Clinical Trial Results:
Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage TICH-2
Summary
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EudraCT number |
2012-004108-37 |
Trial protocol |
GB SE ES HU DK IT IE |
Global end of trial date |
28 Feb 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Aug 2018
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First version publication date |
18 Aug 2018
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
12101
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Additional study identifiers
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ISRCTN number |
ISRCTN93732214 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
CTA reference: 03057/056/001/00001, REC reference: 12/EM/0369 | ||
Sponsors
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Sponsor organisation name |
University of Nottingham
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Sponsor organisation address |
Clinical Sciences Building, Nottingham City Campus, Hucknall Road, Nottingham, United Kingdom, NG5 1PB
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Public contact |
University of Nottingham
Diane Havard Senior Trial Manager
Division of Neurosciences (Stroke), University of Nottingham
Diane Havard Senior Trial Manager
Division of Neurosciences (Stroke), 00 44 (0)115 823 1775, diane.havard@nottingham.ac.uk
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Scientific contact |
University of Nottingham
Nikola Sprigg Professor Stroke Medicine
Division of Neurosciences (Stroke, University of Nottingham
Nikola Sprigg Professor Stroke Medicine
Division of Neurosciences (Stroke, 00 44 (0)115 823 1778, nikola.sprigg@nottingham.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Feb 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Dec 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Feb 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To assess whether tranexamic acid is safe and reduces death or dependency after primary intracerebral haemorrhage (PICH).
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Protection of trial subjects |
Patient lacks capacity to give consent:
Lack of capacity waill be determined by the participant’s attending stroke physician.
If the potential participant lacked capacity to give meaningful consent (e.g. in cases of dysphasia, confusion, or reduced conscious level) the following procedures were employed:
Relatives available: If relatives were present, they were provided with brief information about the trial.
Further information was provided on request. If relatives objected to the inclusion of the patient in the trial, their views were respected and the patient was not be enrolled.
Full informed written consent was obtained from the patient or legal representative afterwards as soon as was practicable.
If relatives were not physically present but available and happy to speak on the telephone, the same procedure was followed. If the relative was unhappy to speak on the telephone or unable to decide, the patient was not enrolled.
Relatives not available: If no relatives were not available, a doctor was recruited, wherever possible unconnected with the trial, provide verbal information relating to the trial and obtain verbal consent for the patient's inclusion in the trial. If a doctor unconnected with the trial was not available patients were not enrolled into the trial.
If enrolled, full informed written consent was obtained from the patient or their legal representative afterwards as soon as practicable.
Serious adverse events:
Serious adverse events are common in haemorrhagic stroke, for a full list of expected SAE that are not subject to expedited reporting, please refer to Appendix ???.
As the IMP was administered once and has a short half life, serious adverse events occurring within the first 7 days were assessed for seriousness, expectedness and causality. In addition fatal SAEs and safety outcome events (VTE, recurrent stroke, TIA, MI, PAD and seizures) were reported until day 90.
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Background therapy |
Tranexamic acid is a licensed anti-fibrinolytic drug that can be administered intravenously or orally and is used in a number of bleeding conditions to reduce bleeding. In a recent mega-trial (CRASH-2) in 20,000 patients with major bleeding following trauma, tranexamic acid significantly reduced mortality, OR 0.91 (0.85-0.97), with no increase in vascular occlusive events. Treatment was most effective when given rapidly; delayed administration was associated with lack of efficacy and potential harm. In a subgroup analysis of patients with traumatic ICH, tranexamic acid showed a non-significant trend to reduced mortality, OR 0.47 (0.21-1.04), and death of dependency, OR 0.66 (0.32-1.36). However, patients in CRASH-2 were younger and had less co-morbidities than those with SICH. In another randomised controlled trial in traumatic intracerebral haemorrhage, tranexamic acid reduced death, OR 0.69 (0.35 -1.39), and death or dependency, 0.76 (0.46 – 1.27), without increased thromboembolic events. Tranexamic acid has been tested in aneurismal subarachnoid haemorrhage, where it reduced the risk of re-bleeding at the expense of increased risk of cerebral ischaemia. However administration was for a week, conferring prolonged exposure to risk of ischaemic events. Additionally, tranexamic acid has been found to restrict haematoma expansion in acute SICH in a small non randomised study, although this did not report on safety. In another small study (n=156), rapid administration of a bolus of tranexamic acid within 24 hours of stroke was observed to reduce haematoma expansion (17.5% vs. 4.3%). In this study, tranexamic acid was given in combination with intensive blood pressure control, suggesting that it may be possible to combine haemostatic and haemodynamic approaches. There have been recent calls in the literature for large clinical trials to examine the use of tranexamic acid in SICH. | ||
Evidence for comparator |
This was a placebo-controlled trial and the placebo in this instance was 0.9% normal saline administered by intravenous infusion.The placebo was supplied, packaged, labelled, QP released and distributed as for the active IMP (tranexamic acid). | ||
Actual start date of recruitment |
01 Mar 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Scientific research | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 3
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Country: Number of subjects enrolled |
Spain: 1
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Country: Number of subjects enrolled |
Sweden: 8
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Country: Number of subjects enrolled |
United Kingdom: 1910
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Country: Number of subjects enrolled |
Denmark: 39
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Country: Number of subjects enrolled |
Hungary: 9
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Country: Number of subjects enrolled |
Ireland: 17
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Country: Number of subjects enrolled |
Italy: 96
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Country: Number of subjects enrolled |
Malaysia: 46
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Country: Number of subjects enrolled |
Georgia: 141
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Country: Number of subjects enrolled |
Switzerland: 46
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Country: Number of subjects enrolled |
Turkey: 9
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Worldwide total number of subjects |
2325
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EEA total number of subjects |
2083
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
837
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From 65 to 84 years |
1198
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85 years and over |
290
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Recruitment
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Recruitment details |
The trial setting was in secondary care, in acute stroke services across the UK and worldwide; 2325 patients recruited from 124 centres (94 UK, 30 non-UK) in 12 countries.Participants will be recruited from the acute stroke unit or emergency admissions department. The initial approach will be from a member of the patient’s usual care team. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Inclusion criteria: Adult (≥18 years) patients with acute SICH within 8 hours of stroke onset. (Where stroke onset time is unknown, the time of when last known well was used. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Randomisation
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
Central randomisation using a secure internet site in real-time involved minimisation on key prognostic factors: age; sex; time since onset; systolic blood pressure; stroke severity (NIHSS); presence of intraventricular haemorrhage; & known history antiplatelet treatment used immediately prior to stroke onset - ensuring concealment of allocation, minimising differences in key baseline prognostic variables, and slightly improving statistical power
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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tranexamic acid | |||||||||||||||||||||||||||
Arm description |
active treatment | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
tranexamic acid
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Investigational medicinal product code |
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Other name |
Cyklokapron, 100mg/ml 5ml ampoules, Pfizer Manufacturing Authorisation: PL 00057/0952)
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as tranexamic acid 1g (10ml in 100ml sodium chloride 0.9% infusion bag) through a venous cannula with a loading dose infusion over 10 minutes followed by 1g infusion (10ml in 250ml sodium chloride 0.9% infusion bag) over 8 hours.
Placebo treatment replaced tranexamic acid 100mg/ml with sodium chloride 0.9%
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Arm title
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Placebo controlled | |||||||||||||||||||||||||||
Arm description |
- | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
sodium chloride 0.9%
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Investigational medicinal product code |
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Other name |
N/A
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as a 100ml sodium chloride 0.9% infusion bag through a venous cannula over 10 minutes followed by a 250ml sodium chloride 0.9% infusion bag over 8 hours.
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Period 2
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Period 2 title |
Day 2 follow-up
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
Central randomisation using a secure internet site in real-time. Randomisation involved minimisation on key prognostic factors: age; sex; time since onset; systolic blood pressure; stroke severity (NIHSS); presence of intraventricular haemorrhage; known history antiplatelet treatment used immediately prior to stroke onset. This approach ensured concealment of allocation, minimised differences in key baseline prognostic variables, and slightly improved statistical power.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Tranexamic Acid | |||||||||||||||||||||||||||
Arm description |
Experimental drug | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
tranexamic acid
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Investigational medicinal product code |
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Other name |
Cyklokapron, 100mg/ml 5ml ampoules, Pfizer Manufacturing Authorisation: PL 00057/0952)
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as tranexamic acid 1g (10ml in 100ml sodium chloride 0.9% infusion bag) through a venous cannula with a loading dose infusion over 10 minutes followed by 1g infusion (10ml in 250ml sodium chloride 0.9% infusion bag) over 8 hours.
Placebo treatment replaced tranexamic acid 100mg/ml with sodium chloride 0.9%
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Control | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
sodium chloride 0.9%
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Investigational medicinal product code |
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Other name |
N/A
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as a 100ml sodium chloride 0.9% infusion bag through a venous cannula over 10 minutes followed by a 250ml sodium chloride 0.9% infusion bag over 8 hours.
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Period 3
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Period 3 title |
Day 7 follow-up
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
Central randomisation using a secure internet site in real-time. Randomisation involved minimisation on key prognostic factors: age; sex; time since onset; systolic blood pressure; stroke severity (NIHSS); presence of intraventricular haemorrhage; known history antiplatelet treatment used immediately prior to stroke onset. This approach ensured concealment of allocation, minimised differences in key baseline prognostic variables, and slightly improved statistical power.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Tranexamic Acid | |||||||||||||||||||||||||||
Arm description |
Experimental drug | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
tranexamic acid
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Investigational medicinal product code |
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Other name |
Cyklokapron, 100mg/ml 5ml ampoules, Pfizer Manufacturing Authorisation: PL 00057/0952)
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as tranexamic acid 1g (10ml in 100ml sodium chloride 0.9% infusion bag) through a venous cannula with a loading dose infusion over 10 minutes followed by 1g infusion (10ml in 250ml sodium chloride 0.9% infusion bag) over 8 hours.
Placebo treatment replaced tranexamic acid 100mg/ml with sodium chloride 0.9%
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Control | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
sodium chloride 0.9%
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Investigational medicinal product code |
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Other name |
N/A
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as a 100ml sodium chloride 0.9% infusion bag through a venous cannula over 10 minutes followed by a 250ml sodium chloride 0.9% infusion bag over 8 hours.
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Period 4
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Period 4 title |
Day 90 follow-up
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Assessor | |||||||||||||||||||||||||||
Blinding implementation details |
Central randomisation using a secure internet site in real-time. Randomisation involved minimisation on key prognostic factors: age; sex; time since onset; systolic blood pressure; stroke severity (NIHSS); presence of intraventricular haemorrhage; known history antiplatelet treatment used immediately prior to stroke onset. This approach ensured concealment of allocation, minimised differences in key baseline prognostic variables, and slightly improved statistical power.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Tranexamic Acid | |||||||||||||||||||||||||||
Arm description |
Experimental drug | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
tranexamic acid
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Investigational medicinal product code |
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Other name |
Cyklokapron, 100mg/ml 5ml ampoules, Pfizer Manufacturing Authorisation: PL 00057/0952)
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as tranexamic acid 1g (10ml in 100ml sodium chloride 0.9% infusion bag) through a venous cannula with a loading dose infusion over 10 minutes followed by 1g infusion (10ml in 250ml sodium chloride 0.9% infusion bag) over 8 hours.
Placebo treatment replaced tranexamic acid 100mg/ml with sodium chloride 0.9%
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Control | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
tranexamic acid
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Investigational medicinal product code |
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Other name |
Cyklokapron, 100mg/ml 5ml ampoules, Pfizer Manufacturing Authorisation: PL 00057/0952)
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Pharmaceutical forms |
Injection, Tablet
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as tranexamic acid 1g (10ml in 100ml sodium chloride 0.9% infusion bag) through a venous cannula with a loading dose infusion over 10 minutes followed by 1g infusion (10ml in 250ml sodium chloride 0.9% infusion bag) over 8 hours.
Placebo treatment replaced tranexamic acid 100mg/ml with sodium chloride 0.9%
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Investigational medicinal product name |
sodium chloride 0.9%
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Investigational medicinal product code |
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Other name |
N/A
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trial treatment was administered as a 100ml sodium chloride 0.9% infusion bag through a venous cannula over 10 minutes followed by a 250ml sodium chloride 0.9% infusion bag over 8 hours.
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Baseline characteristics reporting groups
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Reporting group title |
tranexamic acid
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Reporting group description |
active treatment | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo controlled
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
tranexamic acid
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Reporting group description |
active treatment | ||
Reporting group title |
Placebo controlled
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Reporting group description |
- | ||
Reporting group title |
Tranexamic Acid
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Reporting group description |
Experimental drug | ||
Reporting group title |
Placebo
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Reporting group description |
Control | ||
Reporting group title |
Tranexamic Acid
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Reporting group description |
Experimental drug | ||
Reporting group title |
Placebo
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Reporting group description |
Control | ||
Reporting group title |
Tranexamic Acid
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Reporting group description |
Experimental drug | ||
Reporting group title |
Placebo
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Reporting group description |
Control |
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End point title |
Death or dependency (modified Rankin Scale, mRS) at day 90. | ||||||||||||||||||||||||||||||
End point description |
Death or dependency (modified Rankin Scale, mRS) at day 90.
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End point type |
Primary
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End point timeframe |
from randomisation to day 90
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Statistical analysis title |
Odds ratio | ||||||||||||||||||||||||||||||
Comparison groups |
Tranexamic Acid v Placebo
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Number of subjects included in analysis |
2307
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
= 0.11 | ||||||||||||||||||||||||||||||
Method |
Ordinal logistic regression | ||||||||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||||||||
Point estimate |
0.88
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.76 | ||||||||||||||||||||||||||||||
upper limit |
1.03 |
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End point title |
Disability (Barthel index) at day 90 | ||||||||||||
End point description |
Disability (Barthel index) at day 90
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
from randomisation to day 90
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Quality of Life (EuroQol) at day 90 | ||||||||||||
End point description |
Quality of Life (EuroQol) at day 90
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
from randomisation to day 90
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Cognition | ||||||||||||
End point description |
Cognition and mood at day 90 (TICS and ZDS).
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
from randomisation to day 90
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Seizures | |||||||||
End point description |
Seizures
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
from randomisation to end of study
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Mood | ||||||||||||
End point description |
|||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 90
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Death | |||||||||
End point description |
cause of death
|
|||||||||
End point type |
Other pre-specified
|
|||||||||
End point timeframe |
from randomisation to end of study
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
Adverse events information [1]
|
|||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Day 90
|
||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||
Dictionary version |
1
|
||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||
Reporting group title |
tranexamic acid
|
||||||||||||||||||||||||||||||
Reporting group description |
active treatment | ||||||||||||||||||||||||||||||
Reporting group title |
Placebo controlled
|
||||||||||||||||||||||||||||||
Reporting group description |
- | ||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Only serious adverse events were collected for the trial |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
03 Dec 2012 |
The protocol had to be amended following REC review. The changes relate to participant identifiers and the consent process for potential participants who are not able to consent for themselves and do not have relatives present. |
||
09 Oct 2013 |
Update to Part B Section 3 (Radiation) on the REC and R&D Form. |
||
28 Feb 2014 |
Extension to follow up period, temperature monitoring, co-enrolment. clarification of consent procedures in the emergency situation, typographical errors. |
||
04 Mar 2015 |
addition of MRI sub study. |
||
24 Jul 2015 |
Update to MRI sub study consent forms – to include missing initial box and remove participant signature line on personal legal representative consent form as participant would not sign this form. |
||
09 Nov 2015 |
Minor amendment to MRI sub study consent forms. |
||
26 May 2016 |
Addition of plasma biomarkers sub study in one centre. |
||
01 Sep 2017 |
1 September 2016 - 12 month extension. Recruitment ended September 2017, grant closure February 2018.
|
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
|||
http://www.ncbi.nlm.nih.gov/pubmed/29778325 |