compared to placebo (a dummy solution), will have an improved rate of survival 90 days later. Septic shock is the result of an infection, which triggers a complex response by the body (the inflammatory response) that causes a decrease in blood pressure and subsequently one or more organ systems to fail when blood supply to these organs is reduced. This may result in poor recovery and death. About a quarter of the people who suffer septic shock that is not rapidly reversed, will die. When patients are admitted to Intensive Care with sepsis and/or septic shock they receive a number of therapies. These include fluids given through a drip, antibiotics, drugs to boost your blood pressure and other organ systems. In addition to these therapies, steroids (hydrocortisone) are sometimes administered. Whether steroids are useful or not in the treatment of severe infections has been studied for more than 50 years. Previous research has suggested that the use of low dose steroid may have shortterm benefits in improving the circulation. However, there is no agreement amongst doctors around the world about whether treatment with or without low dose steroids improves the overall recovery and survival in patients with septic shock. This study would allow doctors to make informed decisions about whether the addition of low dose steroid therapy is better for patients with septic shock in intensive care. The study will include 3800 intensive care patients who have septic shock. Each enrolled patient will be randomised to receive either Hydrocortisone 200mg or placebo daily for 7 days as a continuous intravenous infusion while in intensive care. The patient will be followed for 90 days. If the patient is discharged prior to 90 days a telephone call will be made for the followup information. At six months the patient will be contacted again for completion of a quality of life questionnaire.

Official title: A Randomised Blinded Placebo Controlled Trial of Hydrocortisone in Critically Ill Patients With Septic Shock

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: All cause mortality at 90 days after randomisation

Secondary outcome:

All-cause mortality at 28 days and 6 months after randomisation

Time to resolution of shock

Recurrence of shock

Duration of ICU stay

Duration of hospital stay

Frequency and duration of mechanical ventilation

Duration of renal replacement therapy

Development of bacteraemia

Bleeding requiring blood transfusions received in the ICU

Quality of Life assessment at 6 months.

Detailed description: Primary Objective To evaluate the impact of intravenous hydrocortisone versus placebo on all cause mortality at 90 days in critically ill patients with septic shock. The hypothesis is that hydrocortisone, compared to placebo, reduces 90-day all-cause mortality in patients admitted to an ICU with septic shock. 'Shock' is defined as the need for vasopressors or inotropes to maintain a systolic blood pressure > 90 millimetres of mercury (mmHg), or mean arterial blood pressure > 60mmHg or a mean arterial pressure (MAP) target set by the treating clinician for maintaining perfusion. 'Septic shock' is shock that is secondary to sepsis Secondary Objectives To assess the impact of intravenous hydrocortisone versus placebo on the recovery from, and the complications of, septic shock and the development of treatment related adverse reactions. Study Design This study is a multi centre, randomised, blinded, placebo controlled trial comparing intravenous hydrocortisone with placebo in critically ill patients with septic shock. Randomisation will be achieved via a secure interactive web based system using permuted block minimisation. Randomisation will be stratified by participating site and by operative or non-operative admission to the ICU. The primary endpoint for this trial will be death from all causes at 90 days. Pre defined sub groups will include the following categories:

- Operative (admitted to ICU from operating theatre or recovery room) versus

non-operative admission.

- Dose of adrenaline or noradrenaline at randomisation - ≤ 15 mcg / minute versus > 15

mcg / minute.

3,800 patients will be enrolled in this study at approximately 50 - 60 study sites. Eligible

patients will be randomised to receive either intravenous hydrocortisone 200mg or placebo per day for 7 days. For all patients, data will be collected at baseline and then daily whilst the patient is in the ICU. Patients will be followed up to day 14, regardless of where the patient resides in the hospital, to monitor the development of bacteraemia. Additional follow up will occur at 90 days and at 6 months post randomisation.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Aged 18 years or older 2. Documented site of infection, or strong suspicion of infection, with 2 of the 4 clinical signs of inflammation:

- Core temperature > 38°C or < 35°C

- Heart rate > 90 beats per minute

- White cell count > 12 x 109/L or < 4 x 109/L or > 10% immature neutrophils

- Respiratory rate > 20 breaths per minute, or PaCO2 < 32 mmHg, or mechanical

ventilation. 3. Being treated with mechanical ventilation at the time of randomisation 4. Being treated with vasopressors or inotropes to maintain a systolic blood pressure > 90mmHg, or mean arterial blood pressure > 60mmHg, or a MAP target set by the treating clinician for maintaining perfusion 5. Administration of vasopressors or inotropes for = 4 hours and present at time of randomisation. Exclusion Criteria: 1. Met all inclusion criteria more than 24 hours ago 2. Clinician expects to prescribe systemic corticosteroids for an indication other than septic shock (not including nebulised or inhaled corticosteroid) 3. Patients treated with etomidate 4. Patients receiving treatment with Amphotericin B for systemic fungal infections at time of randomisation 5. Patients with documented cerebral malaria at the time of randomisation 6. Patients with documented strongyloides infection at the time of randomisation 7. Death is deemed inevitable or imminent during this admission and either the attending physician, patient or surrogate legal decision maker is not committed to active treatment 8. Death from underlying disease is likely within 90 days 9. Patient has been previously enrolled in the ADRENAL study.

Dorrilyn Rajbhandari, Phone: +61 410 442 828, Email: drajbhandari@georgeinstitute.org.au

Rigshospitalet, Copenhagen 2100, Denmark; Recruiting
Anders Perner, Email: anders.perner@rh.regionh.dk
Anders Perner, Principal Investigator
Rasmus Muller, Sub-Investigator

Auckland City Hospital (CVICU), Auckland 1142, New Zealand; Recruiting
Shay McGuinness, Email: shaymc@adhb.govt.nz
Shay McGuinness, Principal Investigator

Auckland City Hospital (DCCM), Auckland 1142, New Zealand; Recruiting
Colin Macarthur, Email: ColinM@adhb.govt.nz
Colin Macarthur, Principal Investigator

Middlemore Hospital, Auckland 1640, New Zealand; Recruiting
Alex Kazemi, Email: Alex.Kazemi@middlemore.co.nz
Tony Williams, Email: tony.williams@cmdhb.org.nz
Alex Kazemi, Principal Investigator
Tony Williams, Sub-Investigator

Christchurch Hospital, Christchurch 8011, New Zealand; Recruiting
Seton Henderson, Email: seton.henderson@cdhb.govt.nz
David Knight, Email: david.knight@cdhb.govt.nz
Seton Henderson, Principal Investigator
David Knight, Sub-Investigator

Tauranga Hospital, Tauranga 3110, New Zealand; Recruiting
Troy Browne, Email: Troy.Browne@bopdhb.govt.nz
Troy Browne, Principal Investigator

Wellington Hospital, Wellington 6011, New Zealand; Recruiting
Paul Young, Email: paul.young@ccdhb.org.nz
Richard Dinsdale, Email: dick.dinsdale@ccdhb.org.nz
Paul Young, Principal Investigator
Richard Dinsdale, Sub-Investigator

King Abdul Aziz Medical City, Riyadh 11426, Saudi Arabia; Recruiting
Yaseen Arabi, Email: yaseenarabi@yahoo.com
Yaseen Arabi, Principal Investigator
Samir Hadad, Sub-Investigator

King Fahad Medical City, Riyadh 11525, Saudi Arabia; Recruiting
Hani Lababidi, Email: hlababibi@kfmc.med.sa
Mohammad Al Tannir
Hani Lababidi, Principal Investigator
Mohammad Al Tannir, Sub-Investigator

King Khalid University Hospital, Riyadh 11472, Saudi Arabia; Recruiting
Ahmed Abdulmomen, Email: aturk@KSU.EDU.SA
Mariam Al-Ansari, Email: icu_mariam@yahoo.com
Ahmed Abdulmomen, Principal Investigator
Mariam Al-Ansari, Sub-Investigator

Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom; Recruiting
Jeremy Bewley, Email: Jeremy.Bewley@UHBristol.nhs.uk
Jeremy Bewley, Principal Investigator
Sanjoy Shah, Sub-Investigator

Guy's and St Thomas' HNS Foundation Trust, London SE1 9RT, United Kingdom; Recruiting
Marlies Ostermann, Email: Marlies.Ostermann@gstt.nhs.uk
Marlies Ostermann, Principal Investigator
Richard Beale, Sub-Investigator

King's College Hospital NHS Foundation Trust, London SE5 9RS, United Kingdom; Recruiting
Phillip Hopkins, Email: p.hopkins@nhs.net
Phillip Hopkins, Principal Investigator
Julia Wendon, Sub-Investigator

Lewisham Healthcare NHS Trust, London SE 13 6LH, United Kingdom; Recruiting
Oliver Rose, Email: oliver.rose@nhs.net
Oliver Rose, Principal Investigator
Marthinus Mostert, Sub-Investigator
Ashraf Molokhia, Sub-Investigator

St Georges Healthcare NHS Trust, London SW17 0QH, United Kingdom; Recruiting
Andrew Rhodes, Email: andrewrhodes@nhs.net
Andrew Rhodes, Principal Investigator
Aya Hollmann, Sub-Investigator

University Hospital Southampton, Southampton S016 6YD, United Kingdom; Not yet recruiting
Max Jonas, Email: Max.Jonas@uhs.nhs.uk
Max Jonas, Principal Investigator
Rebecca Cusack, Sub-Investigator

North Shore Hospital, North Shore City, Auckland 0622, New Zealand; Recruiting
Janet Liang, Email: Janet.Liang@waitematadhb.govt.nz
Janet Liang, Principal Investigator

Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham B15 2TH, United Kingdom; Not yet recruiting
Tony Whitehouse, Email: tony.whitehouse@uhb.nhs.uk
Tony Whitehouse, Principal Investigator
Catherine Snelson, Sub-Investigator

Waikato Hospital, Hamilton, NZ 3240, New Zealand; Recruiting
Tom O'Rourke, Email: Tom.O'Rourke@waikatodhb.health.nz
Tom O'Rourke, Principal Investigator

Blacktown Hospital, Blacktown, New South Wales 2148, Australia; Recruiting
Graham Reece, Dr, Email: graham_reece@wsahs.nsw.gov.au
Dhaval Ghelani, Email: dhaval.ghelani@wsahs.nsw.gov.au
Graham Reece, Principal Investigator
Dhaval Ghelani, Sub-Investigator

Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia; Recruiting
Heike Koelzow, Email: Heike.Koelzow@sswahs.nsw.gov.au
David Gattas, Email: dgattas@med.usyd.edu.au
Heike Koelzow, Principal Investigator
David Gattas, Sub-Investigator

St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia; Recruiting
Priya Nair, Email: pnair@stvincents.com.au
Priya Nair, pnair@stvincents.com.au, Principal Investigator

St George Hospital, Kogarah, New South Wales 2217, Australia; Recruiting
Manoj Saxena, Email: Manoj.Saxena@sesiahs.health.nsw.gov.au
Manoj Saxena, Principal Investigator

Liverpool Hospital, Liverpool, New South Wales 1871, Australia; Recruiting
Anders Aneman, Email: anders.aneman@sswahs.nsw.gov.au
Anthony Stewart, Email: anthony.stewart@sswahs.health.nsw.gov.au
Anders Aneman, Principal Investigator
Anthony Stewart, Principal Investigator

John Hunter Hospital, Newcastle, New South Wales 2305, Australia; Recruiting
Peter Harrigan, Email: peter.harrigan@hnehealth.nsw.gov.au
Peter Harrigan, Principal Investigator

Nepean Hospital, Penrith, New South Wales 2747, Australia; Recruiting
Ian Seppelt, Email: seppelt@med.usyd.edu.au
Louise Cole, Email: louise.cole@sydney.edu.au
Ian Seppelt, Principal Investigator
Louise Cole, Sub-Investigator

Prince of Wales Hospital, Randwick, New South Wales 2031, Australia; Recruiting
Yahya Shehabi, Email: y.shehabi@unsw.edu.au
Sumesh Arora, Email: Sumesh.Arora@SESIAHS.HEALTH.NSW.GOV.AU
Yahya Shehabi, Principal Investigator
Sumesh Arora, Sub-Investigator

Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia; Recruiting
Anthony Delaney, Email: adelaney@med.usyd.edu.au
Anthony Delaney, Principal Investigator

The George Institute for Global Health, Sydney, New South Wales 2000, Australia; Active, not recruiting

Tamworth Rural Referral Hospital, Tamworth, New South Wales 2340, Australia; Recruiting
Vinodh Madapusi, Email: tmvinodh@hotmail.com
Viji Rao, Email: vijibai@gmail.com
Vinodh Madapusi, Principal Investigator
Viji Rao, Principal Investigator

Tweed Heads District Hospital, Tweeds Head, New South Wales 2485, Australia; Recruiting
Joe Ogg, Email: joeogg@bigpond.com
Joe Ogg, Principal Investigator

Calvary Mater Hospital (Newcastle), Waratah, New South Wales 2298, Australia; Recruiting
Katrina Ellem, Email: katrina.ellem@calvarymater.org.au
Katrina Ellem, Principal Investigator

Wollongong Hospital, Wollongong, New South Wales 2521, Australia; Recruiting
Martin Sterba, Email: martin.sterba@sesiahs.health.nsw.gov.au
Michael Davis, Email: michaeljohndavis.davis@sesiahs.health.nsw.gov.au
Martin Sterba, Principal Investigator
Michael Davis, Sub-Investigator

Royal Darwin Hospital, Darwin, Northern Territory 0810, Australia; Recruiting
Dianne Stephens, Email: dianne.stephens@nt.gov.au
Sidarth Agarwal, Email: sidarth.agarwal@nt.gov.au
Dianne Stephens, Principal Investigator
Sidathr Agarwal, Sub-Investigator

Queen Alexandra Hospital (Portsmouth), Cosham, Portsmouth PO63LY, United Kingdom; Recruiting
David Pogson, Email: david.pogson@porthosp.nhs.uk
David Pogson, Principal Investigator

Wesley Hospital, Auchenflower, Queensland 4066, Australia; Recruiting
Bala Venkatesh, Email: bvenkatesh@georgeinstitute.org.au
Bala Venkatesh, Principal Investigator

Mater Health Services, Brisbane, Queensland 4101, Australia; Recruiting
Jeffery Presneill, Email: jeffrey.presneill@mater.org.au
David Sturgess, Email: d.sturgess@uq.edu.au
Jeffery Presneill, Principal Investigator
David Sturgess, Sub-Investigator

Prince Charles Hospital, Brisbane, Queensland 4032, Australia; Recruiting
Marc Ziegenfuss, Email: mdz66@hotmail.com
Marc Ziegenfuss, Principal Investigator
John Fraser, Sub-Investigator

Gold Coast University Hospital, Gold Coast, Queensland 4215, Australia; Recruiting
James Winearls, Email: james.winearls@health.qld.gov.au
James Winearls, Principal Investigator

Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia; Recruiting
Jeremy Cohen, Email: Jeremy_Cohen@health.qld.gov.au
Jeremy Cohen, Principal Investigator

Ipswich Hospital, Ipswich, Queensland 4307, Australia; Recruiting
Anand Krishnan, Email: anand_krishnan@health.qld.gov.au
Nandan Bhende, Email: nandan_bhende@health.qld.gov.au
Anand Krishnan, Principal Investigator
Nandan Bhende, Sub-Investigator

Logan Hospital, Logan, Queensland 4131, Australia; Recruiting
Hayden White, Email: Hayden_White@health.qld.gov.au
Hayden White, Principal Investigator

Mackay Base Hospital, Mackay, Queensland 4740, Australia; Recruiting
Neeraj Bhadange, Email: Neeraj.Bhadange@health.qld.gov.au
Neeraj Bhadange, Principal Investigator

Nambour Hospital, Nambour, Queensland 4560, Australia; Recruiting
John Moore, Email: john.moore@health.qld.gov.au
Victoria Campbell, Email: victoria.canpbell@health.qld.gov.au
John Moore, Principal Investigator
Victoria Campbell, Sub-Investigator

Redcliffe Hospital, Redcliffe, Queensland 4020, Australia; Recruiting
Tim Warhurst, Email: tim.warhurst@health.qld.gov.au
Hamish Pollock, Email: hamish.pollock@health.qld.gov.au
Tim Warhurst, Principal Investigator
Hamish Pollock, Sub-Investigator

Toowoomba Hospital, Toowoomba, Queensland 4350, Australia; Recruiting
Vasanth Mariappa, Email: vasanth_mariappa@health.qld.gov.au
Vasanth Mariappa, Principal Investigator

Townsville Hospital, Townsville, Queensland 4814, Australia; Recruiting
Siva Senthuran, Email: Siva.Senthuran@health.qld.gov.au
Siva Senthuran, Principal Investigator

Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia; Recruiting
Bala Venkatesh, Email: bvenkatesh@georgeinstitute.org.au
Chris Joyce, Email: chris.joyce@health.qld.gov.au
Bala Venkatesh, Principal Investigator
Chris Joyce, Sub-Investigator

Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia; Recruiting
Marianne Chapman, Email: Marianne.Chapman@health.sa.gov.au
Marianne Chapman, Principal Investigator

Lyell McEwin Hospital, Elizabeth Vale, South Australia 5112, Australia; Recruiting
Peter Thomas, Email: peter.thomas2@health.sa.gov.au
Peter Thomas, Principal Investigator

The Queen Elizabeth Hospital, Woodville South, South Australia 5011, Australia; Recruiting
Sandra Peake, Email: sandra.peake@health.sa.gov.au
Sandra Peake, MBBS, Principal Investigator

Ashford & St.Peter's NHS Foundation Trust, Chertsey, Surrey KT16 0PZ, United Kingdom; Not yet recruiting
Ian White, Email: Ian White
Ian White, Principal Investigator

Royal Surrey County Hospital, Guildford, Surrey GU2 7XX, United Kingdom; Recruiting
Lui Forni, Email: luiforni@nhs.net, lui.forni@wsht.nhs.uk
Lui Forni, Principal Investigator
Ben Creagh-Brown, Sub-Investigator
Justin Kirk-Bayley, Sub-Investigator

Royal Hobart Hospital, Hobart, Tasmania 7000, Australia; Recruiting
David Cooper, Email: david.cooper@dhhs.tas.gov.au
Umesh Kadam, Email: umesh.kadam@dhhs.tas.gov.au
David Cooper, Principal Investigator
Umesh Kadam, Sub-Investigator

Freeman Hospital, Newcaslte Upon Tyne, Tyne & Wear NE7 7DN, United Kingdom; Not yet recruiting
Stephen Wright, Email: stephen.wright@nuth.nhs.uk
Stephen Wright, Principal Investigator

Royal Victoria Infirmary, Newcastle Upon Tyne, Tyne & Wear NE1 4LP, United Kingdom; Not yet recruiting
Simon Baudouin, Email: s.v.baudouin@newcastle.ac.uk
Simon Baudouin, Principal Investigator

Bendigo Hospital, Bendigo, Victoria 3550, Australia; Recruiting
Jason Fletcher, Email: jfletcher@bendigohealth.org.au
John Edington, Email: jedington@bendigohealth.org.au
Jason Fletcher, Principal Investigator
John Edington, Sub-Investigator

Monash Medical Centre, Clayton, Victoria 3168, Australia; Recruiting
Tim Crozier, Email: tim.crozier@southernhealth.org.au
Tim Crozier, Principal Investigator

Dandenong Hospital, Dandenong, Victoria 3175, Australia; Withdrawn

Northern Hospital, Epping, Victoria 3076, Australia; Recruiting
Angaj Ghosh, Email: angaj.ghosh@nh.org.au
John Green, Email: john.green@nh.org.au
Angaj Ghosh, Principal Investigator
John Green, Sub-Investigator

St Vincent's Hospital (Melbourne), Fitzroy, Victoria 3065, Australia; Recruiting
Antony Tobin, Email: antony.tobin@svhm.org.au
John Santamaria, Email: john.santamaria@svhm.org.au
Antony Tobin, Principal Investigator
John Santamaria, Sub-Investigator

Western Hospital, Footscray, Victoria 3011, Australia; Recruiting
Craig French, Email: craig.french@wh.org.au
Forbes McGain, Email: forbes.mcgain@wh.org.au
Craig French, Principal Investigator
Forbes McGain, Sub-Investigator

Geelong Hospital (Barwon Health), Geelong, Victoria 3220, Australia; Recruiting
Martina Chonghaile, Email: mnicho@barwonhealth.com.au
Neil Orford, Email: neilo@barwonhealth.org.au
Martina Chonghaile, Sub-Investigator
Neil Orford, Principal Investigator

Austin Hospital, Heidelburg, Victoria 3084, Australia; Recruiting
Rinaldo Bellomo, Email: rbellomo@georgeinstitute.org.au
Daryl Jones, Email: daryl.jones@austin.org.au
Rinaldo Bellomo, Principal Investigator
Daryl Jones, Sub-Investigator

Royal Melbourne Hospital, Parkville, Victoria 3050, Australia; Recruiting
Rohit D'Costa, Email: Rohit.dcosta@mh.org.au
Shyama Sriram, Email: Shyama.sriram@mh.org.au
Rohit D'Costa, Principal Investigator
Shyama Sriram, Sub-Investigator

Sunshine Hospital, St Albans, Victoria 3021, Australia; Not yet recruiting
Craig French, Email: craig.french@wh.org.au
Craig Fench, Principal Investigator
Forbes McGain, Sub-Investigator

University Hospital of Wales, Cardiff, Wales CF14 4XW, United Kingdom; Recruiting
Mathew Wise, Email: mattwise@doctors.org.uk
Mathew Wise, Principal Investigator
Tom Holmes, Sub-Investigator

Royal Gwent Hospital, Newport, Wales NP20 2UB, United Kingdom; Recruiting
Nicholas Mason, Email: nick.mason@wales.nhs.uk
Nicholas Mason, Principal Investigator
Jack Parry-Jones, Sub-Investigator

Fremantle Hospital, Fremantle, Western Australia 6959, Australia; Terminated

Fiona Stanley Hospital, Murdoch, Western Australia 6150, Australia; Recruiting
Adrian Regli, Email: adrian.regli@health.wa.gov.au
Adrian Regli, Principal Investigator

Royal Perth Hospital, Perth, Western Australia 6000, Australia; Recruiting
Chris Allen, Email: Chris.Allen@health.wa.gov.au
Edward Litton, Email: edward.litton@health.wa.gov.au
Edward Litton, Sub-Investigator
Chris Allen, Principal Investigator

Starting date: June 2012
Last updated: June 23, 2015