ADjunctive coRticosteroid trEatment iN criticAlly ilL Patients With Septic Shock (ADRENAL)

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

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.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Hydrocortisone; Drug: Sterile air filled vial

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.

• Study Type: Interventional
• Enrollment (Actual): 3800
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
    • Liverpool, New South Wales, Australia, 1871
      • Liverpool Hospital
    • Newcastle, New South Wales, Australia, 2305
      • John Hunter Hospital
    • Penrith, New South Wales, Australia, 2747
      • Nepean Hospital
    • Randwick, New South Wales, Australia, 2031
      • Prince of Wales Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Sydney, New South Wales, Australia, 2000
      • The George Institute for Global Health
    • Tamworth, New South Wales, Australia, 2340
      • Tamworth Rural Referral Hospital
    • Tweed Heads, New South Wales, Australia, 2485
      • Tweed Heads District Hospital
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Hospital (Newcastle)
    • Wollongong, New South Wales, Australia, 2521
      • Wollongong Hospital
  • Northern Territory
    • Darwin, Northern Territory, Australia, 0810
      • Royal Darwin Hospital
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • Wesley Hospital
    • Brisbane, Queensland, Australia, 4032
      • Prince Charles Hospital
    • Brisbane, Queensland, Australia, 4101
      • Mater Health Services
    • Gold Coast, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
    • Ipswich, Queensland, Australia, 4307
      • Ipswich Hospital
    • Logan, Queensland, Australia, 4131
      • Logan Hospital
    • Mackay, Queensland, Australia, 4740
      • Mackay Base Hospital
    • Nambour, Queensland, Australia, 4560
      • Nambour Hospital
    • Redcliffe, Queensland, Australia, 4020
      • Redcliffe Hospital
    • Toowoomba, Queensland, Australia, 4350
      • Toowoomba Hospital
    • Townsville, Queensland, Australia, 4814
      • Townsville Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
    • Elizabeth Vale, South Australia, Australia, 5112
      • Lyell McEwin Hospital
    • Woodville South, South Australia, Australia, 5011
      • The Queen Elizabeth Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Bendigo, Victoria, Australia, 3550
      • Bendigo Hospital
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Epping, Victoria, Australia, 3076
      • Northern Hospital
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital (Melbourne)
    • Footscray, Victoria, Australia, 3011
      • Footscray Hospital
    • Geelong, Victoria, Australia, 3220
      • Geelong Hospital (Barwon Health)
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • St Albans, Victoria, Australia, 3021
      • Sunshine Hospital
  • Western Australia
    • Fremantle, Western Australia, Australia, 6959
      • Fremantle Hospital
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
    • Perth, Western Australia, Australia, 6150
      • St John of God Hospital-Murdoch
• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• New Zealand
  • Auckland, New Zealand, 1142
    • Auckland City Hospital (CVICU)
  • Auckland, New Zealand, 1142
    • Auckland City Hospital (DCCM)
  • Auckland, New Zealand, 1640
    • Middlemore Hospital
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
  • Tauranga, New Zealand, 3110
    • Tauranga Hospital
  • Wellington, New Zealand, 6011
    • Wellington Hospital
  • Auckland
    • North Shore, Auckland, New Zealand, 0622
      • North Shore Hospital
  • NZ
    • Hamilton, NZ, New Zealand, 3240
      • Waikato Hospital
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11525
    • King Fahad Medical City
  • Riyadh, Saudi Arabia, 11426
    • King Abdulaziz Medical City
  • Riyadh, Saudi Arabia, 11472
    • King Khalid University Hospital, King Saud University
• United Kingdom
  • England
    • Bristol, England, United Kingdom, BS2 8HW
      • Bristol Royal Infirmary
    • Chertsey, England, United Kingdom, KT16 0PZ
      • Ashford & St.Peter's NHS Foundation Trust
    • Cosham, England, United Kingdom, PO63LY
      • Queen Alexandra Hospital (Portsmouth)
    • Edgbaston, England, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital Birmingham
    • Guildford, England, United Kingdom, GU2 7XX
      • Royal Surrey County Hospital
    • London, England, United Kingdom, SE 13 6LH
      • Lewisham Healthcare Nhs Trust
    • London, England, United Kingdom, SE1 9RT
      • Guy's and St Thomas' HNS Foundation Trust
    • London, England, United Kingdom, SE5 9RS
      • King's College Hospital NHS Foundation Trust
    • London, England, United Kingdom, SW17 0QH
      • St Georges Healthcare NHS Trust
    • Newcastle upon Tyne, England, United Kingdom, NE7 7DN
      • Freeman Hospital
    • Southampton, England, United Kingdom, S016 6YD
      • University Hospital Southampton
  • Wales
    • Newport, Wales, United Kingdom, NP20 2UB
      • Royal Gwent Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydrocortisone	Drug: Hydrocortisone; Hydrocortisone 100mg vial (blinded) is reconstituted with 2ml of water for Injection, agitated for 20 seconds, rested for 3 minutes, contents of vial aspirated and added to 100ml bag of normal saline or 5% dextrose and given intravenously as a continuous infusion at rate of 200mg/per day for 7 days.; Other Names: Solu-Cortef
Placebo Comparator: Sterile air filled vial	Drug: Sterile air filled vial; the "sterile air filled vial" (blinded) is reconstituted with 2ml of water for Injection, agitated for 20 seconds, rested for 3 minutes, contents of vial aspirated and added to 100ml bag of normal saline or 5% dextrose and given intravenously as a continuous infusion. 2 sterile air filled vials per day for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
All cause mortality at 90 days after randomisation	90 days after randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality at 28 days and 6 months after randomisation		28 days and 6 months after randomisation
Time to resolution of shock	Time to resolution of shock - defined as "the time taken to achieve a clinician prescribed mean arterial pressure (MAP) goal for >24 hours without vasopressors or inotropes.	MAP goal for >24 hours without vasopressors or inotropes. Up to 90 days after randomisation.
Recurrence of shock	Recurrence of shock - defined as a new episode of shock after reversal of the initial episode.	Up to90 days after randomisation
Duration of ICU stay		Up to 90 days after randomisation
Duration of hospital stay		Up to 90 days after randomisation
Frequency and duration of mechanical ventilation		Up to 90 days after randomisation
Duration of renal replacement therapy		Up to 90 days after randomisation
Development of bacteraemia		2 and 14 days post randomisation
Bleeding requiring blood transfusions received in the ICU		Up to 90 days after randomisation
Quality of Life assessment at 6 months.		6 months.

Collaborators and Investigators

• Sponsor: The George Institute
• Collaborators: National Health and Medical Research Council, Australia; Australian and New Zealand Intensive Care Society Clinical Trials Group
• Investigators: Study Chair: Balasubramanian Venkatesh, The George Institute

Publications and helpful links

General Publications

• Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J; ADRENAL Trial Investigators and the Australian-New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/NEJMoa1705835. Epub 2018 Jan 19.

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2012
• Primary Completion (Actual): October 22, 2017
• Study Completion (Actual): November 20, 2017

Study Registration Dates

• First Submitted: October 5, 2011
• First Submitted That Met QC Criteria: October 5, 2011
• First Posted (Estimate): October 7, 2011

Study Record Updates

• Last Update Posted (Actual): December 12, 2017
• Last Update Submitted That Met QC Criteria: December 10, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Corticosteroid; Sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone hemisuccinate
• Other Study ID Numbers: GI-CCT372273