Treatment of Intracerebral Hemorrhage in Patients on Non-vitamin K Antagonist Oral Anticoagulants (NOAC) With Tranexamic Acid
Phase: PHASE2
Conditions: Intracerebral Hemorrhage
Sponsor: University Hospital, Basel, Switzerland

TICH-NOAC, Version 1.4 of April 16th 2020 
 
Page 1 of 37 
 
Treatment of intracerebral hemorrhage in patients 
on non-vitamin K oral anticoagulants with 
tranexamic acid 
 
(TICH-NOAC) 
 
Clinical Study Protocol 
 
A randomized, placebo controlled phase-IIb/III multi-center treatment trial. 
 
 
Study Type: 
Clinical trial with Investigational Medicinal Product (IMP) 
Study Categorisation: 
Risk category C 
Study Registration: 
NCT02866838 (clinicaltrials.gov) 
 
Sponsor, 
Sponsor-Investigator 
or 
Principal 
Coordinating 
Investigator: 
Stroke Center, University Hospital Basel 
Prof. Dr. med. Philippe Lyrer  
Stroke Center and Neurology  
Petersgraben 4 
4031 Basel/Switzerland 
 
Investigational Product: 
Tranexamic acid (verum) vs. NaCl 0.9% (Placebo) 
Protocol Version and Date: 
Version 1.4 of April 16th 2020 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the Stroke Center at the 
University Hospital Basel. The information may not - in full or in part - be transmitted, reproduced, 
published, or disclosed to others than the applicable Competent Ethics Committee(s) and Regulatory 
Authority(ies) without prior written authorisation from the sponsor except to the extent necessary to 
obtain informed consent from those who will participate in the study. 
 
 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
Page 2 of 37 
Signature Page(s)  
 
Study number 
NCT02866838 
Study Title 
Treatment of intracerebral hemorrhage in patients on non-vitamin 
K oral anticoagulants with tranexamic acid (TICH-NOAC) 
 
The Sponsor-Investigator and trial statistician have approved the protocol version 1.4 dated April 16rh 
2020, and confirm hereby to conduct the study according to the protocol, current version of the World 
Medical Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable and 
the local legally applicable requirements. 
 
Prof. Dr. med. Philippe Lyrer, Sponsor-Representative and Coordinating Investigator 
 
 
Place/Date 
 
Signature 
 
Prof. Dr. med. Stefan Engelter, Deputy Coordinating Investigator; Local Principal Investigator 
University Hospital Basel 
 
 
Place/Date 
 
Signature 
 
Prof. Dr. med. Nils Peters, Deputy Coordinating Investigator and Executive Trial Manager; Local 
Principal Investigator Klinik Hirslanden Zürich 
 
 
Place/Date 
 
Signature 
 
PD Dr. med. David Seiffge, Scientific Trial Manager 
 
 
Place/Date 
 
Signature 
 
Sabine Schaedelin, MSc, Trial Statistician 
 
 
Place/Date 
 
Signature 
 
 
Marina Maurer, Trial Coordinator 
 
 
Place/Date 
 
Signature 
 
 
 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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Local Principal Investigator at study site*: 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
Site 
 
Principal investigator 
 
 
 
 
Place/Date 
 
Signature Prof. Dr. med. Stefan Engelter 
 
 
 
 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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Table of Contents 
 
STUDY SYNOPSIS ................................................................................................................................. 6 
STUDY SUMMARY IN LOCAL LANGUAGE ......................................................................................... 8 
ABBREVIATIONS ................................................................................................................................... 9 
STUDY SCHEDULE .............................................................................................................................. 10 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 11 
1.1 
Sponsor, Sponsor-Investigator .................................................................................................... 11 
1.2 
Principal Investigator(s) .......................................................... Fehler! Textmarke nicht definiert. 
1.3 
Statistician ("Biostatistician") ....................................................................................................... 11 
1.4 
Trial Pharmacist .......................................................................................................................... 11 
1.5 
Monitoring institution ................................................................................................................... 11 
1.6 
Data Safety Monitoring Board ..................................................................................................... 12 
1.7 
Any other relevant Committee, Person, Organisation, Institution ............................................... 12 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................. 14 
2.1 
Study registration ........................................................................................................................ 14 
2.2 
Categorisation of study ............................................................................................................... 14 
2.3 
Competent Ethics Committee (CEC) .......................................................................................... 14 
2.4 
Competent Authorities (CA) ........................................................................................................ 14 
2.5 
Ethical Conduct of the Study ....................................................................................................... 14 
2.6 
Declaration of interest ................................................................................................................. 14 
2.7 
Patient Information and Informed Consent ................................................................................. 15 
2.8 
Participant privacy and confidentiality ......................................................................................... 15 
2.9 
Early termination of the study ...................................................................................................... 15 
2.10 Protocol amendments ................................................................................................................. 16 
3. 
BACKGROUND AND RATIONALE .............................................................................................. 17 
3.1 
Background and Rationale .......................................................................................................... 17 
3.2 
Investigational Product ................................................................................................................ 18 
3.2.1 Description and Manufacture .............................................................................................. 19 
3.2.2 Blinding and unblinding procedure ...................................................................................... 19 
3.2.3 Trial treatments ................................................................................................................... 19 
3.2.4 Packaging, Labelling and Supply (re-supply) ..................................................................... 19 
3.2.5 Storage Conditions ............................................................................................................. 20 
3.2.6 Known Side Effects ............................................................................................................. 20 
3.3 
Explanation for choice of comparator (or placebo) ..................................................................... 20 
3.4 
Risks / Benefits ............................................................................................................................ 20 
4. 
STUDY OBJECTIVES ................................................................................................................... 22 
4.1 
Overall Objective ......................................................................................................................... 22 
4.2 
Primary Objective ........................................................................................................................ 22 
4.3 
Secondary Objectives ................................................................................................................. 22 
5. 
STUDY OUTCOMES ..................................................................................................................... 22 
5.1 
Primary Outcome ........................................................................................................................ 22 
5.2 
Secondary Outcomes .................................................................................................................. 22 
6. 
STUDY DESIGN ............................................................................................................................ 23 
6.1 
General study design and justification of design ......................................................................... 23 
6.2 
Methods of minimising bias ......................................................................................................... 23 

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6.2.1 Randomisation .................................................................................................................... 23 
7. 
STUDY POPULATION .................................................................................................................. 24 
7.1 
Eligibility criteria ........................................................................................................................... 24 
7.2 
Recruitment and screening ......................................................................................................... 24 
7.3 
Assignment to study groups ........................................................................................................ 24 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................... 24 
8. 
STUDY INTERVENTION ............................................................................................................... 26 
8.1 
Identity of Investigational Products (treatment) ........................................................................... 26 
8.1.1 Experimental Intervention (treatment)................................................................................. 26 
8.1.2 Control Intervention (comparator treatment) ....................................................................... 26 
8.1.3 Packaging, Labelling and Supply (re-supply) ..................................................................... 26 
8.1.4 Storage Conditions, dispense and return ........................................................................... 26 
8.2 
Compliance with study intervention ............................................................................................. 26 
9. 
STUDY ASSESSMENTS ............................................................................................................... 27 
9.1 
Study flow chart(s) / table of study procedures and assessments .............................................. 27 
9.2 
Assessments of outcomes .......................................................................................................... 28 
9.2.1 Assessment of primary outcome ......................................................................................... 28 
9.2.2 Assessment of secondary outcomes .................................................................................. 28 
9.2.3 Assessment of safety outcomes ......................................................................................... 28 
9.2.4 Causality and reporting ....................................................................................................... 29 
10. SAFETY ......................................................................................................................................... 30 
10.1.1 Reporting of SAEs............................................................................................................... 30 
10.1.2 Reporting of SUSARs ......................................................................................................... 30 
11. STATISTICAL METHODS ............................................................................................................. 31 
11.1 Hypothesis ................................................................................................................................... 31 
11.2 Determination of Sample Size ..................................................................................................... 31 
11.3 Statistical criteria of termination of trial ....................................................................................... 31 
11.4 Planned Analyses ........................................................................................................................ 31 
12. QUALITY ASSURANCE AND CONTROL .................................................................................... 33 
12.1 Data handling and record keeping / archiving ............................................................................. 33 
12.1.1 Case Report Forms ............................................................................................................. 33 
12.1.2 Specification of source documents ..................................................................................... 33 
12.1.3 Record keeping / archiving ................................................................................................. 33 
12.2 Monitoring .................................................................................................................................... 33 
12.3 Audits and Inspections ................................................................................................................ 33 
12.4 Confidentiality, Data Protection ................................................................................................... 33 
13. PUBLICATION AND DISSEMINATION POLICY .......................................................................... 33 
14. FUNDING AND SUPPORT ............................................................................................................ 34 
15. INSURANCE .................................................................................................................................. 34 
16. REFERENCES ............................................................................................................................... 35 
 
 
 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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STUDY SYNOPSIS  
 
Title 
Treatment of intracerebral hemorrhage in patients on non-vitamin 
K oral anticoagulants with tranexamic acid (TICH-NOAC) 
Sponsor 
Stroke Center, Universitätsspital Basel, Basel, Switzerland 
Sponsor-
Investigator 
Prof. Dr. Philippe Lyrer  
Steering 
committee 
Prof. Dr. N. Peters, Prof. D. Tskaris, Prof. C. Stippich, Prof. R. Guzman; 
Prof. Dr. C. Nickel, , Prof. Dr. N. Sprigg, S. Schaedelin MSc, PD Dr. D. 
Seiffge 
Trial 
registration 
NCT02866838 
Protocol 
Version 
and 
Date 
Version 1.4 of April 16th 2020   
CRO 
CTU Basel 
Background 
Novel, non-vitamin K antagonist oral anticoagulants (NOAC) target 
selected players in the coagulation cascade as the direct thrombin 
inhibitor dabigatran and the factor Xa-inhibitors apixaban, edoxaban and 
rivaroxaban. Intracerebral hemorrhage (ICH) is the most feared 
complication of NOAC treatment (NOAC-ICH).  
Outcome of NOAC-ICH can be devastating and is a cause of death and 
disability. There is no proven treatment for NOAC-ICH. Hematoma 
expansion (HE) is associated with unfavorable outcome. Tranexamic 
acid (TA) is an anti-fibrinolytic drug that is used in a number of bleeding 
conditions other than ICH.  
Primary 
Research 
Hypothesis 
Treatment with TA as add-on treatment to best medical treatment for 
NOAC-ICH reduces HE  
Primary 
Objective 
To demonstrate that treatment with TA for NOAC-ICH in addition to best 
medical treatment reduces rate of HE compared to best medical 
treatment (includes “antidotes” if available) only 
Methods 
Randomized controlled, double-blinded multicenter trial 
Primary 
Endpoint 
The primary outcome measure will be a surrogate imaging outcome 
measure – hematoma expansion (HE) – that is defined as the difference 
between ICH-volume on baseline CT and on follow-up-CT at 24 ± 3 
hours.  
Secondary 
Endpoints 
1. 
modified Rankin Scale (mRS) 0–4 at three-months;  
2. 
mRS 0–3 at three-months;  
3. 
Categorical shift in mRS at three-months;  
4. 
Absolute ICH growth volume by 24 ± 3 hours, adjusted for 
baseline ICH volume;  
5. 
Symptomatic HE defined as HE associated with neurological 
deterioration of NIHSS >/=4 points or GCS >2 points  
6. 
Death due to any cause by three-months;  

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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7. 
major thromboembolic events (myocardial infarction, ischemic 
stroke, pulmonary embolism) 
8. 
NCH intervention (including craniectomie, EVD, hematoma 
evacuation) 
9. 
In-hospital mortality 
Statistical 
Hypothesis 
TA reduces rate of HE in patients with NOAC-ICH compared to placebo 
in addition to best medical treatment 
Inclusion 
Criteria 
- Acute intracerebral hemorrhage (symptom onset <12h) 
- Prior treatment with a novel direct oral anticoagulant (apixaban, 
dabigatran, edoxaban or rivaroxaban; last intake <48hours OR proven 
NOAC activity by relevant coagulation assays) 
- Age >18 years, No upper age limit 
- Informed consent has been received in accordance to local ethics 
committee requirements 
Exclusion 
Criteria 
- Severe pre-morbid disability (modified Rankin scale >4)  
- Anticoagulation with VKA 
- Secondary intracerebral hemorrhage (e.g., AVM, tumor, trauma) Note it 
is not necessary for investigators to exclude underlying structural 
abnormality prior to enrolment, but where an underlying structural 
abnormality is already known, these patients should not be recruited. 
- Glasgow coma scale <5 
- pregnancy 
- Planned neurosurgical hematoma evacuation within 24 hours (before 
follow-up imaging) 
- Pulmonary embolism/deep vein thrombosis within the last 2 weeks. 
Sample Size 
109 
Study Centers 
Basel (coordinating center), Bern,  Luzern, Zürich, Aarau, St. Gallen, 
Hirslanden  
Randomization 1 : 1  
Intervention 
intravenous tranexamic acid (1g loading dose given as 100 ml infusion 
over 10 minutes, followed by another 1g in 250 ml infused over 8 hours) 
or as comparator placebo (normal saline 0.9%) administered by identical 
regimen. 
Study 
Procedure 
The study contains of 5 study visits (Screening-/Randomization visit, 
Follow-up-visit on day 2, day 7, discharge from primary care hospital and 
90 days) and lasts 3 months. Clinical measures (mRS, NIHSS) and 
adverse events will be obtained at every visit after randomization. On day 
2, a follow-up native head CT-scan for determination of hematoma 
expansion will be performed. 
Calculation of 
Sample Size 
Assuming a rate of hematoma expansion of 54% in the placebo group 
and 27% in the TA group, 109 patients need to be included to yield 80% 
power to detect a significant absolute difference in the proportion of 
patients with hematoma enlargement at 24 h at a two-sided statistical 
significance threshold of P = 0·05. 

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Relevance 
of 
the study 
Use of NOAC is frequent and will still increase in the future. Treatment of 
NOAC-ICH is unsolved. Due to its mode of action, TA is a promising 
compound to be tested for hemostatic treatment in ICH and may improve 
clinical outcome. The results of the present trial will show whether TA is 
beneficial in patients with NOAC-ICH. 
STUDY SUMMARY IN LOCAL LANGUAGE  
Neue, direkte, nicht Vitamin-K antagonisierende orale Antikoagulantien (NOAC oder DOAC) 
sind wirksame Medikamente zur Prophylaxe und Behandlung einer Vielzahl von 
thrombembolischen Erkrankungen wie zum Beispiel der Hirnschlagprophylaxe bei Patienten 
mit Vorhofflimmern. Die gefürchtetste Komplikation einer NOAC-Behandlung ist eine 
Hirnblutung 
(=intracerebral 
hemorrhage, 
ICH). 
Hirnblutungen 
bei 
Patienten 
unter 
Antikoagulantienbehandlung (alte Antikoagulantien wie Vitamin K-Antagonisten oder NOAC) 
weisen häufig Nachblutungen (=Hämatomexpansion, HE) in der Frühphase nach dem Ereignis 
auf, welche ein schlechter prognostischer Faktor sind. Insgesamt ist die Prognose bei 
Patienten mit Hirnblutungen unter Antikoagulantien schlecht mit einer hohen Sterblichkeit (ca. 
20%) sowie einer hohen Rate an Patienten mit dauerhafter neurologischer Behinderung. Seit 
kurzem existieren sogenannte Antidots gegen NOAC, jedoch gibt es keine evidenz-basierte 
Behandlung der NOAC-Hirnblutung, welche nachweislich das klinische Outcome verbessen 
und Nachblutungen verhindern kann. 
Tranexamsäure ist ein seit > 20 Jahren bekanntes Medikament, dass in vielen Bereichen der 
Medizin zur Stillung von Blutungen, zum Beispiel nach Unfällen oder während Operationen, 
eingesetzt wird. Aktuell wird in einer grossen, multi-nationalen Studie die Wirkung von 
Tranexamsäure bei Patienten mit spontanen Hirnblutungen (Patienten, die keine 
Antikoagulantien/NOAC eingenommen haben) erforscht (TICH-2 Studie). 
In der vorliegenden Studie möchten wir in einer Studie an mehreren Zentren die Wirkung von 
Tranexamsäure im Vergleich zu Placebo zusätzlich zur medizinischen Standardbehandlung 
(welche unter Umständen Antidots beinhalten kann) bei Patienten mit NOAC-Hirnblutungen 
testen. Das primäre Ziel ist es, die Rate an HE 24 Stunden nach Aufnahme zu reduzieren. 
Sekundäre Ziele ist eine Reduktion von Tod und neurologischer Behinderung nach 3 Monaten. 
 
 

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ABBREVIATIONS 
AE 
Adverse Event  
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
CRF 
Case Report Form  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin) 
eCRF 
Electronic Case Report Form  
GCP 
Good Clinical Practice  
IB 
Investigator’s Brochure 
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
HFG 
Humanforschungsgesetz (Law on human research) 
HMG 
Heilmittelgesetz  
HRA 
Federal Act on Research involving Human Beings 
IMP 
Investigational Medicinal Product 
IIT 
Investigator-initiated Trial 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
KlinV 
Verordnung über klinische Versuche in der Humanforschung (in English: ClinO, in 
French OClin) 
PI 
Principal Investigator  
SDV 
Source Data Verification  
SOP 
Standard Operating Procedure 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File  
 
 
 

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STUDY SCHEDULE  
Study Periods 
 
Screening 
Randomisation
/Treatment 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
day 
1 
1 
2 
7 
Death/ 
discharge 
90 
Patient 
Information 
and 
Informed Consent 
x 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
In- /Exclusion Criteria 
x 
 
 
 
 
 
NIHSS 
x 
 
x 
x 
 
x 
Vital Signs (RR, heart rate) 
x 
 
x 
x 
 
x 
Laboratory Tests 
x* 
 
 
 
 
 
Pregnancy Test# 
x 
 
 
 
 
 
Randomisation 
 
x 
 
 
 
 
CT scan 
x*  
x1 
x 
 
 
 
Study treatment 
 
x 
 
 
 
 
mRS 
x 
 
x 
x 
x 
x 
Secondary 
outcome 
variables 
 
 
 
 
 
x 
Concomitant 
Therapy, 
Intervention 
 
x 
x 
x 
x 
 
Adverse Events 
 
x 
x 
x 
x 
x 
 
* part of routine work-up (=no study intervention) 
# if applicable 
1 only if no baseline-CT scan performed as part of routine-work up (for example baseline brain imaging 
is MRI) 
 

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1. STUDY ADMINISTRATIVE STRUCTURE  
1.1 Sponsor-Representative, Coordinating Investigator  
Prof. Dr. med. Phlippe Lyrer 
Stroke Center, University Hospital Basel 
Petersgraben 4 
4031 Basel 
 
1.2 Deputy Coodinating Investigators 
Prof. Dr. med.  Stefan Engelter, Principal Investigator Basel 
Stroke Center and Neurology 
Petersgraben 4 
4031 Basel 
Tel. +41 (0) 61 265 25 25 
And  
Prof. Dr. med. Nils Peters, Principal Investigator Hirslanden 
Stroke Center, Klinik Hirslanden 
Witellikerstrasse 40 
8032 Zürich 
Tel. +41 (0) 44 387 21 11 
 
1.3 Statistician ("Biostatistician")  
Sabine Schaedelin, PhD 
Universitätsspital Basel 
Departement Klinische Forschung 
Clinical Trial Unit (CTU) 
Schanzenstr. 55  
4031 Basel 
Tel +41 (0)61 556 51 67 
 
1.4 Trial Pharmacist 
Dr. rer. nat. Stefanie Deuster 
Spital-Pharmazie  
Universitätsspital Basel 
Rossetti-Bau, Spitalstrasse 26 
CH-4031 Basel 
Tel: 0041-61-265 25 25 
 
1.5 Monitoring institution 
Klaus Ehrlich 
Universitätsspital Basel 
Departement Klinische Forschung 
Clinical Trial Unit (CTU) 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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Schanzenstr. 55  
4031 Basel 
Tel +41 (0)61 556 51 67 
 
1.6 Data Safety Monitoring Board  
The study will be terminated early in case of major safety concerns. For this purpose, a DSMB (Data-
Safety-Monitoring-Board) will be installed. The DSMB will be independent of the sponsor, the CIs and 
competing interests. It will comprise of two experienced stroke neurologist or neuroradiologists and one 
statistician. The DSMB will meet after recruitment of 50% and 80% of the patients. It will monitor the 
frequency of the clinically important safety events. In case of serious safety concerns, the DSMB will 
alert the chief investigator in order to terminate the study. 
1.7 Any other relevant Committee, Person, Organisation, Institution  
Day-to-day management of the trial will be the responsibility of the trial executive committee (TEC). The 
TEC will report to the Trial Steering Committee (TSC). An independent Data Safety Monitoring Board 
(DSMB, see 1.6) will monitor safety of participants, and will report to the TSC. Trial co-ordination will be 
through the TEC, in conjunction with the Basel Clinical Trials Unit (CTU). 
 
The Chief Investigators are the data custodian and have overall responsibility for the study and shall 
oversee all study management. 
 
Trial executive committee (TEC) 
The trial executive committee (TEC) will include the Sponsor/Coordinating-Investigator (Prof. Lyrer), the 
deputy Sponsor-Investigator, the Principal Investigator (Prof. N.Peters) and the Scientific Trial Manager 
(PD Dr D. Seiffge). This group, based at the Stroke Center at the University Hospital Basel Unit, will 
meet regularly, once a year. 
 
Prof. Dr. med. Philippe Lyrer (Sponsor-Coordinating Investigator) 
Prof. Dr. med. Stefan Engelter (Deputy Coordinating Investigator, Local PI Basel) 
Prof. Dr. med. Nils Peters (Deputy Coordinating Investigator, Local PI Hirslanden) 
PD  Dr. med. David Seiffge (scientific trial management) 
Stroke Center and Neurology 
Petersgraben 4 
4031 Basel 
Tel. +41 (0) 61 265 25 25 
 
Trial Steering Committee (TSC) 
The Trial Steering Committee (TSC) will provide oversight of the trial. It will meet (in person or by 
telephone conference) prior to commencement of the trial, and then at regular intervals until completion 
(at least annually). Specific tasks of the TSC are: 
• to approve the trial protocol 
• to approve necessary changes to the protocol based on considerations of feasibility 
and practicability 
• to receive reports from the DSMB 
• to resolve problems brought to it by the co-ordinating centre and TEC 
• to ensure publication of the trial results 
 
Members of the trial steering committee (additional persons to TEC; representatives from international 
coordinating centers to be appointed): 
 
Prof. D. Tsakiris (Diagnostic Hematology), Prof. C. Stippich (Neuroradiology) and Prof. R. Guzman 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
Page 13 of 37 
(Neurosurgery), Prof. Dr. C. Nickel (Emergency Departement), Sabine Schädelin, MSc, (trial statistician, 
CTU Basel), Prof Dr. N. Sprigg (Chief Investigator, TICH-2 Study). 
 
 

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2. ETHICAL AND REGULATORY ASPECTS  
Before the study will be conducted, the protocol, the proposed patient information and consent form as 
well as other study-specific documents will be submitted to the EKNZ as the properly constituted regional 
Competent Ethics Committee (CEC) and to the competent authorities (e.g. Swissmedic) in agreement 
with local legal requirements, for formal approval. Any amendment to the protocol must as well be 
approved (if legally required) by these institutions. 
The decision of the CEC and Swissmedic/foreign competent authority concerning the conduct of the 
study will be made in writing to the Sponsor-Investigator before commencement of this study. The 
clinical study can only begin once approval from all required authorities has been received. Any 
additional requirements imposed by the authorities shall be implemented. 
 
2.1 Study registration  
This study is registered under NCT02866838 (Clinical trials.gov) and will be registered in the KOFAM 
registry of the BAG. 
 
2.2 Categorisation of study  
Acccording to Article 19 Categorisation of clinical trials of medicinal products of ClinO, this study is 
Category C. 
2.3 Competent Ethics Committee (CEC)  
The responsible investigator at each site will ensures approval from an appropriately constituted 
Competent Ethics Committee (CEC) is sought for the clinical study.  
In Switzerland, the trial will be submitted to the “Ethikkomittee Nordwest- und Zentralschweiz” (EKNZ) 
as leading ethics committee for Switzerland. 
Reporting duties and allowed time frame and no changes are made to the protocol without prior Sponsor 
and CEC approval, except where necessary to eliminate apparent immediate hazards to study 
participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the study 
is reported to the CEC within 90 days, the final study report shall be submitted within one year after 
study end. Amendments are reported according to chapter 2.10. 
 
2.4 Competent Authorities (CA)  
The Sponsor will obtain approval from the competent authority (e.g. Swissmedic) before the start of the 
clinical trial.  
Reporting duties and allowed time frame to CA including the reporting duties in case of planned or 
premature study end and the final report are the same as for CEC, except of non-substantial 
amendments that shall be reported as soon as possible. Amendments are reported according to chapter 
2.10.    
 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, 
The CEC and regulatory authorities will receive annual safety and interim reports and be informed about 
study stop/end in agreement with local requirements.  
2.6 Declaration of interest  
This study is funded by the Swiss National Science Foundation (SNF). The investigators report no other 
disclosures. 
 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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2.7 Patient Information and Informed Consent 
 
In the pilot phase, the trial setting is in 6 public Stroke Centers in Switzerland (Aarau, Basel, Bern , 
Luzern, St. Gallen, Zürich). An extension to additional national or international centers after a pilot phase 
is intended.  
 
Participants will be recruited from the stroke unit, emergency department or intensive care unit at the 
participating centers. The local investigator will inform the participant or their legal representative, of all 
aspects pertaining to participation in the study.  
 
It will be explained to the potential participant or their legal representative that entry into the trial is 
entirely voluntary and that their treatment and care will not be affected by their decision. If patients are 
unable to consent themselves (for example due to severe neurological deficits including impaired 
consciousness or aphasia) they can be included in the study if there is no information available (for 
example patient decree) providing evidence that the patient does not want to participate in any scientific 
study. In this case, an independent doctor unrelated to the study will ensure patient’s custody. If the 
patients will be able to provide informed consent themselves at a later time point during the study, a 
signed informed consent from the patients will be obtained. If it is likely that the patient will not be able 
to give informed consent throughout the whole study period, a legal representative will be contacted to 
obtain informed consent as to the patient’s presumed will 
It will also be explained that they can withdraw at any time. In the event of their withdrawal it will be 
explained that their data collected so far cannot be erased and we will seek consent to use the data in 
the final analyses where appropriate. 
The participant will be informed that his/her medical records may be examined by authorised individuals 
other than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form 
describing the study and providing sufficient information for participant to make an informed decision 
about their participation in the study.  
The patient information sheet and the consent form will be submitted to the CEC and to the competent 
authority (as applicable) to be reviewed and approved. The formal consent of a participant, using the 
approved consent form, must be obtained before the participant is submitted to any study procedure.   
The participant should read and consider the statement before signing and dating the informed consent 
form, and should be given a copy of the signed document. The consent form must also be signed and 
dated by the investigator (or his designee) and it will be retained as part of the study records. 
 
2.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Anonymity of the participants is guaranteed when presenting the 
data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject 
identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator), a competent 
authority (e.g. Swissmedic), or an ethics committee may require direct access to parts of the medical 
records relevant to the study, including participants’ medical history. 
 
2.9 Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, for 
example: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
safety concerns  
 
on advice of the DSMB 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise 
 
2.10 Protocol amendments 
The principal investigators – on behalf of the steering committee - can amend the protocol. 
Communicating important protocol modifications (e.g., changes to eligibility criteria, outcomes, 
analyses) to relevant parties (e.g., investigators, CEC, competent authorities, trial participants, trial 
registries, journals, regulators) will be assured as to the legal requirements. 
Substantial amendments are only implemented after approval of the CEC and CA respectively. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the sponsor and the CEC/CA. Such 
deviations shall be documented and reported to the sponsor and the CEC/CA as soon as possible. 
All Non-substantial amendments are communicated to the CA as soon as possible if applicable and to 
the CEC within the Annual Safety Report (ASR).  
 
 
 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
 
Background NOAC 
Long-term oral anticoagulation is beneficial for the treatment and prevention of various thromboembolic 
diseases. For years, Vitamin K-antagonists (VKA), that act as indirect anticoagulants which lower the 
functional level of different vitamin-K dependent coagulation factors, have been the only option for oral 
anticoagulation. In contrast, recently developed Non-Vitamin K antagonist oral anticoagulants (NOAC) 
target selected players in the coagulation cascade as the thrombin inhibitor dabigatran or the factor-Xa 
inhibitors apixaban, rivaroxaban and edoxaban1, 2. Onset of the anticoagulatory effect of NOACs is 
sudden (peak levels between 2 and 5 hours after intake) and anticoagulation lasts only for several hours 
to a few days while treatment with VKA results in a sustained, long lasting inhibition of the coagulation 
cascade3. Since 04/2012, NOAC are approved in Switzerland and widely used for prevention of stroke 
and systemic embolism in atrial fibrillation and prevention and treatment of venous thrombosis and 
pulmonary embolism. Further indications for stroke prevention in patients with embolic stroke of 
unknown source (ESUS) are under investigation (NCT02239120 and NCT02313909). 
Intracerebral hemorrhage (ICH) is the most feared complication of anticoagulation treatment. There is 
no proven effective medical or surgical treatment option for ICH related to NOAC treatment (NOAC-
ICH). Up to now, data on characteristics, management and outcome of NOAC-ICH is lacking. 
Nevertheless data on anticoagulation-associated ICH may be derived from patients on VKA that suffer 
ICH (VKA-ICH). Therefore, in the following, we summarize the current knowledge on VKA-ICH and draw 
conclusions by analogy to NOAC-ICH, whenever data about NOAC-ICH are not available or insufficient. 
 
Intracerebral hemorrhage and anticoagulation 
In VKA-ICH, initial hematoma volume is larger4 than in patients not taking anticoagulants. In addition, 
growth of the initial hematoma volume over time - hematoma expansion (HE) - occurs more frequently 
(45% to 56%5-7) than in patients with ICH not associated with the use of anticoagulants (16% to 26%5, 
7). Consequently, VKA-ICH leads to an increase in unfavourable functional outcome and mortality 
compared to ICH without prior anticoagulation4, 7. ICH related to anticoagulation increased from 5% of 
all ICH in the 1980s, to 11% in the 1990s, and up to 20% in the early 2000s8, 9. Recent data link early 
aggressive treatment using a combination of prothrombin complex (PCC) and fresh frozen plasma 
(FFP)10 and fast INR-reversal within 4 hours and lowering of blood pressure11 with improved outcome 
in VKA-ICH. 
 
A reduced rate of intracerebral hemorrhages is reported for all NOAC compared to VKA12. Nevertheless, 
also in patients on NOAC intracerebral hemorrhage (NOAC-ICH) occurs in 0.52 to 0.78% per patient 
per year12. Little is known about management and outcome of patients with NOAC-ICH. Single case 
reports, one small single center retrospective study (n=5) and data extracted from the larger trials 
reported on frequent hematoma expansion, and a high case fatality rate13-19.  
Little is known about the HE-rate in NOAC-ICH. The to date largest study20  found no difference in the 
HE-rates between NOAC-and VKA-ICH patients. None of the patients in the aforementioned study was 
treated with TA.    
 
Treatment strategies for anticoagulation-associated ICH 
For VKA-ICH, guidelines of the American21 and the European Stroke Organisation22 urge acute reversal 
of anticoagulation by administration of PCC or FFP and vitamin-K. But despite effective reversal 
(measured by INR normalization), hematoma expansion in VKA-ICH still occurs in 45% of patients and 
prognosis is poor6 but fast and aggressive treatment is associated with improved outcome10, 11. Thus 
despite acute reversal of VKA-effect in ICH, there is a need for effective add-on treatments. 
In NOAC-ICH, there are only limited data from rodent models23-25 and no clinical data on treatment 
options26. 
 
Antidotes for NOAC   
Recently, specific reversal agents for NOACs have been developed27, 28 and are about to be licensed 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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for clinical use One study published testing ex vivo effect for a specific antibody against dabigatran – 
idarucizumab27. Further specific antidotes include andexanet alfa, a truncated form of enzymatically 
inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: 
rivaroxaban, apixaban and edoxaban) and aripazine, a synthetic small molecule that reverses oral 
dabigatran, apixaban, rivaroxaban. The published data on idarucizumab and andexanet alpha showed 
promising pharmacological reversal of the measurable effect of NOACs in peripheral blood samples. 
One study28 only included healthy individuals while 2 other studies included a mix of patients taking 
dabigatran29 or factor Xa-inhibitors (Apixaban or Rivaroxaban)30 respectively that suffered from major 
bleeding or needed urgent surgery. Patients with NOAC-ICH represented only a minority in both studies 
with 24 respectively 20 patients including in the majority patients with small (<10ml) to medium ICH-
volumes. There were no comparison groups in both studies. Only few clinical outcome parameters from 
this single arm trials were published showing that, mortality was still high of up to 15-20%. None of the 
above mentioned planned or conducted trials includes clinical endpoints as primary outcome measure.  
 
Combined use of antidots with tranexamic acid  
In one ex vivo study investigating the effect of PCC compared to idarucizumab on coagulation 
parameters in an animal model of traumatic systemic bleeding with a prior intake of dabigatran, 
additional treatment with tranexamic acid was beneficial in both treatment regimens – PCC and 
idarucizumab27. 
Current European Stroke Organisation guidelines22 published 2014 for the treatment of NOAC-ICH are 
based on theoretical considerations and expert opinions31. Due to the lack of evidence-based-data there 
is no recommendation for a specific treatment of NOAC-ICH.  
 
Hematoma expansion – a surrogate marker for unfavourable outcome 
Outcome after intracerebral hemorrhage is closely related to whether brain bleeding expands after onset, 
so called hematoma expansion (HE), and is associated with a poor outcome32. Especially, in the 
presence of oral anticoagulation hematoma volume is usually large and HE occurs frequently4. 
Observational studies report rates of HE ranging from 36% in patients with primary ICH (e.g. without 
prior treatment with anticoagulants) to 45-56% in patients on vitamin K-antagonists (VKA)5-7. In patients 
with ICH not-associated with anticoagulation, extravasation of contrast medium within the hematoma – 
the spot-sign – is a radiological biomarker to identify patients with a higher rate of HE of up to 61%33. 
There are no reports on the significance of the spot-sign in NOAC-ICH. HE is used as primary outcome 
measure in trials for ICH in spot-sign positive patients and treatment with tranexamic acid 
(NCT01702636, which excluded patients with NOACS)34 or recombinant factor VIIa (NCT00810888) 
and as a secondary outcome measure in other trials in ICH. 
 
Tranexamic acid 
Tranexamic acid (TA) is an anti-fibrinolytic drug that can be administered intravenously or orally and is 
used in a number of bleeding conditions to reduce bleeding35. In a recent trial (CRASH-2) in 20,000 
patients with major bleeding following trauma, TA significantly reduced mortality with no increase in 
vascular occlusive events36. 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 
intracerebral hemorrhage, TA showed a non-significant trend to reduced mortality and death of 
dependency37. However, patients in CRASH-2 were younger and had less co-morbidities than those 
with spontaneous intracerebral hemorrhage. A single-center randomized pilot-trial showed feasibility of 
rapid administration of TA in patients with intracerebral hemorrhage38. Since 2012, an investigator-
initiated phase III trial (TICH-II) investigates whether TA is safe and reduces death and dependency 
after hyperacute (within 8 hours of onset) primary ICH (i.e. no prior treatment with anticoagulants)39. 
Patients with NOAC-ICH are excluded from this trial. In an animal model of traumatic systemic NOAC-
bleeding, TA was given in addition to treatment with the specific antibody idarucizumab or PCC and was 
beneficial in both treatment regimes27. We therefore hypothesize that TA might be a beneficial treatment 
in NOAC-ICH. 
3.2 Investigational Product 
 

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3.2.1 
Description and Manufacture 
Intravenous tranexamic acid (Cyklokapron, 100mg/ml 5ml ampoules, Pfizer Manufacturing 
Authorisation: PL 00057/0952) or matched placebo of intravenous Sodium Chloride 0.9% 5ml ampoules 
(Hameln, Manufacturing Authorisation: 1502 / 0006R). Tranexamic acid 100mg/ml 5ml ampoules are a 
licensed product and the summary of the product characteristics is available for investigator. 
 
3.2.2 
Blinding and unblinding procedure 
The tailoring and randomisation of the study medication will be performed by the Hospital Pharmacy of 
the USB according to GMP. Each study medication package consists of either experimental or 
comparator using licensed and labelled products packed in an outer box which is blinded. The packed 
and therefore blinded study medication will be provided to the study team after randomization. An 
unblinded study nurse will prepare the study medication and administer it to the patient. The used vials 
are packed again in the outer box and sealed. In case of unblinding, the box with the used vials can be 
opened and assignment is visible.  
 
3.2.3 
Trial treatments  
 
The treatments to be used in this trial are outlined below in Table 1: 
 
Drug 
Dose 
Administration 
Route 
of 
Administration 
Use 
Tranexamic 
acid 
(Cyklokapron)  
2000 
mg 
Loading dose of 1000 mg in 100 ml 
normal saline over 10 minutes 
followed by 1000 mg in 250 ml normal 
saline as a continuous infusion over 8 
hours 
Intravenous 
Experimental 
Normal Saline 
0,9 %  
Loading dose of 10 ml in 100 ml 
normal saline over 10 minutes 
followed by 10 ml in 250 ml normal 
saline as a continuous infusion over 8 
hours 
Intravenous 
Comparator 
Table 1: Trial treatments 
 
3.2.4 
Packaging, Labelling and Supply (re-supply)  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of the study medication in 
accordance with the protocol and any applicable laws and regulations.  
 
Product descriptions 
 
Product name 
Potency 
Dosage Form 
Tranexamic acid (Cyklokapron)  
1000 mg / 10 ml 
Solution for infusion 
NaCl 0,9% Mini-Plasco Fresenius 
0,9%  
Solution for infusion 
 
Study medication will be packed in an outer box and labelled in accordance with regulatory 
requirements. Labels for the infusion bags will also be packed in the outer box.  
 
Receipt and dispensing of study medication must be recorded at the study site. Study medication must 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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not be used for any purpose other than that stated in the protocol.  
3.2.5 
Storage Conditions 
 
Study medication must be stored in a secure, limited-access location under the storage conditions 
specified on the label 
 
3.2.6 
Known Side Effects 
 
Gastrointestinal disorders (nausea, vomiting, diarrhoea) may occur but disappear when the dosage is 
reduced. Hypotension has occasionally been reported after rapid intravenous infusion. Rare instances 
of colour vision disturbances have been reported following long-term use. Rare cases of 
thromboembolic events have been reported. Rare cases of allergic skin reactions have also been 
reported (see Appendix A). Tranexamic acid will counteract the thrombolytic effect of fibrinolytic 
preparations but these would be contra-indicated in patients with haemorrhagic stroke. 
3.3 Explanation for choice of comparator (or placebo)  
 
The comparator of the IMP is placebo in addition to best medical treatment in a Stroke Center according 
to local SOPs following national and international guidelines. The trial steering committee encourages 
all investigators to evaluate the use of idaruzicumab for patients suffering ICH under dabigatran or 
andexanet alpha for patients suffering ICH under treatment with a factor Xa-inhibitor (edoxaban, 
rivaroxaban or edoxaban) if available. This approach guaranties that NOAC-ICH-patients participating 
on TICH-NOAC will have the chance to benefit from a potentially beneficial agent on top of state-of-the-
art treatment, available for all participants.  
3.4 Risks / Benefits  
 
Benefit 
Patients participating in TICH-NOAC may directly benefit from a potentially beneficial treatment 
(tranexamic acid) in addition to standard medical state-of-the-art treatment. This benefit can consist in 
a reduced rate of hematoma expansion and an improved clinical outcome. 
 
Risks: 
Patients may experience an increased risk for thromboembolic complications including ischemic stroke 
or deep venous thrombosis due to treatment with tranexamic acid although this risk was not elevated 
compared to placebo in prior trials involving tranexamic acid36. 
 
Trial Procedures 
Patients suffering intracerebral haemorrhage under a prior treatment with a NOAC will be included in 
this study shortly after admission to a participating center and after informed consent has been obtained 
(see page 17). After inclusion, patients will receive two intravenous infusions containing either 
tranexamic acid or placebo (a bolus containing of 100ml over 10 minutes followed by a 8 hours infusions 
of 250ml). 24 hours after admission, a single run non-contrast CT head scan will be performed (day 2). 
Patients will be followed up in-hospital until day 7/discharge with a final outpatient follow-up at 90 days. 
If patients are unable to come for the follow-up visit to the study center, a telephone interview with the 
patient or care giver will be performed. 
 
Details of radiation materials and dose 
The doses from CT scans will vary between sites with different models of equipment and between 
different sizes of patient. 
A CT of the brain will give an average of 1.5mSv but this could be up to a maximum of 5mSv. So a 
typical dose from CT due to research exposures would be 1.5mSv, but could be as high as 5mSv. 
A 1.5mSv dose would be roughly equivalent to 8 months of exposure to natural background radiation to 
a member of the public resident in Switzerland. A 5mSv dose is roughly equivalent to 2¼ years of 
background received by a member of the public resident in Switzerland. 
A follow-up CT-scan is often performed also in clinical routine, in order to search for either (i) HE or (i) 
complications such as intraventricular expansion or hydrocephalus which is important for management 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
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and prognosis. Thus participation in TICH-NOAC must not necessary mean an exposition to additional 
radiation. Contrast agents are not involved in the study CT-scan at follow-up.   
 
Risk Assessment (induction of fatal cancer) 
Based on a risk coefficient for developing fatal radiation induced cancer (all ages) of 5%/Sv (ICRP), this 
would lead to a risk of radiation exposure incurred as part of the trial similar to the annual risk of dying 
from an accident in the home. This is classed as an intermediate risk and the required benefit should 
be aimed directly at diagnosis, cure or prevention of disease. 
 
 

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4. STUDY OBJECTIVES  
4.1 Overall Objective 
To demonstrate that treatment with TA for NOAC-ICH is beneficial. The results of this trial will determine 
whether TA should be used for the treatment of NOAC-ICH.  
4.2 Primary Objective 
The primary objective is to show that treatment with TA in patients with NOAC-ICH reduces the rate of 
HE as a surrogate marker for unfavourable outcome. 
4.3 Secondary Objectives 
Secondary objectives of this trial are to show that treatment with TA for NOAC-ICH increases the 
proportion of patients having a favourable clinical outcome and to show that TA influences hematoma 
expansion in different definitions. 
5. STUDY OUTCOMES  
5.1 Primary Outcome 
The primary outcome measure is hematoma expansion (HE). In line with prior research33, HE is defined 
as an increase of 33% relative or 6ml absolute growth between ICH-volume on baseline CT and on 
follow-up-CT at 24 ± 3 hours.  
5.2 Secondary Outcomes 
Secondary outcome measures are  
(I) 
modified Rankin Scale (mRS) 0–4 at three-months;  
(II) 
mRS 0–3 at three-months;  
(III) 
Categorical shift in mRS at three-months;  
(IV) 
Absolute ICH growth volume by 24 ± 3 hours, adjusted for baseline ICH volume;  
(V) 
Symptomatic HE defined as HE and neurological deterioration of NIHSS >4 points or GCS 
>2 points 
(VI) 
Death due to any cause by three-months; 
(VII) 
major thromboembolic events (myocardial infarction, ischemic stroke, pulmonary 
embolism – safety endpoints) 
(VIII) 
NCH intervention (including craniectomie, EVD, hematoma evacuation) 
(IX) 
In-hospital mortality 
 
 

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6. STUDY DESIGN  
6.1 General study design and justification of design  
 
This trial is a randomized, controlled, double-blinded, placebo-controlled phase IIb/III trial investigating 
whether tranexamic acid is beneficial for the treatment of NOAC-ICH. Up to now, no evidence proven 
treatment for NOAC-ICH exists. The trial will be performed in 7 Swiss Stroke Centers recruiting 109 
patients. Extension to international centers is intended. 
 
6.2 Methods of minimising bias  
Patients recruited in this trial will be randomly allocated 1:1 to receive either tranexamic acid (TA) or 
placebo. Evaluation of the primary outcome parameter (HE) will be done by 3 independent raters blinded 
to study treatment. 
 
6.2.1 
Randomisation  
Patients will be randomly allocated to TA or placebo in a 1:1 ratio. Randomisation will be performed by 
central computer over the Internet using the eCRF. The investigators will record patient details via a 
secure web interface before randomisation takes place. Investigators may also contact the Trial 
Coordinating Centre via the 24-hours help-line. 
 
The randomisation procedure will include a standard minimisation algorithm which will ensure that the 
treatment groups are balanced for key prognostic factors, such as sex, age, NIHSS score on admission 
and use of specific antidote treatment. To avoid predictable alternation of treatment allocation, and thus 
potential loss of allocation concealment, patients will be allocated with a probability of 0.80 to the 
treatment group that would minimise the difference between the groups on the key prognostic factors. 
 
 
 

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7. STUDY POPULATION  
Consecutive patients admitted to one of the participating stroke centers are enrolled according to the 
following inclusion and exclusion criteria: 
7.1 Eligibility criteria  
 
Inclusion criteria: 
 
Acute intracerebral haemorrhage 
 
Prior treatment with a non-vitamin K antagonist oral anticoagulant (NOAC: apixaban, 
dabigatran, edoxaban or rivaroxaban; last intake <48hours OR proven* NOAC activity by 
relevant coagulation assays) ) 
 
Time of onset <12 hours (or in patients with unknown time of symptom onset, the time patient 
was last known to be well divided by 2) 
 
Age >18 years, No upper age limit 
 
Informed consent has been received in accordance to local ethics committee requirements 
 
*proven NOAC activity is defined as measurable NOAC plasma levels with a suitable specific 
coagulation test (calibrated anti-factor Xa activity, escarin clotting time) if available. 
 
Exclusion criteria: 
 
Severe pre-morbid disability (modified Rankin scale >4)  
 
Anticoagulation with VKA 
 
Secondary intracerebral hemorrhage (e.g., AVM, tumor) Note it is not necessary for 
investigators to exclude underlying structural abnormality prior to enrolment, but where an 
underlying structural abnormality is already known, these patients should not be recruited. 
 
Glasgow coma scale <5 
 
pregnancy 
 
Planned neurosurgical hematoma evacuation within 24 hours (before follow-up imaging) 
 
Recent pulmonary embolism/deep vein thrombosis within the last 2 weeks 
7.2 Recruitment and screening  
Patients will be recruited at the participating centers from the acute stroke unit or emergency department. 
Patients will be approached from a member of the patient’s usual care team (which may include 
investigators). Local investigators or their nominee will inform the participant or their legal representative, 
of all aspects pertaining to participation in the study. It will be explained to the potential participant or 
their legal representative that entry into the trial is entirely voluntary and that their treatment and care 
will not be affected by their decision. It will also be explained that they can withdraw at any time but 
attempts will be made to avoid this occurrence. In the event of their withdrawal it will be explained that 
their data collected so far cannot be erased and we will seek consent to use the data in the final analyses 
where appropriate. If patients are unable to consent themselves (for example due to severe neurological 
deficits including impaired consciousness or aphasia) they can be included in the study if there is no 
information available (for example patient decree) providing evidence that the patient does not want to 
participate in any scientific study. In this case, an independent doctor unrelated to the study will ensure 
patient’s custody. If the patients will be able to provide informed consent themselves at a later time point 
during the study, a signed informed consent from the patients will be obtained. If it is likely that the 
patient will not be able to give informed consent throughout the whole study period, a legal 
representative will be contacted to obtain informed consent as to the patient’s presumed will. 
7.3 Assignment to study groups  
Patients will be randomly assign 1:1 one to receive either Tranexamic acid or placebo by a web-based 
randomization tool. 
7.4 Criteria for withdrawal / discontinuation of participants  
 
Participation in the trial is voluntary and patients are free to withdraw from the trial at any stage without 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
Page 25 of 37 
giving a reason. Study medication may be stopped at any time by the investigators or any treating 
clinician if deemed in the patient’s best interest. Treatment (with tranexamic acid/placebo) will be given 
on top of ‘best medical care’. Participants may be withdrawn from the trial either at their own request or 
at the discretion of the Investigator. The participants will be made aware that this will not affect their 
future care. Participants will be made aware (via the information sheet and consent form) that should 
they withdraw the data collected to date cannot be erased and may still be used in the final analysis. 
Enrolled participants who withdraw before randomisation can be replaced (though keeping their trial ID), 
but participants who withdraw after randomisation will not be replaced. 
 

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8. STUDY INTERVENTION  
8.1 Identity of Investigational Products (treatment)  
  
IMP means intravenous tranexamic acid (1g loading dose given as 100 ml infusion over 10 minutes, 
followed by another 1g in 250 ml infused over 8 hours) or as comparator placebo (normal saline 0.9%) 
administered by identical regimen. 
8.1.1 
Experimental Intervention (treatment) 
IMP means intravenous tranexamic acid (1g loading dose given in 100 ml infusion over 10 minutes, 
followed by another 1g in 250 ml infused over 8 hours)  
8.1.2 
Control Intervention (comparator treatment)  
Control intervention means intravenous saline 0.9% (10ml NaCl 0.9% in 100 ml given as loading dose 
infusion over 10 minutes, followed by another 250 ml NACL 0.9% infused over 8 hours)  
8.1.3 
Packaging, Labelling and Supply (re-supply)  
The web-based system operates as follows: Participating centres will be allocated a batch of trial 
treatment. The container numbers for these batches are tracked by the web-based system to the 
participating site and once receipt has been confirmed they are released for use in the trial. When the 
supplies at the participating centre reach a pre-determined level then a re-order is triggered and a further 
supply of trial treatment is sent to the corresponding participating site. 
8.1.4 
Storage Conditions, dispense and return  
The packs will be stored at room temperature and protected from excessive heat and freezing in a 
restricted access area. Stability data exists which demonstrates that Tranexamic Acid is stable at 
temperatures between -20°C and 50°C. Temperature monitoring will not be required. The IMP will be 
clearly labelled for clinical trial use only. Each pack will be a numbered box containing either tranexamic 
acid or placebo according to a computer-defined sequence. 
 
The local site investigator is responsible for ensuring trial treatment accountability, including 
reconciliation of trial treatment and maintenance of trial treatment records, throughout the course of the 
study in accordance with local regulatory requirements. Responsibility can be delegated to the site 
pharmacy clinical trials staff. 
 
Following randomisation the participant will be allocated a treatment pack number. Specifically 
authorised personnel will retrieve the appropriate pack number and complete the participant name, date 
of randomisation and participant number. Pack number allocation will be checked and countersigned by 
the research staff and the nursing staff administering the treatment. The treatment will be prescribed on 
the participant’s treatment chart as trial medication. The nurse administrating the study treatment is 
unblinded, which represents a potential bias. Nevertheless, all personal will receive order not to 
communicate to anybody the treatment and whether it contains tranexamic acid or placebo. Nursing 
staff administrating the treatment is not involved in the evaluation of any outcome parameters. 
 
Dispensing will be recorded on the appropriate trial specific accountability forms. Trial treatment must 
not be used for any other purpose than the present study. Returned trial treatment that has been 
dispensed to a participant must not be re-dispensed to a different participant. Any unused drug will be 
returned to pharmacy. 
8.2 Compliance with study intervention  
Compliance with study intervention will be monitored by checking prescription drug charts. The 
pharmacist will maintain records of the dispensing of the drug and the research nurse will record 
administration of the drug to the patient. Dispensing details will be recorded on each participant’s CRF. 
Unused and partially used supplies will be returned to pharmacy. This will be recorded in the pharmacy 
study log. 
 
 
 

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9. STUDY ASSESSMENTS  
Participants will be assessed before treatment (day 1), after treatment (day 2), after 7 days, at 
death/discharge and 90 days. See flow chart for more details. 
 
Patients will be assessed clinically at baseline in line with local clinical practice prior to inclusion (day 1), 
end of treatment (day 2), on day 7 and at discharge/death (in hospital – if death/discharge occurs before 
day 7 visit, both visits are performed simultaneously). Follow up at day 90 (+/- 14 days) will be via a 
clinical outpatient visit or – if the patients’ functional status does not allow outpatient visit – by a 
structured telephone interview with the patient, next-to-kin or other care-giver.  
Brain imaging (CT head scan) will be performed as part of routine clinical management prior to 
enrolment (all acute stroke patients have a CT head scan performed on admission to hospital). For the 
purpose of the study the CT head scan will be repeated after treatment, day 2, (tranexamic acid/placebo) 
to assess haematoma expansion. A day 2 CT scan for patients with intracerebral haemorrhage is part 
of standard care in many stroke centers. In this case, routine day 2 CT scan can be used for trial purpose 
and no additional CT scan is required. If a patient received MRI scan on admission as first neuroimaging, 
the patient will undergo a baseline CT scan after inclusion in the trial to assure that hematoma expansion 
can be measured correctly and is comparable throughout all patients included in the study. 
 
9.1 Study flow chart(s) / table of study procedures and assessments 
 
Study Periods 
 
Screening 
Randomisation
/Treatment 
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
day 
1 
1 
2 
7 (+/- 
24h) 
Death/ 
discharge 
90 
(+/-
14 days)
Patient 
Information 
and 
Informed Consent 
x 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
In- /Exclusion Criteria 
x 
 
 
 
 
 
NIHSS 
x 
 
x 
x 
 
x 
Vital Signs (RR, heart rate) 
x 
 
x 
x 
 
x 
Laboratory Tests 
x* 
 
 
 
 
 
Pregnancy Test# 
x 
 
 
 
 
 
Randomisation 
 
x 
 
 
 
 
CT scan 
x*  
x1 
x 
 
 
 
Study treatment 
 
x 
 
 
 
 
mRS 
x 
 
x 
x 
x 
x 
Secondary 
outcome 
variables 
 
 
 
 
 
x 
Concomitant 
Therapy, 
Intervention 
 
x 
x 
x 
x 
 
Adverse Events 
 
x 
x 
x 
x 
x 
NIHSS: National Institute of Health Stroke Severity Scale; mRS: modified Rankin Scale Score; CT: 
computer tomography 
* routine CT scan/laboratory test 
# in woman of childbearing age 
1only if no baseline-CT scan performed as part of routine-work up (for example baseline brain imaging 

TICH-NOAC, Version 1.4 of April 16th 2020 
 
Page 28 of 37 
is MRI) 
9.2 Assessments of outcomes  
9.2.1 
Assessment of primary outcome  
Evaluation of hematoma volume and hematoma expansion will be based on 2 CT scans. All participants 
at one center will be evaluated with identical imaging protocols at baseline and follow-up. The first CT 
scan is part of clinical routine. The follow-up scan on day 2 will be part of the study protocol (if not 
performed in routine clinical care). If a patient received MRI scan on admission as first neuroimaging, 
the patient will undergo a baseline CT scan after inclusion in the trial to assure that hematoma expansion 
can be measured correctly and is comparable throughout all patients included in the study. 
 
In line with prior research33, hematoma expansion (HE) is defined as an increase of 33% relative or 6ml 
absolute growth between ICH-volume on baseline CT and on follow-up-CT at 24 ± 3 hours.  
All images will be evaluated independently by a rater blinded to treatment and outcome (experienced 
stroke neurologist/neuroradiologst) at the imaging core lab in Basel.  
 
Any intraventricular hemorrhage (IVH) components will not be included in ICH volumes. In addition, 
presence or absence of the spot-sign33 on baseline CT-scan will be assessed in the core lab. 
 
Semi-automatic segmentation by region growing will be performed using the Aquarius software (Version 
4.4.8) by Terarecon. The target region (hematoma) will be selected manually and region growing in full 
resolution and medium connectivity will be done automatically (region growing is spherical from seed 
point with regard to houndsfield units connected to seed point). Finally, segmentation and identified 
hematoma in three planes will be controlled manually. Target volumetry will be calculated automatically 
of the segmented area by the software and will result in a volume given in cm3. 
 
9.2.2 
Assessment of secondary outcomes 
The following secondary outcome measures are assessed at day 90 and day 365 visit: (I) modified 
Rankin Scale (mRS) 0–4; (II) mRS 0–3; (III) Categorical shift in mRS; (IV) Death due to any cause. 
The following secondary outcome measures are assessed based on the day 2 CT-scan: (V) Absolute 
ICH growth volume by 24 ± 3 hours, adjusted for baseline ICH volume; (VI) Symptomatic HE defined as 
HE and neurological deterioration of NIHSS >4 points or GCS >2 points  
 
9.2.3 
Assessment of safety outcomes 
Throughout the study, information on the following safety outcome events will be collected at each visit: 
major thromboembolic events (myocardial infarction, ischemic stroke, pulmonary embolism) 
 
9.2.3.1 
Adverse events  
An adverse event is any unfavourable and unintended sign, symptom, syndrome or illness that develops 
or worsens during the period of observation in the study. 
 
An AE does include a / an: 
1. Exacerbation of a pre-existing illness. 
2. Increase in frequency or intensity of a pre-existing episodic event or condition. 
3. Condition detected or diagnosed after medicinal product administration even though it may 
have been present prior to the start of the study. 
4. Continuous persistent disease or symptoms present at baseline that worsen following the start 
of the study. 
 
An AE does not include a / an: 
1. Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); but the 
condition that lead to the procedure is an AE. 
2. Pre-existing disease or conditions present or detected at the start of the study that did not 
worsen. 
3. Situations where an untoward medical occurrence has not occurred (e.g., hospitalisations for 
cosmetic elective surgery, social and / or convenience admissions). 

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4. Disease or disorder being studied or sign or symptom associated with the disease or disorder 
unless more severe than expected for the participant’s condition. 
5. Overdose of concurrent medication without any signs or symptoms. 
 
A Serious Adverse Event (SAE) is any adverse event occurring following study mandated procedures, 
having received the IMP or placebo that results in any of the following outcomes: 
1. Death 
2. A life-threatening adverse event 
3. Inpatient hospitalisation or prolongation of existing hospitalisation 
4. A disability / incapacity 
5. A congenital anomaly in the offspring of a participant 
 
Important medical events that may not result in death, be life-threatening, or require hospitalisation may 
be considered a serious adverse event when, based upon appropriate medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition.  
 
A distinction is drawn between serious and severe AEs. Severity is a measure of intensity whereas 
seriousness is defined using the criteria above. Hence, a severe AE need not necessarily be serious. 
Serious adverse events are common in haemorrhagic stroke, for a full list of expected SAE that are not 
subject to expedited reporting, investigators should refer to Appendix A. 
 
As the IMP is administered once and has a short half-life, serious adverse events occurring within the 
first 7 days will be assessed for seriousness, expectedness and causality. In addition fatal SAEs and 
safety outcome events (VTE, recurrent stroke, TIA, MI, PAD and seizures) will be reported until day 90. 
9.2.4 
Causality and reporting 
 
Not related or improbable: a clinical event including laboratory test abnormality with temporal 
relationship to trial treatment administration which makes a causal relationship incompatible or for which 
other drugs, chemicals or disease provide a plausible explanation. This will be counted as “unrelated” 
for notification purposes. 
 
Possible: a clinical event, including laboratory test abnormality, with temporal relationship to trial 
treatment administration which makes a causal relationship a reasonable possibility, but which could 
also be explained by other drugs, chemicals or concurrent disease. This will be counted as “related” for 
notification purposes. 
 
Probable: a clinical event, including laboratory test abnormality, with temporal relationship to trial 
treatment administration which makes a causal relationship a reasonable possibility, and is unlikely to 
be due to other drugs, chemicals or concurrent disease. This will be counted as “related” for notification 
purposes. 
 
Definite: a clinical event, including laboratory test abnormality, with temporal relationship to trial 
treatment administration which makes a causal relationship a reasonable possibility, and which can 
definitely not be attributed to other causes. This will be counted as “related” for notification purposes. 
 
An AE whose causal relationship to the study IMP is assessed by the Chief Investigator as “possible”, 
“probable”, or “definite” is an Adverse Drug Reaction. With regard to the criteria above, medical and 
scientific judgment shall be used in deciding whether prompt reporting is appropriate in that situation. 
 
Participants will be asked to contact the study site immediately in the event of any serious adverse event. 
All adverse events will be recorded and closely monitored until resolution, stabilisation, or until it has 
been shown that the study medication or treatment is not the cause. The Chief Investigator (delegated 
the sponsor’s responsibilities) shall be informed immediately (within 24 hours) of any serious adverse 
events, occurring within the first 7 days and shall determine seriousness and causality in conjunction 
with any treating medical practitioners. Reporting of SAE to the competent EC will be done in 
accordance with Swiss laws. 
 
 
 

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10. SAFETY  
During hospitalisation in the participating center until day 7, all adverse events (AE) and all serious 
adverse events (SAEs) are collected, fully investigated and documented in source documents and case 
report forms (CRF). After discharge from the participating hospital and/or day 7 (what occurs first), only 
study outcome events (death, ischemic vascular events) are collected as SAE until end of study. Study 
duration encompassed the time from when the participant signs the informed consent until the last 
protocol-specific procedure has been completed.  
10.1.1 Reporting of SAEs 
All SAEs must be reported immediately and within a maximum of 24 hours to the Sponsor-Investigator 
of the study. The Sponsor-Investigator will re-evaluate the SAE and return the form to the site. 
SAEs resulting in death are reported to the local Ethics Committee (via local Investigator) within 7 days. 
The other in the trial involved Ethics Committees receive SAEs resulting in death in Switzerland via 
Sponsor-Investigator within 7 days using the BASEC account. 
Exemptions from expedited reporting may be possible if the SAE is either a clear result of the underlying 
disease or well-known and described in the currently approved product information.  
10.1.2 Reporting of SUSARs 
A SUSAR needs to be reported to the local Ethics Committee (via Sponsor-Investigator in Switzerland 
using BASEC) and to Swissmedic (via Sponsor-Investigator) within 7 days, if the event is fatal, or within 
15 days (all other events). 
The Sponsor-Investigator will inform all Investigators participating in the clinical study of the occurrence 
of a SUSAR. All in the trial involved Ethics Committees will be informed about SUSARs in Switzerland 
via Sponsor-Investigator according to the same timelines. 
 
 
 

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11. STATISTICAL METHODS  
A detailed Statistical Analysis Plan will be drawn up before breaking the randomisation code. 
11.1 Hypothesis  
The null hypothesis (H0) is that tranexamic acid does not alter HE in participants with acute NOAC-ICH. 
The alternative hypothesis (HA) is that HE differs between those participants randomised to tranexamic 
acid versus placebo. 
11.2 Determination of Sample Size  
There exists no retrospective or prospective study reporting rates of HE in NOAC-ICH. Based on the 
largest available studies investigating HE in anticoagulation-related ICH ranging from 54-56% in VKA-
ICH we estimate a 54% rate of HE in placebo NOAC-ICH patients.  
As there are no previous trial data on the effect of TA in NOAC-ICH, we base our sample size estimate 
on feasible recruitment rates and use an adaptive sample size procedure as done in prior research. 
Estimating a rate of 27% of HE in NOAC-ICH patients receiving TA, we provisionally plan our sample 
size at 109 patients. This yields 80% power to detect a significant absolute difference in the proportion 
of patients with hematoma enlargement at 24 h at a two-sided statistical significance threshold of P = 
0·05. 
 
Justified by lack of previous efficacy data, adaptive increase in sample size is planned. An interims 
analysis of the primary endpoint is performed using data from the first 82 patients. As described in Mehta 
&Pocock the sample size is increased if and only if the results of the interim analysis are ‘promising’ (i.e. 
power is in the predefined ’promising’ range). In the interims analysis conditional power is evaluated 
and if it falls within the prespecified ‘promising’ range between 0.33 - 0.8, the sample size will be 
increased to increase the conditional power to 0.8 level, but at most to the predetermined upper limit of 
218 patients. With a sample size of 218 patients, the trial should detect with 80% power an incidence 
rate in relevant hematoma expansion under TA of 35 % assumed a drop-out rate of 5 % and an incidence 
rate of 54 % under placebo. If the estimated sample size exceeds 218, continuation of the trial will be 
discussed with the CIs and the steering committee. The final decision to increase the sample size or 
stop the trial prematurely will be taken by the CIs and the steering committee.  
11.3 Statistical criteria of termination of trial  
 
The DSMC will recommend to the TSC that the trial be stopped if there is proof beyond reasonable 
doubt (with a 99% CI) of overall benefit with the active treatment or if there is a lower level of evidence 
suggesting overall hazard. Evidence of hazard will include effect on the primary outcome (HE) and 
analysis of safety endpoints, as specified in the protocol (death, VTE, ischaemic events, seizures, 
serious adverse events).  
11.4 Planned Analyses  
Analysis will by intention-to-treat; Missing outcome data will be inputed assuming worst possible 
outcome.  
 
The primary outcome (HE) is be compared between treatment and control arms adjusted for baseline 
volume using binary logistic regression. Although both baseline covariate adjusted and unadjusted 
results will be reported, baseline covariate adjusted analysis is prespecified as the primary outcome 
analysis for this trial.  
 
As secondary outcome analyses, the proportions of mRS 0–4, mRS 0–3, and mortality outcomes will 
be compared between active and placebo arms of the trial adjusted for baseline volume using a binary 
logistic regression model. Analysis of the categorical shift in mRS will also be undertaken on the full 
range of the mRS using the Cochran–Mantel–Haenszel shift test and proportional odds logistic 
regression, subject to the validity of shift analysis model assumptions. Other secondary outcome 
analyses will be carried out according to standard statistical principles for comparison of parametric or 
nonparametric distributions as appropriate. 
 
Exploratory analysis will be run on the primary and secondary outcomes, with adjustments for baseline 

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variables such as age, Glasgow coma scale (GCS), presence of IVH, and ICH location, and in the 
following subgroups: onset-to-treatment time (<six vs. >six-hours), baseline ICH volume (<30 vs. >30 
ml), anatomical location (deep, lobar, or cerebellar), IVH (absent vs. present), GCS (>12 vs. 8–12), and 
age (<70 vs. >70), presence of spot-sign. These analyses will be hypothesis generating, as the trial is 
not powered for them. 
 
 

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12. QUALITY ASSURANCE AND CONTROL  
12.1 Data handling and record keeping / archiving  
All patients will be assigned a unique code number. The patient data will be linked to this number, and 
the patients’ names or other personal identifiers will not be included in the database. The patient 
database will be kept on a separate, secure computer. The code will be stored on another, secure 
computer, and will be deleted 15 years after the results of the trial have been published. The trial’s 
procedures for data protection will conform to the Swiss applicable regulatory requirements, and to the 
conditions set by the Swiss Data Inspectorate. 
12.1.1 Case Report Forms  
Patients’ data will be collected using a web-based electronic case report form located at the Clinical 
Trial Unit in Basel. Case report forms will be filled in by local investigators. 
 
12.1.2 Specification of source documents  
Source data must be available at the site to document the existence of the study participants. Source 
data must include the original documents relating to the study, as well as the medical treatment and 
medical history of the participant. 
12.1.3 Record keeping / archiving  
All study data must be archived for a minimum of 10 years after study termination or premature 
termination of the clinical trial. 
12.2 Monitoring  
During the course of the trial the Data Safety and Monitoring Board (DSMB) will after recruitment of 50% 
and 80% of the trial population perform an review of SAEs, in all patients; in case of concerns, unblinding 
will be requested. If, in their view, there is credible evidence of harm, or overwhelming evidence of 
efficacy, the committee will advise the CIs. Unless this happens, the CIs and the Steering Committee 
will remain ignorant of all interim results. 
 
The DSMB will also be responsible for monitoring the overall conduct of the trial, and may formulate 
recommendations relating to the selection, recruitment, or retention of participants, or their management, 
or to improving their adherence to protocol-specified regimens, and the procedures for data 
management and quality control. 
12.3 Audits and Inspections  
The study documentation and the source data/documents are accessible to auditors/inspectors (also 
CEC and CA) and questions are answered during inspections. All involved parties must keep the 
participant data strictly confidential. 
12.4 Confidentiality, Data Protection  
Direct access to source documents will be permitted for purposes of monitoring, audits and inspections. 
13. PUBLICATION AND DISSEMINATION POLICY  
The trial will be published in accordance with the CONSORT guidelines and will be presented by a 
writing committee on behalf of the investigators. All participating centres and collaborators will be 
acknowledged in the main publication. The primary results and results of any substudies will be 
presented at international meetings and in public media. 
 
 
 

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14. FUNDING AND SUPPORT  
This study is funded by a grant from the Swiss National Science Foundation (grant no: 32003B_163378) 
15. INSURANCE  
Insurance will be provided by the Sponsor. A copy of the certificate is filed in each investigator site file 
and the trial master file. 
 
 

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