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Clinical Trial Results:
Ultra-early tranexamic acid after subarachnoid hemorrhage. A prospective, randomized, multicenter study.

Summary
EudraCT number	2012-000343-26
Trial protocol	NL
Global end of trial date	20 Jan 2020

Results information
Results version number	v1(current)
This version publication date	20 Dec 2021
First version publication date	20 Dec 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ULTRA12

ISRCTN number

US NCT number

NCT02684812

WHO universal trial number (UTN)

Sponsor organisation name

AmsterdamUMC

Sponsor organisation address

Meibergdreef 9, Amsterdam, Netherlands, 1105AZ

Public contact

ULTRA contact point, Academic Medical Center Amsterdam, +31 205666564, D.Verbaan@amc.uva.nl

Scientific contact

ULTRA contact point, Academic Medical Center Amsterdam, 0031 205666564, D.Verbaan@amc.uva.nl

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Oct 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Oct 2019

Global end of trial reached?

Yes

Global end of trial date

20 Jan 2020

Was the trial ended prematurely?

Main objective of the trial

To evaluate whether a group of patients with subarachnoid hemorrhage (SAH) treated by standard, state-of-the-art SAH management with additional ultra-early and short-term tranexamic acid (TXA) administration (TXA group) has a significantly higher percentage of patients with a favourable outcome after six months (score 0-3 on the Modified Rankin Scale) compared to a group treated by standard, state-of-the-art SAH management without additional TXA administration (control group).

Protection of trial subjects

safety and efficacy board monitoring

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Jan 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 955

Worldwide total number of subjects

955

EEA total number of subjects

955

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

641

From 65 to 84 years

302

85 years and over

Subject disposition

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Recruitment details

Screening details

no severe renal failure, no pregnancy

Period 1 title

Baseline (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Tranexamic acid

Arm description

Treatment with tranexamic acid (TXA)

Arm type

Experimental

Investigational medicinal product name

tranexamic acid

Investigational medicinal product code

Other name

cyclocapron

Pharmaceutical forms

Concentrate and solvent for solution for infusion

Routes of administration

Infusion

Dosage and administration details

1g bolus, 1gram every 8 hours until max. 24h or until aneurysm treatment

Control

Arm description

Standard care

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Tranexamic acid	Control
Started	480	475
Completed	480	475

Baseline characteristics

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Reporting group title

Baseline

Reporting group description

Reporting group values	Baseline	Total
Number of subjects	955	955
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	58.4 ± 12.4	-
Gender categorical
Gender
Units: Subjects
Female	644	644
Male	311	311
WFNS
WFNS
Units: Subjects
Grade 1	358	358
Grade 2	189	189
Grade 3	40	40
Grade 4	187	187
Grade 5	168	168
Missing	13	13
Fisher
Fisher Grade Score
Units: Subjects
Grade 2	56	56
Grade 3	277	277
Grade 4	622	622
Missing	0	0
Aneurysm location
Location of ruptured aneursysm
Units: Subjects
Anterior circ	659	659
Posterior circ	153	153
None	135	135
Unknown	8	8
Treatment modality
Aneurysm treatment modality
Units: Subjects
Endovascular	530	530
Clipping	175	175
None	108	108
Not Applicable	142	142

End points

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Reporting group title

Tranexamic acid

Reporting group description

Treatment with tranexamic acid (TXA)

Reporting group title

Control

Reporting group description

Standard care

Primary: mRS at 6 months

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End point title

mRS at 6 months

End point description

Clinical outcome assessed by modified Rankin Scale Score

End point type

Primary

End point timeframe

Six months

End point values	Tranexamic acid	Control
Number of subjects analysed	475	470
Units: 0-1
Good clinical outcome (mRS 0-3)	287	300
Poor clinical outcome (mRS 4-6)	188	170

Attachments

Distrubution of mRS at 6 months in IIT

Primary outcome analysis

Statistical analysis description

Differences between treatment groups are listed with odds ratio (OR) and 95% CI.

Comparison groups

Tranexamic acid v Control

Number of subjects included in analysis

945

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: All-cause mortality 30d

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End point title

All-cause mortality 30d

End point description

All-cause mortality during the first 30 days

End point type

Secondary

End point timeframe

During first 30 days

End point values	Tranexamic acid	Control
Number of subjects analysed	480	475
Units: 0-1
alive at 30 days	377	371
diseased at 30 days	128	104

No statistical analyses for this end point

Secondary: All-cause mortality 6 months

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End point title

All-cause mortality 6 months

End point description

End point type

Secondary

End point timeframe

During first 6 months

End point values	Tranexamic acid	Control
Number of subjects analysed	480	475
Units: 0-1
Alive at 6 mo	352	361
Diseased at 6 mo	128	114

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

During hospital admission

Assessment type

Non-systematic

Dictionary name

pre defined def

Dictionary version

Reporting group title

Tranexamic acid

Reporting group description

Reporting group title

Control

Reporting group description

Standard care

Serious adverse events	Tranexamic acid	Control
Total subjects affected by serious adverse events
subjects affected / exposed	386 / 480 (80.42%)	372 / 475 (78.32%)
number of deaths (all causes)	128	114
number of deaths resulting from adverse events
Vascular disorders
Subarachnoid haemorrhage
Additional description: Recurrent bleeding
alternative assessment type: Systematic
subjects affected / exposed	49 / 480 (10.21%)	66 / 475 (13.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ruptured cerebral aneurysm
Additional description: Recurrent bleeding confirmed by CT
alternative assessment type: Systematic
subjects affected / exposed	42 / 480 (8.75%)	57 / 475 (12.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
alternative assessment type: Systematic
subjects affected / exposed	29 / 480 (6.04%)	34 / 475 (7.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Thrombosis
Additional description: During endovascular treatment
subjects affected / exposed ^[1]	29 / 272 (10.66%)	33 / 258 (12.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ruptured cerebral aneurysm coil
Additional description: Per-Procedural rupture during coiling
alternative assessment type: Systematic
subjects affected / exposed ^[2]	16 / 272 (5.88%)	12 / 258 (4.65%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ruptured cerebral aneurysm clip
Additional description: Per-procedural rupture during clipping
alternative assessment type: Systematic
subjects affected / exposed ^[3]	17 / 86 (19.77%)	22 / 88 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Hydrocephalus
alternative assessment type: Systematic
subjects affected / exposed	292 / 480 (60.83%)	262 / 475 (55.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infarction DCI
Additional description: Delayed cerebral ischemia
alternative assessment type: Systematic
subjects affected / exposed	108 / 480 (22.50%)	106 / 475 (22.32%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infarction
Additional description: Cerebral infarction related to clipping procedure
alternative assessment type: Systematic
subjects affected / exposed ^[4]	22 / 86 (25.58%)	18 / 88 (20.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	59 / 480 (12.29%)	40 / 475 (8.42%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	65 / 480 (13.54%)	60 / 475 (12.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombosis
Additional description: Deep venous thrombosis
alternative assessment type: Systematic
subjects affected / exposed	0 / 480 (0.00%)	2 / 475 (0.42%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
alternative assessment type: Systematic
subjects affected / exposed	6 / 480 (1.25%)	5 / 475 (1.05%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
Additional description: Severe <=125mmol/L
alternative assessment type: Systematic
subjects affected / exposed	12 / 480 (2.50%)	9 / 475 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
General symptom
Additional description: All other SAE not pre-specified
subjects affected / exposed	134 / 480 (27.92%)	126 / 475 (26.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Eye haemorrhage
Additional description: Terson Syndrome
subjects affected / exposed	18 / 480 (3.75%)	18 / 475 (3.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary tract infection
subjects affected / exposed	44 / 480 (9.17%)	45 / 475 (9.47%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	63 / 480 (13.13%)	67 / 475 (14.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis
alternative assessment type: Systematic
subjects affected / exposed	37 / 480 (7.71%)	31 / 475 (6.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Subset of patients
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Subset of patients
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Subset of patients
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Subset of patients

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Tranexamic acid	Control
Total subjects affected by non serious adverse events
subjects affected / exposed	277 / 480 (57.71%)	254 / 475 (53.47%)
General disorders and administration site conditions
Other adverse events
Additional description: All not prespecified adverse events
subjects affected / exposed	277 / 480 (57.71%)	254 / 475 (53.47%)
occurrences all number	0	0

More information

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Treatment with tranexamic acid was not masked. Relative high proportion of patient without underlying aneurysm

http://www.ncbi.nlm.nih.gov/pubmed/23680226
http://www.ncbi.nlm.nih.gov/pubmed/32070395
http://www.ncbi.nlm.nih.gov/pubmed/33357465

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Clinical trials

Clinical Trial Results:
Ultra-early tranexamic acid after subarachnoid hemorrhage. A prospective, randomized, multicenter study.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: mRS at 6 months

Primary: mRS at 6 months

Secondary: All-cause mortality 30d

Secondary: All-cause mortality 30d

Secondary: All-cause mortality 6 months

Secondary: All-cause mortality 6 months

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Ultra-early tranexamic acid after subarachnoid hemorrhage. A prospective, randomized, multicenter study.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: mRS at 6 months

Primary: mRS at 6 months

Secondary: All-cause mortality 30d

Secondary: All-cause mortality 30d

Secondary: All-cause mortality 6 months

Secondary: All-cause mortality 6 months

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Ultra-early tranexamic acid after subarachnoid hemorrhage. A prospective, randomized, multicenter study.