Trial from ClinicalTrials.gov

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Trial ID
NCT01728558
Ethics application status
Date submitted
4/11/2012
Date registered
4/11/2012
Date last updated
12/04/2016

Titles & IDs
Public title
Early Goal-Directed Sedation Compared With Standard Care in Mechanically Ventilated Critically Ill Patients
Scientific title
Early Goal-Directed Sedation Compared With Standard Care in Mechanically Ventilated Critically Ill Patients: a Prospective Multicentre Randomised Controlled Trial
Secondary ID [1] 0 0
ANZIC-RC/YS003
Universal Trial Number (UTN)
Trial acronym
SPICE III RCT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical Illness and Mechanical Ventilation 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Early goal Directed Sedation
Other interventions - Standard care sedation

Other: Early Goal Directed Sedation - Early Goal Directed Sedation process of care involves:
Early delivery of proposed intervention, shortly after initiating mechanical ventilation;
Effective analgesia provided simultaneously and early (analgesia first).
Regular and frequent assessment of patient wakefulness/sedative state;
Avoidance of benzodiazepines and minimisation of use of propofol;
Reduced overall sedation depth with targeted light sedation; Patients randomised to the EGDS arm will receive a sedative infusion of Dexmedetomidine withor without minimal propofol in order to maintain a RASS of -2 to +1.
Dexmedetomidine infusion will be continued until sedation is no longer clinically indicated up to a maximum of 28 days after enrolment.

Active Comparator: Standard care Sedation Arm - Patients randomised to the standard care sedation arm will receive process of care sedation directed by the treating clinician. Based on the information from our observational study and the EGDS Pilot trial, most patients in this group are likely to receive midazolam and /or propofol. These agents will be infused to achieve the default target of Light sedation (RASS -2 to +1) whenever clinically appropriate and as specified by the treating clinician. The use remifentanil or dexmedetomidine for initial and maintenance sedation will be precluded.


Other interventions: Early goal Directed Sedation


Other interventions: Standard care sedation


Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Mortality
Timepoint [1] 0 0
Day 90 post randomisation
Secondary outcome [1] 0 0
Ventilation free days
Timepoint [1] 0 0
at 28 days following randomisation
Secondary outcome [2] 0 0
Proportion of RASS measurements in target range
Timepoint [2] 0 0
up to day 28
Secondary outcome [3] 0 0
Incidence and duration of delirium measured by delirium free days
Timepoint [3] 0 0
up to 28 days
Secondary outcome [4] 0 0
Length of ICU stay
Timepoint [4] 0 0
up to 180 days
Secondary outcome [5] 0 0
Proportion of patients who receive a tracheostomy Proportion of patients who require: re-intubation, physical restraints,or unplanned extubation,
Timepoint [5] 0 0
up to day 28
Secondary outcome [6] 0 0
Cumulative dose of midazolam, propofol, dexmedetomidine, fentanyl, and morphine
Timepoint [6] 0 0
up to 28 days
Secondary outcome [7] 0 0
Duration of treatment with midazolam, propofol, dexmedetomidine, fentanyl, and morphine
Timepoint [7] 0 0
up to 28 days
Secondary outcome [8] 0 0
Mortality at hospital discharge
Timepoint [8] 0 0
at hospital discharge up to 180 days
Secondary outcome [9] 0 0
Length of hospital stay
Timepoint [9] 0 0
up to 180 days
Secondary outcome [10] 0 0
Readmission to ICU
Timepoint [10] 0 0
at 90 days
Secondary outcome [11] 0 0
EQ-5D questionnaire
Timepoint [11] 0 0
at 180 days
Secondary outcome [12] 0 0
Cognitive function
Timepoint [12] 0 0
at 180 days
Secondary outcome [13] 0 0
Mortality at ICU discharge
Timepoint [13] 0 0
up to 180 days
Secondary outcome [14] 0 0
Full time institutional dependency at 180 days
Timepoint [14] 0 0
up to 180 days
Secondary outcome [15] 0 0
Discharge destination
Timepoint [15] 0 0
up to 180 days

Eligibility
Key inclusion criteria
- Patient has been intubated and is receiving mechanical ventilation

- The treating clinician expects that the patient will remain intubated until the day
after tomorrow (unlikely to be extubated the following day).

- The patient requires immediate ongoing sedative medication for comfort, safety, and to
facilitate the delivery of life support measures.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Age less than 18 years

- Patient is pregnant and/or lactating

- Has been intubated (excluding time spent intubated within an operating theatre or
transport) for greater than 12 hours in an intensive care unit.

- Proven or suspected acute primary brain lesion such as traumatic brain injury,
intracranial haemorrhage, stroke, or hypoxic brain injury.

- Proven or suspected spinal cord injury or other pathology that may result in permanent
or prolonged weakness.

- Admission as a consequence of a suspected or proven drug overdose or burns.

- Administration of ongoing neuromuscular blockade.

- A mean arterial blood (MAP) pressure that is less than 50 mmHg despite adequate
resuscitation and vasopressor therapy at time of randomisation

- Heart rate less than 55 beats per minute unless the patient is being treated with a
beta-blocker or a high grade atrio-ventricular block in the absence of a functioning
pacemaker.

- Known sensitivity to any of the study medications or the constituents of propofol
(egg, soya or peanut protein)

- Acute fulminant hepatic failure

- Patient has been receiving full time residential nursing care.

- Death is deemed to be imminent or inevitable during this admission and either the
attending physician, patient or substitute decision maker is not committed to active
treatment.

- Patient has an underlying disease that makes survival to 90 days unlikely

- Patient has been previously enrolled in the SPICE 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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,VIC,WA
Recruitment hospital [1] 0 0
Blacktown Hospital - Blacktown
Recruitment hospital [2] 0 0
St Vincent's Hospital Sydney - Darlinghurst
Recruitment hospital [3] 0 0
Gosford Hospital - Gosford
Recruitment hospital [4] 0 0
Hornsby Ku-ring-gai Hospital - Hornsby
Recruitment hospital [5] 0 0
Nepean Hospital - Penrith
Recruitment hospital [6] 0 0
Royal North Shore Hospital - St. Leonards
Recruitment hospital [7] 0 0
Prince of Wales Hospital - Sydney
Recruitment hospital [8] 0 0
Westmead Hospital - Westmead
Recruitment hospital [9] 0 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [10] 0 0
Sunshine Coast Hospital (Nambour Hospital) - Buderim
Recruitment hospital [11] 0 0
Royal Brisbane and Women's hospital - Herston
Recruitment hospital [12] 0 0
Redcliffe Hospital - Redcliffe
Recruitment hospital [13] 0 0
Gold Coast Hospital & Health Service - Southport
Recruitment hospital [14] 0 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [15] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [16] 0 0
Lyell McEwan Hospital - Elizabeth Vale
Recruitment hospital [17] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [18] 0 0
Launceston General Hospital - Launceston
Recruitment hospital [19] 0 0
Bendigo Hospital - Bendigo
Recruitment hospital [20] 0 0
Dandenong Hospital - Dandenong
Recruitment hospital [21] 0 0
Northern Hospital - Epping
Recruitment hospital [22] 0 0
Frankston Hospital - Frankston
Recruitment hospital [23] 0 0
Geelong Hospital - Geelong
Recruitment hospital [24] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [25] 0 0
Royal Melbourne Hospital - Melbourne
Recruitment hospital [26] 0 0
Monash Medical Centre - Melbourne
Recruitment hospital [27] 0 0
Central Gippsland Health Service - Sale
Recruitment hospital [28] 0 0
Royal Perth Hospital - Perth
Recruitment hospital [29] 0 0
St John Of God, Subiaco - Perth
Recruitment postcode(s) [1] 0 0
2148 - Blacktown
Recruitment postcode(s) [2] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 0 0
2250 - Gosford
Recruitment postcode(s) [4] 0 0
2077 - Hornsby
Recruitment postcode(s) [5] 0 0
2750 - Penrith
Recruitment postcode(s) [6] 0 0
2065 - St. Leonards
Recruitment postcode(s) [7] 0 0
2031 - Sydney
Recruitment postcode(s) [8] 0 0
2145 - Westmead
Recruitment postcode(s) [9] 0 0
0811 - Tiwi
Recruitment postcode(s) [10] 0 0
4556 - Buderim
Recruitment postcode(s) [11] 0 0
4029 - Herston
Recruitment postcode(s) [12] 0 0
4020 - Redcliffe
Recruitment postcode(s) [13] 0 0
4215 - Southport
Recruitment postcode(s) [14] 0 0
4350 - Toowoomba
Recruitment postcode(s) [15] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [16] 0 0
5112 - Elizabeth Vale
Recruitment postcode(s) [17] 0 0
7000 - Hobart
Recruitment postcode(s) [18] 0 0
7250 - Launceston
Recruitment postcode(s) [19] 0 0
3550 - Bendigo
Recruitment postcode(s) [20] 0 0
3175 - Dandenong
Recruitment postcode(s) [21] 0 0
3076 - Epping
Recruitment postcode(s) [22] 0 0
3199 - Frankston
Recruitment postcode(s) [23] 0 0
3220 - Geelong
Recruitment postcode(s) [24] 0 0
3084 - Heidelberg
Recruitment postcode(s) [25] 0 0
3050 - Melbourne
Recruitment postcode(s) [26] 0 0
3168 - Melbourne
Recruitment postcode(s) [27] 0 0
3850 - Sale
Recruitment postcode(s) [28] 0 0
6001 - Perth
Recruitment postcode(s) [29] 0 0
6008 - Perth
Recruitment outside Australia
Country [1] 0 0
New Zealand
State/province [1] 0 0
Auckland
Country [2] 0 0
New Zealand
State/province [2] 0 0
Christchurch
Country [3] 0 0
New Zealand
State/province [3] 0 0
North Shore City
Country [4] 0 0
New Zealand
State/province [4] 0 0
Wellington
Country [5] 0 0
New Zealand
State/province [5] 0 0
Rotorua

Funding & Sponsors
Primary sponsor type
Other
Name
Australian and New Zealand Intensive Care Research Centre
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
National Health and Medical Research Council, Australia
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The Use of sedative drugs in intensive care is widespread. A cohort study conducted in
Australia and New Zealand in 2010 revealed a high prevalence of deep sedation within the
first 48 hours of mechanical ventilation which was independently linked to prolonged
ventilation, hospital and 180 days mortality. Clinical practice is moving towards the use of
lighter levels of sedation. Recent RCTs in Europe (JAMA 2012) and previous RCTs (JAMA 2009)
supports growing evidence that dexmedetomidine facilitates rousable sedation, shortens
ventilation time and attenuates delirium when compared to midazolam and propofol.

The investigators confirmed in a pilot study the feasibility, efficacy and safety of a
process of care known as Early Goal Directed Sedation (EGDS) that delivers:

1. Early randomization after intubation or arrival in the ICU (intubated).

2. Early Adequate analgesia after randomization.

3. Goal directed sedation titrated to achieve light sedation.

4. Dexmedetomidine based algorithm as the primary sedative agent with avoidance of
benzodiazepines.

The aim of this study is to assess the effectiveness of Early Goal Directed Sedation when
compared to standard care sedation in critically ill patients.

The study hypothesis is that Early Goal-Directed Sedation (EGDS), compared to standard care
sedation, reduces 90-day all-cause mortality in critically ill patients who require
mechanical ventilation.
Trial website
Trial related presentations / publications
Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur C, Seppelt IM, Webb S, Weisbrodt L; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012 Oct 15;186(8):724-31. doi: 10.1164/rccm.201203-0522OC. Epub 2012 Aug 2.
Public notes

Contacts
Principal investigator
Name 0 0
Yahya Shehabi, MD, FCICM, FANZCA, EMBA
Address 0 0
University New South Wales, Prince of Wales Hospital, ANZIC-RC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Belinda D Howe, RN
Address 0 0
Country 0 0
Phone 0 0
+61 3 9903 0340
Fax 0 0
Email 0 0
belinda.howe@monash.edu
Contact person for scientific queries
Contact person responsible for updating information