ANZCTR - Registration

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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]

Nil Known

Universal Trial Number (UTN)

Trial acronym

FRONTIER-AP

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Stroke

Ischaemic stroke

Condition category

Condition code

Stroke

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]

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]

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]

Disability will be measured at 90 days from stroke onset

Primary outcome [2]

vessel perforations or symptomatic intracranial haemorrhage will be assessed using CT brain 24 hour after procedure.

Timepoint [2]

vessel perforations or symptomatic intracranial haemorrhage will be assessed using CT brain. This will be performed 24 hour after procedure.

Secondary outcome [1]

recanalization of arterial occlusion.

Timepoint [1]

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?

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]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [2]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [3]

Liverpool Hospital - Liverpool

Recruitment hospital [4]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [5]

Prince of Wales Hospital - Randwick

Recruitment hospital [6]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [7]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3050 - Parkville

Recruitment postcode(s) [2]

3168 - Clayton

Recruitment postcode(s) [3]

2170 - Liverpool

Recruitment postcode(s) [4]

5000 - Adelaide

Recruitment postcode(s) [5]

2031 - Randwick

Recruitment postcode(s) [6]

3220 - Geelong

Recruitment postcode(s) [7]

3084 - Heidelberg

Recruitment outside Australia

Country [1]

China

State/province [1]

Beijing

Country [2]

Taiwan, Province Of China

State/province [2]

Taipei

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC Clinical Trial and Cohort

Address [1]

Medical Research Future Fund International Clinical Trial and Cohort
Sirius Building
23 Furzer Street
Phillip ACT 2606

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Not yet submitted

Ethics committee name [1]

Monash Health Human Research Ethics Committee

Ethics committee address [1]

Monash Health Human Research Ethics Committee,
246 Clayton Rd, Clayton, 3168, VIC

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/02/2022

Approval date [1]

18/10/2022

Ethics approval number [1]

Summary

Brief summary

The distal ischaemic stroke thrombectomy against medical therapy trial is the last FRONTIER in stroke trial and builds on the success of Australian led thrombectomy trial, EXTEND IA. It is an Australian led trial in the Asia-Pacific region (FRONTIER-AP) which seeks to answer an important clinical conundrum on the optimal treatment approach for patients with clot in medium sized vessels (MVO) in the brain. Following the results of multiple randomized clinical trials some states in Australia have structured clinical pathways for treatment of patients with large vessel occlusion (LVO). Such knowledge does not exist for MVO. There is clinical equipoise to proceed with phase II clinical trials given the conflicting data from observations from multiple observational studies and small sample size of data from randomised clinical trial . Our primary hypothesis is that the clinical outcome of ischaemic stroke patients treated with endovascular therapy within 9 hours will be superior compared with that of standard medical therapy. This trial will require moderately large sample (n=240) and thus may not be achievable even in our large network of collaborators in Australia. We will leverage the opportunity provided by the International Clinical Trial Collaborations (ICTC) to recruit 50% of the patients for this trial by our international partners. If the trial shows superiority of thrombectomy for MVO then it may lead to significant restructuring of acute stroke care across multiple states as the current model of care is that hospitals that provide thrombolysis therapy can treat patients with MVO. In anticipation of this change we have built an implementation phase into this grant incorporating statistical analysis, health economics analysis, operational research and geospatial analysis. We will also seek support from Stroke Foundation and engage with their network of consumers to determine their perception of the impact on new model of care and other changes that they would like to see given their experiences  These analyses will inform the scalability of our findings as well as design of phase III such that full implementation will be achievable. Within the first 12 months, we would have the trial registration, submit the trial to Australasian Stroke Trial Network, develop educational material for trialists and clinicians to recognise MVO, published protocol paper as well as recruitment of the initial group of patients .

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Thanh Phan

Address

Monash Health, 246 Clayton Rd Clayton 3168 VIC

Country

Australia

Phone

+61385722612

Fax

+61395946241

thanh.phan@monash.edu

Contact person for public queries

Name

Thanh Phan

Address

Monash Health, 246 Clayton Rd Clayton 3168 VIC

Country

Australia

Phone

+61385722612

Fax

+61395946241

thanh.phan@monash.edu

Contact person for scientific queries

Name

Thanh Phan

Address

Monash Health, 246 Clayton Rd Clayton 3168 VIC

Country

Australia

Phone

+61385722612

Fax

+61395946241

thanh.phan@monash.edu

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 thanh.phan@monash.edu (Thanh Phan) or bernard.yan@mh.org.au (Bernard Yan)

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
13997	Study protocol	Study protocol				382718-(Uploaded-08-11-2021-18-26-03)-Study-related document.docx

Results publications and other study-related documents

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