Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001746820p
Ethics application status
Not yet submitted
Date submitted
4/09/2021
Date registered
21/12/2021
Date last updated
29/02/2024
Date data sharing statement initially provided
21/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
FRONTIER-AP: Randomized controlled trial of the clinical outcome and safety of endovascular versus standard medical therapy for stroke with medium sized vessel occlusion
Scientific title
FRONTIER-AP: Randomized controlled trial of the clinical outcome and safety of endovascular versus standard medical therapy for stroke with medium sized vessel occlusion
Secondary ID [1] 305222 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
FRONTIER-AP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 323494 0
Ischaemic stroke 323495 0
Condition category
Condition code
Stroke 321062 321062 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients randomised to the thrombectomy arm will have clot extraction by Stent retriever or aspiration catheter. This will be performed by certified interventional radiologist. In brief, it involves performing digital subtraction angiography, navigating the catheter to the site of the clot and performing the extraction. The procedure is anticipated to be around 1 hour but can take up to 2 hours on average.

The standard care arm is alteplase or tenecteplase within 4.5 hours and between 4.5 - 9 hours, it’s alteplase or tenecteplase or best medical therapy according to the local guidelines. Post-intervention: A non-contrast Computed Tomography (CT) and CT Angiography will be performed 24 to 48 hr post intervention. At the investigator’s discretion, a repeat CT Perfusion or Magnetic Resonance Imaging (MRI) may be performed at 24 to 48 hr. For MRI (if used for baseline selection and at 24 to 48hrs), an initial scout view will be followed by isotropic Difiusion-weighted Imaging/DWI (created from DWI images obtained with diffusion sensitizing gradients applied in 3 orthogonal planes) using b values between 0 sec/mm2, equivalent to a T2-weighted image, and 1000 sec/mm2. Whole brain imaging will use 25 contiguous axial slices each 5 mm in thickness. The imaging time for DWI is approximately 3 minutes. Time of Flight MR Angiography will be obtained to determine the presence or absence of medium vessel occlusion (MVO). A T2*-weighted gradient echo sequence will be performed to assess for presence of intracerebral haemorrhage (ICH). A FLAIR sequence is also acquired. This protocol is identical between the acute and sub-acute (24 h) imaging.
Intervention code [1] 321618 0
Treatment: Devices
Comparator / control treatment
Standard medical care per local guidelines e.g. Living Stroke Guidelines in Australia. This can be alteplase, tenecteplase or best medical therapy
Control group
Active

Outcomes
Primary outcome [1] 328835 0
Disability will be measured by modified Rankin Scale (mRS). mRS is defined as 0-1 or no change from baseline at 90 days or 3 months if the mRS is 2 at the time of recruitment
Timepoint [1] 328835 0
Disability will be measured at 90 days from stroke onset
Primary outcome [2] 328836 0
vessel perforations or symptomatic intracranial haemorrhage will be assessed using CT brain 24 hour after procedure.
Timepoint [2] 328836 0
vessel perforations or symptomatic intracranial haemorrhage will be assessed using CT brain. This will be performed 24 hour after procedure.
Secondary outcome [1] 402776 0
recanalization of arterial occlusion.
Timepoint [1] 402776 0
CT or MR Angiography perform 24 hours post procedure.

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Patients presenting with acute ischaemic stroke within 9 hours of stroke onset
2. (NIHSS greater if equal to 5 or dysphasia if NIHSS less than 5)
3. Pre-stroke modified Rankin Score (mRS) score of 0 or 1 or 2
4. Patient’s age is equal or greater than 18 years (or as per local requirements)
5. Endovascular therapy expected to commence (arterial puncture) within 90 minutes of initial non-contrast CT brain.
6. Arterial occlusion on CT Angiography (CTA) or MR Angiography (MRA) of the M2 (proximal, mid or distal), M3, A1, and A2.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. Patients presenting with acute ischaemic stroke >9 hours of stroke onset
2. Intracranial haemorrhage (ICH) identified by CT or MRI
3. Rapidly improving symptoms at the discretion of the investigator
4. Pre-stroke modified Rankin Score (mRS) score of greater than 2 (indicating previous disability)
5. Hypodensity in >1/2 MCA or ACA territory on non-contrast CT
6. ICA occlusion ipsilateral to the distal MCA or ACA clot
7. Contraindication to imaging with contrast agents
8. Any terminal illness such that the patient would not be expected to survive more than 1 year.
9. Patients with active cancer and undergoing treatment for cancer are excluded,
10. Any condition that, in the judgment of the investigator, could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study.
11. Pregnant women

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)
Yes. Allocation concealment is performed by central randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerised sequence generation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical analysis, Sample size and stopping rule: We monitor the efficacy endpoint using the 2-arm Bayesian optimal phase 2 (BOP2) design. Specifically, let n denote the interim sample size and N denote the maximum sample size. Let pcon denote the probability of response in control treatment, pexp denote the probability of response in experimental treatment.

We define the null hypothesis H0:pexp<=pcon , under which the experimental arm is deemed as unacceptable, with respective to the control. We employ the following Bayesian rule to make a go/no-go decision:

(Futility stopping) stop enrolling patients and claim that the experimental arm is unacceptable if

Pr(pexp>pcon |data)<Lambda*(n/N )^a

(Superiority stopping) stop enrolling patients and claim that the experimental arm is acceptable if
Pr(p_exp>p_con |data)>2 *Phi* Z_((1+ Lambda)/2) v(n/N))-1

where Lambda=0.96 and a=0.94 are design parameters optimised to maximize the power under H1:pcon = 0.4 and pexp = 0.6, while controlling the type I error rate at 0.05 under pcon = pexp = 0.4. This optimization is performed assuming a vague prior Beta (0.4,0.6) for pcon and a vague prior Beta (0.6,0.4) for pcon. The above decision rule corresponds to the following stopping boundaries and yields a statistical power of 0.91

We perform the interim analysis when the number of enrolled patients reaches 60, 120, 180. When the total number of patients reaches the maximum sample size of 240, we reject the null hypothesis and conclude that the experimental arm is acceptable, compared to the control, if the futility stopping boundary is not crossed.

Specific stopping boundaries for futility and superiority are generated for each interim analysis depending on the number of observed responses in control group. For example, for the interim analysis at 90 control participants and 90 intervention participants, if the observed number of control participants with positive outcome is 15-16, the trial can be stopped for futility if the corresponding number in treatment arm is 18 or below, while stopping for superiority can happen if this number is 29 or above.

This design exhibits the following operational characteristics on 10,000 simulations using the BOP2 web application: the probability of early stopping of 0.78 (for futility: 0.03; for superiority: 0.75) with average sample size of 171.

The proportions of participants with positive outcome will be used as inputs for the decision to declare futility, superiority, or acceptability of the intervention compared to control that will be based on the Bayesian decision rules specified above in the trial design section.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2024
Actual
Date of last participant enrolment
Anticipated
28/06/2027
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 20468 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 20469 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 20470 0
Liverpool Hospital - Liverpool
Recruitment hospital [4] 20471 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 20472 0
Prince of Wales Hospital - Randwick
Recruitment hospital [6] 20473 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [7] 20474 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 35237 0
3050 - Parkville
Recruitment postcode(s) [2] 35238 0
3168 - Clayton
Recruitment postcode(s) [3] 35239 0
2170 - Liverpool
Recruitment postcode(s) [4] 35240 0
5000 - Adelaide
Recruitment postcode(s) [5] 35241 0
2031 - Randwick
Recruitment postcode(s) [6] 35242 0
3220 - Geelong
Recruitment postcode(s) [7] 35243 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 24094 0
China
State/province [1] 24094 0
Beijing
Country [2] 24095 0
Taiwan, Province Of China
State/province [2] 24095 0
Taipei

Funding & Sponsors
Funding source category [1] 309599 0
Government body
Name [1] 309599 0
NHMRC Clinical Trial and Cohort
Country [1] 309599 0
Australia
Primary sponsor type
Government body
Name
Medical Research Future Fund International Clinical Trial and Cohort
Address
Medical Research Future Fund International Clinical Trial and Cohort
Sirius Building
23 Furzer Street
Phillip ACT 2606
Country
Australia
Secondary sponsor category [1] 310611 0
None
Name [1] 310611 0
Address [1] 310611 0
Country [1] 310611 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 309374 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 309374 0
Ethics committee country [1] 309374 0
Australia
Date submitted for ethics approval [1] 309374 0
01/02/2022
Approval date [1] 309374 0
18/10/2022
Ethics approval number [1] 309374 0

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

Contacts
Principal investigator
Name 113930 0
Prof Thanh Phan
Address 113930 0
Monash Health, 246 Clayton Rd Clayton 3168 VIC
Country 113930 0
Australia
Phone 113930 0
+61385722612
Fax 113930 0
+61395946241
Email 113930 0
[email protected]
Contact person for public queries
Name 113931 0
Thanh Phan
Address 113931 0
Monash Health, 246 Clayton Rd Clayton 3168 VIC
Country 113931 0
Australia
Phone 113931 0
+61385722612
Fax 113931 0
+61395946241
Email 113931 0
[email protected]
Contact person for scientific queries
Name 113932 0
Thanh Phan
Address 113932 0
Monash Health, 246 Clayton Rd Clayton 3168 VIC
Country 113932 0
Australia
Phone 113932 0
+61385722612
Fax 113932 0
+61395946241
Email 113932 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
anonymised trial data including randomisation allocation, baseline characteristics and outcome
When will data be available (start and end dates)?
The data will be available 24 months after publication of trial results and for 5 years
Available to whom?
trialists on request
Available for what types of analyses?
individual data metaanalysis
How or where can data be obtained?
from principal investigators [email protected] (Thanh Phan) or [email protected] (Bernard Yan)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13997Study protocolStudy protocol   382718-(Uploaded-08-11-2021-18-26-03)-Study-related document.docx



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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