Clinical trial NCT01448109: ADjunctive coRticosteroid trEatment iN criticAlly ilL Patients With Septic Shock
Official title: A Randomised Blinded Placebo Controlled Trial of Hydrocortisone in Critically Ill Patients With Septic Shock
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Septic Shock
Keywords: Sepsis
Corticosteroid
Lead sponsor: The George Institute
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
name: Australian and New Zealand Intensive Care Society Clinical Trials Group
First posted: 2011-10-07
Enrollment: 3800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: All cause mortality at 90 days after randomisation
timeFrame: 90 days after randomisation
Secondary outcomes:
measure: All-cause mortality at 28 days and 6 months after randomisation
timeFrame: 28 days and 6 months after randomisation
measure: Time to resolution of shock
timeFrame: MAP goal for >24 hours without vasopressors or inotropes. Up to 90 days after randomisation.
measure: Recurrence of shock
timeFrame: Up to90 days after randomisation
measure: Duration of ICU stay
timeFrame: Up to 90 days after randomisation
measure: Duration of hospital stay
timeFrame: Up to 90 days after randomisation
measure: Frequency and duration of mechanical ventilation
timeFrame: Up to 90 days after randomisation
measure: Duration of renal replacement therapy
timeFrame: Up to 90 days after randomisation
measure: Development of bacteraemia
timeFrame: 2 and 14 days post randomisation
measure: Bleeding requiring blood transfusions received in the ICU
timeFrame: Up to 90 days after randomisation
measure: Quality of Life assessment at 6 months.
timeFrame: 6 months.
Other outcomes:
Locations:
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Penrith
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: The George Institute for Global Health
state: New South Wales
city: Tamworth
country: Australia
facility: Tamworth Rural Referral Hospital
state: New South Wales
city: Tweed Heads
country: Australia
facility: Tweed Heads District Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Hospital (Newcastle)
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Darwin
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Auchenflower
country: Australia
facility: Wesley Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Mater Health Services
state: Queensland
city: Gold Coast
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Ipswich
country: Australia
facility: Ipswich Hospital
state: Queensland
city: Logan
country: Australia
facility: Logan Hospital
state: Queensland
city: Mackay
country: Australia
facility: Mackay Base Hospital
state: Queensland
city: Nambour
country: Australia
facility: Nambour Hospital
state: Queensland
city: Redcliffe
country: Australia
facility: Redcliffe Hospital
state: Queensland
city: Toowoomba
country: Australia
facility: Toowoomba Hospital
state: Queensland
city: Townsville
country: Australia
facility: Townsville Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Woodville South
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Bendigo Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Epping
country: Australia
facility: Northern Hospital
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincent's Hospital (Melbourne)
state: Victoria
city: Footscray
country: Australia
facility: Footscray Hospital
state: Victoria
city: Geelong
country: Australia
facility: Geelong Hospital (Barwon Health)
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: St Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Fremantle
country: Australia
facility: Fremantle Hospital
state: Western Australia
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Perth
country: Australia
facility: St John of God Hospital-Murdoch
state: Western Australia
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: North Shore
country: New Zealand
facility: North Shore Hospital
state: Auckland
city: Hamilton
country: New Zealand
facility: Waikato Hospital
state: NZ
city: Auckland
country: New Zealand
facility: Auckland City Hospital (CVICU)
city: Auckland
country: New Zealand
facility: Auckland City Hospital (DCCM)
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Tauranga
country: New Zealand
facility: Tauranga Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Riyadh
country: Saudi Arabia
facility: King Khalid University Hospital, King Saud University
city: Riyadh
country: Saudi Arabia
facility: King Fahad Medical City
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
state: England
city: Chertsey
country: United Kingdom
facility: Ashford & St.Peter's NHS Foundation Trust
state: England
city: Cosham
country: United Kingdom
facility: Queen Alexandra Hospital (Portsmouth)
state: England
city: Edgbaston
country: United Kingdom
facility: Queen Elizabeth Hospital Birmingham
state: England
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: England
city: London
country: United Kingdom
facility: Lewisham Healthcare NHS Trust
state: England
city: London
country: United Kingdom
facility: Guy's and St Thomas' HNS Foundation Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: St Georges Healthcare NHS Trust
state: England
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
state: England
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
state: England
city: Newport
country: United Kingdom
facility: Royal Gwent Hospital
state: Wales
Study officials:
affiliation: The George Institute
name: Balasubramanian Venkatesh
role: STUDY_CHAIR
References:
citation: 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.