Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001057673
Ethics application status
Approved
Date submitted
28/07/2023
Date registered
3/10/2023
Date last updated
24/03/2024
Date data sharing statement initially provided
3/10/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Sedation, Temperature and Pressure After Cardiac Arrest and Resuscitation- STEPCARE Trial
Scientific title
Assessing the impact of Sedation, Temperature and Blood Pressure After Cardiac Arrest and Resuscitation- STEPCARE Trial
Secondary ID [1] 310209 0
NCT05564754
Universal Trial Number (UTN)
Trial acronym
STEPCARE Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiac Arrest 330885 0
Hypoxia, Brain 330886 0
Condition category
Condition code
Cardiovascular 327673 327673 0 0
Coronary heart disease
Neurological 327674 327674 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Sedation strategy: deep continuous sedation target for at least 36h
• For patients randomized to continuous sedation a continuous infusion of a short-acting usual care sedative agent (eg. propofol) should be started at randomization and continue for 36hrs.
• Short-acting drugs by continuous infusion (eg. propofol) are preferred to benzodiazepines (by either continuous infusion or bolus dosing).
• Medical records will be reviewed by research staff to monitor adherence to the intervention.

Sedation strategy: light sedation target with early wakening.
• In patients randomized to minimal sedation sedative agents shall not be used unless needed for usual clinical care.
• If sedatives are required, short-acting drugs by continuous infusion (eg. propofol) are preferred to benzodiazepines (by either continuous infusion or bolus dosing). Weaning from sedatives should be performed as early as possible, ideally within 6 hours of randomization if not at the time of ICU admission.
• Medical records will be reviewed by research staff to monitor adherence to the intervention.

Temperature strategy: fever management (<37.5°C) using standard care cooling devices
• Temperature will preferentially be recorded via a bladder thermometer. If the patient is oliguric, or if a bladder recording is not available then core temperature will be assessed by an esophageal or intravascular probe.
• Standard cooling devices include endovascular cooling devices with closed loop systems (heat exchange pads attached to the body surface or with heat exchange catheters introduced in a central vein) and surface cooling devices with closed loop systems ( cold fluid or cold air is circulated through blankets or pads that are wrapped around the patient).
• The duration of the intervention is for up to 72 hours post-cardiac arrest.
• ICU nurses will administer the intervention.
• Medical records will be reviewed by research staff to monitor adherence to the intervention.

Temperature strategy: fever management primarily with medications (no standard care cooling devices)
• Temperature will preferentially be recorded via a bladder thermometer. If the patient is oliguric, or if a bladder recording is not available then core temperature will be assessed by an esophageal or intravascular probe.
• Fever management in this group should not differ from other critically ill patients in the ICU. No specific temperature target will be set. Antipyretics and non-pharmacological cooling measures may be used on the same indications as for any ICU patient.
• The duration of the intervention is for up to 72 hours post-cardiac arrest.
• Medical records will be reviewed by research staff to monitor adherence to the intervention.

Blood pressure strategy: A Mean Arterial Pressure target of >85mmHg
• The means of achieving the targeted MAP will be up to the treating clinician according to local protocols, usually intravenous fluid boluses and vasoactive/inotropic therapies. The most common vasoactive and inotropic drugs used in intensive care units include noradrenaline, adrenaline, phenylephrine, vasopressin, milrinone, dobutamine, dopamine and levosimendan. The dose of the vasoactive and inotropic drugs is dependent on patient weight.
• Participants allocated to a MAP target of at least 85 mmHg will have their vasopressor infusions increased until a MAP of at least 85 mmHg is achieved for the first 72 hours after randomization. After the 72-hour intervention period, the MAP target is decided by the treating clinician.
• Blood pressure monitoring will occur at the following timepoints after randomization into the study: 0, 2, 4, 6, 8, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 48, 56, 72 hours.
• Medical records will be reviewed by research staff to monitor adherence to the intervention.

Blood pressure strategy: A Mean Arterial Pressure target of >65mmHg
• The means of achieving the targeted MAP will be up to the treating clinician according to local protocols, usually intravenous fluid boluses and vasoactive/inotropic therapies. The most common vasoactive and inotropic drugs used in intensive care units include noradrenaline, adrenaline, phenylephrine, vasopressin, milrinone, dobutamine, dopamine and levosimendan. The dose of the vasoactive and inotropic drugs is dependent on patient weight.
• Participants allocated to a MAP target of at least 65 mmHg will have their vasopressor infusions increased until a MAP of at least 65 mmHg is achieved for the first 72 hours after randomization. After the 72-hour intervention period, the MAP target is decided by the treating clinician.
• Blood pressure monitoring will occur at the following timepoints after randomization into the study: 0, 2, 4, 6, 8, 12, 14, 16, 18, 20, 22, 24, 28, 32, 36, 40, 48, 56, 72 hours.
• Medical records will be reviewed by research staff to monitor adherence to the intervention.

Intervention Arms

All patients will be randomized to three allocation groups, and each strategy will be studied separately regarding safety and reporting of results.

Sedation, temperature device and high MAP -continuous deep sedation for 36 hours, fever management with a feedback-controlled device if temperature above 37.7°C and a mean arterial pressure target of >85mmHg.

Sedation, no temperature device and high MAP -continuous deep sedation for 36 hours, fever management without a feedback-controlled device and a mean arterial pressure target of >85mmHg.

Sedation, temperature device and low MAP -continuous deep sedation for 36 hours, fever management with a feedback-controlled device if temperature above 37.7°C and a mean arterial pressure target of >65mmHg.

Sedation, no temperature device and low MAP -continuous deep sedation for 36 hours, fever management without a feedback-controlled device and a mean arterial pressure target of >65mmHg.

Minimal sedation, temperature device and high MAP -minimal sedation (and early extubation if possible), fever management with a feedback-controlled device if temperature above 37.7°C and a mean arterial pressure target of >85mmHg.

Minimal sedation, no temperature device and high MAP -minimal sedation (and early extubation if possible), fever management without a feedback-controlled device and a mean arterial pressure target of >65mmHg.

Minimal sedation, temperature device and low MAP -minimal sedation (and early extubation if possible), fever management with a feedback-controlled device if temperature above 37.7°C and a mean arterial pressure target of >65mmHg.
Intervention code [1] 327063 0
Treatment: Other
Comparator / control treatment
Minimal sedation, no temperature device and low MAP -minimal sedation (and early extubation if possible), fever management without a feedback-controlled device and a MAP target of >65mmHg.
Control group
Active

Outcomes
Primary outcome [1] 335471 0
Mortality -All-cause mortality assessed at 6 months after randomisation
Timepoint [1] 335471 0
6 months after randomisation
Secondary outcome [1] 424763 0
Functional outcome - Proportion of participants who have a Modified Rankin Scale (mRS) score of 4-6
Timepoint [1] 424763 0
30 days, 6 and 12 months after randomisation
Secondary outcome [2] 424764 0
Health-related quality of life - EQ5D-5L (VAS included and part of this tool)
Timepoint [2] 424764 0
6 and 12 months after randomisation
Secondary outcome [3] 424771 0
Proportion of patients who had a pre-defined safety event or death in the ICU.

Pre-defined safety events include:
• Sepsis and septic shock, according to the 3rd international consensus definitions for sepsis and septic shock.
• Moderate or severe bleeding, according to the GUSTO criteria.
• Arrhythmia or cardiac arrest requiring defibrillation/cardioversion or chest compressions (ventricular fibrillation, ventricular tachycardia, PEA or asystole, atrial fibrillation or other supraventricular tachycardia)
• Venous thromboembolism (pulmonary embolism verified with imaging, other venous thrombosis verified with imaging (catheter- or device-related thrombus, deep-vein thrombosis in extremity))
• Reintubation
• Non-planned extubation
• Ischemic complications (gut ischemia verified by imaging, endoscopy, or requiring surgery, limb or digital necrosis)
• Events which might reasonably occur as a consequence of the trial intervention and which are not part of the natural history of critical illness, the process which caused the cardiac arrest, or the cardiac arrest itself. These events should only be reported if they are life-threatening, prolong hospitalization or result in meaningful harm to the participant.

All safety events will be reported in the eCRF during the intensive care unit stay. Events that occur after discharge from the intensive care unit will not be reported. The specific safety events described above will be reported whether they are considered related to the intervention or not.
Timepoint [3] 424771 0
ICU discharge
Secondary outcome [4] 426681 0
Cognitive decline -Montreal Cognitive Assessment (MoCA)
Timepoint [4] 426681 0
6 and 12 months after randomisation
Secondary outcome [5] 426682 0
Acquired brain injury -Symbol Digit Modalities Test (SDMT)
Timepoint [5] 426682 0
6 and 12 months after randomisation
Secondary outcome [6] 426683 0
Severity of cognitive impairments -Informant Questionnaire on Cognitive Decline in the Elderly -Cardiac Arrest Version (IQCODE-CA)
Timepoint [6] 426683 0
6 and 12 months after randomisation
Secondary outcome [7] 426684 0
Lower extremity strength -Time Stands Test (TST)
Timepoint [7] 426684 0
6 and 12 months after randomisation
Secondary outcome [8] 426685 0
This is composite secondary outcome. Maximum isometric strength of the hand and forearm muscles -Hand Grip Strength. For face-to-face visits this will be performed using a hand dynamometer. For telephone calls and digital meetings this will not be able to be performed.
Timepoint [8] 426685 0
6 and 12 months after randomisation
Secondary outcome [9] 426686 0
This is composite secondary outcome. Anxiety and depression -Hospital Anxiety and Depression Scale (HADS) (this is one questionnaire that the participant and caregiver will be given).
Timepoint [9] 426686 0
6 and 12 months after randomisation
Secondary outcome [10] 426687 0
Post-Traumatic Stress Disorder (PTSD) -PTSD Checklist (PCK-5)
Timepoint [10] 426687 0
6 and 12 months after randomisation
Secondary outcome [11] 426688 0
Health and disability -World Health Organization Disability Assessment Scale (WHODAS) 2.0 (36 items version)
Timepoint [11] 426688 0
6 and 12 months after randomisation
Secondary outcome [12] 426689 0
Effects of fatigue in terms of physical, cognitive and psychosocial functioning -Modified Fatigue Impact Scale (MFIS)
Timepoint [12] 426689 0
6 and 12 months after randomisation
Secondary outcome [13] 426690 0
Life Satisfaction (Visual Analogue Scale (VAS Scale) by the World value survey)
Timepoint [13] 426690 0
6 and 12 months after randomisation
Secondary outcome [14] 426691 0
This is composite secondary outcome. Simple questions about return to work and rehabilitation asked to participant. This is self-reported by the participant.
Timepoint [14] 426691 0
6 and 12 months after randomisation
Secondary outcome [15] 426692 0
Caregiver burden -Zarit Burden Interview (ZBI) (22 questions)
Timepoint [15] 426692 0
6 and 12 months after randomisation

Eligibility
Key inclusion criteria
1. Out-of-hospital cardiac arrest of non-traumatic origin
2. A minimum of 20 minutes without chest compressions (20 minutes of spontaneous circulation without the need for chest compressions is called “stable return of spontaneous circulation (ROSC)”)
3. Unconsciousness defined as not being able to obey verbal commands (FOUR-score motor response of <4) or being intubated and sedated because of agitation after sustained ROSC
4. Eligible for intensive care without restrictions or limitations
5. Inclusion within 4 hours of ROSC (240 minutes from ROSC or 220 minutes from stable ROSC)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. On extracorporeal membrane oxygenation (ECMO) prior to randomization
2. Pregnancy
3. Suspected or confirmed intracranial hemorrhage
4. Previously randomized in the STEPCARE trial

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)
Trial sites will have access to an internet-based randomisation application to allow for immediate allocation and to ensure adequate concealment and adequate generation of allocation sequence.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed with permuted blocks, stratified for trial site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Factorial
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Previous RCTs of cardiac arrest in the intensive care setting have based calculations on a minimal important difference corresponding to an absolute risk reduction (ARR) of up to 25%. In TTM1 and 2 we used 10% and 7.5% ARR, respectively which we believe are clinically relevant. With an overall survival of less than 50% we suggest a trial should strive for detecting or rejecting a 5% ARR risk reduction (clinically highly relevant but also realistic in terms of expectations on an intervention).

Based on the results of the TTM1-trial, TTM2-trial, and information in the International cardiac arrest registry, (INTCAR) we estimate a total mortality of approximately 60%. The power calculation is based on a 60% mortality in control arms and a 54.4% mortality in the intervention arms, at 6 months for all three interventions.

To demonstrate a relative risk of 0.91 with 90% power at a significance level of 0.05, 1638 participants are required in each group, a total of 3278 participants. The sample size calculation corresponds to a relative risk reduction (RRR) of 9.3%, and an ARR of 5.6%.

Factors that might influence the power calculation include adjustments for site, a significant interaction effect between two allocation arms, loss to follow-up, withdrawn consent and a large intervention effect in one on the three studied interventions.

We have investigated the possible effects of adjustment for site and possible interactions between interventions using simulations. These simulations indicate that no adjustment of sample size is needed to account for site effects, but that a slight increase in sample size (~5%) would be needed to account for possible interactions.

The combined effect of withdrawn consent and missing data on the primary outcome in the TTM2-trial resulted in a reduced sample size by approximately 2%. We assume a similar result in the current trial (1.8%).

A large intervention effect is an inherent limitation to trials with a factorial design and we have not taken this into account when deciding on the final sample size.

Taking the above-mentioned factors into account we will increase the sample size by 6.8% and recruit 3500 participants a sample size which is compatible with funding and a realistic time frame.

The analyses of the outcomes will be based on the intention-to-treat (ITT) principle, i.e., all randomized participants will be included in the analysis regardless of how much treatment they have received.

Sample size calculation
Test used: Power calculation for two proportions
Probability of death in the control group: 60%
Probability of death in the intervention group: 54.4%
Effect size: 2*asin(sqrt(p1))-2*asin(sqrt(p2)) = 0.113
Required sample size: 3278
Final sample size: Required sample size + 6.8% =3500

Analysis methods
Dichotomous outcomes will be analyzed using mixed effect logistic regression and continuous outcomes will be analyzed using mixed effect linear regression. All outcomes will initially be performed with adjustments made for site as a random intercept.

Primary outcome
The primary outcome will be analyzed as a binary variable (alive versus dead) at six months.

Secondary outcome
Functional outcome will be evaluated by dichotomizing the modified Rankin scale (0-3 versus 4- 6), or if this is missing; dependent or independent in basic activities of daily life (moving indoors, eating, dressing, personal hygiene). The secondary outcome HRQoL will be presented as the difference in the continuous VAS-scale included in the EQ5D-5L among survivors.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/11/2023
Actual
4/11/2023
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
1/01/2027
Actual
Sample size
Target
3500
Accrual to date
186
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 25270 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 25271 0
John Hunter Hospital - New Lambton
Recruitment hospital [3] 25272 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 25273 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 25274 0
St George Hospital - Kogarah
Recruitment hospital [6] 25275 0
The Sutherland Hospital - Caringbah
Recruitment hospital [7] 25276 0
Westmead Hospital - Westmead
Recruitment hospital [8] 25277 0
Liverpool Hospital - Liverpool
Recruitment hospital [9] 25278 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [10] 25279 0
The Prince Charles Hospital - Chermside
Recruitment hospital [11] 25280 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [12] 25281 0
The Northern Hospital - Epping
Recruitment hospital [13] 25282 0
Victorian Heart Hospital - Clayton
Recruitment postcode(s) [1] 40943 0
2139 - Concord
Recruitment postcode(s) [2] 40944 0
2305 - New Lambton
Recruitment postcode(s) [3] 40945 0
2747 - Kingswood
Recruitment postcode(s) [4] 40946 0
2065 - St Leonards
Recruitment postcode(s) [5] 40947 0
2217 - Kogarah
Recruitment postcode(s) [6] 40948 0
2229 - Caringbah
Recruitment postcode(s) [7] 40949 0
2145 - Westmead
Recruitment postcode(s) [8] 40950 0
2170 - Liverpool
Recruitment postcode(s) [9] 40951 0
4102 - Woolloongabba
Recruitment postcode(s) [10] 40952 0
4032 - Chermside
Recruitment postcode(s) [11] 40953 0
3084 - Heidelberg
Recruitment postcode(s) [12] 40954 0
3076 - Epping
Recruitment postcode(s) [13] 40955 0
3168 - Clayton
Recruitment outside Australia
Country [1] 25662 0
Finland
State/province [1] 25662 0
Helsinki
Country [2] 25664 0
Sweden
State/province [2] 25664 0
Skane
Country [3] 25665 0
New Zealand
State/province [3] 25665 0
Wellington
Country [4] 25672 0
United Kingdom
State/province [4] 25672 0
Bristol

Funding & Sponsors
Funding source category [1] 314375 0
Government body
Name [1] 314375 0
NHMRC Medical Research Future Fund Grant
Country [1] 314375 0
Australia
Primary sponsor type
Hospital
Name
Region Skane
Address
Region Skåne – Skånes Sjukhus Nordväst - Helsingborgs Hospital S Vallgatan 5, 251 87 Helsingborg, Sweden
Country
Sweden
Secondary sponsor category [1] 316327 0
Other Collaborative groups
Name [1] 316327 0
The George Institute for Global Health
Address [1] 316327 0
1 King StNewtown, NSW, 2042, Australia
Country [1] 316327 0
Australia
Other collaborator category [1] 282765 0
University
Name [1] 282765 0
Lund University
Address [1] 282765 0
Ole Romers Road 3, 223 63Lund, Sweden
Country [1] 282765 0
Sweden
Other collaborator category [2] 282766 0
Hospital
Name [2] 282766 0
Copenhagen Trial Unit, Center for Clinical Intervention Research
Address [2] 282766 0
Copenhagen Clinical Trial UnitCopenhagen University HospitalRigshospitaletBlegdamsvej 9, DK-2100 Copenhagen Ø Denmark
Country [2] 282766 0
Denmark
Other collaborator category [3] 282768 0
University
Name [3] 282768 0
University of Helsinki
Address [3] 282768 0
P.O. Box 4 (Yliopistonkatu 3)00014 Helsinki
Country [3] 282768 0
Finland

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313468 0
Royal Prince Alfred Hosiptal HREC
Ethics committee address [1] 313468 0
Ethics committee country [1] 313468 0
Australia
Date submitted for ethics approval [1] 313468 0
28/11/2022
Approval date [1] 313468 0
02/03/2023
Ethics approval number [1] 313468 0
X22-0393 & 2022/ETH02125

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128270 0
A/Prof Niklas Nielsen, PhD
Address 128270 0
Helsingborgs Hospital S Vallgatan 5, 251 87 Helsingborg, Sweden
Country 128270 0
Sweden
Phone 128270 0
+46708899770
Fax 128270 0
Email 128270 0
[email protected]
Contact person for public queries
Name 128271 0
Josef Dankiewicz, PhD
Address 128271 0
Lund UniversityOle Romers Road 3, 223 63Lund, Sweden
Country 128271 0
Sweden
Phone 128271 0
+46708899770
Fax 128271 0
Email 128271 0
[email protected]
Contact person for scientific queries
Name 128272 0
Niklas Nielsen, PhD
Address 128272 0
Helsingborgs Hospital S Vallgatan 5, 251 87 Helsingborg, Sweden
Country 128272 0
Sweden
Phone 128272 0
+46708899770
Fax 128272 0
Email 128272 0
[email protected]

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?




Results publications and other study-related documents

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