ADjunctive coRticosteroid trEatment iN criticAlly ilL Patients With Septic Shock

Septic Shock Clinical Trial

— ADRENAL  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01448109
• Other study ID #: GI-CCT372273
• Status: Completed
• Phase: Phase 4
• First received: October 5, 2011
• Last updated: December 10, 2017
• Start date: June 13, 2012
• Est. completion date: November 20, 2017

Study information

• Verified date: September 2017
• Source: The George Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3800
• Est. completion date: November 20, 2017
• Est. primary completion date: October 22, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Critical Illness
• Septic Shock
• Shock
• Shock, Septic

Intervention

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.
• 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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Wesley Hospital	Auchenflower	Queensland
Australia	Bendigo Hospital	Bendigo	Victoria
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Mater Health Services	Brisbane	Queensland
Australia	Prince Charles Hospital	Brisbane	Queensland
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Centre	Clayton	Victoria
Australia	St Vincent's Hospital	Darlinghurst	New South Wales
Australia	Royal Darwin Hospital	Darwin	Northern Territory
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	Northern Hospital	Epping	Victoria
Australia	St Vincent's Hospital (Melbourne)	Fitzroy	Victoria
Australia	Footscray Hospital	Footscray	Victoria
Australia	Fremantle Hospital	Fremantle	Western Australia
Australia	Geelong Hospital (Barwon Health)	Geelong	Victoria
Australia	Gold Coast University Hospital	Gold Coast	Queensland
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Ipswich Hospital	Ipswich	Queensland
Australia	St George Hospital	Kogarah	New South Wales
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Logan Hospital	Logan	Queensland
Australia	Mackay Base Hospital	Mackay	Queensland
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Nambour Hospital	Nambour	Queensland
Australia	John Hunter Hospital	Newcastle	New South Wales
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Nepean Hospital	Penrith	New South Wales
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	St John of God Hospital-Murdoch	Perth	Western Australia
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Redcliffe Hospital	Redcliffe	Queensland
Australia	Sunshine Hospital	St Albans	Victoria
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Australia	The George Institute for Global Health	Sydney	New South Wales
Australia	Tamworth Rural Referral Hospital	Tamworth	New South Wales
Australia	Toowoomba Hospital	Toowoomba	Queensland
Australia	Townsville Hospital	Townsville	Queensland
Australia	Tweed Heads District Hospital	Tweed Heads	New South Wales
Australia	Calvary Mater Hospital (Newcastle)	Waratah	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Denmark	Rigshospitalet	Copenhagen
New Zealand	Auckland City Hospital (CVICU)	Auckland
New Zealand	Auckland City Hospital (DCCM)	Auckland
New Zealand	Middlemore Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Waikato Hospital	Hamilton	NZ
New Zealand	North Shore Hospital	North Shore	Auckland
New Zealand	Tauranga Hospital	Tauranga
New Zealand	Wellington Hospital	Wellington
Saudi Arabia	King Abdulaziz Medical City	Riyadh
Saudi Arabia	King Fahad Medical City	Riyadh
Saudi Arabia	King Khalid University Hospital, King Saud University	Riyadh
United Kingdom	Bristol Royal Infirmary	Bristol	England
United Kingdom	Ashford & St.Peter's NHS Foundation Trust	Chertsey	England
United Kingdom	Queen Alexandra Hospital (Portsmouth)	Cosham	England
United Kingdom	Queen Elizabeth Hospital Birmingham	Edgbaston	England
United Kingdom	Royal Surrey County Hospital	Guildford	England
United Kingdom	Guy's and St Thomas' HNS Foundation Trust	London	England
United Kingdom	King's College Hospital NHS Foundation Trust	London	England
United Kingdom	Lewisham Healthcare NHS Trust	London	England
United Kingdom	St Georges Healthcare NHS Trust	London	England
United Kingdom	Freeman Hospital	Newcastle upon Tyne	England
United Kingdom	Royal Gwent Hospital	Newport	Wales
United Kingdom	University Hospital Southampton	Southampton	England

Sponsors (3)

Lead Sponsor	Collaborator
The George Institute	Australian and New Zealand Intensive Care Society Clinical Trials Group, National Health and Medical Research Council, Australia

Countries where clinical trial is conducted

Australia,  Denmark,  New Zealand,  Saudi Arabia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All cause mortality at 90 days after randomisation		90 days after randomisation
Secondary	All-cause mortality at 28 days and 6 months after randomisation		28 days and 6 months after randomisation
Secondary	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.
Secondary	Recurrence of shock	Recurrence of shock - defined as a new episode of shock after reversal of the initial episode.	Up to90 days after randomisation
Secondary	Duration of ICU stay		Up to 90 days after randomisation
Secondary	Duration of hospital stay		Up to 90 days after randomisation
Secondary	Frequency and duration of mechanical ventilation		Up to 90 days after randomisation
Secondary	Duration of renal replacement therapy		Up to 90 days after randomisation
Secondary	Development of bacteraemia		2 and 14 days post randomisation
Secondary	Bleeding requiring blood transfusions received in the ICU		Up to 90 days after randomisation
Secondary	Quality of Life assessment at 6 months.		6 months.