Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000011088
Ethics application status
Approved
Date submitted
23/04/2009
Date registered
6/01/2010
Date last updated
4/12/2019
Date data sharing statement initially provided
4/12/2019
Date results provided
4/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
EXTEND : Extending the time for Thrombolysis in Emergency
Neurological Deficits
Scientific title
To test the hypothesis that ischaemic stroke patients selected with significant penumbral mismatch at 4.5 - 9 hours post onset of stroke will have improved clinical outcomes when given intravenous Tissue Plasminogen Activator (tPA) compared to placebo
Secondary ID [1] 1239 0
NCT00887328 (ClinicalTrials.gov)
Secondary ID [2] 1240 0
ISRCTN#NTA09001 (Stroke trials registry, Washington University)
Universal Trial Number (UTN)
Trial acronym
EXTEND
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 4648 0
Condition category
Condition code
Stroke 4951 4951 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tissue Plasminogen Activator
Dose: 0.9mg/kg up to a maximum of 90mg, intravenous, 10% as bolus and the remainder over 1 hour.
Dose will be determined at clinicians discretion, total duration of treatment will be 1 hour.
Intervention code [1] 4412 0
Treatment: Drugs
Comparator / control treatment
Placebo, 10% as bolus and the remainder over 1 hour. The investigational product is supplied as 50mg lyophilised powder in glass vials. These are to be reconstituted before use with 50mL of sterile water supplied with the vials.
Control group
Placebo

Outcomes
Primary outcome [1] 5799 0
Modified Rankin Scale score of 0-1
Timepoint [1] 5799 0
3 months post initial treatment
Secondary outcome [1] 241796 0
Categorial shift in Modified Rankin Score (mRS)
Timepoint [1] 241796 0
3 months post initial treatment
Secondary outcome [2] 262484 0
A change of greater than or equal to 8 points on the National Institute for Health Stroke Scale (NIHSS), or reaching less than or equal to 1 point on this scale (ie 0 or 1)
Timepoint [2] 262484 0
3 months post initial treatment
Secondary outcome [3] 273057 0
Death due to any cause
Assessed by patient/relative interview or review of medical records
Timepoint [3] 273057 0
3 months post initial treatment
Secondary outcome [4] 273058 0
Symptomatic intracerebral haemorrhage (ICH)
Assessed on 24hr MRI scan or earlier CT/MRI scan if clinical deterioration should occur.
Timepoint [4] 273058 0
24 hours following randomisation
Secondary outcome [5] 273059 0
Reperfusion at 24 hrs post stroke
Assessed using MRI perfusion-weighted imaging (PWI)
Timepoint [5] 273059 0
24 hours post stroke onset
Secondary outcome [6] 273060 0
Recanalisation at 24 hrs post stroke
Assessed using magnetic resonance angiography (MRA)
Timepoint [6] 273060 0
24 hours post stroke onset
Secondary outcome [7] 273061 0
Infarct growth assessed using MRI diffusion-weighted imaging (DWI) within 24 hrs
Timepoint [7] 273061 0
24 hours post stroke onset
Secondary outcome [8] 273062 0
Recurrent stroke at 3 and 12 months
Assessed by patient interview or review of medical records, corroborated with imaging (CT or MRI)
Timepoint [8] 273062 0
3 and 12 months following randomisation
Secondary outcome [9] 273063 0
Depression (Montgomery-Asberg Depression Rating Scale
[MADRS]) at 3 months and 12 months
Timepoint [9] 273063 0
3 and 12 months following randomisation
Secondary outcome [10] 273064 0
Quality of life (Stroke Impact Scale) at 3 months and 12
months.
Timepoint [10] 273064 0
3 and 12 months following randomisation

Eligibility
Key inclusion criteria
1. Patients presenting with hemispheric acute ischaemic stroke 2. Patient, family member or legally responsible person depending on local ethics requirements has given informed consent 3. Patient’s age is >=18 years 4. Treatment onset can commence within 4.5 – 9 hours after stroke onset according to registered product information, or between 3 – 9 hours according to locally accepted guidelines 5. Patients who wake with stroke may be included if neurological and other exclusion criteria are satisfied. These ‘wake up’ strokes are defined as having no symptoms at sleep onset, but stroke symptoms on waking. The time of stroke onset is to be taken as the mid-point between sleep onset (or last known to be normal) and time of waking. The maximum time window for randomisation is then 9 hours from the mid-point as described. 6. NIHSS score of >=4 - 26 with clinical signs of hemispheric infarction. 7. Penumbral imaging** –Using a Tmax>6 second delay, a perfusion (PWI) volume to diffusion (DWI) volume ratio of > 1.2, a DWI lesion <=70ml and PWI-DWI difference of >10ml ** Patients may be consented before or after penumbral screening depending upon local practice. The entire cohort of patients consented onto the study will be followed up with clinical assessments and biomarker studies regardless of eligibility for randomisation to treatment based on penumbral mismatch criteria.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Intracranial haemorrhage (ICH) identified by computed tomography (CT) or Magnetic Resonance Imaging (MRI) 2. Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient having an NIHSS score of < 4 at randomization 3. Pre-stroke MRS score of >=2 (indicating previous disability) 4. Contra indication to imaging with MR with contrast agents 5. Infarct core >1/3 Middle Cerebral Artery (MCA) territory qualitatively 6. Participation in any investigational study in the previous 30 days 7. Any terminal illness such that patient would not be expected to survive more than 1 year 8. Any condition that could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study (this applies to patients with severe microangiopathy such as haemolytic uremic syndrome or thrombotic thrombocytopenic purpura). The judgment is left to the discretion of the Investigator. 9. Pregnant women (clinically evident) 10. Previous stroke within last three months 11. Recent past history or clinical presentation of ICH, subarachnoid haemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm. At the discretion of each Investigator. 12. Current use of oral anticoagulants and a prolonged International Normalized Ratio (INR) > 1.6 13. Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and a prolonged activated partial thromboplastin time exceeding the upper limit of the local laboratory normal range. 14. Use of glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single or dual agent oral platelet inhibitors (clopidogrel and/or low-dose aspirin) prior to study entry is permitted. 15. Clinically significant hypoglycaemia. 16. Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or >110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure to within these limits. The definition of “aggressive treatment” is left to the discretion of the responsible Investigator. 17. Hereditary or acquired haemorrhagic diathesis 18. Gastrointestinal or urinary bleeding within the preceding 21 days 19. Major surgery within the preceding 14 days which poses risk in the opinion of the investigator. 20. Exposure to a thrombolytic agent within the previous 72 hours

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)
Screening Evaluation: Baseline physical examination will be performed on potentially eligible patients. Whole brain non-contrast CT will be performed to assess for ICH. Neurological impairment and functional scores (NIHSS, mRS) will be assessed by a neurologist or trained health care professional. Bloods for standard care diagnostic evaluations will be collected and analysed. Patients will be assessed for trial eligibility according to the Inclusion/Exclusion criteria. Informed consent will be obtained from patients or their authorised representative according to the Independent Ethics Committee (IEC) approved patient information and informed consent procedure and documentation. Consented patients will then be referred for trial-specific penumbral imaging procedures. Randomisation: The randomisation system for investigational product will be based on computer generated randomisation lists, with stratification for time from onset of stroke to randomisation (3-6 hrs, 6-9hrs or Wake up stroke). Blinding/Unblinding: All those involved in the conduct of the study will be blinded to treatment allocation. The Data Safety Monitoring Committee (DMC) will have access to data that is grouped, but not unblinded in terms of treatment allocation. Code break envelopes will be provided with blinded vials of investigational product, and held at the Central Drug Distribution centre. In the case of reported Suspected Unexpected Serious Adverse Reactions (SUSARs), or if treatment identification is necessary for emergency patient management, cases may be unblinded by contacting the local Clinical Trials Pharmacist. Details (date, time, reason) should be recorded in the electronic Case Report Form (eCRF). Product Labelling: Vials of investigational product will be labelled with storage conditions (store below 25 degrees Celsius, protect from light) and expiry date by the supplier, Boehringer Ingelheim. Details on the labels will include: Protocol name and identification number, name, address and contact number of the sponsor, the subject randomisation number, and the words ‘for clinical trial use only’. Labelling of the investigational product will comply with Therapeutic Goods Administration (TGA) code of Good Manufacturing Practice (GMP) for medicinal products, Annex 13, section 17 in Australia, or applicable national and/or local requirements for international sites. Handling and Storage of Study Drugs: Investigational product will be stored centrally at, and distributed to study sites from, the Central Drug Distribution Centre. Vials will be identical in appearance and blinded as to their contents, and be provided with randomisation codes and code break envelopes. Appropriate arrangements will be made for the distribution of the investigational product to the study sites. Vials will be distributed according to the process outlined in the Study Pharmacy Manual. Vials will be stored at ambient temperature until use. The investigator or his/her designee must maintain an adequate record regarding the receipt, distribution, and return of all investigational product. Accountability documentation will also reside with the Central Drug Distribution Centre and be retained in the Trial Master File at NSRI. The investigator must agree to use the investigational product only in accordance with the protocol.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation: Patients eligible for treatment based on penumbral mismatch criteria will be randomised to receive either tPA or placebo according to a centralised procedure coordinated via the on-line electronic case report form (eCRF), and linked to the central Drug Distribution Centre. Randomisation codes and further permuted block randomisation sequences will be generated by a computer software program. Patients will be stratified according to time from stroke onset (three strata: greater than 3 hours to 6 hours, greater than 6 hours to 9 hours, Wake up stroke).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
10/01/2010
Actual
25/08/2010
Date of last participant enrolment
Anticipated
Actual
2/06/2018
Date of last data collection
Anticipated
Actual
27/08/2018
Sample size
Target
310
Accrual to date
Final
225
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment outside Australia
Country [1] 7573 0
Taiwan, Province Of China
State/province [1] 7573 0
None
Country [2] 7574 0
Finland
State/province [2] 7574 0
Helsinki

Funding & Sponsors
Funding source category [1] 4829 0
Government body
Name [1] 4829 0
Commonwealth Scientific and Industrial Research Organisation (CSIRO)
Country [1] 4829 0
Australia
Primary sponsor type
Other
Name
The Florey Institute of Neuroscience and Mental health
Address
The Florey Institute of Neuroscience and Mental Health
245 Burgundy St
Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 4370 0
None
Name [1] 4370 0
Nil
Address [1] 4370 0
Nil
Country [1] 4370 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258230 0
Melbourne Health Human Research Ethics Committee, Royal Melbourne Hospital, Parkville, 3050
Ethics committee address [1] 258230 0
Ethics committee country [1] 258230 0
Australia
Date submitted for ethics approval [1] 258230 0
01/05/2009
Approval date [1] 258230 0
29/10/2009
Ethics approval number [1] 258230 0
2009.078
Ethics committee name [2] 258231 0
Hunter New England Area Health Service Ethics Committee, John Hunter Hospital, Newcastle, NSW 2310
Ethics committee address [2] 258231 0
Ethics committee country [2] 258231 0
Australia
Date submitted for ethics approval [2] 258231 0
01/05/2009
Approval date [2] 258231 0
16/09/2009
Ethics approval number [2] 258231 0
09/07/15/3.04
Ethics committee name [3] 304885 0
Royal Adelaide Hospital HREC
Ethics committee address [3] 304885 0
Ethics committee country [3] 304885 0
Australia
Date submitted for ethics approval [3] 304885 0
19/10/2010
Approval date [3] 304885 0
13/12/2010
Ethics approval number [3] 304885 0
101117
Ethics committee name [4] 304886 0
Royal Brisbane & Women's HREC
Ethics committee address [4] 304886 0
Ethics committee country [4] 304886 0
Australia
Date submitted for ethics approval [4] 304886 0
24/08/2010
Approval date [4] 304886 0
25/10/2010
Ethics approval number [4] 304886 0
HREC/10/QRBW/341

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

Contacts
Principal investigator
Name 29522 0
Prof Geoffrey Donnan
Address 29522 0
The Florey Institute of Neuroscience and Mental Health
Level 5 Kenneth Myer Building
30 Royal Parade
Parkville Vic 3052
AUSTRALIA
Country 29522 0
Australia
Phone 29522 0
+61 3 9035 6626
Fax 29522 0
Email 29522 0
[email protected]
Contact person for public queries
Name 12769 0
Michele Sallaberger
Address 12769 0
Neuroscience Trials Australia
The Florey Institute of Neuroscience and Mental Health
245 Burgundy St
Heidelberg VIC 3084
Country 12769 0
Australia
Phone 12769 0
+61 3 9035 7269
Fax 12769 0
+61 3 8344 3572
Email 12769 0
[email protected]
Contact person for scientific queries
Name 3697 0
Professor Geoffrey Donnan
Address 3697 0
The Florey Institute of Neuroscience and Mental Health
Level 5 Kenneth Myer Building
30 Royal Parade
Parkville Vic 3052
Country 3697 0
Australia
Phone 3697 0
+61 3 9035 6626
Fax 3697 0
Email 3697 0
[email protected]

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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
6028Study protocol  [email protected]
6029Statistical analysis plan  [email protected]



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseFunctional outcome of intravenous thrombolysis in patients with lacunar infarcts in the wake-up trial.2019https://dx.doi.org/10.1001/jamaneurol.2019.0351
N.B. These documents automatically identified may not have been verified by the study sponsor.