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Trial registered on ANZCTR


Registration number
ACTRN12623000812695
Ethics application status
Approved
Date submitted
24/03/2023
Date registered
27/07/2023
Date last updated
26/08/2024
Date data sharing statement initially provided
27/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of prehospital fibrinogen early in severe trauma study: A feasibility phase II study (PRE-FEISTY II) (Stage 1).
Scientific title
Efficacy and safety of prehospital fibrinogen early in severe trauma study: A fphase II study (PRE-FEISTY II)(Stage 1)
Secondary ID [1] 308135 0
None
Universal Trial Number (UTN)
U1111-1283-6951
Trial acronym
PRE-FEISTY II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute traumatic haemorrhage

 327852 0
Condition category
Condition code
Blood 324929 324929 0 0
Clotting disorders
Emergency medicine 327519 327519 0 0
Other emergency care
Injuries and Accidents 327520 327520 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous or intraosseous administration of three vials (approximately 3g) of fibrinogen concentrate (RiaStap®) following the conclusion of initial resuscitation and stabilisation, anticipated to be in the timeframe of approximately 15 to 60 minutes following arrival of a prehospital medical team.
The intervention will be delivered once.
Adherence to the intervention will be monitored by regular ongoing audit of all patients treated by our service who receive prehospital blood transfusion. This audit is already embedded in our routine clinical governance procedures.
Intervention code [1] 325734 0
Treatment: Drugs
Comparator / control treatment
Stage one - no control group, all participants will receive the intervention.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334256 0
Percentage of patients with a fibrinogen level > 2.0 g/L assessed by laboratory testing following hospital arrival.
Timepoint [1] 334256 0
On first testing following arrival in hospital (anticipated within 30 minutes of hospital arrival).
Secondary outcome [1] 419986 0
In-hospital mortality (alive/dead). Assessed by review of the electronic medical record by a member of the research team.
Timepoint [1] 419986 0
24 hours following hospital arrival
Secondary outcome [2] 419987 0
Length of stay in acute hospital in calendar days - assessed by review of electronic medical record by a member of the research team.
Timepoint [2] 419987 0
At hospital discharge or death - assessed by review of electronic medical record by a member of the research team.
Secondary outcome [3] 419988 0
Number of calendar days of mechanical ventilation
Timepoint [3] 419988 0
At hospital discharge or death - assessed by review of electronic medical record by a member of the research team.
Secondary outcome [4] 419989 0
Total number of blood products (packed cells, platelets, plasma and cryoprecipitate) administered - assessed by review of the electronic medical record by a member of the research team.
Timepoint [4] 419989 0
24 hours from time of hospital arrival.
Secondary outcome [5] 419990 0
Requirement for a haemorrhage control procedure - either surgical operation or via interventional radiology - assessed by review of the electronic medical record by a member of the research team.
Timepoint [5] 419990 0
Within 24 hours of hospital arrival.
Secondary outcome [6] 419991 0
Radiologically proven occurrence of venous thromboembolic disease (pulmonary embolism or deep vein thrombosis) - assessed by review of the electronic medical record by a member of the research team.
Timepoint [6] 419991 0
Within 28 days of hospital admission

Eligibility
Key inclusion criteria
Adult patient (aged greater than or equal to 18 years).
Judged to have ongoing haemorrhage by the treating clinician.
Receiving pre-hospital blood transfusion
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Injury judged incompatible with survival
2. Enrolment unable to occur within 6 hours of injury
3. Known pregnancy
4. Known genetic or drug induced coagulation disorder
5. Known objection to blood products
6. Dedicated prior fibrinogen replacement
7. Participation in a competing study

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Single arm interventional study, with all eligible participants to receive intervention. If satisfactory effect, as measured by > 40% of participants with an arrival fibrinogen level >2.0 g/L, progress to stage two (separately registered).
.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

This should be read in conjunction with the registration for Stage 2 of this study.

Conventional phase II clinical trials use either a single- or multi-arm comparison scheme to examine the therapeutic effects of the experimental drug. Both single- and multi-arm evaluations have their own merits; for example, single-arm phase II trials are easy to conduct and often require a smaller sample size, while multi-arm trials are randomised and typically lead to a more objective comparison. To bridge the single- and double-arm schemes in one trial, a two-stage design has been selected, in which the first stage takes a single-arm comparison of FCH with the base normal fibrinogen rate (standard major trauma treatment alone) and the second stage imposes a two-arm comparison by adding an active control arm. The design is calibrated using the detectable treatment difference to balance the trade-offs between futility termination, power, and sample size. The base normal fibrinogen rate (standard major trauma treatment alone) is assumed to be 33% (p_0=0.33) which is based on the expert opinion of study investigators. The desirable target rate is 58% (p_1=0.58).

The design parameters required are the number of subjects in the experimental arm of the single arm stage (n_1), the number of subjects in each arm of the double-arm stage (n_2) and the minimum number of responses to achieve in the single-arm stage in order for the trial to proceed on to the next stage (r_1). Similar to sample size calculations in other study designs, calibration of these design parameters required the minimally required level for the response rate to be clinically meaningful (p_0), the desirable target rate (p_1), the type I error rate constraints for both stages (a_1,a_2) and the type II error rate constraints for both stages, (ß_1,ß_2)

These were specified as:
p_0=0.33,p_1=0.58,a_1=0.2,ß_1=0.1 (power=90%),a_2=0.1,ß_2=0.2 (power=80%)

The optimal set of (n_1,n_2,r_1) was chosen by minimising the average sample number (ASN), which is the average of the expected sample size under the null (ESS_0) and under the alternative (ESS_1) hypotheses, i.e., ASN=(ESS_0+ESS_1)/2, with
ESS_0=n_1 + 2n_2 P(x_1>r_1¦p_E=p_0 )
ESS_1=n_1 + 2n_2 P(x_1>r_1¦p_E=p_1 )

The computation of the expected sample sizes ESS_0 and ESS_1 was based on the probability of continuing to the second stage under the null and the alternative hypotheses, respectively. (When the null hypothesis is true, the trial would ideally be terminated early for sample size saving. On the other hand, when the alternative hypothesis is true, we would want the trial to continue on to the second stage.)

The reason for using ASN as the criterion is because it takes into account both the null and alternative scenarios.
The following numerical algorithm was used to optimise n_1,n_2,r_1:
Set n_1 from 10 to N, where N is the required sample size in each arm under a conventional two-arm scheme with equal randomisation and the type I and type II error rates of a_2 and ß_2.
Given n_1, find the value of r_1 such that the type I and type II error rates in Equations (1) and (2) are below a_1 and ß_1, respectively.

Set the critical value for the Z-test to be c=Z_a with a_2 given in Equation (3). Given n_1 and r_1, find the value of n_2 that satisfies the type II error rate constraint of ß_2 according to Equation (4).

Enumerate all possible values of ?(n?_1, n_2, r_1) and choose the one that minimises the ASN.

Results of samples size calculations:
Number of participants required in stage one, n_1=23
Number of participants required in each arm of stage two, n_2=30
Total number of participants =83

Results:

Descriptive statistics will be used to report the results of the stage 1 (single-arm) element of this trial (discussed in a separate registration).

Differences between groups in the second stage (which will incorporate results from stage 1 to increase power) will be determined using the chi-squared test for categorical data, and either the student's t-test or the Mann-Whitney test depending on the normality of distribution.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2023
Actual
10/12/2023
Date of last participant enrolment
Anticipated
1/09/2024
Actual
Date of last data collection
Anticipated
1/10/2024
Actual
Sample size
Target
23
Accrual to date
17
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment hospital [1] 25235 0
NSW Ambulance Aeromedical Operations- Bankstown Base - Condell Park
Recruitment hospital [2] 25236 0
NSW Ambulance Aeromedical Operations- Wollongong Base - Albion Park Rail
Recruitment hospital [3] 25237 0
NSW Ambulance Aeromedical Operations- Orange Base - Huntley
Recruitment hospital [4] 25238 0
Lismore Retrieval Service Helicopter Base - Loftville
Recruitment postcode(s) [1] 39925 0
2200 - Bankstown Aerodrome
Recruitment postcode(s) [2] 39927 0
2170 - Liverpool
Recruitment postcode(s) [3] 39928 0
2480 - Lismore
Recruitment postcode(s) [4] 39929 0
2305 - New Lambton Heights
Recruitment postcode(s) [5] 39931 0
4215 - Southport
Recruitment postcode(s) [6] 39932 0
2217 - Kogarah
Recruitment postcode(s) [7] 39933 0
2145 - Westmead
Recruitment postcode(s) [8] 39934 0
2065 - St Leonards
Recruitment postcode(s) [9] 39935 0
2800 - Orange
Recruitment postcode(s) [10] 40907 0
2200 - Condell Park
Recruitment postcode(s) [11] 40908 0
2527 - Albion Park Rail
Recruitment postcode(s) [12] 40909 0
2800 - Huntley
Recruitment postcode(s) [13] 40910 0
2480 - Loftville

Funding & Sponsors
Funding source category [1] 312391 0
Government body
Name [1] 312391 0
NSW Ambulance
Country [1] 312391 0
Australia
Primary sponsor type
Government body
Name
New South Wales Ambulance
Address
Locked Bag 105
Rozelle
NSW
2039
Country
Australia
Secondary sponsor category [1] 313963 0
None
Name [1] 313963 0
Address [1] 313963 0
Country [1] 313963 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311747 0
Sydney Local Health District (RPAH zone) Human Research Ethics Committee
Ethics committee address [1] 311747 0
Ethics committee country [1] 311747 0
Australia
Date submitted for ethics approval [1] 311747 0
09/09/2022
Approval date [1] 311747 0
29/11/2022
Ethics approval number [1] 311747 0
2022/ETH00820

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

Contacts
Principal investigator
Name 122230 0
Dr Ian Ferguson
Address 122230 0
Aeromedical Retrieval Service
NSW Ambulance
33 Nancy Ellis Leebold Drive
Bankstown Aerodrome
NSW
2200
Country 122230 0
Australia
Phone 122230 0
+61 0403 859555
Fax 122230 0
Email 122230 0
ian.ferguson@health.nsw.gov.au
Contact person for public queries
Name 122231 0
Ian Ferguson
Address 122231 0
Aeromedical Retrieval Service
NSW Ambulance
33 Nancy Ellis Leebold Drive
Bankstown Aerodrome
NSW
2200
Country 122231 0
Australia
Phone 122231 0
+61403859555
Fax 122231 0
Email 122231 0
ian.ferguson@health.nsw.gov.au
Contact person for scientific queries
Name 122232 0
Ian Ferguson
Address 122232 0
Aeromedical Retrieval Service
NSW Ambulance
33 Nancy Ellis Leebold Drive
Bankstown Aerodrome
NSW
2200
Country 122232 0
Australia
Phone 122232 0
+61 0403 859555
Fax 122232 0
Email 122232 0
ian.ferguson@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
This study is being conducted under a waiver of informed consent. Whilst consent for data use will be sought subsequent to enrolment, we are taking steps to minimise the risk of holding data in these circumstances.


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.