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Trial registered on ANZCTR


Registration number
ACTRN12623000044628
Ethics application status
Approved
Date submitted
5/01/2023
Date registered
16/01/2023
Date last updated
14/03/2023
Date data sharing statement initially provided
16/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A multicenter randomized study comparing an approach of individualized blood pressure targets to standard care among critically ill patients with shock
Scientific title
Individualised Blood Pressure Targets versus Standard Care among Critically Ill patients with Shock - A Multicentre Randomised Controlled Trial comparing mortality outcomes.
Secondary ID [1] 308698 0
None
Universal Trial Number (UTN)
U1111-1209-8560
Trial acronym
RElative hypotension and Adverse Clinical outcomes among patienTs with Shock Randomised Controlled Trial
[REACT SHOCK RCT]
Linked study record
ACTRN12618000571279, which is a pilot phase of the current RCT.

Health condition
Health condition(s) or problem(s) studied:
Critically ill patients with shock 328630 0
Condition category
Condition code
Cardiovascular 325635 325635 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention in this phase 3 RCT is identical to that of the linked pilot-phase protocol (ACTRN12618000571279). The project will test an intervention that initially targets a patient's own pre-illness mean arterial pressure (MAP) during vasopressor support in ICU. The pre-illness MAP will be estimated from most recent pre-illness BP readings following a standardized method (Panwar et al,. Blood Press. 2017:1-9) and will be targeted for the duration of vasopressor therapy for up to a maximum of five days. The treating clinician can tailor these BP targets as deemed suitable for current clinical state. The type of vasopressor that will be used is at the discretion of the treating clinician.

The range for MAP target is 55-95 mmHg. During the period of study treatment, a range of ±2 mmHg around the set target is acceptable.

If the total additional vasopressor dose required to achieve these individualized MAP targets exceeds 0.75 microgram/kg/minute, or if in the opinion of the treating clinician the patient may be suffering possible adverse effects from high vasopressor dose, then the BP targets may be adjusted as deemed fit by the treating clinician. Protocol adherence for participants will be monitored during the screening rounds. Protocol deviation will be defined as failure to adjust dose of vasopressor agents while the MAP remained at least 6 mmHg above or below the set target for 4 consecutive hours, without a documented change of MAP target by the treating clinician.

Study intervention will cease if a patient is considered well enough by the treating clinician for discharge out of ICU. If a patient is transported out of ICU for procedural intervention, then standard (non-study) treatment should be provided.
Intervention code [1] 325162 0
Prevention
Comparator / control treatment
The comparator or the control group will be comprised of patients assigned to standard care, where vasopressor support will be titrated to maintain a default MAP of 65 mmHg, in accordance with standard recommendations, unless the treating clinician considers a different MAP target as more appropriate. The default target MAP, if revised, will be recorded.
Control group
Active

Outcomes
Primary outcome [1] 333482 0
Mortality
Timepoint [1] 333482 0
14 days from randomisation
Secondary outcome [1] 417219 0
Time to death through day 14 (assessed using medical records)
Timepoint [1] 417219 0
First 14 days of randomisation
Secondary outcome [2] 417220 0
Major Adverse Kidney Events (defined as a composite of death, new renal replacement therapy, or final serum creatinine level >= 200% of the latest preillness creatinine level), as assessed from patient medical records.
Timepoint [2] 417220 0
14 days from randomisation
Secondary outcome [3] 417221 0
Renal replacement therapy free days until day 28 (assessed using medical record)
Timepoint [3] 417221 0
28 days from randomisation
Secondary outcome [4] 417222 0
Peak increase in serum creatinine levels
Timepoint [4] 417222 0
28 days from randomisation
Secondary outcome [5] 417223 0
Time to death through day 90 (assessed from medical record))
Timepoint [5] 417223 0
First 90 days of randomisation
Secondary outcome [6] 417224 0
Death
Timepoint [6] 417224 0
90 days from randomisation

Eligibility
Key inclusion criteria
• ICU patients aged greater than or equal to 40 years
• The patient is deemed to be in shock, defined as clinician-initiated vasopressor/inotropic therapy AND supported by any of the following within the last 24 hours:
o Lactate level greater than or equal to 2 mmol/l or base deficit greater than or equal to 3 mmol/l,
o Urine output less than or equal to 0.5 ml/kg/h or <40 ml/h for 2 or more consecutive hours
o Respiratory rate >22 per minute
o Altered mentation (Glasgow Coma Score <14)
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patients who are moribund, or have documented not-for-resuscitation orders
• At least 24 hours have lapsed from the time of initiation of vasopressor or inotropic support
• Patients who are either receiving or are deemed to imminently need renal replacement therapy.
• Patients who already have an increase in serum creatinine of >350 µmol/l from baseline.
• End stage renal disease
• Patients where trauma is the main reason for the current ICU admission.
• Previously enrolled in the REACT Shock RCT
• Pregnancy, if known
• Active bleeding (clinical suspicion or >2 packed red blood cells within last 24 hours)
• Insufficient (less than two) pre-illness BP readings are available.
• Patients on extracorporeal support (such as extracorporeal membrane oxygenation, intra-aortic balloon pump, or ventricular assist device).
• Potential contraindications to either higher or lower BP targets (including but not limited to)
o Cerebral perfusion pressure guided therapy e.g. intracranial hemorrhage or subarachnoid hemorrhage or traumatic brain injury
o Abdominal perfusion pressure guided therapy
o Aortic injury (e.g. dissection or post-operative)
o Post cardiac surgery
o Any other condition requiring higher or lower BP target specifically

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Yes, enrolled patients will be randomly allocated to either standard blood pressure target arm or individualized blood pressure target arm using sealed opaque envelopes or a centralised web-based randomisation..
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be undertaken centrally in a concealed fashion, with a unique computer-generated, site stratified, permuted block randomisation method with random block sizes between 2 to 8. Enrolled patients will be randomly allocated in a 1:1 ratio to either standard care arm or intervention arm.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This is a parallel-group, multicentre, international, randomised controlled trial (the REACT Shock RCT) among 1,260 participants. This sample size is required to detect an absolute risk reduction of 6% in the primary endpoint (14- day mortality) in the intervention arm, assuming a 20% incidence of 14-day mortality in the control arm, at an alpha level of 0.05 and power of 80%. Analyses will be carried out by a biostatistician using a standard statistical software. All randomised patients will be included in an intention-to-treat analysis. Continuous normally distributed variables will be compared using student t-tests and reported as mean (± standard deviation or 95% confidence interval), whilst non-normally distributed data will be compared using Wilcoxon Rank Sum tests and reported as median (interquartile range). Between- group comparison of categorical variables will be made using Chi-square tests and reported as numbers (%). Time-to-event data for day-14 and day-90 mortality will be displayed as Kaplan- Meier curves and analysed using a log-rank test. A two-sided p-value of 0.05 will be considered statistically significant. Effect estimates for 14-day and 90-day mortality will be derived from multivariable logistic regression models adjusted for the time between T0 and randomisation, APACHE score, site, type of shock and any other variable with significant baseline difference in between the two groups. Patients enrolled in the pilot phase of this study may also be included in the main analysis, Subgroup analyses including forest plots showing two-sided 95% confidence intervals for the between-group difference in 14-day mortality, specific to each subgroup, will be conducted. Pre-specified subgroups will be- age 65 years or less vs. greater than 65 years, gender, Australian vs. non-Australian region, presence of acute kidney injury vs. no acute kidney injury at the time of randomisation, invasive mechanical ventilation vs. non-invasive mechanical ventilation at the time of randomisation, and cardiogenic shock vs. non-cardiogenic shock.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2023
Actual
Date of last participant enrolment
Anticipated
31/01/2028
Actual
Date of last data collection
Anticipated
1/05/2028
Actual
Sample size
Target
1260
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,VIC
Recruitment outside Australia
Country [1] 25198 0
Ireland
State/province [1] 25198 0
Country [2] 25199 0
United Kingdom
State/province [2] 25199 0
Country [3] 25200 0
United States of America
State/province [3] 25200 0
Country [4] 25201 0
Singapore
State/province [4] 25201 0

Funding & Sponsors
Funding source category [1] 312925 0
Government body
Name [1] 312925 0
National Health and Medical Research Council
Country [1] 312925 0
Australia
Primary sponsor type
Government body
Name
Hunter New England Local Health District
Address
ICU, John Hunter Hospital,
Lookout road, New Lambton, NSW 2305
Country
Australia
Secondary sponsor category [1] 314607 0
None
Name [1] 314607 0
Address [1] 314607 0
Country [1] 314607 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312197 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 312197 0
Hunter New England Human Research Ethics Committee,
Locked Bag No. 1
New Lambton, NSW 2305
Ethics committee country [1] 312197 0
Australia
Date submitted for ethics approval [1] 312197 0
04/01/2023
Approval date [1] 312197 0
02/03/2023
Ethics approval number [1] 312197 0
2018/ETH00019

Summary
Brief summary
Aim
The aim of the proposed RCT is to determine effectiveness of a strategy, where MAP targets during vasopressor therapy for shock in ICU are individualized based on patients’ own pre-illness MAP that would be derived as an average of up to five most recent pre-illness blood pressure readings.

Hypothesis
We hypothesize that targeting a patient’s pre-illness MAP during management of shock can minimize the degree of MAP-deficit (measure of relative hypotension), which may help reduce the risk of 14-day mortality and major adverse kidney events by day 14 in ICU.


Endpoints
The primary endpoint will be the all-cause mortality rate at day 14. Secondary endpoints will be the time to death through day 14 and day 90, major adverse kidney events (MAKE-14), renal replacement therapy (RRT) free days until day 28, and 90-day all-cause mortality.

Significance
To date no major RCT has tested this strategy among ICU patients with shock. This pivotal trial will provide evidence to fulfil a crucial knowledge gap regarding a common and a fundamental intervention in critical care. This is an opportunity for the clinicians to support a clinical trial that aims to compare the effects of a simple intervention of individualized blood pressure targets over standard care for patients with shock in ICU.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123818 0
A/Prof Rakshit Panwar
Address 123818 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 123818 0
Australia
Phone 123818 0
+61 410218808
Fax 123818 0
Email 123818 0
rakshit.panwar@health.nsw.gov.au
Contact person for public queries
Name 123819 0
A/Prof Rakshit Panwar
Address 123819 0
CU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 123819 0
Australia
Phone 123819 0
+61 410218808
Fax 123819 0
Email 123819 0
rakshit.panwar@health.nsw.gov.au
Contact person for scientific queries
Name 123820 0
A/Prof Rakshit Panwar
Address 123820 0
CU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 123820 0
Australia
Phone 123820 0
+61 410218808
Fax 123820 0
Email 123820 0
rakshit.panwar@health.nsw.gov.au

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.