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Trial registered on ANZCTR


Registration number
ACTRN12620001088932p
Ethics application status
Not yet submitted
Date submitted
17/07/2020
Date registered
20/10/2020
Date last updated
20/10/2020
Date data sharing statement initially provided
20/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of early sedation with dexmedetomidine compared with placebo on 90-day mortality in older critically ill patients
Scientific title
The effect of Early Sedation with Dexmedetomidine vs. Placebo on 90-day mortality in Older Ventilated Critically Ill Patients. A Prospective, Multi-Centre, Double-Blind, Randomized, Controlled Trial

Secondary ID [1] 301800 0
NHMRC 1186863
Universal Trial Number (UTN)
U1111-1255-5865
Trial acronym
SPICE IV - Old SPICE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critically ill patients 318277 0
Mechanical Ventilation 318278 0
Sedation 318279 0
Condition category
Condition code
Anaesthesiology 316293 316293 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous infusion of dexmedetomidine started shortly after commencement of mechanical ventilation, at a recommended dose of 1 mcg/kg/hr without a loading dose. The infusion will be adjusted between 0 and 1 mcg/kg/hr to achieve target sedation assessed by the Richmond Agitation Sedation Scale (RASS). The default target is RASS score of -1 to+1. The infusion would continue in intensive care until sedation is no longer required or to a max of 28-days whichever comes first. The need for ongoing sedation will be determined by the attending clinician based on frequent clinical assessment.
Adherence to the intervention will be monitored by onsite research support staff and the study PI at individual sites. In addition, monitoring through study website via built in queries will be regularly conducted.
Intervention code [1] 318102 0
Treatment: Drugs
Intervention code [2] 318682 0
Treatment: Other
Comparator / control treatment
The comparator is placebo in the form of equivalent volume of normal saline will be used.
As the study design is double-blind, staff, including clinicians and bedside carers will be blinded to the intervention. The study algorithm prescribe a sedation target for participants. Therefore, additional supplemental sedatives would be added, as per usual or routine care in ICU, to achieve desired sedation target. The infusion of study medication, active or placebo, will therefore continue, as above, until sedation is no longer required or to a maximum of 28 days in ICU.
Control group
Placebo

Outcomes
Primary outcome [1] 324462 0
All-cause mortality will be collected through a phone follow-up by the sites research support staff. This is then entered into the study database.
Timepoint [1] 324462 0
90-days following randomization
Secondary outcome [1] 384733 0
A composite of Number of days alive and free of coma and delirium. This is collected through medical records and direct patient assessment for delirium, coma (RASS of < or = -4 unresponsive to voice or painful stimulus).
Timepoint [1] 384733 0
at 28 days following randomization
Secondary outcome [2] 384734 0
A composite score of Number of days alive and ventilator free collected directly from medical records and entered into study database.
Timepoint [2] 384734 0
at 28 days following randomization
Secondary outcome [3] 384735 0
Major Adverse Kidney Events (Mortality + Acute Kidney Injury > stage II, defined by Kidney Disease Improving Global Outcome (KDIGO) definition). This is collected directly from medical records and entered into study database.
Timepoint [3] 384735 0
at 28 days following randomization
Secondary outcome [4] 384736 0
Duration of mechanical ventilation in survivors This is collected directly from medical records and entered into study database.
Timepoint [4] 384736 0
ICU discharge
Secondary outcome [5] 384737 0
Hospital length of stay in survivors. This is collected directly from medical records and entered into study database.
Timepoint [5] 384737 0
Hospital discharge

Eligibility
Key inclusion criteria
1. Age is equal to or older than 65 years
2. Intubated and receiving invasive mechanical ventilation in an intensive care unit
3. The treating clinicians believe that the patient will remain intubated and ventilated until the day after tomorrow (unlikely to be extubated next day)
4. The patient requires immediate ongoing sedative medication for comfort, safety and to facilitate the delivery of life support measures.
Minimum age
65 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant and/or lactating
2. Has been intubated (excluding time spent intubated within an operating theatre or transport) for greater than 12 hours in an intensive care unit
3. Proven or suspected acute primary brain lesion such as traumatic brain injury, intracranial haemorrhage, stroke, or hypoxic brain injury
4. Proven or suspected spinal cord injury or other pathology that may result in permanent or prolonged weakness
5. Admission with a suspected or proven drug overdose or burns.
6. Administration of ongoing neuromuscular blockade
7. Mean arterial blood (MAP) pressure that is less than 50 mmHg despite adequate resuscitation and vasopressor therapy at time of randomization
8. Heart rate less than 55 beats per minute unless the patient is being treated with a betablocker or a high grade atrio-ventricular block in the absence of a functioning pacemaker
9. Known sensitivity to dexmedetomidine
10. Acute fulminant hepatic failure
11. Receiving full time residential nursing care
12. 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
13. Patient has an underlying disease that makes survival to 90 days unlikely
14. Previously enrolled in the SPICE IV 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)
Central randomisation via study website
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
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
NIL
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical analyses will be conducted on an intention-to-treat basis. Comparison of 90-day mortality between treatment arms will be performed using a chi-square test for equal proportion and hierarchical logistic regression to account for multi-centre variability. Sensitivity to missingness and baseline imbalance will be conducted using multiple imputation and covariate adjusted logistic regression respectively. Secondary outcomes will be analysed using standard statistical methods for binomial and continuous data with Bonferroni adjustment for multiplicity. Time-to-event data will be assessed using Cox regression and presented as Kaplan Meier curves with log-rank comparison. A detailed statistical analysis plan will be developed in accordance with the SPICE III analysis plan and published prior to study completion.

Recruitment
Recruitment status
Not yet recruiting
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,VIC
Recruitment hospital [1] 17104 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [2] 17105 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 17106 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [4] 17107 0
Prince of Wales Hospital - Randwick
Recruitment hospital [5] 17108 0
Nepean Hospital - Kingswood
Recruitment hospital [6] 17109 0
Royal Darwin Hospital - Tiwi
Recruitment postcode(s) [1] 30780 0
3168 - Clayton
Recruitment postcode(s) [2] 30781 0
3084 - Heidelberg
Recruitment postcode(s) [3] 30782 0
4029 - Herston
Recruitment postcode(s) [4] 30783 0
2031 - Randwick
Recruitment postcode(s) [5] 30784 0
2747 - Kingswood
Recruitment postcode(s) [6] 30785 0
0810 - Tiwi
Recruitment outside Australia
Country [1] 22744 0
New Zealand
State/province [1] 22744 0

Funding & Sponsors
Funding source category [1] 306232 0
Government body
Name [1] 306232 0
The Australian National Health and Medical Research Council (NHMRC)
Address [1] 306232 0
16 Marcus Clarke St, Canberra ACT 2601
Country [1] 306232 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Level 5, E Block - Monash Medical Centre - 246 Clayton Rd, Clayton Victoria 3168
Country
Australia
Secondary sponsor category [1] 306715 0
Individual
Name [1] 306715 0
Professor Yahya Shehabi
Address [1] 306715 0
E Block, Level 5, Monash Medical Centre, 246 Clayton Rd, Clayton VIC 3168
Country [1] 306715 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 306443 0
Human Research Ethics Committee, Monash Health
Ethics committee address [1] 306443 0
Level 2, I Block, Monash Medical Centre, Clayton, VIC 3468
Ethics committee country [1] 306443 0
Australia
Date submitted for ethics approval [1] 306443 0
04/11/2020
Approval date [1] 306443 0
Ethics approval number [1] 306443 0

Summary
Brief summary
The proportion of elderly patients presenting to intensive care units following complex
surgery or life threatening medical illness requiring mechanical ventilation, cardiovascular and other organ support is rising. More than 180,000 patients are admitted to intensive care units in Australia every year. More than 50% are over the age of 65. The SPICE III study, evaluated the use of early dexmedetomidine (DEX) as primary sedative agent in ventilated critically ill patients compared with usual care. In a pre-specified subgroup analysis, SPICE III found a significant interaction between age and DEX treatment on 90-day mortality with a significant reduction of mortality in mechanically ventilated adults older than the cohort median age of 63.7 yrs. These compelling findings, need to be urgently confirmed because their confirmation will change the practice of sedation in older adults worldwide.
Accordingly, we will conduct a complementary multicentre randomised controlled trial in ventilated patients, who are older than 65 years, and expected to remain ventilated for longer than 24 hours. Patients will be randomised to receive DEX infusion started at 1 µg/kg/h or Usual-Care and titrated to target Richmond Agitation Sedation Score of -1 to +1. The primary outcome will be 90-day mortality. A sample size of 3500 will be recruited to detect a 5% reduction in mortality (baseline 37%). Such a cohort will then be merged into a harmonised individual patient based meta-analysis with the 1834 patients of > 63 years of age randomized in the recently completed SPICE III study to provide the most efficient and robust (90% power to detect 4.4% difference) assessment of the effect of dexmedetomidine on mortality in older ventilated adults to date, transform sedation practice, and save thousands of lives in Australia and worldwide.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103894 0
Prof Yahya Shehabi
Address 103894 0
Level 5, E Block, Monash Medical Centre, 246 Clayton Rd, Clayton VIC 3168
Country 103894 0
Australia
Phone 103894 0
+61 419296986
Fax 103894 0
Email 103894 0
yahya.shehabi@monashhealth.org
Contact person for public queries
Name 103895 0
Ms Belinda Howe
Address 103895 0
Australian New Zealand Intensive Care Research Centre
553 St Kilda Rd, Melbourne, VIC 3004
Country 103895 0
Australia
Phone 103895 0
+61399030340
Fax 103895 0
Email 103895 0
Belinda.howe@monash.edu
Contact person for scientific queries
Name 103896 0
Prof Yahya Shehabi
Address 103896 0
Level 5, E Block, Monash Medical Centre, 246 Clayton Rd, Clayton VIC 3168
Country 103896 0
Australia
Phone 103896 0
+61 419296986
Fax 103896 0
Email 103896 0
yahya.shehabi@monashhealth.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results