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Trial registered on ANZCTR


Registration number
ACTRN12616001200471
Ethics application status
Approved
Date submitted
26/07/2016
Date registered
31/08/2016
Date last updated
26/09/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effects of Sedating Medications on the levels of Physiological Stress in Critically Unwell Patients
Scientific title
Allostasis and Sedation Practices in Intensive Care Evaluation (All-SPICE) - A substudy of a Randomised multi-centre Sedation Practices in Intensive Care Evaluation (SPICE-III) study, to determine the effect of sedation medications on levels of physiological stress
Secondary ID [1] 289755 0
Nil Known
Universal Trial Number (UTN)
U1111-1185-7278
Trial acronym
All-SPICE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multi-Organ Failure 299607 0
Shock 299608 0
Critical Illness 299609 0
Condition category
Condition code
Other 299575 299575 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
All-SPICE will be a prospective parallel-group multi-centre observational substudy of SPICE-III utilising the the SPICE-III study screening. The SPICE-III study (NCT01728558) is a prospective, un-blinded, randomised controlled trial of Early Goal-Directed Sedation compared with Standard care and will recruit 4000 patients worldwide. The SPICE-III study will recruit patients who are intubated and ventilated in a participating ICU, are expected to remain intubated the day after enrolment and need immediate and ongoing sedation.

Following recruitment, patients will be randomised to either the intervention arm, Early Goal-Directed Sedation (EGDS) or the control arm, standard sedation practice (STDS).
Patients in the EGDS arm will receive a dexmedetomidine infusion starting at 1 mcg/kg/hr without loading dose to achieve a target Richmond Agitation Sedation Scale (RASS) [10] -2 to +1 at all times, unless otherwise clinically indicated. If dexmedetomidine alone is insufficient, propofol will be administered, by bolus or infusion (10-70 mg/hr) or both, to achieve the targeted level of sedation.
Patients in the STDS will receive sedative medications (either midazolam or propofol or both), as determined by the treating clinician, to achieve clinically appropriate sedation target as chosen by the treating clinician, although a target of RASS -2 to +1 is encouraged (default) at all times in this arm.

Patients enrolled in the SPICE-III study will be eligible for inclusion in the All-SPICE sub-study. A total of 100 patients from approximately 4 ICUs will be enrolled in All-SPICE. Immediately following randomisation on day 1, patients will have blood samples taken, which will be repeated on days 2, 4 and 6.
Intervention code [1] 295404 0
Early Detection / Screening
Comparator / control treatment
Patients in the standard care arm will receive sedative medications (either midazolam or propofol or both), as determined by the treating clinician, to achieve clinically appropriate sedation target as chosen by the treating clinician.
Control group
Active

Outcomes
Primary outcome [1] 299052 0
A change in the components of the stress panel measured by serum assay over a 5-day course comparing EDGS to standard care.
Timepoint [1] 299052 0
At Day 6 following randomisation in the SPICE-III study
Secondary outcome [1] 326015 0
Correlation of changes in stress panel components with sedation level (RASS)
Timepoint [1] 326015 0
At day 6 following randomisation in the SPICE-III study
Secondary outcome [2] 326090 0
Multivariate analysis of stress panel components against duration of delirium (delirium free days at 28 days) as assessed by clinical examination by the SPICE-III investigators.
Timepoint [2] 326090 0
28 Days post randomisation in the SPICE-III study
Secondary outcome [3] 326091 0
Correlation of changes in stress panel components with Ventilator free days at day 28 as assessed by review of the medical record
Timepoint [3] 326091 0
28 Days post randomisation in the SPICE-III study
Secondary outcome [4] 326092 0
Correlation of changes in stress panel components with Mortality at ICU discharge
Timepoint [4] 326092 0
At ICU discharge
Secondary outcome [5] 326093 0
Correlation of changes in stress panel components with Length of ICU stay as assessed by review of the medical record
Timepoint [5] 326093 0
At ICU discharge
Secondary outcome [6] 326094 0
Correlation of changes in stress panel components with Mortality at hospital discharge
Timepoint [6] 326094 0
At Hospital Discharge
Secondary outcome [7] 326097 0
Correlation of changes in stress panel components with Length of hospital stay as assessed by review of the medical record
Timepoint [7] 326097 0
At hospital discharge
Secondary outcome [8] 326098 0
Correlation of changes in stress panel components with dose of dexmedetomidine as recorded by the SPICE-III Study investigators from admission to day 5 post randomisation.
Timepoint [8] 326098 0
5 Days post randomisation in the SPICE-III study

Eligibility
Key inclusion criteria
Enrolled in the SPICE-III study
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Nil

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
General principles
All analyses will be based on the intention-to-treat principle. As no sequential or interim analyses are planned, a P-value less than 0.05 will be used as the level of significance throughout.

Trial profile
All patients who provide informed consent will be accounted for in the final statistical report. A CONSORT- style flow diagram will illustrate patient progression through the trial from initial screening for eligibility to completion of the final primary outcome assessment. Number (percentage) by treatment group will be given for patients in the ITT population, reasons for study withdrawal, and major protocol deviations and violations.

Demographic and baseline characteristics
Patient demographics and baseline characteristics will be presented according to treatment group. Discrete (binary and categorical) variables will be summarised as percentages with the denominator stated when data are missing. Continuous variables will be summarised according to their underlying distribution. Normally distributed data will be presented as mean (SD) whilst non-normal data will be presented as median (IQR). Ranges (minimum, maximum) for each variable will be supplied in an appendix to the paper.

Analytical methodology
Data distributions will be checked for normality using a Shapiro-Wilk test.
For demographic and baseline data, differences between groups will be assessed using either a two-tailed t-test for normal data or a Mann-Whitney test for non-normal variables.
The effect of treatment allocation constitutes a repeated measures series and will be analysed as a longitudinal and correlated dataset using a mixed effect general linear model. A mixed effect model is preferred as there are elements of fixed effect (e.g. age, gender, weight) and random effect (e.g. inotrope dose, sedation strategy) in the dataset. Models will examine the effect of treatment allocation on the components of the stressor panel. Survival time will be analysed using Cox regression with the results presented as Kaplan-Meier plots.
Mortality data will be analysed using multivariable logistic regression adjusted for important predictors of outcome (e.g. age, gender, APACHE score, admission source, stress panel components etc.). Significant predictor variables will be identified by sequential elimination with a likelihood-ratio test performed between successive iterations.
Regression results will be presented as the regression slope (beta), the level of significance of that slope (P-value) and the coefficient of determination for the model (R2). A slope significantly different from zero will be interpreted as a significant rise (positive slope) or fall (negative slope) of the variable under consideration over time. The coefficient of determination relates to the proportion of rise or fall in the variable under consideration that is explained by the timebase.

Calculation of numbers required
As there are no data upon which to base a rigorous calculation of the numbers required, a total of 100 was arbitrarily chosen as being likely to be both sufficient and practical in the time permitted for the study.

Data presentation
Data will be presented in both tabular and graphical format with estimates of central tendency, precision and level of significance.

Subgroup analyses
Whilst no subgroup analyses are planned, should they occur they will be treated as supplementary and exploratory with the intention of generating new hypotheses.

Statistical tools
Stata (version 14.1) will be used for all analyses

Recruitment
Recruitment status
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,QLD
Recruitment hospital [1] 6246 0
Nambour General Hospital - Nambour
Recruitment hospital [2] 6247 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [3] 6248 0
Gold Coast University Hospital - Southport
Recruitment hospital [4] 6249 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 8681 0
Nepean Hospital - Kingswood
Recruitment postcode(s) [1] 16792 0
2747 - Kingswood
Recruitment postcode(s) [2] 13674 0
4029 - Herston
Recruitment postcode(s) [3] 13673 0
4215 - Southport
Recruitment postcode(s) [4] 13672 0
4350 - Toowoomba
Recruitment postcode(s) [5] 13671 0
4560 - Nambour

Funding & Sponsors
Funding source category [1] 294139 0
Government body
Name [1] 294139 0
Sunshine Coast Hospital and Health Service
Address [1] 294139 0
Study Education and Research Trust Fund
Nambour Hospital
Hospital Road
PO Box 547
Nambour QLD 4560
Country [1] 294139 0
Australia
Primary sponsor type
Government body
Name
Sunshine Coast Hospital and Health Service
Address
Nambour Hospital
Hospital Road
PO Box 547
Nambour QLD 4560
Country
Australia
Secondary sponsor category [1] 292968 0
None
Name [1] 292968 0
N/A
Address [1] 292968 0
N/A
Country [1] 292968 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295551 0
The Prince Charles Hospital
Ethics committee address [1] 295551 0
Rode Rd
Chermside
QLD 4032
Ethics committee country [1] 295551 0
Australia
Date submitted for ethics approval [1] 295551 0
26/05/2016
Approval date [1] 295551 0
31/05/2016
Ethics approval number [1] 295551 0
HREC/16/QPCH/141

Summary
Brief summary
The survival of an organism in the face of internal and external events requires a measured and appropriate stress response. It has been hypothesised that an abnormal stress response is linked to the likelihood of the development and severity of critical illness and multi-organ failure. The stress response is coordinated by the primitive brain structures of the diencephalon and brainstem in response to somatosensory inputs and comprises a broad range of neuro-hormonal and immune effects. We hypothesise that the use of sedating medications confuses the normal generation of a stress response. If this is confirmed, this may be a fundamental underlying cause for the abnormal haemodynamics, metabolic disturbances and organ dysfunction observed in critical illness.
The large multi-centre randomised-controlled SPICE-III study offers the opportunity to study two similar groups of patients who may have differing levels of physiological stress as a result of an Early Goal-Directed Sedation (EGDS) strategy as compared to standard care.
We aim to conduct a substudy to determine whether a strategy of EGDS and the resultant reduced sedation level results in a differing physiological stress response in critically unwell patients as measured by a panel of blood-borne markers.
We hypothesise that the application of an early goal directed sedation protocol and the resultant reduced sedation level in the first 5 days of critical illness will result in a differing pattern of stress as measured by metabolic, sympathetic, hormonal and inflammatory responses.

All-SPICE will be a prospective parallel-group multi-centre observational sub-study of the the SPICE-III study. The SPICE-III study is a prospective, un-blinded, randomised controlled trial of Early Goal-Directed Sedation compared with Standard care. The SPICE-III study will recruit patients who are intubated and ventilated in a participating ICU, are expected to remain intubated the day after enrolment and need immediate and ongoing sedation. Due to the immediate need to choose a sedative regimen for ongoing patient safety and comfort, it is proposed that study enrolment will occur using deferred consent. A total of 100 patients from approximately 4 ICUs will be enrolled in All-SPICE. Immediately following randomisation on day 1, patients will have blood samples taken, which will be repeated on days 2, 4 and 6. These samples will be assessed for various blood-borne markers which are considered to be potentially affected by the coordination of the stress response.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67690 0
Dr John Moore
Address 67690 0
Sunshine Coast Institute for Critical Care Research
Department of Intensive Care
Nambour Hospital
Hospital Rd,
Nambour QLD 4560
Country 67690 0
Australia
Phone 67690 0
+61 7 54706600
Fax 67690 0
Email 67690 0
sciccr@health.qld.gov.au
Contact person for public queries
Name 67691 0
Ms Lauren Murray
Address 67691 0
Sunshine Coast Institute for Critical Care Research
Department of Intensive Care
Nambour Hospital
Hospital Rd,
Nambour QLD 4560
Country 67691 0
Australia
Phone 67691 0
+61 7 54706600
Fax 67691 0
Email 67691 0
sciccr@health.qld.gov.au
Contact person for scientific queries
Name 67692 0
Dr John Moore
Address 67692 0
Sunshine Coast Institute for Critical Care Research
Department of Intensive Care
Nambour Hospital
Hospital Rd,
Nambour QLD 4560
Country 67692 0
Australia
Phone 67692 0
+61 7 54706600
Fax 67692 0
Email 67692 0
sciccr@health.qld.gov.au

No information has been provided regarding IPD availability
Summary results
No Results