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Trial registered on ANZCTR
Registration number
ACTRN12625000590460
Ethics application status
Approved
Date submitted
2/05/2025
Date registered
6/06/2025
Date last updated
6/06/2025
Date data sharing statement initially provided
6/06/2025
Type of registration
Prospectively registered
Titles & IDs
Public title
FRONTIER-AP-X: Randomized controlled trial of endovascular versus standard medical therapy for stroke with medium sized vessel occlusion
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Scientific title
FRONTIER-AP-X: Randomized controlled trial of endovascular versus standard medical therapy or patients presenting with acute ischaemic stroke with medium sized vessel occlusion
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Secondary ID [1]
314348
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Nil Known
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Universal Trial Number (UTN)
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Trial acronym
FRONTIER-APX
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Linked study record
This record is a follow up study to previously registered ACTRN12621001746820. ACTRN12621001746820 has now been closed and this record will now recommence a similar trial with updated inclusion criteria to include only occlusion related to branches of the middle cerebral arteries due to results from recent trials.
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Health condition
Health condition(s) or problem(s) studied:
Stroke
337328
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ischemic stroke
337330
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Condition category
Condition code
Stroke
333715
333715
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0
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Ischaemic
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
330961
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Treatment: Devices
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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
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Control group
Active
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Outcomes
Primary outcome [1]
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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
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Assessment method [1]
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modified Rankin scale
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Timepoint [1]
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90 days from stroke onset
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Primary outcome [2]
341310
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vessel perforations or symptomatic intracranial haemorrhage will be assessed using CT brain 24 hour after procedure.
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Assessment method [2]
341310
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vessel perforations or symptomatic intracranial haemorrhage will be assessed using CT brain. This will be performed 24 hour after procedure
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Timepoint [2]
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24 hours after procedure
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Secondary outcome [1]
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recanalization of arterial occlusion.
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Assessment method [1]
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CT or MR Angiography perform 24 hours post procedure.
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Timepoint [1]
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24 hours after procedure
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Eligibility
Key inclusion criteria
1. Patients presenting with acute ischaemic stroke within 24 hours of stroke onset.
2. National Institute of Health Stroke Scale (NIHSS) greater or equal 8 and penumbra mismatch volume greater or equal 10 mL and penumbra ratio greater or equal to 1.2
3. Patient’s age is greater or equal to 18 years (or as per local requirements)
4. Endovascular therapy (arterial puncture) within 90 minutes of initial CT brain.
5. Arterial occlusion on CT Angiography (CTA) or MR Angiography (MRA) of the MeVO affecting M2/M3
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1. Patients presenting with acute ischaemic stroke >24 hours of stroke onset16.
2. Intracranial haemorrhage identified by CT or MRI 16.
3. Anterior Cerebral Artery (ACA) or Posterior Cerebral Artery (PCA) occlusion
4. Rapidly improving symptoms at the discretion of the investigator
5. Pre-stroke modified Rankin Score (mRS) score of >2 (indicating previous disability)
6. Hypodensity in >1/3 MCA territory on non-contrast CT.
7. ICA (large vessel) occlusion ipsilateral to the distal MCA or ACA clot
8. Contraindication to imaging with contrast agents (requirement for performing thrombectomy)
9. Any terminal illness such that the patient has life expectance less than 1 year.
10. Patients with active cancer and undergoing treatment for cancer are excluded.
11. 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.
12. Pregnancy
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Yes. Allocation concealment is performed by central randomisation
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerised sequence generation
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Not Applicable
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Type of endpoint/s
Efficacy
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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:pexppcon |data)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.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/07/2025
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Actual
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Date of last participant enrolment
Anticipated
28/06/2027
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Actual
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
240
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
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Recruitment hospital [1]
27868
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Royal Melbourne Hospital - City campus - Parkville
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Recruitment hospital [2]
27869
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Liverpool Hospital - Liverpool
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Recruitment hospital [3]
27870
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The Royal Adelaide Hospital - Adelaide
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Recruitment hospital [4]
27871
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Prince of Wales Private Hospital - Randwick
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Recruitment hospital [5]
27872
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Barwon Health - Geelong Hospital campus - Geelong
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Recruitment hospital [6]
27873
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The Alfred - Melbourne
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Recruitment hospital [7]
27874
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Austin Health - Austin Hospital - Heidelberg
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Recruitment postcode(s) [1]
44063
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3050 - Parkville
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Recruitment postcode(s) [2]
44064
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2170 - Liverpool
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Recruitment postcode(s) [3]
44065
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5000 - Adelaide
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Recruitment postcode(s) [4]
44066
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2031 - Randwick
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Recruitment postcode(s) [5]
44067
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3220 - Geelong
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Recruitment postcode(s) [6]
44068
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3004 - Melbourne
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Recruitment postcode(s) [7]
44069
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3084 - Heidelberg
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Recruitment outside Australia
Country [1]
27029
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China
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State/province [1]
27029
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Beijing
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Country [2]
27030
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Taiwan, Province Of China
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State/province [2]
27030
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Taipei
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Funding & Sponsors
Funding source category [1]
318867
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Government body
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Name [1]
318867
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NHMRC
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Address [1]
318867
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Country [1]
318867
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Australia
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Primary sponsor type
Government body
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Name
Melbourne Health
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Address
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Country
Australia
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Secondary sponsor category [1]
321329
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None
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Name [1]
321329
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Address [1]
321329
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Country [1]
321329
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
317481
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Metro South Human Research Ethics Committee
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Ethics committee address [1]
317481
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https://metrosouth.health.qld.gov.au/research/about-us/hrec
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Ethics committee country [1]
317481
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Australia
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Date submitted for ethics approval [1]
317481
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01/02/2022
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Approval date [1]
317481
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06/05/2025
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Ethics approval number [1]
317481
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RES-22-0000-123A
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Summary
Brief summary
FRONTIER-APX 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. In 2025, several trials on medium vessel occlusion reported no superiority of thrombectomy over standard care. The DISTAL trial recruited patients with occlusion of the second to fourth order branch of the middle cerebra artery, first to third order branch of the anterior cerebral artery and posterior cerebral artery. Analyses of the data suggest that equipoise remains for patients with occlusion of the second to third order branch of the middle cerebral artery (M2-3) but not for the anterior or posterior cerebral arteries. These lessons have been adapted into the FRONTIER-APX trial and is reflected in the inclusion and exclusion criteria.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Thanh Phan
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Address
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Monash Health, 246 Clayton Rd Clayton 3168 VIC
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Country
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Australia
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Phone
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+613 85722612
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Fax
141190
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Email
141190
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[email protected]
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Contact person for public queries
Name
141191
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Thanh Phan
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Address
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Monash Health, 246 Clayton Rd Clayton 3168 VIC
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Country
141191
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Australia
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Phone
141191
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+613 85722612
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Fax
141191
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Email
141191
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[email protected]
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Contact person for scientific queries
Name
141192
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Thanh Phan
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Address
141192
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Monash Health, 246 Clayton Rd Clayton 3168 VIC
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Country
141192
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Australia
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Phone
141192
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+613 85722612
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Fax
141192
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Email
141192
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[email protected]
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Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
•
Researchers
Conditions for requesting access:
•
Yes, conditions apply:
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Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
What individual participant data might be shared?
•
De-identified individual participant data:
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All outcomes data
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Published results
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Primary outcome(s)
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Safety data
What types of analyses could be done with individual participant data?
•
Systematic reviews and meta-analyses
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Health economic analyses
When can requests for individual participant data be made (start and end dates)?
From:
After publication of main results
To:
A finite period of:
5
years
Where can requests to access individual participant data be made, or data be obtained directly?
•
Email of trial custodian, sponsor or committee:
from principal investigators
[email protected]
(Thanh Phan) or
[email protected]
(Bernard Yan)
Are there extra considerations when requesting access to individual participant data?
No
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.
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