ANZCTR - Registration

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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]

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

Shock

Critical Illness

Condition category

Condition code

Other

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]

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]

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]

At Day 6 following randomisation in the SPICE-III study

Secondary outcome [1]

Correlation of changes in stress panel components with sedation level (RASS)

Timepoint [1]

At day 6 following randomisation in the SPICE-III study

Secondary outcome [2]

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]

28 Days post randomisation in the SPICE-III study

Secondary outcome [3]

Correlation of changes in stress panel components with Ventilator free days at day 28 as assessed by review of the medical record

Timepoint [3]

28 Days post randomisation in the SPICE-III study

Secondary outcome [4]

Correlation of changes in stress panel components with Mortality at ICU discharge

Timepoint [4]

At ICU discharge

Secondary outcome [5]

Correlation of changes in stress panel components with Length of ICU stay as assessed by review of the medical record

Timepoint [5]

At ICU discharge

Secondary outcome [6]

Correlation of changes in stress panel components with Mortality at hospital discharge

Timepoint [6]

At Hospital Discharge

Secondary outcome [7]

Correlation of changes in stress panel components with Length of hospital stay as assessed by review of the medical record

Timepoint [7]

At hospital discharge

Secondary outcome [8]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/09/2016

Actual

18/04/2017

Date of last participant enrolment

Anticipated

30/10/2017

Actual

Date of last data collection

Anticipated

1/01/2018

Actual

Sample size

Target

100

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD

Recruitment hospital [1]

Nambour General Hospital - Nambour

Recruitment hospital [2]

Toowoomba Hospital - Toowoomba

Recruitment hospital [3]

Gold Coast University Hospital - Southport

Recruitment hospital [4]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [5]

Nepean Hospital - Kingswood

Recruitment postcode(s) [1]

4560 - Nambour

Recruitment postcode(s) [2]

4350 - Toowoomba

Recruitment postcode(s) [3]

4215 - Southport

Recruitment postcode(s) [4]

4029 - Herston

Recruitment postcode(s) [5]

2747 - Kingswood

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Sunshine Coast Hospital and Health Service

Address [1]

Study Education and Research Trust Fund
Nambour Hospital
Hospital Road
PO Box 547
Nambour QLD 4560

Country [1]

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]

None

Name [1]

N/A

Address [1]

N/A

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Prince Charles Hospital

Ethics committee address [1]

Rode Rd
Chermside
QLD 4032

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/05/2016

Approval date [1]

31/05/2016

Ethics approval number [1]

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

Dr John Moore

Address

Sunshine Coast Institute for Critical Care Research
Department of Intensive Care
Nambour Hospital
Hospital Rd,
Nambour QLD 4560

Country

Australia

Phone

+61 7 54706600

Fax

sciccr@health.qld.gov.au

Contact person for public queries

Name

Lauren Murray

Address

Sunshine Coast Institute for Critical Care Research
Department of Intensive Care
Nambour Hospital
Hospital Rd,
Nambour QLD 4560

Country

Australia

Phone

+61 7 54706600

Fax

sciccr@health.qld.gov.au

Contact person for scientific queries

Name

John Moore

Address

Sunshine Coast Institute for Critical Care Research
Department of Intensive Care
Nambour Hospital
Hospital Rd,
Nambour QLD 4560

Country

Australia

Phone

+61 7 54706600

Fax

sciccr@health.qld.gov.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Allostasis and sedation practices in intensive care evaluation: an observational pilot study.	2018	https://dx.doi.org/10.1186/s40635-018-0179-0
Embase	Stress response during early sedation with dexmedetomidine compared with usual-care in ventilated critically ill patients.	2022	https://dx.doi.org/10.1186/s13054-022-04237-0

N.B. These documents automatically identified may not have been verified by the study sponsor.

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