Clinical trial NCT03413891
Conditions: Tooth Extraction
Keywords: Anticoagulants Tranexamic Acid
Sponsor: Universitaire Ziekenhuizen KU Leuven
Start date: 2018-02-07; Completion date: 2020-03-19
Enrollment: 222 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In patients treated with direct oral anticoagulants, bleeding events during or after tooth extraction can lead to unscheduled interruption of the antithrombotic treatment and a potential increased risk of thrombo-embolic events. Therefore, an optimal strategy to minimize bleeding events after tooth extractions is required. In this study, the investigators want to assess whether adding tranexamic acid mouthwash reduces the number of bleeding events in patients treated with direct oral anticoagulants and undergoing a tooth extraction.

Detailed description:
Interventional phase IV, randomized, double-blind, placebo-controlled trial:

* Feasibility: a 3-day regimen of tranexamic acid mouthwash in patients treated with direct oral anticoagulants
* Efficacy: reduction of bleeding events after tooth extraction compared to placebo
* Safety: any non-oral bleeding or thrombo-embolic events

Arms: arm 1: 10mL water as mouthwash with white cherry flavor in oral syringes. Once before tooth extraction and 3 times daily during 3 days post-extraction (starting day after extraction). arm 2: 10mL tranexamic acid mouthwash 10% in oral syringes. Once before tooth extraction and 3 times daily during 3 days post-extraction (starting day after extraction).
Interventions: intervention 1: Tranexamic Acid intervention 2: Placebo
Intervention descriptions: intervention 1: Mouthwash intervention 2: Mouthwash

Protocol documents:
Prot_SAP_000.pdf: 
Tranexamic Acid To Reduce Bleeding in Patients 
Treated with New Oral Anticoagulants Undergoing 
Dental Extraction (EXTRACT-NOAC) 
 
 
Protocol Identifying Number: 1 
EUDRACT number: 2017-001426-17 
CTC number: S60131 
Draft or Version Number:  v.1.1 
6 July 2017  
 
Sponsor:  
University Hospitals Leuven, Herestraat 49, 3000 Leuven 
 
 
 
 
 
 
Principal Investigator:  
Peter Verhamme 
UZ Leuven Gasthuisberg 
Cardiovascular Medicine 
Herestraat 49 
3000 Leuven 
peter.verhamme@uzleuven.be 
 
 


ii 
 
Table of Contents 
LIST OF ABBREVIATIONS ....................................................................................................................................... 1 
STATEMENT OF COMPLIANCE ............................................................................................................................. 2 
PROTOCOL SUMMARY ........................................................................................................................................... 3 
SCHEMATIC OF STUDY DESIGN .......................................................................................................................... 4 
1 
KEY ROLES .................................................................................................................................................... 5 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................ 7 
2.1 
Background Information ...................................................................................................................... 7 
2.2 
Rationale ............................................................................................................................................... 8 
2.3 
Potential Risks and Benefits .............................................................................................................. 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits ................................................................................................ 9 
3 
OBJECTIVES AND PURPOSE .................................................................................................................. 10 
4 
STUDY DESIGN AND OUTCOMES ......................................................................................................... 11 
4.1 
Description of the Study Design ...................................................................................................... 11 
4.2 
STUDY OUTCOMES ........................................................................................................................ 11 
4.2.1 
Primary Outcome ........................................................................................................... 11 
4.2.2 
Secondary Outcomes .................................................................................................... 11 
4.2.3 
Exploratory Outcomes ................................................................................................... 12 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................................................... 13 
5.1 
Participant Inclusion Criteria ............................................................................................................ 13 
5.2 
Participant Exclusion Criteria ........................................................................................................... 13 
5.3 
Strategies for Recruitment and Retention ...................................................................................... 13 
5.4 
Participant Withdrawal or termination ............................................................................................. 13 
5.4.1 
Reasons for Withdrawal or Termination ..................................................................... 13 
5.4.2 
Handling of Participant Withdrawals or termination .................................................. 14 
5.5 
Premature Termination or Suspension of Study ........................................................................... 14 
6 
STUDY AGENT ............................................................................................................................................ 15 
6.1 
Study Agent(s) and Control Description ......................................................................................... 15 
6.1.1 
Acquisition ....................................................................................................................... 15 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 15 
6.1.3 
Product Storage and Stability ....................................................................................... 15 
6.1.4 
Preparation ...................................................................................................................... 15 
6.1.5 
Dosing and Administration ............................................................................................ 15 
6.1.6 
Route of Administration ................................................................................................. 15 
6.1.7 
Starting Dose and Dose Escalation Schedule ........................................................... 15 
6.1.8 
Dose Adjustments/Modifications/Delays .................................................................... 15 
6.1.9 
Duration of Therapy ....................................................................................................... 15 
6.1.10 
Tracking of Dose ............................................................................................................ 16 
6.2 
Study agent Accountability Procedures .......................................................................................... 16 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................................................. 17 
7.1 
Study Procedures/Evaluations ......................................................................................................... 17 
7.1.1 
Study specific procedures ............................................................................................. 17 
7.1.2 
Standard of care study procedures ............................................................................. 17 
7.2 
Laboratory Procedures/Evaluations ................................................................................................ 17 
7.3 
Study Schedule .................................................................................................................................. 17 


iii 
 
7.3.1 
Screening ........................................................................................................................ 17 
7.3.2 
Enrollment/Baseline ....................................................................................................... 18 
7.3.3 
Follow-up ......................................................................................................................... 19 
7.3.4 
Final Study Visit .............................................................................................................. 20 
7.3.5 
Early Termination Visit .................................................................................................. 20 
7.3.6 
UNSCHEDULED VISIT ................................................................................................. 20 
7.3.7 
Schedule of Events Table ............................................................................................. 21 
7.4 
Justification for Sensitive Procedures ............................................................................................. 21 
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 21 
7.6 
Prohibited Medications, Treatments, and Procedures ................................................................. 21 
7.7 
Prophylactic Medications, Treatments, and Procedures ............................................................. 21 
7.8 
Rescue Medications, Treatments, and Procedures ..................................................................... 21 
7.9 
Participant Access to Study Agent At Study Closure ................................................................... 21 
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 22 
8.1 
Specification of Safety Parameters ................................................................................................. 22 
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 22 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 22 
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 22 
8.2 
Classification of an Adverse Event ................................................................................................. 22 
8.2.1 
Severity of Event ............................................................................................................ 22 
8.2.2 
Relationship to Study Agent ......................................................................................... 23 
8.2.3 
Expectedness ................................................................................................................. 23 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 23 
8.4 
Reporting Procedures ....................................................................................................................... 23 
8.5 
Study Halting Rules AND SAFETY OVERSIGHT ........................................................................ 24 
9 
CLINICAL MONITORING ............................................................................................................................ 24 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 25 
10.1 
Statistical and Analytical Plans ........................................................................................................ 25 
10.2 
Statistical Hypotheses ....................................................................................................................... 25 
10.3 
Analysis Datasets .............................................................................................................................. 25 
10.4 
Description of Statistical Methods ................................................................................................... 25 
10.4.1 
General Approach .......................................................................................................... 25 
10.4.2 
Analysis of the Primary Efficacy Outcome(s) ............................................................. 25 
10.4.3 
Analysis of the Secondary Outcome(s) ...................................................................... 25 
10.4.4 
Safety Analyses .............................................................................................................. 26 
10.4.5 
Adherence and Retention Analyses ............................................................................ 26 
10.4.6  
Baseline Descriptive Statistics ..................................................................................... 26 
10.4.7 
Planned Interim Analyses ............................................................................................. 26 
10.4.9 
Multiple Comparison/Multiplicity................................................................................... 27 
10.4.10 
Tabulation of Individual Response Data ..................................................................... 27 
10.4.11 
Exploratory Analyses ..................................................................................................... 27 
10.5 
Sample Size ....................................................................................................................................... 27 
10.6 
Measures to Minimize Bias .............................................................................................................. 27 
10.6.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 27 
10.6.2 
Evaluation of Success of Blinding ............................................................................... 27 
10.6.3 
Breaking the Study Blind/Participant Code ................................................................ 27 


iv 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 28 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 28 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 29 
13.1 
Ethical Standard ................................................................................................................................. 29 
13.2 
Institutional Review Board ................................................................................................................ 29 
13.3 
Informed Consent Process ............................................................................................................... 29 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants.... 29 
13.3.2 
Consent Procedures and Documentation .................................................................. 29 
13.4 
Participant and data Confidentiality ................................................................................................ 30 
13.4.1 
Research Use of Stored Human Samples,Specimens or Data .............................. 30 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 30 
14.1 
Data Collection and Management Responsibilities ...................................................................... 30 
14.2 
Study Records Retention .................................................................................................................. 30 
14.3 
Protocol Deviations............................................................................................................................ 31 
14.4 
Publication and Data Sharing Policy ............................................................................................... 31 
15 
STUDY ADMINISTRATION ........................................................................................................................ 31 
15.1 
Study Leadership ............................................................................................................................... 31 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 31 
17  
LITERATURE REFERENCES.................................................................................................................... 32 
APPENDIX ................................................................................................................................................................. 33 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
LMWH 
Low Molecular Weight Heparin 
NOAC 
New Oral Anticoagulant 
NSAID 
Non-steroidal anti-inflammatory drug 
SAE 
Serious Adverse Event 
SAP 
Statistical and Analytical Plan 
TXA 
Tranexamic Acid 
VAS 
Visual Analogue Scale 
VKA 
Vitamin K Antagonist 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with Good Clinical Practice (GCP, ICH E6). The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Institutional Review Board (IRB), except 
where necessary to eliminate an immediate hazard(s) to the trial participants.  
Principal Investigator: Prof. Dr. Peter Verhamme 
Signed: _____________________________________ Date: ______________  
 
 
 


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PROTOCOL SUMMARY 
Title: 
Tranexamic Acid To Reduce Bleeding in Patients Treated with New Oral 
Anticoagulants Undergoing Dental Extraction 
Acronym: 
EXTRACT-NOAC 
Précis: 
Two hundred thirty-six patients treated with NOACs and scheduled for dental 
extraction will be randomized to tranexamic acid mouthwash 10% or placebo: 
one administration before extraction and 3 times daily on day 1 till day 3 after 
extraction. Bleeding events will be evaluated on day 2 and day 7.  
 
Objectives: 
 
Primary objective: To evaluate whether TXA mouthwash reduces the number 
of oral bleeding events in patients who undergo dental extraction and are 
treated with NOACs . 
 
 
Outcome: 
Primary outcome: Any oral bleeding (early or delayed; minor or clinically 
relevant) from randomization till end of study follow-up) 
 
Population: 
Patients treated with a NOAC, aged 18 years or older undergoing dental 
extraction 
 
Phase: 
Phase IV 
 
Number of Sites 
enrolling participants: 
2 
 
Site 1: University Hospitals Leuven, Belgium 
Site 2: Ziekenhuis Oost-Limburg, Genk, Belgium 
 
Description of Study 
Agent : 
 
Tranexamic acid mouthwash (1g in 10ml, 10%) before extraction and 3 times 
daily on day 1 till day 3 after extraction 
Study Duration: 
 
24 months 
Participant Duration: 
7 days 
 
 
 


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SCHEMATIC OF STUDY DESIGN 
 
 
 
 
N=236 
Screening: inclusion and exclusion criteria. Obtain informed consent. 
Standard-of-care: No NOAC on the day of extraction. 
Inclusion and randomization: 
online platform 
TXA group 
N=118 
Placebo group 
N=118 
• 
Study intervention: perform mouthwash before extraction 
• 
Perform dental extraction 
• 
Physician records baseline patient demographics and 
procedure characteristics and sends form to study coordinator 
• 
Restart NOAC 
• 
Study intervention: mouthwash 3 times a day for 3 days 
Day of 
extraction 
Day 1 after 
extraction 
Day 2 after 
extraction 
• 
Follow-up assessment of compliance and bleeding events by 
phone call 
Day 7 after 
extraction 
• 
Follow-up assessment of compliance, bleeding events and 
safety outcome by phone call 


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1 
KEY ROLES 
1. Principal Investigator 
 
Name 
Peter Verhamme, MD, PhD 
Title 
Principal investigator 
Address 
UZ Leuven. Cardiovascular Medicine. Herestraat 49, 3000 Leuven. Belgium. 
Phone 
0032 16 344235 
E-mail 
peter.verhamme@uzleuven.be 
 
2. Assistant 
 
Name 
Isabel Craessaerts 
Title 
Assistant 
Address 
UZ Leuven. Bloedings- en vaatziekten. Herestraat 49, 3000 Leuven. Belgium. 
Phone 
0032 16 343533 
E-mail 
isabel.craessaerts@uzleuven.be 
 
3. Study Coordinator 
 
Name 
Barbara Debaveye 
Title 
Research coordinator 
Address 
UZ Leuven. Studiesecretariaat BLV. Herestraat 49, 3000 Leuven. Belgium 
Phone 
0032 16 343474 
Fax 
0032 16 343493 
E-mail 
barbara.debaveye@uzleuven.be 
 
4. Pharmacy 
 
Name 
Stefanie Goris 
Title 
Pharmacist 
Address 
UZ Leuven. Apotheek. Herestraat 49, 3000 Leuven. Belgium 
Phone 
0032 16 342835 
E-mail 
stefanie.1.goris@uzleuven.be 
 
 


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5. Manufacturing contractor (unblinded) 
 
Name 
Els Ampe 
Title 
Investigational Medicinal Product - Responsible 
Address 
Center for Clinical Pharmacology. Herestraat 49, 3000 Leuven. Belgium 
Phone 
0032 16 342020 
E-mail 
els.ampe@uzleuven.be 
 
6. Co-principal Investigators 
 
Name 
Constantinus Politis, MD, PhD 
Title 
co-principal investigator 
Address 
UZ Leuven Sint-Rafael. Mond-Kaak en Aangezichtschirurgie. Kapucijnenvoer 
33, 3000 Leuven 
Phone 
0032 16 332462 
E-mail 
stan@politis.be 
 
Name 
Isabel Miclotte, MD 
Title 
co-principal investigator 
Address 
UZ Leuven Sint-Rafael. Mond-Kaak en Aangezichtschirurgie. Kapucijnenvoer 
33, 3000 Leuven 
Phone 
0032 16 332462 
E-mail 
isabel.miclotte@uzleuven.be 
 
Name 
Thomas Vanassche, MD, PhD 
Title 
co-principal investigator 
Address 
UZ Leuven. Cardiovascular Medicine. Herestraat 49, 3000 Leuven. Belgium. 
Phone 
0032 16 344235 
E-mail 
thomas.vanassche@uzleuven.be 
 
Name 
Maarten Vanhaverbeke, MD 
Title 
co-principal investigator 
Address 
UZ Leuven. Cardiovascular Medicine. Herestraat 49, 3000 Leuven. Belgium. 
Phone 
0032 16 344235 
E-mail 
maarten.vanhaverbeke@uzleuven.be 


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2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
Since the introduction of new oral anticoagulant drugs (NOACs), the number of patients treated with this 
class of antithrombotics is steadily increasing. For major surgical procedures, vitamin K antagonists (VKAs) 
are discontinued prior to the procedure and resumed thereafter. Temporary interruption of VKA treatment 
confers both an ischemic as well as bleeding risk. This is caused by complex pharmacokinetics during 
interruption, the long half-life of VKA, and concomitant bridging therapy with low molecular weight heparins 
(LMWH). Since there is no increased risk of major bleeding when performing minor procedures such as 
dental extractions on stable VKA treatment, it is current practice not to discontinue VKAs for dental 
extractions (1).  
In contrast to VKA, little evidence is available for the periprocedural management of NOACs in dental 
extractions (2). The current guidelines of the European Heart Rhythm Association advise to perform dental 
extractions at trough level (3-6). However, in clinical practice it can be complicated to schedule the 
extraction at the time of the day corresponding to trough plasma levels.  
We have therefore recently shown that a standardized pragmatic approach in patients who undergo dental 
extractions, by skipping only the dose on the morning of the extraction, regardless of timing of extraction, 
drug regimen or renal function, is feasible and safe (7). In a total of 52 patients, there was no difference in 
the procedural bleeding score or in early bleeding between NOAC patients and controls (patients without 
any antithrombotics). However, delayed bleeding between day 1 and day 7 occurred more frequently in 
anticoagulated compared to non-anticoagulated patients (7 versus none, p=0.01). Similarly, an increase in 
bleeding during the first postoperative week was reported in a retrospective study in patients undergoing 
dental extraction under uninterrupted NOAC treatment (8). The combination of peak plasma levels of the 
NOAC with an immature coagulum at the extraction site could trigger bleeding. 
Since bleeding events can lead to unscheduled interruption of NOAC treatment and subsequent increased 
risk of thrombo-embolic events, an optimal strategy to minimize bleeding events after dental extractions is 
required. In this interventional phase IV study, we want to assess whether adding tranexamic acid (TXA) 
mouthwash reduces the number of bleeding events in patients treated with NOACs undergoing a dental 
extraction. 
 
 
 


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2.2 
RATIONALE  
The aim of this study is to evaluate whether adding TXA 10% mouthwash to standard-of-care (i.e. 
performing the extraction at trough level by skipping the NOAC on the day of the extraction) will decrease 
the number of bleeding events. 
TXA is an antifibrinolytic agent that reversibly inhibits plasminogen, preventing plasmin from degrading 
fibrin. Oral administration of TXA is approved in the United States by the FDA to prevent bleeding in patients 
with hemophilia undergoing dental extraction. To avoid any possible prothrombogenic effects in an 
unselected patient population or accumulation in case of renal insufficiency, there is increased interest in 
topical administation of TXA. It has been shown that upon systemic administration of 1g TXA, peak plasma 
levels reach 7µg/mL, whithout detectable levels in saliva. However, when administering a 10ml 5% TXA 
mouthwash, plasma levels remained low (below 2µg/mL) while the levels in saliva remained at therapeutic 
level for two hours (9). TXA mouth wash is therefore the suitable route of administration, and is considered 
safe without evidence for prothrombotic effects (10). 
Two studies have shown that TXA 5% mouthwash during 7 days after dental extraction significantly reduces 
the number of bleeding events in patients treated with VKA (11, 12). A third study showed no difference 
between a 2-day TXA regimen compared to 5 days (13). In Belgium, 10% TXA mouthwash unidoses are 
commercially available in packages of 10 doses. Therefore, we opt to treat patients with 10% TXA 
mouthwash for 3 days, 3 times a day (9 doses) starting on the day after the dental extraction. In order not 
to mechanically dislodge the immature coagulum, there is no post-extraction mouthwash, but one additional 
mouthwash is performed immediately prior to the dental procedure.  
The control group will receive a water solution, which does not confer any issues. All patients older than 18 
years, treated with a NOAC and scheduled for dental extraction are eligible for inclusion. 
 
 
 


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2.3 
POTENTIAL RISKS AND BENEFITS  
2.3.1 KNOWN POTENTIAL RISKS  
Potential risks of systemic administration of TXA, as reported by the package insert, include convulsions, 
blurred vision, haematuria and thrombo-embolism. However, none of these potential risks have been shown 
to be present in case of mouthwash as compared to systemic administration (10). This can be explained 
by the low systemic TXA levels in case of administration by mouthwash (9). 
Therefore, the immediate potential risk of TXA mouthwash is limited to: 
 
Allergic reaction 
 
Bleeding in case of extensive or traumatic mechanical rinsing 
There are no known long-term risks. Because of these limited potential risks, the potential benefit of this 
treatment is expected to outweigh the risks. 
2.3.2 KNOWN POTENTIAL BENEFITS  
Local administration of TXA is known to reduce bleeding, resulting in immediate potential benefits: 
 
In patients on VKA treatment, TXA 5% mouthwash reduced the number of bleeding events (11, 
12). 
 
In patients undergoing surgery, local administration of TXA significantly reduced the number of 
bleeding events (10). 
Since a reduction of bleeding would possibly result in less unplanned discontinuation of the NOAC, a 
reduction in thrombo-embolic events caused by NOAC cessation can be expected, although the current 
study will not be powered to evaluate this long-term benefit. 
 


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3 
OBJECTIVES AND PURPOSE 
Primary objective:  
 
To evaluate whether TXA mouthwash 10% reduces the number of oral bleeding events in patients 
treated with NOACs and undergoing dental extraction. 
Secondary objectives:  
 
To evaluate whether TXA mouthwash before the extraction reduces the bleeding during the 
procedure. 
 
To evaluate whether TXA mouthwash reduces early and/or delayed bleeding events 
 
To evaluate whether TXA mouthwash reduces minor, clinically relevant or major bleeding events 
or reinterventions. 
 
To evaluate whether TXA mouthwash reduces the number of unplanned NOAC interruptions. 
 
To evaluate the safety of skipping the dose of the NOAC on the day of the extraction. 
Exploratory analyses: 
 
To investigate the potential relationship between time of last NOAC dose administered prior to the 
extraction (regardless of specific NOAC type), time of resuming NOAC after the procedure, and 
bleeding events  
 
To investigate the potential benefit of TXA in subgroups of patients (molar versus non-molar 
extraction)  
 
 


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4 
STUDY DESIGN AND OUTCOMES 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multi-center phase IV clinical trial assessing the 
benefit of TXA mouthwash. 
4.2 
STUDY OUTCOMES 
The procedural bleeding score is a visual analogue score (VAS) ranging from 0 (no bleeding) to 10 
(unstoppable bleeding). 
A reintervention is defined as any procedure in the oral cavity for the treatment of bleeding, performed by 
any dentist or maxillofacial surgeon, except for rinsing the extraction socket with saline. 
All suspected bleeding events and reinterventions will be adjudicated by a blinded adjudicator, unaware of 
the assigned treatment. 
Bleedings are defined as previously published (7): 
 
Minor bleeding: any oral bleeding experienced by the patient that does not require medical contact. 
Eg. blood on the pillow, bleeding requiring the use of additional gauzes, clear red bleeding when 
spitting out the mouthwash 
 
Clinically relevant non-major bleeding: any oral non-major bleeding requiring unplanned medical 
contact (by phone or with any health care professional (dentist, general practitioner, maxillofacial 
surgeon), with or without re-intervention 
 
Major bleeding: any oral bleeding requiring blood transfusion, hospitalization or resulting in death 
 
Early bleeding: any oral bleeding occurring after the extraction up to and including day 1 after the 
extraction 
 
Delayed bleeding: any oral bleeding occurring between day 2 and day 7 
4.2.1 PRIMARY OUTCOME 
 
Any oral bleeding (early or delayed; minor or clinically relevant) 
4.2.2 SECONDARY OUTCOMES 
 
The procedural bleeding score 
 
Early and delayed bleeding 
 
Minor, clinically relevant non-major and major bleeding 
 
Clinically-relevant bleeding (non-major and major) 


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 
The number of reinterventions 
 
The number of unplanned NOAC interruptions 
Safety outcomes: 
 
Any non-oral bleeding 
 
All thrombotic events including myocardial infarction, stroke, systemic embolism and venous 
thrombo-embolism up to the endo of study follow-up.  
4.2.3 EXPLORATORY OUTCOMES 
The following subgroup analyses are planned: 
 
Risk factor analysis for bleeding, eg. patient demographics and procedural characteristics 
 
The number of bleeding events in patients in relation to the time since stopping and resuming 
NOAC in relation to the dental extraction, e.g. in patients who stopped/resumed NOAC treatment 
within 24 hours prior/after extraction compared to more than 24 hours prior/after extraction. 
 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 
 
Patients scheduled for dental extraction and treated with edoxaban, apixaban, rivaroxaban or 
dabigatran 
 
Not having taken the NOAC on the day of the extraction 
 
Provision of signed and dated informed consent form    
 
Stated willingness to comply with all study procedures and availability for the duration of the 
study   
 
18 years or older 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
 
Subjects with any condition that as judged by the Investigator would place the subject at 
increased risk of harm if he/she participated in the study. 
 
Pregnancy or lactation 
 
Known allergic reaction to TXA 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
All patients undergoing dental extraction at the outpatient clinic of the registered sites will be screened for 
eligibility before their dental extraction. Standard-of-care (discontinuation of the NOAC on the day of the 
procedure) is already implemented in the participating site. Adherence to the study protocol will be 
assessed by phone call on day 2 and day 7. 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may terminate participation in the study if:  
 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant    
 
The participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation. 


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5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
When a participant is withdrawn from the study, planned follow-up by phone call will be continued, unless 
the patients does not provide consent to follow-up. However, all data collected prior to discontinuation from 
the study will be retained in the database. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party. If the study is prematurely terminated or suspended, the PI will promptly 
inform the IRB and will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
 
Determination of unexpected, significant, or unacceptable risk to participants    
 
Insufficient compliance to protocol requirements    
 
Data that are not sufficiently complete and/or evaluable    
Study may resume once concerns about safety, protocol compliance, data quality are addressed 
 
 


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6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
6.1.1 ACQUISITION 
Blinded 10% TXA mouthwash or placebo will be manufactured in collaboration with the Center of Clinical 
Pharmacology, University Hospitals Leuven 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Active treatment: 10 doses of 10% TXA mouthwash 10ml, blinded, in oral syringes, labeled 
according to randomization scheme 
 
Placebo: 10 doses of 10ml water with addition of white cherry flavor, in oral syringes, labeled 
according to randomization scheme 
6.1.3 PRODUCT STORAGE AND STABILITY 
Repackaged TXA 10% in 10ml oral syringes (Exacta-Med, Bayer) will be submitted for stability testing to 
Phasius, Stevinstraat 137, 1000 Brussels. As backup, 100ml TXA 10% in glass bottles will be tested for 
stability (room temperature and refrigerated). Batches of 100 syringes (equivalent of 10 patients) will be 
delivered to the sites. 
6.1.4 PREPARATION 
TXA 10% oral ampoules will be repackaged into blinded and labeled 10ml Exacta-Med oral syringes. For 
placebo, white cherry flavor will be added to water up to 10ml and packaged in blinded and labeled 10ml 
Exacta-Med oral syringes. 
6.1.5 DOSING AND ADMINISTRATION 
 
10ml 10% TXA mouthwash before dental extraction 
 
10ml 10% TXA mouthwash from day 1 until day 3, 3 times a day (morning, noon, evening) 
6.1.6 ROUTE OF ADMINISTRATION 
10 ml mouthwash 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
1g TXA in 10ml (10%) mouthwash 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No dose adjustments 
6.1.9 DURATION OF THERAPY 


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Until and including day 3 after extraction. 
6.1.10 TRACKING OF DOSE 
Adherence to study treatment will be assessed during the follow-up phone calls at day 2 and day 7. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
TXA 10% mouthwash is used on-label in this study. A service level agreement between the investigators 
and manufacturing contractor will be made in agreement with good clinical, pharmacological and 
manufacturing practice.  
 
 


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7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  
 
Mouthwash: patients are instructed to gently rinse the mouth with 10ml of 10% TXA or placebo for 1 
minute and to spit out the mouthwash thereafter. 
 
Patients will be given 9 vials of 10ml 10% TXA or placebo and instructed to rinse 3 times a day for 3 
days, starting the day after the procedure. Patients will be instructed to monitor and record bleeding 
events.  
 
Patients will be contacted be telephone call on day 2 and day 7, and the prespecified outcomes will 
be assessed. 
 
In case of unplanned medical contact, the prespecified outcomes will be assessed as planned by 
phone call, and in addition, additional relevant medical data on the type of unplanned medical 
contact will be identified from the medical file. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
 
No NOAC dose is to be taken on the day of the procedure 
 
Dental extraction is then performed according to the current and local standard-of-care, at the 
discretion of the treating physician. The use of additional hemostatic measures is permitted but will 
be recorded. 
 
Patients will be instructed to restart the NOAC the day after the extraction, according to current 
standard-of-care. 
 
Any other antithrombotic medication is to be continued 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
Not applicable 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
 
Review medical history and medication to determine eligibility based on inclusion/exclusion criteria 
(age and use of NOAC). 
 
Obtain informed consent of potential participant verified by signature on study informed consent 
form.  
 
Randomize patient (investigator takes next batch of pre-randomized study medication) 
 


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7.3.2 ENROLLMENT/BASELINE 
 
Assess patient characteristics: 
o 
Age 
o 
Sex 
o 
Date of birth 
o 
Alcohol and tobacco use 
o 
Phone number for follow-up calls 
o 
NOAC type: rivaroxaban, apixaban, dabigatran, edoxaban 
o 
NOAC dose and regimen 
o 
NOAC indication 
o 
Date and time of last NOAC dose 
o 
Serum creatinine when available (up to 12 months before inclusion) 
o 
Other antithrombotic drugs: aspirin (Asaflow®, Cardio-aspirine®), clopidogrel (Plavix®), 
ticagrelor (Brilique®), prasugrel (Efient®), dipyridamole (Aggrenox®), LMWH 
o 
Non-steroidal anti-inflammatory drug use (eg. ibuprofen) 
o 
Record full list of medication in the medical file 
 
Administer the study treatment 
 
Perform dental extraction 
 
Assess procedure characteristics: 
o 
Date and time of extraction 
o 
Number of extracted teeth 
o 
Teeth numbers 
o 
Stitches: yes/no 
o 
Persistent infection: yes/no 
o 
Burring: yes/no 
o 
Procedural bleeding score (0-10) 
o 
Use of additional hemostatic measures: eg. tranexamic acid gauze 
o 
Prophylactic antibiotics: yes/no 
 
Instructions to patient: 
o 
Supply patient with 9 vials of mouthwash  
o 
Supply patients with instructions to perform mouthwash starting 1 day after extraction, 3 
times a day for 3 days 
o 
Instruct patients to restart NOAC the day after the extraction according to their normal 
regimen 
o 
Instruct patients to write down any signs of bleeding 


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7.3.3 FOLLOW-UP  
Follow-up assessment on day 2 (phone call). In case this would be a Saturday, follow-up can be 
performed on Friday afternoon. In case this would be a Sunday, follow-up can be performed on Monday. 
 
 
Date and time of assessment 
 
Date and time of restarting NOAC 
 
Did patient use mouthwash day after the extraction: yes/no 
 
Bleeding assessment: 
o 
Blood on pillow, additional gauze, other: yes/no  
o 
Blood when brushing teeth: yes/no 
o 
Blood when rinsing with mouthwash: yes/no 
o 
Date and time of bleeding 
o 
Unplanned medical contact (by phone, new consultation or hospitalization) with any 
health care professional (dentist, general practioner, maxillofacial surgeon): yes/no 
 
In case of unplanned medical contact: 
o 
Date and time 
o 
Reason (adjudicated): bleeding - infection - death - other (specify) 
o 
Treatment: no treatment - oral antibiotics - only rinsing with saline - hemostasis with 
gauze - hemostasis with coagulation - removal of false coagulum - new sutures - blood 
transfusion - hospitalization 
 
Unplanned interruption of NOAC: yes/no 
 
AE and SAE assessment 
 
 


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7.3.4 FINAL STUDY VISIT 
Follow-up assessment on day 7 (phone call). In case this would be a Saturday, follow-up can be 
performed on Friday afternoon. In case this would be a Sunday, follow-up can be performed on Monday. 
 
 
Date and time of assessment 
 
Number of used study drug vials 
 
Bleeding assessment between day 2 and day 7: 
o 
Blood on pillow, additional gauze, other: yes/no  
o 
Blood when brushing teeth: yes/no 
o 
Blood when rinsing with mouthwash: yes/no 
o 
Date and time of bleeding 
o 
Unplanned medical contact (by phone, new consultation or hospitalization) with any 
health care professional (dentist, general practioner, maxillofacial surgeon): yes/no 
 
In case of unplanned medical contact: 
o 
Date and time 
o 
Reason (adjudicated): bleeding - infection - death - other (specify) 
o 
Treatment: no treatment - oral antibiotics - only rinsing with saline - hemostasis with 
gauze - hemostasis with coagulation - removal of false coagulum - new sutures - blood 
transfusion - hospitalization 
 
Unplanned interruption of NOAC: yes/no 
 
Any signs or symptoms or established diagnosis of stroke, myocardial infarction, deep vein 
thrombosis or pulmonary embolism  
 
Any non-oral bleeding 
 
AE and SAE assessment 
7.3.5 EARLY TERMINATION VISIT 
Not applicable. 
7.3.6 UNSCHEDULED VISIT 
In case of unplanned medical contact, the prespecified outcomes will be assessed as planned by phone 
call, and in addition, additional relevant medical data on the type of unplanned medical contact will be 
identified from the medical file. All suspected bleeding events and reinterventions will be adjudicated by a 
blinded adjudicator, unaware of the assigned treatment. 
 
 


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7.3.7 SCHEDULE OF EVENTS TABLE 
 
Procedures 
Screening 
Day 0 
Baseline 
Day 2 
Follow-up 
Day 7 
Follow-up 
Assess inclusion and 
exclusion criteria 
x 
 
 
 
Informed consent 
x 
 
 
 
Randomization 
x 
 
 
 
Patient characteristics 
 
x 
 
 
Procedure characteristics 
 
x 
 
 
Study drug administration 
 
x 
x (up to day 3) 
 
Outcome assessment 
 
 
x 
x 
Adverse events 
 
 
x 
x 
Serious adverse events 
 
 
x 
x 
 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not applicable 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
The use of the concomitant medication will be recorded in the CRF, including: 
 
Other antithrombotic drugs: aspirin (Asaflow®, Cardio-aspirine®), clopidogrel (Plavix®), ticagrelor 
(Brilique®), prasugrel (Efient®), dipyridamole (Aggrenox®), LMWH 
 
Non-steroidal anti-inflammatory drug use (eg. ibuprofen) 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
In patients treated with NOACs, the use of NSAIDs should be limited according to the current standard-of-
care, and is left at the discretion of the treating physician. 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
Not applicable 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
The treatment of a bleeding event is considered standard-of-care and may include (at the discretion of the 
treating physician): 
 
Rinsing the extraction socket, applying hemostatic measures, removal of the false coagulum, 
stitching 
 
Interruption of the NOAC when necessary 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
TXA 10% mouthwash is commercially available. 


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8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
In this phase IV study with on-label use of TXA mouthwash, no serious adverse reactions are anticipated.  
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product (ICH E2A Guideline. Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
Any untoward medical occurrence that at any dose: 
 
Results in death; 
 
Is life-threatening; 
 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
 
Results in persistent or significant disability/incapacity; 
 
Is a congenital anomaly/birth defect; or 
 
Is an important medical event.  
 
In addition, suspected transmission of an infectious agent, pathogenic or nonpathogenic are considered a 
SAE. Although pregnancy, overdose and cancer are not always serious by regulatory definition, these 
events are handled as SAEs. An overdose is defined as the accidental or intentional administration of any 
dose of a product that is considered both excessive and medically important. 
 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
Not applicable. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 SEVERITY OF EVENT 
The following definitions will be used to assess intensity of AEs per the NCI CTCAE 
criteria: 


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 
Grade 1 Mild AE 
 
Grade 2 Moderate AE 
 
Grade 3 Severe AE 
 
Grade 4 Life-threatening consequences; urgent intervention indicated 
 
Grade 5 Death related to AE 
 
8.2.2 RELATIONSHIP TO STUDY AGENT 
Adverse events will be recorded during the follow-up visit at day 7. The relationship to the study agent will 
be adjudicated: 
 
Related – The AE is known to occur with the study agent, there is a reasonable possibility that the 
study agent caused the AE, or there is a temporal relationship between the study agent and event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between the 
study agent and the AE.    
 
Not Related – There is not a reasonable possibility that the administration of the study agent caused 
the event, there is no temporal relationship between the study agent and event onset, or an 
alternate etiology has been established.    
8.2.3 EXPECTEDNESS  
No adverse events are expected, therefore any adverse event will be unexpected. 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
Adverse events will be assessed at day 2 and 7 follow-up. 
8.4 
REPORTING PROCEDURES 
Following the subject’s written consent to participate in the study, all AEs and SAEs, related to the study 
agent (tranexamic acid, IMP) will be collected.  
Although no drugs other than the study agent will be provided by the sponsor to the subjects participating 
in this interventional study, investigators may become aware of (S)AEs in subjects possibly in relation to 
marketed drugs as a part of their ongoing therapies. Data on SAEs will be collected, and relatedness of 
these events to the use of marketed drugs associated with this study (where applicable) will be assessed 
by the investigator. SAEs determined to be related, including exposure during pregnancy and overdose, 
will be recorded and reported. A form will be completed for any event where doubt exists regarding its status 
of seriousness, including overdose and cancer. Reporting of SAEs of marketed drugs will follow regulatory 
guidelines. Pending on the marketed drug, reconciliation of SAEs cases (case level only) with the 
manufacturer is indicated. (E.g. for apixaban, frequency of reconciliation is planned every 3 months and 


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prior to the database lock or final data summary. BMS GPV&E will email, upon request from the Sponsor, 
the 
GPV&E 
reconciliation 
report. 
Requests 
for 
reconciliation 
should 
be 
sent 
to 
aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation report will be used 
for case identification purposes. If the Sponsor determines a case was not transmitted to BMS GPV&E, the 
case will be sent immediately to BMS. For apixaban, BMS will be contacted at Worldwide.Safety@BMS.com 
for SAE. Adverse Events of special interest for apixaban include potential or suspected cases of liver injury, 
including but not limited to liver test abnormalities, jaundice, hepatitis or cholestasis, regardless of whether 
the events are classified as serious or unexpected.) 
 
8.5 
STUDY HALTING RULES AND SAFETY OVERSIGHT 
Interim analysis will be performed after inclusion of 100 patients to assess thrombotic events, allergic 
reaction and non-oral bleeding. 
9 
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
 
 


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10 
STATISTICAL CONSIDERATIONS  
 
10.1 STATISTICAL AND ANALYTICAL PLANS 
There is no external statistical and analytical plan. 
10.2 STATISTICAL HYPOTHESES 
This is a superiority study. The null hypothesis is that there is no difference in any oral bleeding between 
the intervention group and the control group (primary outcome). 
10.3 ANALYSIS DATASETS 
 
The primary analysis set of interest will first be the intention-to-treat population (all randomized 
patients according to their randomized treatment). 
 
In addition, a sensitivity analysis will be done on the per-protocol population. The per-protocol 
population is defined as the subjects without major protocol deviations who complied to the 
assigned treatment for at least 80%. The per-protocol population will be finalized prior to the 
unblinding of the data. 
10.4 DESCRIPTION OF STATISTICAL METHODS 
10.4.1 GENERAL APPROACH 
 
Categorical and continuous data will be presented by randomized treatment group using 
appropriate summary statistics. 
 
The overall significance level for the primary endpoint of this study is set at 5% (2-sided).  To 
account for the planned interim analysis (see section…), the methods as described by Cui, Hung 
& Wang (1999) will be used to preserve the overall Type I error.  
 
For the secondary endpoints, no adjustment will be made to the significance level to account for 
multiple testing. 
 
For all primary and secondary endpoints, an estimate of the treatment effect and associated 95% 
confidence interval will be presented.  E.g. for the primary endpoint, the risk difference and its 95% 
confidence interval will be presented. 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY OUTCOME(S) 
The number of bleeding events up to day 7 will be analysed in terms of a risk difference between the two treatment 
groups, using the methods described by Cui, Hung & Want (1999).  
10.4.3 ANALYSIS OF THE SECONDARY OUTCOME(S) 


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 
The number of all different type of bleeding events, number of reinterventions and number of 
unplanned NOAC interruptions in the TXA group and placebo group will be compared using the 
Fisher Exact Test or Chi Square test, depending on the number of events. The effect of treatment 
will be estimated by the risk difference and presented along with its associated 95% confidence 
interval. 
The procedural bleeding score in the TXA group and placebo group will be compared using the Student t-
test of Mann-Whitney U-test, as appropriate.  The effect of treatment will be estimated by the difference 
between treatments and presented along with its associated 95% confidence interval. 
 
10.4.4 SAFETY ANALYSES 
 
The number of non-oral bleeding, allergic reactions and thrombotic complications in the TXA group 
and placebo group will be compared using the Fisher Exact Test or Chi Square test, depending on 
the number of events. 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
No formal testing for adherence is planned, but the number of vials of the study drug will be recorded. 
Compliance will be calculated as the total number of vials taken divided by the required number of vials.  Patients 
with less than 80% compliance will be excluded from the Per Protocol Set. 
10.4.6  
BASELINE DESCRIPTIVE STATISTICS 
Baseline characteristics will be presented by randomized treatment group, using appropriate summary statistics. 
10.4.7 PLANNED INTERIM ANALYSES  
10.4.7.1 
SAFETY REVIEW 
After inclusion of 100 patients, a safety reviewed is planned to assess thrombotic events, allergic reaction 
and non-oral bleeding. 
10.4.7.2 
EFFICACY REVIEW 
After 100 patients have reached their 7-day visit, an efficacy review is planned to reassess the required 
sample size.  This will be done using the methods described by Cui, Hung & Wang (1999).  The sample 
size re-estimation (SSR) will be based on the observed conditional power at the time of the interim analysis.  
The re-estimated sample size will be required to be between 150 and 300 patients. Full details for the 
methodology of the SSR will be provided in an Interim Statistical Analysis Plan. 
 
 


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10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
A number of exploratory subgroup analyses is planned, for which the study is not powered, including: 
 
The number of bleeding events in patients who resumed their NOAC treatment within 24 hours 
after extraction compared to later than 24 hours after extraction, stratified per treatment group. 
 
Risk factor analysis for bleeding, eg. patient demographics and procedural characteristics 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
A limited number of predefined subgroup analyses will be tested. No adjustment to the significance level 
will be made. 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
Individual data will be collected and stored. 
10.4.11 
EXPLORATORY ANALYSES 
Defined under subgroup analysis. 
10.5 SAMPLE SIZE 
 
Based on the previously cited pilot study, we estimate the rate of the primary outcome at 30% in 
the placebo group (7). 
 
We estimate to show an absolute risk reduction (ARR) of 15% This means an incidence of 15% in 
the tranexamic acid group.  
 
Confidence level is set to 95%, power is set to 80%. 
 
Under the above assumptions, in order to have 80% to detect a statistically significant risk difference 
between treatments, 118 patients per group or 236 patients in total will be required. 
10.6 MEASURES TO MINIMIZE BIAS 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
A computer-generated block-randomization list will be generated by an independent person for treatment 
allocation. Labeling of the study drug and matched placebo will occur by an independent person. Sealed 
envelopes will contain patient number and randomization group. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
Not applicable. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 


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All patients can be continued to be treated based on standard-of-care irrespective of the study allocation. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in compliance 
with ICH E6 and regulatory and institutional requirements for the protection of confidentiality of participants  
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
Following written SOPs, the investigators and study coordinators  will verify that the clinical trial is conducted 
and data are generated, documented (recorded), and reported in compliance with the protocol, GCP. 
 
 


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13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1 ETHICAL STANDARD  
The investigator will ensure that this study is conducted in full conformity with the Declaration of Helsinki 
and GCP. 
13.2 INSTITUTIONAL REVIEW BOARD  
The protocol, informed consent form, recruitment materials, and all participant materials will be submitted 
to the IRB for review and approval. Approval of both the protocol and the consent form must be obtained 
before any participant is enrolled. Any amendment to the protocol will require review and approval by the 
IRB before the changes are implemented to the study. All changes to the consent form will be IRB approved; 
a determination will be made regarding whether previously consented participants need to be re-consented. 
13.3 INFORMED CONSENT PROCESS  
13.3.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting intervention/administering study 
product.  
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB-
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential risks 
of the study and of their rights as research participants. Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done specifically for the 
study. The participants may withdraw consent at any time throughout the course of the trial. A copy of the 
informed consent document will be given to the participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study  


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13.4 PARTICIPANT AND DATA CONFIDENTIALITY  
 Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be released 
to any unauthorized third party without prior written approval of the principal investigator.  
 Participant details and research data, for follow-up, statistical analysis and scientific reporting, will be 
transmitted to and stored at the University Hospitals Leuven. Participant details and anonymized research 
data will be stored separately, the latter by using a unique study identification number. The study data entry 
and study management systems used by clinical sites and by the University Hospitals Leuven research 
staff will be secured. At the end of the study, all study databases will be archived at the University Hospitals 
Leuven.   
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES,SPECIMENS OR DATA 
Data collected under this protocol may be used for future patient-level meta-analyses, retrospective studies 
or other additional studies, eg. risk factor identification, after approval by the principal investigator. 
 
14 
DATA HANDLING AND RECORD KEEPING  
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
Copies of the CRF will be provided for use as source documents and maintained for recording data for each 
participant enrolled in the study. Data reported in the eCRF derived from source documents should be 
consistent with the source documents or the discrepancies should be explained and captured in a progress 
note and maintained in the participant’s official electronic study record.  
Clinical data (patient and procedure characteristics) and safety and efficacy outcome will be anonymized 
and entered into a clinical database. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents.  
 
14.2 STUDY RECORDS RETENTION  
Study documents will be retained according to local institution guidelines and GCP. 


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14.3 PROTOCOL DEVIATIONS  
Protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All deviations 
must be addressed in study source documents, or reported to the IRB.  
14.4 PUBLICATION AND DATA SHARING POLICY 
Publication of the data is the responsibility of the principal investigator. The results of the study will be 
submitted to a peer-reviewed journal for publication.  
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. The ICMJE does not review specific studies to determine whether registration is 
necessary; instead, the committee recommends that researchers who have questions about the need to 
register err on the side of registration or consult the editorial office of the journal in which they wish to 
publish.  
15 
STUDY ADMINISTRATION 
15.1 STUDY LEADERSHIP 
The oversight of the study will be performed by the principal investigator. 
16 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the trial.  
 


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17  
LITERATURE REFERENCES  
1. 
Bacci C, Maglione M, Favero L, Perini A, Di Lenarda R, Berengo M, Zanon E. Management of dental 
extraction in patients undergoing anticoagulant treatment. Results from a large, multicentre, prospective, case-
control study. Thrombosis and haemostasis. 2010;104(5):972-5. 
2. 
Johnston S. An evidence summary of the management of patients taking direct oral anticoagulants 
(DOACs) undergoing dental surgery. Int J Oral Maxillofac Surg. 2016;45(5):618-30. 
3. 
Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, 
European Heart Rhythm A. European Heart Rhythm Association Practical Guide on the use of new oral 
anticoagulants in patients with non-valvular atrial fibrillation. Europace : European pacing, arrhythmias, and 
cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular 
electrophysiology of the European Society of Cardiology. 2013;15(5):625-51. 
4. 
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, 
Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, 
Committee R-LS, Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. The New England 
journal of medicine. 2009;361(12):1139-51. 
5. 
Vanassche T, Hirsh J, Eikelboom JW, Ginsberg JS. Organ-specific bleeding patterns of anticoagulant 
therapy: lessons from clinical trials. Thrombosis and haemostasis. 2014;112(5):918-23. 
6. 
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini 
JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, Investigators RA. Rivaroxaban versus warfarin 
in nonvalvular atrial fibrillation. The New England journal of medicine. 2011;365(10):883-91. 
7. 
Miclotte I, Vanhaverbeke M, Agbaje JO, Legrand P, Vanassche T, Verhamme P, Politis C. Pragmatic 
approach to manage new oral anticoagulants in patients undergoing dental extractions: a prospective case-control 
study. Clin Oral Investig. 2016. 
8. 
Hanken H, Grobe A, Heiland M, Smeets R, Kluwe L, Wikner J, Koehnke R, Al-Dam A, Eichhorn W. 
Postoperative bleeding risk for oral surgery under continued rivaroxaban anticoagulant therapy. Clin Oral Investig. 
2015. 
9. 
Sindet-Pedersen S. Distribution of tranexamic acid to plasma and saliva after oral administration and 
mouth rinsing: a pharmacokinetic study. J Clin Pharmacol. 1987;27(12):1005-8. 
10. 
Ker K, Beecher D, Roberts I. Topical application of tranexamic acid for the reduction of bleeding. The 
Cochrane database of systematic reviews. 2013(7):CD010562. 
11. 
Ramstrom G, Sindet-Pedersen S, Hall G, Blomback M, Alander U. Prevention of postsurgical bleeding in 
oral surgery using tranexamic acid without dose modification of oral anticoagulants. Journal of oral and 
maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 
1993;51(11):1211-6. 
12. 
Sindet-Pedersen  S, Ramström  G, Bernvil  S, Blombäck  M. Hemostatic Effect of Tranexamic Acid 
Mouthwash in Anticoagulant-Treated Patients Undergoing Oral Surgery. New England Journal of Medicine. 
1989;320(13):840-3. 
13. 
Carter G, Goss A. Tranexamic acid mouthwash--a prospective randomized study of a 2-day regimen vs 5-
day regimen to prevent postoperative bleeding in anticoagulated patients requiring dental extractions. Int J Oral 
Maxillofac Surg. 2003;32(5):504-7. 


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APPENDIX 
 
Version 
Date 
Significant Revisions  
0.1 
6 Jan 2017 
Initial version 
1.0 
1 Mar 2017 
Updated study drug preparation and blinding, AE and 
SAE reporting 
1.1 
6 Jul 2017 
Added details on interim analysis