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Trial registered on ANZCTR


Registration number
ACTRN12611001042932
Ethics application status
Approved
Date submitted
28/09/2011
Date registered
5/10/2011
Date last updated
27/06/2019
Date data sharing statement initially provided
27/06/2019
Date results information initially provided
27/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised blinded placebo controlled trial of hydrocortisone in critically ill patients with septic shock.
Scientific title
A multi-centre, blinded, randomised, placebo controlled trial to determine whether hydrocortisone therapy reduces 90-day mortality in patients admitted to intensive Care with septic shock.
Secondary ID [1] 263097 0
Nil
Universal Trial Number (UTN)
Trial acronym
ADRENAL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Septic shock 270850 0
Condition category
Condition code
Infection 271027 271027 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Hydrocortisone 200mg per day given intravenously as a continuous infusion for 7 days
Intervention code [1] 269444 0
Treatment: Drugs
Comparator / control treatment
"Sterile air filled vial" that contained 0.2ml of water for injection for sterilisation purposes. It will be reconstituted with water for injection, diluted and given as a continuous infusion (2 per day) for 7 days.
Control group
Placebo

Outcomes
Primary outcome [1] 279685 0
All cause mortality at 90 days after randomisation
Timepoint [1] 279685 0
90 days after randomisation
Secondary outcome [1] 294203 0
All-cause mortality at 28 days and 6 months after randomisation
Timepoint [1] 294203 0
28 days and 6 months after randomisation
Secondary outcome [2] 294204 0
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.
Timepoint [2] 294204 0
MAP goal for >24 hours without vasopressors or inotropes. Up to 90 days after randomisation.
Secondary outcome [3] 294205 0
Recurrence of shock - defined as a new episode of shock after reversal of the initial episode.
Timepoint [3] 294205 0
Up to90 days after randomisation
Secondary outcome [4] 294206 0
Duration of ICU stay
Timepoint [4] 294206 0
Up to 90 days after randomisation
Secondary outcome [5] 294207 0
Duration of hospital stay
Timepoint [5] 294207 0
Up to 90 days after randomisation
Secondary outcome [6] 294208 0
Frequency and duration of mechanical ventilation
Timepoint [6] 294208 0
Up to 90 days after randomisation
Secondary outcome [7] 294209 0
Duration of renal replacement therapy
Timepoint [7] 294209 0
Up to 90 days after randomisation
Secondary outcome [8] 294210 0
Development of bacteraemia between 2 and 14 days post randomisation
Timepoint [8] 294210 0
2 and 14 days post randomisation
Secondary outcome [9] 294211 0
Bleeding requiring blood transfusions received in the ICU
Timepoint [9] 294211 0
Up to 90 days after randomisation
Secondary outcome [10] 294212 0
Quality of Life - EQ5D assessment at 6 months.
Timepoint [10] 294212 0
6 months.

Eligibility
Key inclusion criteria
1. Aged 18 years or older 2. Documented site of infection, or strong suspicion of infection 3. 2 of the 4 clinical signs of inflammation: i. Core temperature > 38 degrees C or < 35 degrees C ii. Heart rate > 90 beats per minute iii. White cell count > 12 x 109/L or < 4 x 109/L or > 10% immature neutrophils iv. Respiratory rate > 20 breaths per minute, or PaCO2 < 32 mmHg, or mechanical ventilation. 4. Being treated with mechanical ventilation at the time of randomisation 5. 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 6. Administration of vasopressors or inotropes for greater than or equal to 4 hours and present at time of randomisation.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be achieved using a minimisation algorithm via a password-protected encrypted web based interface. Randomisation will be stratified according to participating site and operative or non-operative admission to the ICU. Following successful randomisation, each patient will be assigned a unique ‘patient study number’ and a unique ‘study treatment number’. The unique study treatment number is matched to blinded study treatment with sufficient study drug to last the 7 day course of treatment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be achieved using a minimisation algorithm.
Stratification will occur at centre level and by operative and non operative.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 5134 0
Blacktown Hospital - Blacktown
Recruitment hospital [2] 5135 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [3] 5136 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [4] 5137 0
Liverpool Hospital - Liverpool
Recruitment hospital [5] 5138 0
Nepean Hospital - Kingswood
Recruitment hospital [6] 5139 0
Prince of Wales Hospital - Randwick
Recruitment hospital [7] 5140 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [8] 5141 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [9] 5142 0
St George Hospital - Kogarah
Recruitment hospital [10] 5143 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [11] 5144 0
Tamworth Rural Referral Hospital - Tamworth
Recruitment hospital [12] 5145 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [13] 5146 0
Wollongong Hospital - Wollongong
Recruitment hospital [14] 5147 0
Gold Coast Hospital - Southport
Recruitment hospital [15] 5148 0
Ipswich Hospital - Ipswich
Recruitment hospital [16] 5149 0
Logan Hospital - Meadowbrook
Recruitment hospital [17] 5150 0
Mater Private Hospital - South Brisbane
Recruitment hospital [18] 5151 0
Mackay Base Hospital - Mackay
Recruitment hospital [19] 5152 0
Nambour General Hospital - Nambour
Recruitment hospital [20] 5153 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [21] 5154 0
Redcliffe Hospital - Redcliffe
Recruitment hospital [22] 5155 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [23] 5157 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [24] 5158 0
The Townsville Hospital - Douglas
Recruitment hospital [25] 5159 0
The Wesley Hospital - Auchenflower
Recruitment hospital [26] 5160 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [27] 5161 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [28] 5162 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [29] 5163 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [30] 5164 0
Royal Hobart Hospital - Hobart
Recruitment hospital [31] 5165 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [32] 5166 0
Bendigo Health Care Group - Bendigo Hospital - Bendigo
Recruitment hospital [33] 5167 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [34] 5168 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [35] 5169 0
The Northern Hospital - Epping
Recruitment hospital [36] 5170 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [37] 5171 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [38] 5172 0
Western Hospital - Footscray
Recruitment hospital [39] 5173 0
Fremantle Hospital and Health Service - Fremantle
Recruitment hospital [40] 5174 0
Royal Perth Hospital - Perth
Recruitment hospital [41] 5175 0
Gold Coast Hospital - Southport
Recruitment hospital [42] 5177 0
The Prince Charles Hospital - Chermside
Recruitment hospital [43] 5178 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [44] 7937 0
Gosford Hospital - Gosford
Recruitment hospital [45] 7938 0
St John of God Hospital, Murdoch - Murdoch
Recruitment postcode(s) [1] 12598 0
2148 - Blacktown
Recruitment postcode(s) [2] 12599 0
2298 - Waratah
Recruitment postcode(s) [3] 12600 0
2305 - New Lambton
Recruitment postcode(s) [4] 12601 0
1871 - Liverpool
Recruitment postcode(s) [5] 12602 0
2747 - Kingswood
Recruitment postcode(s) [6] 12603 0
2031 - Randwick
Recruitment postcode(s) [7] 12604 0
2065 - St Leonards
Recruitment postcode(s) [8] 12605 0
2050 - Camperdown
Recruitment postcode(s) [9] 12606 0
2217 - Kogarah
Recruitment postcode(s) [10] 12607 0
2010 - Darlinghurst
Recruitment postcode(s) [11] 12608 0
2340 - Tamworth
Recruitment postcode(s) [12] 12609 0
2485 - Tweed Heads
Recruitment postcode(s) [13] 12610 0
2521 - South Coast Mc
Recruitment postcode(s) [14] 12611 0
4215 - Southport
Recruitment postcode(s) [15] 12612 0
4305 - Ipswich
Recruitment postcode(s) [16] 12613 0
4131 - Meadowbrook
Recruitment postcode(s) [17] 12614 0
4101 - South Brisbane
Recruitment postcode(s) [18] 12615 0
4740 - Mackay
Recruitment postcode(s) [19] 12616 0
4560 - Nambour
Recruitment postcode(s) [20] 12617 0
4102 - Woolloongabba
Recruitment postcode(s) [21] 12618 0
4020 - Redcliffe
Recruitment postcode(s) [22] 12619 0
4006 - Herston
Recruitment postcode(s) [23] 12621 0
4350 - Toowoomba
Recruitment postcode(s) [24] 12622 0
4814 - Douglas
Recruitment postcode(s) [25] 12623 0
4066 - Auchenflower
Recruitment postcode(s) [26] 12624 0
0810 - Tiwi
Recruitment postcode(s) [27] 12625 0
5112 - Elizabeth Vale
Recruitment postcode(s) [28] 12626 0
5000 - Adelaide
Recruitment postcode(s) [29] 12627 0
5011 - Woodville South
Recruitment postcode(s) [30] 12628 0
7000 - Hobart
Recruitment postcode(s) [31] 12629 0
3084 - Heidelberg
Recruitment postcode(s) [32] 12630 0
3550 - Bendigo
Recruitment postcode(s) [33] 12631 0
3220 - Geelong
Recruitment postcode(s) [34] 12632 0
3168 - Clayton
Recruitment postcode(s) [35] 12633 0
3076 - Epping
Recruitment postcode(s) [36] 12634 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [37] 12635 0
3065 - Fitzroy
Recruitment postcode(s) [38] 12636 0
3011 - Footscray
Recruitment postcode(s) [39] 12637 0
6959 - Fremantle
Recruitment postcode(s) [40] 12638 0
6000 - Perth
Recruitment postcode(s) [41] 15905 0
2250 - Gosford
Recruitment postcode(s) [42] 15906 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 3858 0
Denmark
State/province [1] 3858 0
Copenhagen
Country [2] 3861 0
United Kingdom
State/province [2] 3861 0
England
Country [3] 3862 0
Saudi Arabia
State/province [3] 3862 0
Riyadh
Country [4] 8875 0
New Zealand
State/province [4] 8875 0
North and South Island

Funding & Sponsors
Funding source category [1] 269921 0
Government body
Name [1] 269921 0
Australian National Health and Medical Research Council (NHMRC)
Address [1] 269921 0
Level 1, 16 Marcus Clarke Street, Canberra ACT 2601
Country [1] 269921 0
Australia
Funding source category [2] 285599 0
Government body
Name [2] 285599 0
Health Research Council of New Zealand
Address [2] 285599 0
Level 3, 110 Stanley Street,
Auckland, PO Box 5541,
Wellesley Street,
Auckland 1010, New Zealand
Country [2] 285599 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
The George Institute for Global Health
Address
Level 3, 50 Bridge Street, Sydney, NSW, 2000, Australia
Country
Australia
Secondary sponsor category [1] 268938 0
None
Name [1] 268938 0
Address [1] 268938 0
Country [1] 268938 0
Other collaborator category [1] 252268 0
Other Collaborative groups
Name [1] 252268 0
Australian and New Zealand Intensive Care Society Clinical Trials Group
Address [1] 252268 0
10 Levers Terrace
Carlton South
VIC 3053
Country [1] 252268 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 271906 0
Sydney South West Area Health Service Human Research Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 271906 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road,
CAMPERDOWN NSW 2050
Ethics committee country [1] 271906 0
Australia
Date submitted for ethics approval [1] 271906 0
Approval date [1] 271906 0
04/07/2011
Ethics approval number [1] 271906 0
EC00113

Summary
Brief summary
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.
Trial website
Trial related presentations / publications
Publication: Venkatesh B, Myburgh J, Finfer S, Webb S, Cohen J, Bellomo R, McArthur C, Joyce C, Rajbhandari D, Glass P, Harward M and the ANZICS CTG Investigators. The ADRENAL protocol paper. Crit Care Resus 2013;15:83-88.
Public notes

Contacts
Principal investigator
Name 33194 0
Prof Balasubramanian Venkatesh
Address 33194 0
Princess Alexandra Hospital Intensive Care 199 Ipswich Road. Woolloongabba QLD 4102
Country 33194 0
Australia
Phone 33194 0
+61 7 3176 2111
Fax 33194 0
Email 33194 0
Bala.Venkatesh@uchealth.com.au
Contact person for public queries
Name 16441 0
Prof Professor Balasubramanian Venkatesh
Address 16441 0
Princess Alexandra Hospital
Intensive Care
199 Ipswich Road.
Woolloongabba QLD 4102
Country 16441 0
Australia
Phone 16441 0
+61 7 3176 2111
Fax 16441 0
+61 7 3176 2155
Email 16441 0
Bala.Venkatesh@uchealth.com.au
Contact person for scientific queries
Name 7369 0
Prof Professor Balasubramanian Venkatesh
Address 7369 0
Princess Alexandra Hospital
Intensive Care
199 Ipswich Road.
Woolloongabba QLD 4102
Country 7369 0
Australia
Phone 7369 0
+61 7 3176 2111
Fax 7369 0
+61 7 3176 2155
Email 7369 0
Bala.Venkatesh@uchealth.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 2517 0
Venkatesh B, etal, Adjunctive Glucocorticoid Therapy in Patients with Septic Shock, NEJM, January 19,2018. DOI: 10.1056/NeJMoa1705835
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary