A Double-blind, Randomised Controlled Trial Evaluating the Safety and Efficacy of Antifibrinolytics (Tranexamic Acid) in Patients With Haematological Malignancies With Severe Thrombocytopenia
Phase: PHASE3
Conditions: Hematologic Neoplasms, Hemorrhage, Hematopoietic Stem Cell Transplantation
Sponsor: NHS Blood and Transplant

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Acronym: TREATT 
 
TRial to EvaluAte Tranexamic acid 
therapy in Thrombocytopenia 
 
A double blind, randomised controlled 
trial evaluating the safety and efficacy 
of tranexamic acid in patients with 
haematological malignancies with 
severe thrombocytopenia 
 
 
 
Version: 3.1 
 
 
Date: 30 July 2018  
 
 
 
 
 
CTU Ref:  
 
12-01-CSU 
 
ISRCTN:  
 
73545489 
 
REC:  
 
14/SC/1290 
 
MHRA CTA:   
25224/0002/001-0001 
 
EudraCT 
 
2014-001513-35 
 
ClinicalTrials: 
NCT03136445 
 

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Protocol Development Group: 
 
Name  
Affiliation 
Authors’ Contributions 
Lise Estcourt 
NHSBT CTU 
 LE and SS conceived the UK study.  
 
LE and SS initiated the study design 
and CD, GP, AD, CL helped with 
implementation. 
  
SS is the grant holder.  
 
DC and CH provided statistical 
expertise in clinical trial design and 
CH is conducting the primary 
statistical analysis.  
 
All authors contributed to refinement 
of the study protocol and approved 
the final version 
Simon 
Stanworth 
NHSBT CTU 
Claire Dyer 
NHSBT CTU 
Gillian Powter 
NHSBT CTU 
Dave Collett 
NHSBT Statistics & 
Clinical Studies 
Cara Hudson 
NHSBT Statistics & 
Clinical Studies 
Alison Deary 
NHSBT CTU 
Charlotte 
Llewelyn 
NHSBT CTU 
Erica Wood 
Monash University, 
Melbourne, 
Australia 
Lekha Bakrania 
NHSBT CTU 
Mike Murphy 
NHSBT CTU 
 
Approved by: 
 
 
 
Name  
Role 
Signature 
Date 
Simon 
Stanworth  
Chief Investigator 
 
 
Lise Estcourt 
Chief Investigator 
 
 
Alison Deary 
Head of Operations 
 
 
Helen Thomas 
Lead Statistician 
 
 
 

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General Information 
This document was constructed using the National Health Service Blood and Transplant 
Clinical Trials Unit (NHSBT CTU) Protocol Template, and incorporates the SPIRIT 
guidelines 2013 (1, 2). It describes the TREATT trial, coordinated by the NHSBT CTU, and 
provides information about procedures for entering patients/participants into it. The protocol 
should not be used as an aide-memoire or guide for the treatment of other patients. Every 
care has been taken in drafting this protocol, but corrections or amendments may be 
necessary. These will be circulated to the registered investigators in the trial, but sites 
entering participants for the first time are advised to contact the Trial Manager to confirm 
they have the most up to date version.  
 
Compliance 
The trial will be conducted in compliance with the approved protocol, the Declaration of 
Helsinki 2013, the Principles of Good Clinical Practice (GCP), European Commission 
Directive 2005/28/EC with the implementation in national legislation in the UK by Statutory 
Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, the UK 
Policy Framework for Health and Social Care Research the Australian National Health and 
Medical Research Council (NHMRC) National Statement on Ethical Conduct in Research 
Involving Humans (March 2007) and any other applicable national regulations.  
 
Sponsor 
The NHSBT is the primary trial sponsor and has delegated responsibility for the overall 
management of the TREATT trial to the NHSBT CTU. Queries relating to the NHSBT 
sponsorship of the trial should be addressed to the National Research Manager, c/o R&D 
Office, NHSBT, 500 North Bristol Park, Northway, Filton, Bristol, BS34 7QH, email 
research.office@nhsbt.nhs.uk or via the trial team.  
 
Funding 
The TREATT trial is funded by a five year grant from the NHSBT Research and 
Development Committee, number 12-01-CSU, and a five-year grant from the NHMRC 
(#1085062). 
 
Authorisations and Approvals 
This trial was approved by NIHR Clinical Research Network and is, therefore, part of the 
Haematology CSG and Haematology Oncology research network portfolio. 
 
Trial Registration 
This trial is registered with the ISCRTN clinical trials database: ISRCTN73545489, and the 
ClinicalTrials.gov database: NCT03136445.  
 
 
 
Trial Administration 
Please direct all enquiries to the Trial Manager in the first instance. Clinical queries will be 
passed to the Chief Investigator via the Trial Manager. 
 
 

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CTU Details 
NHSBT CTU 
Administration Office: 01223 588088 
NHS Blood and Transplant 
Fax: 01223 5848136 
Long Road 
Email: TREATT@nhsbt.nhs.uk  
Cambridge 
 
 
CB2 0PT 
 
 
 
Coordinating CTU Staff Details 
Trial Manager 
Gillian Powter 
 
Tel: 
+44 (0) 1865 387903 
Email: 
gillian.powter@nhsbt.nhs.uk 
Trial Administrator 
Anna Welford 
Tel 
+44 (0) 1865 387710 
Email 
Anna.welford@nhsbt.nhs.uk 
Data Manager 
Siobhan Martin  
Tel 
+44 (0) 1223 588924 
Email 
Siobhan.martin@nhsbt.nhs.uk  
Senior Data Manager 
Katie Keen 
Tel 
+44 (0) 1223 588177 
 
 
Email 
Katie.keen@nhsbt.nhs.uk  
Statistician 
Elinor Curnow 
Tel 
+44 (0) 117 975 7474 
Email 
Elinor.curnow@nhsbt.nhs.uk 
Project Manager 
Claire Dyer 
Tel: 
+44 (0) 1865 387942 
Email: 
claire.dyer@nhsbt.nhs.uk  
 
Chief Investigator 
Dr  
Simon Stanworth 
Tel: +44 (0) 186 538 7976 
 
Consultant Haematologist 
Email: simon.stanworth@nhsbt.nhs.uk  
Hospital 
NHS Blood and 
Transplant 
Fax: +44 (0) 186 538 7957 
Address Line 1 
John Radcliffe Hospital 
 
 
Address Line 2 
Headington 
 
 
City 
Oxford 
 
 
County, Post Code 
OX3 9BQ 
 
 
Country 
UK 
 
 
 
 
 
 
Dr  
Lise Estcourt 
Tel: +44 (0) 186 538 7976 
 
Consultant Haematologist 
Email: lise.estcourt@nhsbt.nhs.uk  
Hospital 
NHS Blood and 
Transplant 
Fax: +44 (0) 186 538 7957 
Address Line 1 
John Radcliffe Hospital 
 
 
Address Line 2 
Headington 
 
 
City 
Oxford 
 
 
County, Post Code 
OX3 9BQ 
 
 
Country 
UK 
 
 

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Co-Investigators 
 
Dr Erica Wood (Australian lead 
investigator) 
erica.wood@monash.edu 
Dr Zoe McQuilten 
Zoe.mcquilten@monash.edu 
Dr Michael Desborough (Fibrinolysis Sub-
Study) 
michael.desborough@ouh.nhs.uk 
Professor Stephen Morris 
(Health Economics) 
steve.morris@ucl.ac.uk 
 
For full details of Trial Committees, please refer to Section 16 

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Trial Synopsis 
Scientific title of clinical trial 
A double-blind, randomised controlled trial evaluating the 
safety and efficacy of antifibrinolytics (tranexamic acid) in 
patients with haematological malignancies with severe 
thrombocytopenia 
Public title of clinical trial 
TRial to EvaluAte Tranexamic acid therapy in 
Thrombocytopenia 
Protocol Short Title/Acronym 
TREATT 
Protocol Version and Date 
3.1  30/07/2018 
Primary Sponsor  
NHS Blood and Transplant 
Funders 
NHS Blood and Transplant and NHMRC (Australia) 
Primary Clinical Trials 
Registry number  
ISRCTN73545489  
Date Trial Registered 
25 / 03 / 2015 
Secondary Identifying 
Numbers 
None 
Trial design 
 Phase III 
 
 Randomised, 
double-blind, 
placebo-controlled, 
parallel, 
superiority trial 
 Participants will be randomised to receive tranexamic acid or 
a matching placebo in a 1:1 ratio, stratified by site. 
Randomisation will further be balanced within blocks of varying 
undisclosed sizes.  
 
 
Health Condition(s) or 
Problem(s) Studied 
Patients with haematological malignancies receiving intensive 
chemotherapy and/or stem cell transplantation.   
 
Key inclusion and exclusion 
criteria 
Participant inclusion criteria: 
Patients are eligible for this trial if: 
1. Aged ≥ 18 years of age 
2. Confirmed diagnosis of a haematological malignancy 
3. Undergoing, or planning to undergo, chemotherapy or 
haematopoietic stem cell transplantation 
4. Anticipated to have a hypoproliferative 
thrombocytopenia resulting in a platelet count of ≤ 
10x109/L for ≥ 5 days  
5. Able to comply with treatment and monitoring 
 
Participant exclusion criteria: 
A patient will not be eligible for this study if he/she fulfils one or 
more of the following criteria: 
 
6. Patients with a past history or current diagnosis of arterial 
or venous thromboembolic disease including myocardial 
infarction, peripheral vascular disease and retinal arterial 
or venous thrombosis. 
7. Diagnosis of acute promyelocytic leukaemia (APML) and 
undergoing induction chemotherapy 

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8. Patients with a diagnosis/previous history of veno-
occlusive disease (also called sinusoidal obstruction 
syndrome) 
9. Patients with known inherited or acquired prothrombotic 
disorders e.g. 
a. Lupus anticoagulant 
b. Positive antiphospholipids 
10. Patients receiving any pro-coagulant agents (e.g. 
DDAVP, recombinant Factor VIIa or Prothrombin 
Complex Concentrates (PCC) within 48 hours of 
enrolment, or with known hypercoagulable state 
11. Patients receiving L-asparaginase as part of their current 
cycle of treatment  
12. History of immune thrombocytopenia (ITP), thrombotic 
thrombocytopenic purpura (TTP) or haemolytic uraemic 
syndrome (HUS) 
13. Patients with overt DIC (See Appendix 3 in the protocol 
for definition) 
14. Patients requiring a platelet transfusion threshold 
>10x109/L at time of randomisation. (This refers to 
patients who require their platelet count to be maintained 
at a certain specified level on an ongoing basis, and 
excludes a transient rise in the threshold due to sepsis.) 
15. Patients with a known inherited or acquired bleeding 
disorder e.g. 
a. Acquired storage pool deficiency 
b. Paraproteinaemia with platelet inhibition 
16. Patients receiving anticoagulant therapy or anti-platelet 
therapy 
17. Patients with visible haematuria at time of randomisation 
18. Patients with anuria (defined as urine output < 10 mls/hr 
over 24 hours). 
19. Patients with severe renal impairment (eGFR ≤30 
ml/min/1.73m2) 
20. Patients with a previous history of epilepsy, convulsions, 
fits or seizures 
21. Patients who are pregnant or breast-feeding 
22. Allergic to tranexamic acid. 
23. Patients enrolled in other trials involving platelet 
transfusions, anti-fibrinolytics, platelet growth factors or 
other pro-coagulant agents. 
24. Patients previously randomised into this trial at any stage 
of their treatment. 
Setting 
Haematology wards and clinics 
Interventions to be compared Administration of Trial treatment 
 

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Trial treatment will be started as per randomisation assignment. 
Either as soon as possible within 24 hours, and no later than 72 
hours, of the first recorded platelet count ≤ 30 x 109/L, 
OR if the participant was admitted with a platelet count already 
below 30 x 109/L as soon as possible within 24 hours, and no 
later than 72 hours after the start of chemotherapy or conditioning 
for a stem cell transplant.   
 
All participants will start with Intravenous administration  
 
The trial treatment (Tranexamic acid 1g/placebo) will be 
administered intravenously as a slow IV bolus over 10 minutes 
every 8 hours.  
 
If the participant is well enough they can switch to: 
 
Oral administration 
The trial treatment (Tranexamic acid 1.5g/placebo) will be 
administered orally as 3 X 500mg tablets every 8 hours. 
 
Trial hypothesis 
The hypothesis is that in patients with haematological 
malignancies, during a period of severe thrombocytopenia, 
prophylactic use of antifibrinolytics will decrease bleeding or 
death and the demand for platelet transfusions. 
Primary outcome measure(s) 
Primary Outcome 
Estimated proportion of participants who died or had bleeding of 
WHO grade 2 or above during the first 30 days of the trial. 
Starting from the first administration of trial treatment  
 
Secondary outcome 
measure (s) 
Secondary Efficacy Outcomes   
(all measured during first 30 days of the trial from the first 
administration of trial treatment  
 Proportion of days with bleeding (WHO grade 2 or above) 
 Time to first episode of bleeding of WHO grade 2 or greater 
for those participants who bled 
 Highest grade of bleeding a participant experiences  
 Number of platelet transfusions/participant  
 Number of red cell transfusions/participant  
 Proportion of participants surviving at least 30 days without 
a platelet transfusion  
 Proportion of participants surviving at least 30 days without 
a red cell transfusion 
 Quality of life 
 
Secondary Safety Outcomes 
 Number of thrombotic events from first administration of trial 
treatment up to and including 120 days after the first dose of 
trial treatment is administered, per day at risk 
 Number of participants developing Veno-occlusive Disease 
(VOD; Sinusoidal obstructive syndrome, SOS) within 60 
days of first administration of trial treatment 
 All-cause mortality during the first 30 days and the first 120 
days after the first dose of trial treatment is administered 
 Death due to thrombosis during the first 120 days after the 
first dose of trial treatment is administered 

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 Death due to bleeding during the first 30 days after the first 
dose of trial treatment is administered 
 Number of serious adverse events from first administration 
of trial treatment until 60 days after the first dose of trial 
treatment is administered 
 
Other outcomes  
(all measured during the first 30 days of the trial from the first 
administration of trial treatment 
Proportion of days with thrombocytopenia (≤10x109/L, ≤30x109/L, 
≤50 x 109/L) 
Proportion of days with fever (highest daily temperature ≥ 38.1°C) 
of days spent in hospital, up to study day 30Reasons for platelet 
and red cell transfusions 
 
Sub-group analyses 
Sub-group analyses will be performed for the primary outcome 
for the following variables in the main analysis: 
 
 
Country of participant (UK vs. Australia), if evidence of 
heterogeneity between UK and Australian participants is 
identified in the interim analysis  
 
Platelet count at consent (≤30x109/L vs. > 30x109/L) 
 
Treatment compliance during first 30 days of the trial 
(withdrawal of consent for trial treatment vs. no 
withdrawal of consent)  
 
 
Duration of Trial 
Duration of recruitment – The trial will be recruiting over 4½ 
years. 
 
Duration of intervention  
The trial treatment will be started within 24 hours (and no more 
than 72 hours) after the platelet count falls to ≤30x109/L, or if the 
participant was admitted with a platelet count already below 30 
x 109/L, starting from the first day of chemotherapy or 
conditioning for a stem cell transplant, and continued until the 
platelet count is >30x109/L for 3 consecutive days without 
platelet transfusion support, or until the participant has received 
30 days of treatment. 
 
The main data collection for efficacy endpoints will continue for 
30 days from commencement of trial treatment. 
 
Duration of follow-up for each participant 
Adverse event data will be collected for 60 days after the first 
dose of trial treatment is administered, and long-term safety 
data regarding thromboembolic events will be collected by 
telephone call 120 days after the first dose of trial treatment is 
administered. 
 
The telephone call or participant visit 4 months (120 days) after 
the start of the trial will define the end of the trial.  
 
Duration of trial  
The planned trial duration is 5 years from initiation of first site to 
completion of analysis. 

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Countries of recruitment 
UK 
Australia 
Target Sample Size 
616 participants at UK and Australian trial sites  
308 subjects will be enrolled to receive TXA and 308 to receive 
the placebo 
 
Date of first enrolment 
June 2015 
Recruitment Status 
Recruiting: participants are being recruited  
 
Ancillary Studies/sub-studies 
At selected centres, additional blood samples will be collected 
from recruited participants and stored, for later central analysis, 
to explore the pathways of fibrinolysis and the mechanisms of 
action of tranexamic acid.  
Contact Details for Public 
Queries 
TREATT@nhsbt.nhs.uk  
 
Contact Details for Scientific 
Queries 
Dr Lise Estcourt; lise.estcourt@nhsbt.nhs.uk  
CTU Project Manager 
Claire Dyer 
Lay Summary of Trial 
Patients with cancers of the blood often develop low blood cell 
counts either as a consequence of the disease or the treatment 
by chemotherapy or stem cell transplantation. Platelet 
transfusions are commonly given to raise any low platelet count 
and reduce the risk of clinical bleeding (prophylaxis) or stop 
active bleeding (therapy). But recent studies have indicated that 
many patients continue to experience bleeding, despite the use 
of platelet transfusions. Tranexamic acid is a type of drug that is 
called an antifibrinolytic. These drugs act to reduce the 
breakdown of clots formed in response to bleeding. These 
drugs have been used widely in both elective and emergency 
surgery and have been shown to decrease blood loss and the 
use of red cell transfusions. The purpose of this study is to test 
whether giving tranexamic acid to patients receiving treatment 
for blood cancers reduces the risk of bleeding or death, and the 
need for platelet transfusions. Participants will be randomised to 
receive tranexamic acid (given intravenously through a drip, or 
orally) or a placebo. We will measure the rates of bleeding daily 
using a short structured assessment of bleeding, and we will 
record the number of transfusions given to participants.  
 
 

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Trial Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DAY 60 (± 3 DAYS) 
All SAEs and unexpected adverse reactions reported up to this day 
(All secondary outcomes are not classified as SAEs) 
STOP Trial treatment: 
 
Thrombosis 
 
Veno-occlusive disease (sinusoidal obstructive syndrome) 
 
Visible haematuria (risk of clot retention) 
 
Started any other pro-coagulant agent 
 
Started any anticoagulant or anti-platelet therapy 
 
Platelets > 30 x 109/L without platelet transfusion support for 3 days  
 
Spontaneous increase in platelet count from ≤ 30 x 109/L to > 50 x 109/L 
 
Anuria  
 
Subject on study drug for 30 days 
STUDY DAY 30 (± 2 DAYS) 
Quality of life assessment, Health economic assessment and thrombotic assessment  
START TRIAL TREATMENT  
Platelet count ≤ 30 x 109/L 
OR first day of chemotherapy / conditioning for stem cell transplant if platelet count ≤ 30 x 109/L on admission 
(STUDY DAY 1) 
WHO grade 2 bleeding OR pre-procedure 
TRANSFUSE PLATELETS AT PHYSICIAN’S 
DISCRETION 
No Bleeding OR WHO grade 1 bleeding 
TRANSFUSE PLATELETS IF MORNING 
PLATELET COUNT ≤ 10 X 109/L 
Placebo 8hrly 
 
Tranexamic Acid (TXA) 1g 8hrly IV  
OR  
1.5g 8hrly PO 
Subjects screened, consented, and enrolled 
RANDOMISE Platelet count ≤ 50 x 109/L 
START BLEEDING ASSESSMENTS 
STUDY DAY 120 (± 14 DAYS) 
Quality of life assessment, Health economic assessment and thrombotic assessment  
END OF STUDY 

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Trial Schedule (Assessments) 
Trial 
Assessment 
Enrolment 
(Consent) 
Days between 
enrolment and 
randomisation 
Day R 
Day of 
randomisation 
platelet count 
≤ 50x109/l 
Days 
between 
Day R 
and study 
day 1 
Day 1 
 
Day 2 
 
Days 3 
- 11 
Day 12 
(± 2) 
Days 
13 -29 
Day 30 
(± 2) 
Day 60 
(± 3) 
Day 120 
(± 14) 
Demographics 
and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Assessment 
X 
 
X 
 
X 
(Prior to 
starting 
drug) 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Transfusion 
requirements 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Bleeding 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Trial treatment 
accountability 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Quality of life 
assessment 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
Health 
economic 
evaluation 
 
 
 
 
 
 
 
 
 
X 
 
X 
Thrombotic 
Assessment 
Medical 
notes 
 
Medical notes 
Medical 
notes 
Medical 
notes 
Medical 
notes 
Medical 
notes 
Medical 
notes 
Medical 
notes 
Face to 
face OR 
Telephone 
follow-up 
 
Face to 
face OR 
Telephone 
follow-up 
Highest recorded 
temperature each 
day 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
SAE 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 

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Trial Schedule (Investigations) 
Trial Assessment 
Enrol
ment 
Days between 
enrolment and 
randomisation 
Day R 
Day of 
randomisation 
platelet count ≤ 
50x109/l 
Days between 
Day R and 
study day 1 
Day 1 
 
Day 2 
 
Days 3 -11 
Day 12 
(± 2) 
Days 13 -29 
Day 30 
(± 2) 
Pregnancy Test 
(if applicable) 
X 
 
 
 
 
 
 
 
 
 
Urine dipstick 
X 
 
 
 
 
 
 
 
 
 
Haemoglobin  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Platelet count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prothrombin Time 
(or INR if PT not 
available) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum creatinine 
(U&E) 
X 
 
X 
 
X 
X 
Three times 
a week or 
as SOC 
X 
Three times a week 
or as SOC 
X 
Liver function 
tests: bilirubin and 
albumin 
X 
 
X 
 
 
 
Required if 
VOD is 
reported/ 
suspected 3 
times a 
week 
 
Required if VOD is 
reported/suspected 3 
times a week 
 
 
 
 
 
 
 
 
 
 
 
 
HLA Antibody 
screen† 
X 
 
 
 
 
 
 
 
 
 
INVESTIGATIONS ONLY TO BE PERFORMED AT SELECTED PARTICIPATING CENTRES 
Assays for 
fibrinolysis 
X 
 
X 
 
 
X 
 
 
Required three times 
a week 
 
X: measurement required 
† HLA Antibodies to be rechecked if participant becomes refractory to platelet transfusions please see section 6.4.1 

 
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Contents 
General Information ........................................................................................................ 3 
Trial Administration ......................................................................................................... 3 
Trial Synopsis ................................................................................................................. 6 
Trial Schema ................................................................................................................. 11 
Trial Schedule (Assessments) ....................................................................................... 12 
Trial Schedule (Investigations) ...................................................................................... 13 
Contents ....................................................................................................................... 14 
Abbreviations and Glossary .......................................................................................... 17 
1. 
Background ............................................................................................................. 18 
1.1. 
Introduction ....................................................................................................... 18 
1.2. 
Summary of existing knowledge ........................................................................ 18 
1.3. 
Need for a trial of Tranexamic Acid ................................................................... 19 
1.4. 
Dose selection of intervention ........................................................................... 19 
1.5. 
Explanation for choice of comparator ................................................................ 20 
1.6. 
Potential benefits and risks of Intervention ........................................................ 20 
1.7. 
Specific objectives or hypotheses ..................................................................... 20 
1.8. 
Description of trial design .................................................................................. 20 
2. 
Trial Setting .............................................................................................................. 20 
3. 
Selection of Sites/Clinicians ................................................................................... 20 
3.1. 
Site/Investigator Inclusion Criteria ..................................................................... 21 
3.2. 
Site/Investigator Exclusion Criteria .................................................................... 21 
3.3. 
Recruitment ....................................................................................................... 21 
4. 
Selection of Participants ......................................................................................... 21 
4.1. 
Participant Inclusion Criteria .............................................................................. 21 
4.2. 
Participant Exclusion Criteria............................................................................. 21 
4.3. 
Co-Enrolment Guidelines .................................................................................. 22 
4.4. 
Screening/Recruitment ...................................................................................... 22 
5. 
Randomisation ........................................................................................................ 23 
5.1. 
Allocation – sequence generation ..................................................................... 23 
5.2. 
Allocation – concealment mechanism ............................................................... 23 
5.3. 
Allocation – implementation .............................................................................. 23 
5.4. 
Stratification and Randomisation ....................................................................... 23 
5.5. 
Randomisation Practicalities ............................................................................. 23 
5.6. 
Randomisation Codes ....................................................................................... 24 
5.7. 
Co-enrolment Guidelines ................................................................................... 24 
5.8. 
Blinding ............................................................................................................. 25 
5.9. 
Unblinding ......................................................................................................... 25 
6. 
Treatment of Participants ....................................................................................... 25 
6.1. 
Introduction ....................................................................................................... 25 
6.2. 
Interventions ..................................................................................................... 26 
6.2.1. 
CTIMP to be studied .................................................................................. 26 
6.2.2. 
Description of Trial Drug ............................................................................ 26 
6.2.3. 
Blinding of Trial treatment .......................................................................... 26 
6.2.4. 
Administration of Trial treatment ................................................................ 26 
6.2.5. 
Dose Adjustment of Trial treatment in Renal Insufficiency ......................... 27 
6.2.6. 
Discontinuation of Trial treatment .............................................................. 27 
6.3. 
Adherence to intervention ................................................................................. 28 
6.4. 
Concomitant Care ............................................................................................. 28 
6.4.1. 
Platelet transfusions .................................................................................. 28 

 
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6.4.2. 
Red Cell Transfusions ............................................................................... 29 
6.4.3. 
Medications Not Permitted ......................................................................... 29 
6.5. 
Co-enrolment guidelines ................................................................................... 29 
6.6. 
Ancillary and post-trial care ............................................................................... 30 
7. 
Trial Outcomes ........................................................................................................ 30 
7.1. 
Primary Outcome Measure ............................................................................... 30 
7.2. 
Secondary Outcome Measures ......................................................................... 30 
7.2.1. 
Secondary Efficacy Outcomes ................................................................... 30 
7.2.2. 
Secondary Safety Outcomes ..................................................................... 30 
7.2.3. 
Other outcomes ......................................................................................... 30 
8. 
Assessments and Follow-up .................................................................................. 31 
8.1. 
Trial Assessment Schedule ............................................................................... 31 
Please see study schedules Pages 12 & 13 .................................................................. 31 
8.2. 
Procedures for Assessing Efficacy .................................................................... 31 
8.2.1. 
Bleeding Assessment ................................................................................ 31 
8.3. 
Procedures for Assessing Safety ...................................................................... 32 
8.3.1. 
Thrombotic Assessment ............................................................................ 32 
8.3.2. 
Interval Medical Events/Serious Adverse Events ....................................... 32 
8.4. 
Other Measurements ........................................................................................ 32 
8.5. 
Loss to Follow-Up ............................................................................................. 34 
8.6. 
Trial Closure ...................................................................................................... 34 
9. 
Safety Reporting ...................................................................................................... 34 
9.1. 
Definitions of Adverse Events ............................................................................ 34 
9.2. 
Investigator Responsibilities .............................................................................. 35 
9.2.1. 
Investigator Assessment of Adverse Events .............................................. 36 
9.3. 
Adverse Event Reporting .................................................................................. 37 
9.3.1. 
Adverse Events that Require Expedited Reporting (within 24 hours) ......... 37 
9.3.2. 
Adverse Events that Require Reporting (within 5 working days) ................ 37 
9.3.3. 
Investigator Notification ............................................................................. 38 
9.4. 
Sponsor’s Responsibilities ................................................................................ 38 
9.5. 
Statutory Reporting ........................................................................................... 38 
10. Quality Assurance and Control .............................................................................. 39 
10.1. 
Risk Assessment ............................................................................................... 39 
10.2. 
Central Monitoring at CTU ................................................................................. 39 
10.3. 
On-Site Monitoring ............................................................................................ 39 
10.3.1. 
Direct access to participant records ........................................................... 39 
10.3.2. 
Confidentiality ............................................................................................ 39 
10.4. 
Auditing ............................................................................................................. 39 
11. Statistical Considerations ....................................................................................... 39 
11.1. 
Method of Generating Allocation Sequence ...................................................... 39 
11.2. 
Outcome Measures ........................................................................................... 40 
11.3. 
Sample size ...................................................................................................... 40 
11.3.1. 
Minimal Clinically Important Difference (MCID) .......................................... 40 
11.3.2. 
Primary efficacy outcomes ......................................................................... 40 
11.3.3. 
Safety outcomes ........................................................................................ 41 
11.3.4. 
Health economic evaluation ....................................................................... 41 
11.4. 
Interim Monitoring and Analyses ....................................................................... 41 
11.5. 
Analysis Plan (Brief) .......................................................................................... 43 

 
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11.5.1. 
Analysis of primary and secondary outcomes ............................................ 43 
11.5.2. 
Other Analyses .......................................................................................... 44 
11.5.3. 
Analysis Population and Missing Data ....................................................... 44 
12. Ancillary Studies ..................................................................................................... 45 
12.1. 
Fibrinolysis Study  ............................................................................................. 45 
12.2. 
Health Economic Evaluation ............................................................................. 45 
13. Ethical and Regulatory Issues ................................................................................ 46 
13.1. 
Compliance ....................................................................................................... 46 
13.1.1. 
Site Compliance ........................................................................................ 46 
13.1.2. 
Data Collection and retention .................................................................... 46 
13.1.3. 
Access to Data .......................................................................................... 46 
13.2. 
Ethical Conduct of the Trial ............................................................................... 46 
13.3. 
Ethical Considerations....................................................................................... 47 
13.4. 
Consent ............................................................................................................ 47 
13.5. 
Confidentiality ................................................................................................... 48 
14. Indemnity ................................................................................................................. 48 
15. Finance ..................................................................................................................... 48 
15.1. 
Funding ............................................................................................................. 48 
15.2. 
Declaration of interests...................................................................................... 49 
16. Oversight and Trial Committees ............................................................................. 49 
16.1. 
Trial Management group (TMG) ........................................................................ 49 
16.2. 
Trial Steering Committee (TSC) ........................................................................ 49 
16.4. 
Role of Trial Sponsor ........................................................................................ 50 
16.5. 
Role of Trial Funder(s) ...................................................................................... 50 
17. Publication ............................................................................................................... 51 
17.1. 
Dissemination ................................................................................................... 51 
17.2. 
Authorship ......................................................................................................... 51 
17.3. 
Approvals .......................................................................................................... 51 
17.4. 
Identification ...................................................................................................... 51 
17.5. 
Timing ............................................................................................................... 51 
17.6. 
Acknowledgements ........................................................................................... 51 
18. Protocol Amendments ............................................................................................ 51 
19. References ............................................................................................................... 55 
20. Appendices .............................................................................................................. 58 
20.1. 
Adverse Reactions ............................................................................................ 58 
20.3.1. 
Toxicities associated with Tranexamic Acid (TA) ....................................... 58 
20.3.2. 
Toxicities Related to Platelet Transfusion .................................................. 58 
20.3.3. 
Additional access to central venous catheters ........................................... 58 
20.3.4. 
Discomfort Related to Venesection ............................................................ 58 
20.2. 
WHO Grading System ....................................................................................... 59 
20.3. 
Definitions of Bleeding Signs ............................................................................. 63 
20.4. 
Other Definitions ............................................................................................... 65 
20.6.1. 
Definition of DIC (ISTH) (43) ...................................................................... 65 
20.6.2. 
Definition of deep vein thrombosis ............................................................. 65 
20.6.3. 
Definition of pulmonary embolism .............................................................. 67 

 
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Abbreviations and Glossary 
AE 
Adverse event 
AR 
Adverse reaction 
BSA 
Body Surface Area 
CF 
Consent form 
CI 
Chief Investigator 
CI 
Count Increment 
CLRN 
Comprehensive Local Research Network 
COM 
Clinical Operations Manager 
CRF 
Case Report Form 
CTU 
NHSBT Clinical Trials Unit 
DCF 
Data Clarification Form 
DH 
Department of Health 
DMC 
Data Monitoring Committee 
DM 
Data Manager 
ERC 
Endpoint Review Committee 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HE 
Health Economics 
IB 
Investigator’s Brochure 
IMP 
Investigational Medicinal Product  
ISRCTN 
International standard randomised controlled trial number 
IRAS 
Integrated Research Application System 
MHRA 
Medicines and Healthcare Regulatory Authority 
MRC 
Medical Research Council 
NHMRC 
National Health and Medical Research Council, Australia 
NHS 
National Health Service 
NHSBT 
NHS Blood and Transplant 
NIHR 
National Institute for Health Research 
NIHR-CSP 
National Institute for Health Research Coordinated System for gaining NHS Permission 
NRES 
National Research Ethics Service 
PALS 
Patient Advice and Liaison Service 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
QoL 
Quality of Life 
R&D 
Research and Development 
REC 
Research Ethics Committee 
RCT 
Randomised Controlled Trial 
SABRE 
Serious Adverse Blood Reactions and Events 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SHOT 
Serious Hazards of Transfusion 
SOC 
Standard of Care 
SOP 
Standard operating procedure 
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TGA 
Therapeutic Goods Administration (Australia) 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UAR 
Unexpected Adverse Reaction 
 

 
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1. Background 
1.1. Introduction 
Patients with haematological malignancies often develop severe thrombocytopenia either 
as a consequence of the disease or its treatment, including chemotherapy and stem cell 
transplantation. Platelet transfusions are commonly administered, in this situation, to raise 
the low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active 
bleeding (therapy). Many audits have indicated that the most common indication for 
administration of platelet transfusions to thrombocytopenic patients with haematological 
malignancies is prophylaxis (up to 69%) (3-7). (8, 9). 
 
However, recent studies (described below) have raised questions about the effectiveness of 
platelet transfusions to reduce clinical bleeding, and many patients experience bleeding 
despite use of prophylactic platelets.  In addition to this, platelet transfusions are not without 
risks. Adverse events may range from mild reactions, such as fever (one in five transfusions) 
(10) to more serious and even life threatening events such as bacterial sepsis from 
transfusion transmitted infection (one in 10,000 transfusions)(10) or transfusion-related 
acute lung injury (TRALI)(11). Patients may also become refractory to platelet transfusions, 
the incidence of which increases with the number of platelet transfusions a patient receives 
(12). Once refractory, the ability to treat bleeding with platelet transfusions becomes more 
difficult requiring expensive, specially matched platelet transfusions that are difficult to 
source. Platelet transfusions are a limited and expensive resource, and demand for these 
components is rising in many countries, raising concerns about future shortages in the 
supply of platelets.  
 
Any treatment that could reduce reliance on platelet transfusion support would have major 
cost-saving implications. Around 302,000 adult doses of platelets are issued in the UK each 
year (13) at an annual cost of approximately £68.5 million (14) and up to two thirds (67%) of 
these are given to patients with haematological malignancies (3, 6, 15). Tranexamic acid is 
an antifibrinolytic drug that has been widely used in surgery to reduce clinical bleeding and 
need for transfusion, but few studies have evaluated use of this drug in patients with 
haematological malignancies.  
1.2. Summary of existing knowledge  
Recent clinical research has focused on the optimal dose for platelet transfusion (PLADO 
(16) and SToP (17)), or the threshold level of platelet counts for prophylactic platelet 
transfusions (Rebulla (18)). PLADO was a multicentre trial in the US, in which haematology 
patients receiving intensive chemotherapy or a stem cell transplant were randomised to 
receive low, medium or high dose prophylactic platelet transfusions (1.1 x 1011 platelets/m2 
body surface area; 2.2 x 1011/m2; and 4.4 x 1011 /m2, respectively). A total of 1,351 patients 
were enrolled at 26 sites in the United States. In PLADO, rates of bleeding were 69 to 71% 
for patients in each dose arm of the study, when defined as WHO Grade 2 to 4. A spectrum 
of bleeding was observed, from skin changes to, less commonly, intracranial haemorrhage.  
 
More recently, two RCTs have been completed which have evaluated the role of prophylactic 
platelet transfusions (8, 19, 20). TOPPS was an RCT that assessed whether a policy of no-
prophylactic platelet transfusions was non-inferior to a policy of prophylactic platelet 
transfusions (20). The primary outcome was WHO grade 2 to 4 bleeding. Prophylactic 
platelet transfusions were given at a platelet count threshold of <10x109/L, which represents 
the current standard of practice in patients with haematological malignancies. Six hundred 
patients (301 no-prophylaxis, 299 prophylaxis) were randomised across 14 sites in the UK 
and Australia between 2006 and 2011. A WHO grade 2-4 bleed grade occurred in 50% 
(151/300) of patients in the no-prophylaxis group compared to 43% (128/298) of patients in 
the prophylaxis group (adjusted difference in proportions 8.4%, 90% CI 1.7-15.2%).  

 
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Several themes have emerged from the findings of these platelet RCTs: 
A significant proportion of patients develop bleeding at some stage during the period of 
thrombocytopenia despite prophylactic platelet transfusions.  
A general result across all platelet transfusion trials of dose and threshold, including the two 
largest studies (16, 18), has been no difference in haemostatic outcomes between trial arms 
(i.e. no increased bleeding in the restrictive policy arms for transfusion by lower threshold or 
dose). 
There is a lack of a relationship between platelet count and bleeding risk, except at very low 
platelet counts. PLADO reported that patients had similar rates of bleeding (17%) with 
morning platelet counts within the wide range of 6 to 80 x 109/L (16).  
The burden of bleeding varies in sub-groups of patients, e.g. higher bleeding rates in patients 
with acute leukaemia or receiving an allogeneic stem cell transplant (SCT), lower rates in 
patients receiving an autologous SCT(21). 
 
Taken together, these findings suggest that current policies for prophylactic platelet 
transfusions have a limited role in reducing much of the bleeding seen in haematology 
patients undergoing intensive chemotherapy and/or stem cell transplantation. There is a 
need for new treatment strategies to minimise the burden of bleeding, particularly in high 
risk groups of patients. 
1.3. Need for a trial of Tranexamic Acid 
One approach is to administer anti-fibrinolytics. The fibrinolytic system acts to prevent blood 
clots from growing excessively away from the site of damage, and conversely, delayed 
processes of breakdown of fibrin clots would be expected to enhance localised clot formation 
and, crucially, stability. 
 
Tranexamic acid (TXA) is a lysine analogue that is a competitive inhibitor of plasminogen 
activation and, at higher concentrations, non-competitive inhibitor of plasmin (22). TXA is 
the only lysine analogue currently licensed in the UK and Australia. 
1.4. Dose selection of intervention 
Antifibrinolytics have been used widely in both elective and emergency surgery and have 
been shown to decrease blood loss and the use of red cell transfusions. In a recent 
Cochrane review (23) of over 25,000 patients the use of TXA, epsilon aminocaproic acid 
(EACA)  and another antifibrinolytic, aprotonin1, were assessed on their ability to minimise 
peri-operative blood transfusions. In this review, 65 trials compared TXA with control; 16 
trials compared EACA with control and 10 trials compared TXA with EACA. Both drugs 
decreased the need for allogeneic blood transfusions (relative reduction of 39% (TXA) 19% 
(EACA)). The profile for the use of these drugs has also been raised by their therapeutic use 
in CRASH-2 (25-27), a recent large RCT that showed TXA decreased the mortality rate in 
trauma patients.  
 
A small number of RCTs and other studies have been identified in a recently completed 
systematic review into their use of antifibrinolytics in patients with haematological 
malignancies (28). Overall, the results suggest a reduction in platelet transfusion usage 
when platelet transfusions were only given if patients bled (29, 30), with a possible reduction 
in the number of bleeds (29). However, there are significant methodological limitations to 
                                               
1Aprotonin was commonly used in the past, but is now rarely used due to concerns over increased cardiovascular 
complications and death [21, 22], (24. 
Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A 
comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008 May 29;358(22):2319-31. 23.
 
Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, et al. Anti-fibrinolytic use for minimising 
perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011(3):CD001886.). 
 

 
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these studies, limiting the strength of these conclusions. Moreover, the sample sizes were 
small. In addition, since all the RCTs are 15 to 20 years old the management and supportive 
care of haematology patients has changed dramatically.  
 
In the peri-operative Cochrane review (23), the use of TXA was not associated with an 
increased risk of mortality, myocardial infarction, DVT, stroke, incidence of renal dysfunction, 
or length of hospital stay. In the CRASH-2 study there were fewer deaths due to arterial or 
venous thrombosis [RR 0.69; 95% CI 0.44 to 1.07)) in the TXA arm of the study, although 
this was not statistically significant (P = 0.096)(27). 
1.5. Explanation for choice of comparator 
This study is designed as a placebo controlled trial, to provide the most robust evidence. 
There is no ‘gold standard’ standard for comparison and TXA is not commonly used as 
prophylaxis in this clinical setting.  
1.6. Potential benefits and risks of Intervention 
Although it can be hypothesised that antifibrinolytics may decrease the risk of severe and 
life-threatening bleeding and decrease patients’ exposure to blood components, these drugs 
also have the potential to increase the rate of thromboembolism. Patients with an underlying 
malignancy have a higher rate of thromboembolic disease. In a retrospective cohort study 
of thromboembolism in hospitalised neutropenic cancer patients, 4%  (593/14,600) of acute 
leukaemia patients developed venous thromboembolism (VTE) and 1.9% (279/14,600) of 
patients with acute leukaemia developed arterial thromboembolism (31). A meta-analysis of 
29 different cohorts of patients with lymphoma gave an estimate of 6.4% (95% confidence 
interval 6.1 to 6.9%) (32). The one year incidence of symptomatic VTE in patients 
undergoing stem cell transplantation has been estimated at 3.7% (33). The most common 
type of venous thromboembolism in this group of patients is line associated thrombosis with 
an estimated incidence of 2.6 to 5% (33, 34). 
1.7. Specific objectives or hypotheses 
The hypothesis is that in patients with haematological malignancies, during a period of 
severe thrombocytopenia, prophylactic use of antifibrinolytics would decrease bleeding and 
the demand for platelet transfusions. There may also be additional benefits for patients such 
as improved quality of life during their in-patient stay and earlier discharge home. Given the 
importance of understanding the cost-effectiveness of new treatments, this trial proposal will 
also incorporate a health economic analysis. 
1.8. Description of trial design  
This is a double-blind, placebo controlled parallel group trial to assess the safety and efficacy 
of tranexamic acid at reducing bleeding in patients with haematological malignancies and 
severe thrombocytopenia. Participants will be randomised to receive TXA or placebo.  
 
 
2. Trial Setting 
This trial will be conducted in the haematology wards of participating hospitals in the UK and 
Australia.  
3. Selection of Sites/Clinicians 
 
Centre selection in UK will be based on the presence of appropriate clinical and research 
infrastructure including adequate local resources and facilities to support recruitment, and 
adequate qualified staff to conduct the trial properly and safely. Therefore recruiting centres 

 
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will be drawn from those involved in TOPPS (20) who have experience of conducting platelet 
studies..  
 
The trial management group (TMG) will invite eligible centres and will discuss the resources 
required for conducting the trial, including the importance of delivering training and education 
to the clinical staff on the use of the bleeding assessment tool. 
 
All UK local laboratories should be Clinical Pathology Accreditation accredited, and National 
External Quality Assurance Scheme participants. Australian centres will be NATA/RCPA 
accredited. 
3.1. Site/Investigator Inclusion Criteria 
To participate in the TREATT trial, investigators and clinical trial sites must fulfil a set of 
basic criteria that have been prepared by the TREATT Trial Management Group (TMG) and 
are defined below.  
PI Qualifications and Agreements 
The investigator should be qualified by education, training and experience to assume 
responsibility for the proper conduct of the trial at their site and should provide evidence of 
such qualifications through an up to date curriculum vitae and/or other relevant 
documentation requested by the Sponsor, the REC, and/or the regulatory authorities. 
3.2. Site/Investigator Exclusion Criteria  
The General Medical Council’s List of Registered Medical Practitioners, or the Australian 
Health Practitioner Regulation Agency, will be consulted to ensure all potential PIs are 
licensed to practice.  Any PI without a current licence or with a history of non-fitness to 
practice should not be approached.  
3.3. Recruitment 
The site selection process will include a rigorous evaluation of the site’s potential rate of 
accrual to the trial, which will include a review of types of patient treated, an assessment of 
how many would be eligible, and how many may be recruited given the site level resource 
and any barriers to recruitment such as other trials competing to recruit the same patient 
population.  
4. Selection of Participants 
 
There will be no exceptions to eligibility requirements at the time of randomisation. 
Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion 
criteria and none of the exclusion criteria detailed below.  
4.1. Participant Inclusion Criteria 
Patients are eligible for this trial if: 
1. Aged ≥18 years of age 
2. Confirmed diagnosis of a haematological malignancy 
3. Undergoing chemotherapy, or chemotherapy is planned, or haematopoietic stem cell 
transplantation 
4. Anticipated to have a hypoproliferative thrombocytopenia resulting in a platelet count 
of ≤10x109/L for ≥ 5 days  
5. Able to comply with treatment and monitoring 
 
4.2. Participant Exclusion Criteria 
A patient will not be eligible for this trial if he/she fulfils one or more of the following criteria: 

 
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1. Patients with a past history or current diagnosis of arterial or venous thromboembolic 
disease including myocardial infarction, peripheral vascular disease and retinal 
arterial or venous thrombosis. 
2. Diagnosis of acute promyelocytic leukaemia (APML) and undergoing induction 
chemotherapy 
3. Patients with a diagnosis/previous history of veno-occlusive disease (also called 
sinusoidal obstruction syndrome) 
4. Patients with known inherited or acquired prothrombotic disorders e.g. 
a. Lupus anticoagulant 
b. Positive antiphospholipids 
5. Patients receiving any pro-coagulant agents (e.g. DDAVP, recombinant Factor VIIa 
or Prothrombin Complex Concentrates (PCC) within 48 hours of enrolment, or with 
known hypercoagulable state 
6. Patients receiving L-asparaginase as part of their current cycle of treatment  
7. History of immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura 
(TTP) or haemolytic uraemic syndrome (HUS) 
8. Patients with overt DIC (See Appendix 3 in the protocol for definition) 
9. Patients requiring a platelet transfusion threshold >10x109/L at time of 
randomisation. (This refers to patients who require their platelet count to be 
maintained at a certain specified level on an ongoing basis, and excludes 
a transient rise in the threshold due to sepsis.)  
10. Patients with a known inherited or acquired bleeding disorder e.g. 
a. Acquired storage pool deficiency 
b. Paraproteinaemia with platelet inhibition 
11. Patients receiving anticoagulant therapy or anti-platelet therapy 
12. Patients with visible haematuria at time of randomisation 
13. Patients with anuria (defined as urine output < 10 mls/hr over 24 hours). 
14. Patients with severe renal impairment (eGFR ≤30 ml/min/1.73m2) 
15. Patients with a previous history of epilepsy, convulsions, fits or seizures 
16. Patients who are pregnant or breast-feeding 
17. Allergic to tranexamic acid. 
18. Patients enrolled in other trials involving platelet transfusions, anti-fibrinolytics, 
platelet growth factors or other pro-coagulant agents. 
19. Patients previously randomised into this trial at any stage of their treatment. 
 
4.3. Co-Enrolment Guidelines 
Please refer to Section 5.7 
4.4. Screening/Recruitment 
 
A screening log will be completed on all patients admitted to the participating units with a 
haematological malignancy and undergoing chemotherapy or a stem cell transplant who are 
expected to develop a hypoproliferative thrombocytopenia resulting in a platelet count of 
≤10x109/L for ≥5 days. The log will include main diagnosis and treatment plan. It will include 

 
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patients approached but in whom consent was not obtained for the trial (with reasons) and 
therefore will define how representative randomised patients are as a group relative to the 
group of eligible patients who were not randomised. 
 
The local PI or delegate will be responsible for identifying suitable patients and inviting them 
to participate in the trial. 
 
Each participant will be assigned a unique trial number consisting of 6 digits, the first 3 digits 
denoting the centre number and the remaining 3 the participant number from 001 to 999. 
The trial number will be recorded on the screening log. 
 
The eligibility checklist will be completed. 
 
Consent from eligible patients will be sought using the participant information sheet and 
consent form.  
 
When the consented participant’s platelet count falls to ≤50x109/L, the PI or delegate will 
access the on-line randomisation system to randomise the participant (see section 5.5 for 
further details.) 
 
5. Randomisation 
5.1. Allocation – sequence generation 
See Section 11.1 
5.2. Allocation – concealment mechanism 
Participants will be randomised using an online randomisation service (SealedEnvelope). 
Following confirmation of site number and eligibility criteria, a randomisation number will be 
issued by the system. 
5.3. Allocation – implementation 
An unblinded NHSBT statistician, independent of the trial team, will generate the 
randomisation list in accordance with the protocol. A site specific list of coded treatment 
allocations will also be provided to the trial pharmacist at each site by the same independent 
NHSBT statistician to enable the pharmacist to dispense the correct trial treatment.  Supplies 
of active and placebo trial treatment will be provided to the hospital pharmacies, labelled 
with a code so the pharmacist does not know which is active and which placebo.  
5.4. Stratification and Randomisation 
Participants will be randomised to receive tranexamic acid or a matching placebo in a 1:1 
ratio, stratified by site. Randomisation will be balanced within blocks of varying undisclosed 
sizes.  
 
5.5. Randomisation Practicalities 
There will be no exception to eligibility requirements at the time of randomisation. 
 
Eligibility for randomisation will be assessed with reference to the specific inclusion and 
exclusion criteria. 
 
When a consented participant’s platelet count falls to ≤50x109/L, the PI or delegate will 
complete the trial registration/randomisation form and access the web based randomisation 

 
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service to randomise the participant. If a patient’s platelet count is ≤50x109/L on admission 
to hospital because they have a newly diagnosed haematological malignancy or refractory 
disease the patient should be approached for randomisation as soon as possible. 
 
Following randomisation, the randomisation service will e-mail confirmation of the 
randomisation number to the PI and Trial Manager.  
 
The local PI/delegate is responsible for informing the participant’s consultant/physician of 
the patient’s participation in the trial, and for placing a label indicating trial participation on 
the cover of the patient’s medical notes. 
 
The PI/delegate will be responsible for immediately telephoning the pharmacy and speaking 
with the trials pharmacist, informing them of a patient’s participation in the trial and their trial 
number. A written prescription for trial medication will then be sent to the pharmacy, along 
with written confirmation of the randomisation number (for example the print-out from the 
randomisation system). These documents must be received by the clinical trials pharmacist 
before trial medication may be dispensed.   
 
The trial treatment will be dispensed to the ward to be stored appropriately. Note: the trial 
treatment shall be commenced as soon as possible within 24, and not later than 72 hours of 
the first recorded platelet count of ≤30x109/L. If a patient’s platelet count is ≤30x109/L on 
admission to hospital because they have a newly diagnosed haematological malignancy or 
refractory disease the patient should be approached for randomisation and commenced on 
trial treatment within 24, and not later than 72 hours of starting intensive chemotherapy 
treatment or conditioning for stem cell transplant. 
 
 
The PI/delegate must update the centre’s screening log by remembering to add trial 
numbers for all patients randomised. 
 
 
 
 
 
 
 
 
 
 
If difficulties are experienced using the randomisation website, then please contact the Trial 
Manager, who will be able to randomise the patient on your behalf. 
5.6. Randomisation Codes 
The randomisation service will send confirmation to the PI of the randomisation number and 
inform the Trial Manager.  
5.7. Co-enrolment Guidelines 
Participants should not be enrolled in other trials involving platelet transfusions, anti-
fibrinolytics, platelet growth factors or other pro-coagulant agents. Co-enrolment in any other 
trial will be dependent upon the rules stipulated in that trial protocol, and should be discussed 
with the CI for the other trial.  
RANDOMISATIONS 
To randomise, please visit 
 
www.sealedenvelope.com 
 
choose the TREATT trial from the drop down list and log-on as instructed 

 
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5.8. Blinding 
In this trial, the participants, the PI, the ward nurses, ward pharmacist, all other site staff, 
and all members of the TMG will be blinded to treatment allocation. The clinical trial 
pharmacists at each centre will be semi-blinded, in that they will know which participants are 
in each group, but not what the group is.  
 
5.9. Unblinding 
In general, there should be no need to unblind the allocated treatment. Unblinding should 
be done only in those rare cases when the clinician believes that clinical management 
depends importantly upon knowledge of whether the participant is receiving TXA or 
placebo. In those few cases when urgent unblinding is considered necessary, the PI will be 
given access to the web-based service (www.sealedenvelope.com). Details of this shall be 
in the Site File. The person performing the unblinding will be sent an e-mail detailing a 
participant’s treatment allocation. The NHSBT 24-hour telephone number is also available: 
0300 123 2323; this will enable the investigator to contact the CI out of hours. 
                           
 
6. Treatment of Participants 
6.1. Introduction 
This trial has an intervention arm and a control arm. These are described in the sections 
below.  
 
Trial treatment will be started as per randomisation assignment as soon as possible within 
24 hours, and no later than 72 hours, of the first recorded platelet count ≤ 30 x 109/L, or if 
the participant was admitted with a platelet count already below 30 x 109/L as soon as 
possible within 24 hours, and no later than 72 hours, after the start of chemotherapy or 
conditioning for a stem cell transplant  
 
The participant’s eligibility criteria MUST be rechecked to ensure they are still eligible prior 
to first administration of the trial treatment. 
 
The period of time between randomisation and initiation of the trial treatment will allow time 
for pharmacy to prepare and dispense the trial treatment. 
 
During their inpatient stay haematology patients may experience severe nausea and 
vomiting, diarrhoea, or significant mucositis. This may impair their ability to tolerate or absorb 
an orally administered medication. Therefore the trial treatment will initially be given by 
intravenous administration until the participant is well and able to tolerate the oral 
medication. The treating physician can then switch the medication to its oral formulation. 
The date on which the participant is switched from IV to oral formulation will be documented. 
The participant must receive at least one dose of the IV formulation before transferring to 
oral.  Participants can return to IV after commencing oral IMP, this must be documented, but 
care must be taken to ensure the correct dose is prescribed. 
 
If the participant has not met the stopping criteria when they are ready for discharge oral 
IMP should be prescribed. 
In other patient groups the dose of tranexamic acid is the same whether it is given 
therapeutically or prophylactically. Due to differences in bioavailability 1g IV is equivalent to 
1.5g PO.  This dose is similar to the doses given in the three previous RCTs that have been 
performed (See Investigator Brochure for further information).  
 

 
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6.2. Interventions 
6.2.1. CTIMP to be studied 
Tranexamic acid (TXA).  
Dose schedule TXA 1g every eight hours IV or 1.5g every eight hours PO. 
 
Comparator or placebo 
Placebo (saline) if administration is IV. 
Placebo capsule or tablet matched for appearance to TXA if oral. 
 
6.2.2. Description of Trial Drug 
 
Tranexamic acid (Cyklokapron) is trans-4-(aminomethyl)cyclohexanecarboxylic acid, which 
acts as an inhibitor of fibrinolysis. At the dose used in this study it is a competitive inhibitor 
of plasminogen activation. Each 10mL vial contains 1g of tranexamic acid (100mg/mL) as 
an aqueous solution. Vials should be stored between 15° to 25°C. Do not Freeze. 
Tranexamic acid Injection is administered by infusion, utilising the usual compatible 
intravenous vehicles (e.g., Sterile Water for Injection, Sodium Chloride for Injection, 5% 
Dextrose or Ringer’s Injection), or slow IV bolus. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration, whenever 
solution and container permit. 
 
The oral preparation will consist of identical tablets from July 2018 (further details available 
in the Investigator Brochure).  
 
These will be supplied to the clinical trials pharmacist in containers, from which . the 
pharmacist will dispense the required number (according to the randomisation schedule) for 
the participant. 
 
6.2.3. Blinding of Trial treatment 
For intravenous treatment the local investigational drug pharmacy will receive boxes of nine 
glass vials containing either active drug or placebo. Each box will have a tear off label 
indicating A or B. Thus, the clinical trials pharmacist will be aware that the participant is 
receiving treatment A or treatment B; the clinical staff, ward pharmacist and participant will 
be unaware of the randomisation, as the tear off portion of the label will be removed before 
dispensing. When a subject is randomised to the trial, the randomiser will receive a 
randomisation number for the participant and will send confirmation of this, along with a 
prescription for trial treatment to the clinical trials pharmacist. The clinical trials pharmacist 
will consult the randomisation list supplied and dispense the trial treatment allocated to the 
randomisation number. 
 
 
Labelling of the trial treatment has been changed from Tranexamic acid/placebo to TREATT 
Trial IMP to prevent inadvertent use of local pharmacy stock TXA. 
 
6.2.4. Administration of Trial treatment 
The trial treatment will be started as per randomisation assignment as soon as possible, 
ideally within 24 hours, and no later than 72 hours, of the first recorded platelet count 
≤30x109/L. Or, if a patient’s platelet count is ≤30x109/L on admission to hospital because 
they have a newly diagnosed haematological malignancy or refractory disease the patient 
should be approached for randomisation and commenced on trial treatment within 24 hours, 

 
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and no later than 72 hours, of starting intensive chemotherapy treatment or conditioning for 
a stem cell transplant. 
 
 
The IV preparation of trial treatment will be administered as a slow IV bolus over 10 
minutes every eight hours.  
The IV preparation may also be given as an infusion and centres are advised to follow 
local pharmacy practice for TXA. 
IV Tranexamic acid / placebo may be mixed with most solutions for infusion such as 
electrolyte solutions, carbohydrate solutions, amino acid solutions and dextran solutions.  
 
The IV trial treatment must not be mixed with blood. 
 
The IV trial treatment must not be mixed with solutions containing penicillin. 
 
Three tablets of the oral preparation must be taken with water every eight hours.  
 
6.2.5. Dose Adjustment of Trial treatment in Renal Insufficiency 
 
Renal impairment 
In renal insufficiency leading to a risk of accumulation, the use of tranexamic acid is 
contraindicated in patients with severe renal impairment.  For patients with mild to moderate 
renal impairment, the dosage of tranexamic acid should be reduced according to the serum 
creatinine level: 
 
Serum creatinine 
Dose IV 
Dose PO 
Administration 
μmol/l 
mg/10 ml 
 
 
120 to 249 
1.35 to 2.82 
10 mg/kg BW 
15 mg/kg BW 
Every 12 hours 
250 to 500 
2.82 to 5.65 
10 mg/kg BW 
15 mg/kg BW 
Every 24 hours 
> 500 
> 5.65 
5 mg/kg BW 
Omit dose 
Every 24 hours 
Oral suggested doses 
If creatinine 120 to 249  
 
If creatinine 250 to 500  
Participants < 50 kg 
500mg BD 
500mg OD 
Participants 50 to 83 kg 
1g BD 
1g OD 
Participants  84 to 116 kg 
1.5g BD 
1.5g OD 
Participants > 117 kg 
2g BD 
2g OD 
Hepatic impairment  
No dose adjustment is required in patients with hepatic impairment. 
6.2.6. Discontinuation of Trial treatment 
The trial treatment will be permanently discontinued as soon as any one of the following 
situations occurs: 

 
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1. It has been 30 days since the participant first started the randomised trial treatment. 
2. The participant has a spontaneous increase in platelet count from <30x109/L to 
>50x109/L. 
3. The participant has had 3 consecutive days with morning platelet counts >30x109/L, 
and no requirement for platelet or granulocyte transfusion, or stem cell transplant. 
4. The participant receives open label tranexamic acid, other antifibrinolytic agent or 
procoagulant drug, (e.g., DDAVP, recombinant Factor VIIa, or Prothrombin Complex 
Concentrates). Use of these agents will be recorded in trial data.  
5. The participant begins anticoagulant or antiplatelet therapy. 
6. The participant has visible haematuria. 
7. The participant has a diagnosis of thrombosis. 
8. The participant becomes anuric (defined as urine output <10mls/hr over 24 hours). 
9. The participant develops sinusoidal obstructive syndrome (SOS, Veno-occlusive 
Disease, VOD) 
 
Note: If the trial treatment is discontinued it must not be restarted while the participant 
remains in the trial. 
 
In addition to the reasons stated above participants may stop treatment early or be stopped 
early for any of the following reasons: 
 
 
Disease progression. 
 
Unacceptable adverse reaction 
 
Any change in the participant’s condition that justifies the discontinuation of 
treatment in the opinion of the clinician. 
 
Withdrawal of consent. 
 
In consenting to the trial, participants are consenting to the trial treatment, trial follow up and 
data collection. As the participant’s participation in the trial is entirely voluntary they may 
choose to discontinue the trial treatment at any time without penalty or loss of benefits to 
which they are otherwise entitled. Although the participant is not required to give a reason 
for discontinuing their trial treatment, a reasonable effort should be made to establish this 
reason whilst fully respecting the participant’s rights.  
Participants will remain in the trial for the purpose of follow up and data analysis, unless they 
withdraw their consent from all stages of the trial, in which case, they should be withdrawn. 
Data collected up until the time of withdrawal will be retained and included in the analysis.  
6.3. Adherence to intervention 
Daily trial treatment accountability will be performed. Any unused medication will be 
collected by the research nurse from the ward (if participant is an inpatient) or participant (if 
participant is an outpatient) and returned to the local trial pharmacist. The pharmacist will 
document the amount dispensed and returned for each study participant. 
6.4. Concomitant Care 
6.4.1. Platelet transfusions 
Prophylactic platelet transfusions will be given at threshold counts of less than or equal to 
10 x 109/L. A single adult dose should be given on the same day that a platelet count is 
recorded as less than or equal to 10x109/L, and continued on a daily basis until the platelet 
count is greater than 10x109/L.  
 
Therapeutic platelet transfusions may also be given following objective and documented 
signs or symptoms of bleeding at WHO Grade 2, 3, or 4 or in accordance with the local 
physicians’ usual practice. 

 
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Prior to planned invasive procedures; physicians will be allowed to increase the transfusion 
dose and/or threshold in keeping with their current practice.  
Clinicians can exercise discretion to transfuse platelets for any reason should they feel there 
is a clinical reason to do so; the rationale must be clearly recorded on the daily transfusion 
data form. There is no justification to prescribe platelet transfusions pre-emptively above the 
defined threshold, if for example the participant’s platelet count appears to be falling just 
prior to a weekend. 
 
In the UK, recommendations for platelet transfusion practice are provided in the BCSH 
guidelines (35). All platelet components are leucoreduced, around 80% are collected by 
apheresis, and common hospital practice is to transfuse ABO and RhD identical platelets. 
In Australia, relevant guidance is provided in the national Patient Blood Management 
Guidelines available at https://www.blood.gov.au/pbm-guidelines 
. The type (apheresis or pooled platelets prepared from whole blood) and the dose of platelet 
transfusion will not be specified.   
 
If a participant develops platelet refractoriness (defined as two sequential transfusions with 
a 24 hour platelet increment < 5x109/L), a serum sample will be drawn for lymphocytotoxic 
antibodies. If the panel reactive antibody (PRA) is ≥20%, the participant will be presumed to 
be alloimmune platelet refractory and may be given either HLA-matched or cross-match 
compatible platelet transfusions. If the PRA is <20%, local practice will be followed to treat 
the refractoriness. The participant will remain in the trial and data will continue to be collected 
on the participant. 
 
6.4.2. Red Cell Transfusions 
As a low haematocrit has been associated with an increased bleeding risk (36-38) a 
common policy to guide red cell transfusion support according to the BCSH Guidelines 
(UK) and in Australia the national Patient Blood Management Guidelines will be followed, 
available at   https://www.blood.gov.au/pbm-guidelines 
.This threshold for red cell transfusion (in the absence of blood loss due to bleeding) will be 
a Hb value of less than 80g/L.  
 
All transfusion components in the U.K. and Australia, including red cells, are standardised 
and will conform to national specifications. All allogeneic blood components produced in the 
U.K. and Australia have been subjected to a pre-storage leucocyte filtration process. 
 
No other medication changes are directed in this protocol, and standard care will otherwise 
be followed. 
6.4.3. Contraception 
Women of childbearing potential must use effective contraception while receiving the trial 
treatment. Examples would include the use of the male or female condom, or diaphragm 
with spermicide. Women of child bearing potential will be excluded if they are sexually active 
and not using a reliable form of contraception. 
6.4.4. Medications Not Permitted 
Whilst in receipt of trial medication, participants must not be given any other antifibrinolytic 
agent or procoagulant drug, (e.g., DDAVP, recombinant Factor VIIa, or Prothrombin 
Complex Concentrates), nor open label tranexamic acid.  
6.5. Co-enrolment guidelines 
Please refer to Section 5.7 for details. 

 
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6.6. Ancillary and post-trial care 
There is no reason why participants could not be prescribed therapeutic tranexamic acid 
after completion of study period (this will be recorded). 
 
7. Trial Outcomes 
7.1. Primary Outcome Measure 
Estimated proportion of participants who died or had bleeding of WHO grade 2 or above 
during the first 30 days of the trial from the first day of trial treatment  
 
A time-to-event analysis will be used to determine this proportion to ensure that all 
participants are included in the primary outcome analysis, not just those who are followed 
up for the full 30 days. Any participants lost to follow-up will be included in the analysis and 
censored at the time that they were lost. 
7.2. Secondary Outcome Measures 
7.2.1. Secondary Efficacy Outcomes   
All measured during first 30 days of the trial, i.e. from the first day of trial treatment. 
  Proportion of days with bleeding (WHO grade 2 or above) 
 Time to first episode of bleeding of WHO grade 2 or greater  
 Highest grade of bleeding a participant experiences  
 Number of platelet transfusions/participant  
 Number of red cell transfusions/participant  
 Proportion of participants surviving up to 30 days without a platelet transfusion  
 Proportion of participants surviving up to 30 days without a red cell transfusion 
 Quality of life 
7.2.2. Secondary Safety Outcomes 
 
Number of thrombotic events from first administration of trial treatment up to and 
including 120 days after the first dose of trial treatment is administered, per day at 
risk 
 
Number of participants developing Veno-occlusive Disease (VOD; Sinusoidal 
obstructive syndrome, SOS) within 60 days of first administration of trial treatment 
 
All-cause mortality during the first 30 days and the first 120 days after the first dose 
of trial treatment is administered 
 
Death due to thrombosis during the first 120 days after the first dose of trial treatment 
is administered 
 
Death due to bleeding during the first 30 days after the first dose of trial treatment is 
administered 
 
Number of serious adverse events from first administration of trial treatment until 60 
days after the first dose of trial treatment is administered 
 
7.2.3. Other outcomes  
All measured during first 30 days of the trial, i.e. from the first dose of trial treatment  
 
 
Proportion of days with thrombocytopenia (≤10x109/L, ≤30x109/L, ≤50x109/L) 
 
Proportion of days with fever (highest daily temperature ≥ 38.1°C) of days spent in 
hospital, up to study day 30 
 
Reasons for platelet and red cell transfusions 

 
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7.3. Sub-group analyses 
Subgroup analyses will be performed for the primary outcome for the following variables in 
the main analysis: 
 
 
Country of participant (UK vs. Australia), if evidence of heterogeneity between UK 
and Australian participants is identified in the interim analysis  
 
Platelet count at consent (≤30x109/L vs. > 30x109/L) 
 
Treatment compliance during first 30 days of the trial (withdrawal of consent for trial 
treatment vs. no withdrawal of consent)  
 
 
8. Assessments and Follow-up 
8.1. Trial Assessment Schedule  
Please see study schedules Pages 13 & 14 
8.2. Procedures for Assessing Efficacy 
8.2.1. Bleeding Assessment 
Bleeding assessment will commence when the participant is randomised and stopped when 
one of the following occurs: 
 
 It has been 30 days since the trial treatment was commenced 
 Or in those cases where trial treatment was not started, 30 days from platelet count 
≤30 x 109/L or the commencement of chemotherapy/stem cell conditioning therapy 
 The participant dies. 
 Participant withdraws his/her consent to having bleeding assessments performed. 
 Site investigator withdraws the participant from all further study assessments. 
 
Bleeding assessments will be conducted using a tool based upon that used in the recent 
TOPPS trial (20)  and further developed by an international working group – the BEST 
collaborative (46). If a participant is an out-patient between day of randomisation and trial 
treatment starting they will be asked to inform the research team if they have had any 
bleeding at home. Simple guidance notes will be provided to assist with this. 
 
Rates of recorded bleeding are known to vary considerably between trials.  Reasons for this 
variability have been explored and published through a review organised by the BEST 
collaboration, and include different patient groups and bleeding definitions, and variable 
follow up periods (39).  
 
In the TREATT trial, a number of measures will be taken to standardise documentation and 
recording of bleeding, including trained assessors, monitoring and education. In the recent 
TOPPS (20) trial, where completeness of bleeding outcome documentation was excellent, 
a bleeding assessment was completed on 93% (8405/9030) of days for patients in the no-
prophylaxis group, and 97% (8733/8970) of days in the prophylaxis group. The majority of 
patients in both arms had bleeding information collected on each trial day (median no-
prophylaxis 30 days (IQR 29 to 30); median prophylaxis 30 days (IQR 30 to 30)). 
 
For inpatients, bleeding assessments will be performed using the bleeding assessment tool 
which includes a physical assessment of the participant, patient interview (if possible) and 
review of patient chart and laboratory data. Research staff will perform the physical 
assessment and interview before reviewing the participant’s charts, medical notes and 

 
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laboratory data to allow an objective assessment. Research staff will perform the bleeding 
assessment at approximately the same time each day. 
 
All participants who are discharged home before completion of the trial study period (30 days 
from commencement of the trial treatment) will be asked to complete a daily diary. 
Participants will be provided with clear guidance notes to assist them in self-assessment of 
bleeding. They will be asked to respond with a yes/no answer as to whether they have 
experienced any bleeding on that day.  
If a participant reports no bleeding on their bleeding diary this will be recorded as a WHO 
grade 0 bleed. If the participant does report bleeding they are asked to consult with their 
haematology care team.  If the clinical team consider the bleeding to be significant then the 
participant should be reviewed and a bleeding assessment will be conducted by a member 
of the research team. If the haematology team considers the bleeding to be clinically 
insignificant, this will be recorded as WHO grade 1  
 
Additionally, all participants at home will be contacted by the local research staff on day 30 
from first dose of the trial treatment to review the diary and confirm arrangements to collect 
all completed forms, which will be forwarded on to the data manager for entry into the trial 
database. 
 
Local research staff completing the daily assessments will receive training and have guide 
notes to help them collect these data. 
 
8.2.2. Assigning a grade to a bleed 
 
Grade of bleed (WHO Grading System - see 20.2) will be assigned centrally by means of a 
computer algorithm at the time of analysis.  
 
8.3. Procedures for Assessing Safety 
8.3.1. Thrombotic Assessment 
For in-patients, medical chart notes and imaging studies will be reviewed daily for 
documentation of any thrombotic events. For out-patients, the local research nurses will 
attempt to contact the participant directly, and if contact is not made, the participants’ local 
physician / GP will be contacted.   
Safety outcomes will include recording symptomatic thrombotic events that occur during the 
study period and up to 120 days (+/-7) after the first dose of the trial treatment is 
administered. 
 
8.3.2. Interval Medical Events/Serious Adverse Events 
A member of the research team will contact the participant in person or by telephone to ask 
them about any interval medical events or serious adverse events after discharge from 
hospital. If the research team are unable to contact the participant directly, their local 
physician/GP will be contacted. 
8.4. Other Measurements 
The following data will be collected: 
   
Demographics and Medical History 
This will include: 
 
Weight 

 
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 
Height 
 
Date of birth 
 
Gender 
 
Ethnic origin 
 
Diagnosis (disease and type or treatment: i.e. chemotherapy or type of stem cell 
transplant) 
 
If receiving allogeneic transplant, whether HLA matched or mismatched 
 
Type and date of transplant or first day of other treatment  
 
Previous co-morbidities 
 
Renal impairment 
 
Previous fungal infection 
 
Laboratory Studies (All study centres)  
 
Urine dipstick (at enrolment) 
 
Haemoglobin and platelet count, required daily when participant is an in-patient and 
3 times a week, or as Standard of Care, when participant is an out-patient 
 
Coagulation profile (PT or INR), at randomisation.  
 
Serum creatinine (required at enrolment, randomisation, study days 1&2, and then 
3 times a week on Monday, Wednesday and Friday, or as SOC, when participant is 
on trial treatment) 
 
Liver function tests including bilirubin and albumin required if VOD suspected / 
reported three times a week 
 
HLA antibody screen - required at enrolment, and repeated if a participant develops 
platelet refractoriness (defined as two sequential transfusions with a 24 hour platelet 
increment <5x109/L) 
 
Laboratory Studies (Selected study centres) 
 
Fibrinolysis assay (central/local lab) – sub-study 
 
C-reactive protein (CRP) (this is required daily when participant is an in-patient if it 
is measured routinely at the participating hospital) 
 
Immature platelet fraction (this is required daily when participant is an in-patient and 
at least 3 times per week, when participant is an out-patient  
 
 
Transfusions given during study (from enrolment to study day 30) 
 
Data on platelet, granulocyte or stem cell transfusion 
 
Reason for transfusion (prophylaxis, invasive procedure, active bleeding, risk of 
significant bleeding, other) 
 
Data on red cell transfusions 
 
Number of units transfused 
 
Reason for transfusion (anaemia, active bleeding, other) 
 
Fever 
 
Highest temperature within each 24 hour period (defined as 8am to 8am) when 
participant is an inpatient  
 
Quality of Life Assessment 
 
Quality of life assessment (EQ5D & FACT-Th) at randomisation, day 12 (±2) and day 
30 (±2). EQ-5D at day 120 (±7). 
 
Health economic analysis (from study day 1 to study day 120) 
 
Number of hospital admissions, and duration of stay 
 
Number of ITU admissions and duration of stay 
 
Number of day unit admissions 

 
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 
Number of hospital outpatient visits  
 
Yes/No question as to whether the participant has had any further treatment for their 
haematological malignancy 
 
Whether the participant has active haematological disease at day 120 
8.5. Loss to Follow-Up 
If the local research team are unable to contact a participant to obtain follow-up data, 
consent will be obtained on enrolment to the trial to contact their family physician / General 
Practitioner.   
 
 
Death 
Data will be recorded on all-cause mortality, mortality due to bleeding and mortality due to 
thrombosis. 
 
 
Discontinuation of Trial treatment 
Participants are free to stop the trial treatment at any time. The date will be recorded, along 
with the reason, on a designated trial treatment discontinuation form. In the event of the 
participant stopping the trial treatment, the participant will still be followed for all trial 
outcomes according to the protocol, unless they have specifically withdrawn consent for 
further data collection.  
 
 
Withdrawals 
Participants may withdraw or be withdrawn from the trial at any time for any of the following 
reasons: 
1. Participant withdraws consent 
2. Investigator withdraws participant from the trial 
3. Death 
 
 
End of trial for each participant 
The trial end date for each participant will be the date of the last telephone call or outpatient 
visit at study day 120. 
8.6. Trial Closure 
The trial will be closed to recruitment when the required number of participants has been 
recruited and the last participant has completed the trial intervention period (to Day 30). 
 
9. Safety Reporting 
 
The principles of ICH GCP require that both investigators and sponsors follow specific 
procedures when notifying and reporting adverse events or reactions in clinical trials. These 
procedures are described in this section.  
In general, investigators should report adverse events as diseases or syndromes whenever 
possible, instead of reporting individual component symptoms, signs, laboratory 
abnormalities or sequelae.  
9.1. Definitions of Adverse Events 
The definitions to be applied to adverse events occurring during this trial are given in Table 
9a below.  When an adverse event occurs, the PI or delegate should first classify the event 
according to table 9a below. Events of interest and that require to be reported are any: 
 
Unexpected Adverse Reactions 
 
Serious Adverse Events  

 
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that occur during the trial period that are not already listed as primary or secondary 
outcomes. Any other adverse event does not need to be recorded.  
 
Table 9a: Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence affecting a trial participant during the 
course of a clinical trial and which does not necessarily have to have a 
causal relationship with participation in the research. 
Adverse reaction to an 
investigational medicinal 
product (AR) 
An adverse event when there is at least a possibility that it is causally 
linked to a trial drug or intervention. 
Unexpected Adverse 
Reaction 
(UAR) 
An unexpected adverse reaction is an AR in which the nature or severity 
of the reaction is not consistent with the known side effects of the trial 
drug or intervention. There need only be an index of suspicion that the 
event is a previously unreported reaction to a trial drug or intervention. 
Serious Adverse Event 
(SAE) or serious adverse 
reaction (SAR)  
 
Any adverse event (AE) or adverse reaction (AR) that meets any of the 
following criteria: 
 
results in death 
 
is life-threatening 
 
requires hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability or incapacity, results in 
a congenital anomaly/birth defect 
 
any other adverse event that, based upon appropriate medical 
judgment, may jeopardise the subject’s health and may require 
medical or surgical intervention to prevent one of the other 
outcomes listed in this definition   
Suspected Unexpected 
Serious Adverse Reaction 
(SUSAR) 
 
A suspected unexpected serious adverse reaction is an unexpected 
occurrence of a SAR; in which the nature or severity of the reaction is 
not consistent with the known side effects of the trial drug or 
intervention. There need only be an index of suspicion that the event is 
a previously unreported reaction to a trial drug or intervention. 
 
Unanticipated problem 
involving risks to subjects 
or others (UP) 
Any incident, experience, or outcome that meets all of the following 
criteria:  
a. unexpected (in terms of nature, severity, or frequency) given (a) 
the research procedures that are described in the protocol-related 
documents, such as the REC-approved research protocol and 
informed consent document; and (b) the characteristics of the 
subject population being studied;  
b. related or possibly related to a subject’s participation in the 
research; and  
c. suggests that the research places subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social 
harm) related to the research than was previously known or 
recognised 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations. Important AEs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent one 
of the other outcomes listed in the definition above, should also be considered serious. 
 
9.2. Investigator Responsibilities 
The Chief Investigator (CI) has overall responsibility for the conduct of the trial. As this is a 
multi-site trial, the Principal Investigator (PI) has responsibility for the research at their local 

 
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site and is responsible for informing the CTU of all reportable serious or unexpected adverse 
events or reactions that occur at their site following the flow chart and guidelines below. 
9.2.1. Investigator Assessment of Adverse Events 
 
Causality 
The causality of all AEs should be assessed by the PI (or delegate) using table 9b below. 
There are 5 categories: unrelated, unlikely, possible, probable and definitely related.  
Table 9b: Definitions of Causality 
Relationship 
Description 
Unrelated 
There is no evidence of any causal relationship 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event did 
not occur within a reasonable time after administration of the trial treatment or 
intervention).  There is another reasonable explanation for the event (e.g. the 
patient’s clinical condition, other concomitant treatment). 
Possible 
There is some evidence to suggest a causal relationship (e.g. because the event 
occurs within a reasonable time after administration of the trial treatment or 
intervention).  However, the influence of other factors may have contributed to the 
event (e.g. the patient’s clinical condition, other concomitant treatments). 
Probable 
The evidence is clearly in favor of attributing the adverse reaction to the trial 
treatment or intervention 

 
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Definitely 
There is conclusive evidence beyond reasonable doubt attributing the adverse 
reaction to the trial treatment or intervention. 
 
Seriousness 
When an AE or AR occurs, the investigator responsible for the care of the patient must 
assess whether or not the event is serious using the definitions in Table 9a: definitions. If 
the event is serious and is on the list of expected events in section 9.1, then the details must 
be recorded on the SAE form within five working days. If the event is a SUSAR it must be 
recorded on the SAE form and sent to the CTU within 24 hours of becoming aware of it.  
 
Expectedness  
For all events and reactions, the Investigator must assess the expectedness. Please refer 
to the Investigator Brochure Section 8 for a list of expected serious adverse reactions to the 
trial treatment. This is the reference safety information for the trial. 
 
Additional information on expected adverse reactions is available in Section 4.8 of the 
Summary of Product Characteristics (found in Section 16 of the Investigator Brochure) for a 
list of expected adverse reactions to the oral trial treatment and in Section 7 of the 
investigator brochure for the intravenous trial treatment. 
 
 
9.3. Adverse Event Reporting 
9.3.1. Adverse Events that Require Expedited Reporting (within 24 hours) 
Any SAEs (related or unrelated) or unexpected (but not serious) adverse reactions must be 
reported within 24 hours of the PI becoming aware of the event, unless they have been 
specifically excluded from expedited reporting (see section 9.3.2). 
9.3.2.   Trial Specific Exceptions to Expedited SAE Notification (within 5 
working days) 
These are SAEs that are associated with the disease that the participants will be suffering 
from, and will not impact on the scientific interpretation of the results of the trial. 
 
Due to the seriousness of the disease(s) the patients in this trial are suffering from, the 
following situations that fulfil the definition of an SAE are excluded from expedited 
notification, but should be recorded on the SAE form and reported within five working days: 
 
Elective hospitalisation to evaluate the treatment management plan for the patient’s 
disorder, or for procedures 
 
Elective hospitalisation for pre-existing conditions that, in the investigator’s opinion, 
have not been exacerbated by trial treatment 
 
Admission to the intensive care unit 
 
Severe sepsis 
 
Major organ dysfunction 
 
Any other serious event related to the underlying disease or medication used to treat 
the disease 
 
Death as a result of disease progression 
 
Any event that does not meet the above definitions does not need to be recorded at all.  
 

 
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9.3.3. Investigator Notification  
 
The CTU should be notified as soon as possible and within 24 hours of the 
investigator becoming aware of any SAE that has occurred, unless it has been 
excluded from expedited reporting.  
 
The SAE form must be completed by the Investigator (the consultant named on the 
delegation of responsibilities log who is responsible for the patient’s care). In the 
absence of the Investigator, the form should be completed by a member of the site 
trial team and sent to CTU. The responsible Investigator should subsequently check, 
annotate and sign the form and send to the CTU as soon as possible. The initial 
report must be followed by detailed written reports as appropriate.  
 
The Investigator must record all SAEs that occur during the trial period on the SAE 
form. They are required to notify the CTU within five working days of becoming aware 
of an SAE that has been excluded from expedited reporting. 
 
The investigator must follow-up all reported SAEs until resolution or the event is 
considered stable. 
 
The CTU should be notified within 24 hours of the investigator becoming aware of 
an UAR that has occurred. The severity of an UAR will be graded by the CTU using 
MedDra terminology (Medical Dictionary for Regulatory Activities, Version 17.1, 
September 2014, and as updated from time to time. The Investigator must supply 
the CTU, REC and relevant NHS Trust R&D with any supplementary information 
they request. 
9.4. Sponsor’s Responsibilities 
 
The CTU (Sponsor) will forward all adverse reactions, SAEs and major safety 
outcome reports received to the Chief Investigator (or a medically qualified delegate) 
for review.  
 
As thromboembolism and mortality are the main safety outcomes of interest, these 
will be reported to the DMC as they occur, within a time frame to be determined by 
the DMC. The DMC may wish to view unblinded or partially unblinded data.  
 
The CTU will review all SAE reports and forward to the DMC for review, as often as 
instructed by them, and also provide them as listings for review at DMC meetings. 
These will be copied to the Chief Investigator for review.  
 
Agree the planned content of both blinded and unblinded DMC reports with DMC 
members prior to the inclusion of the first trial participant. 
 
The CTU is undertaking the duties of trial sponsor and is responsible for the reporting 
of any SUSARs to the MHRA or its equivalent and to the research ethics committee 
(REC) in all countries participating in the trial, and for preparing annual safety reports 
to the MHRA and the REC. The reporting time-frames for SUSARs will be according 
to the current national regulations for the participating countries. In the UK this will 
be in accordance with European Directive 2001/20/EC. 
9.5. Statutory Reporting 
Hospital staffs remain responsible for reporting all transfusion-related adverse events to 
SHOT/SABRE according to standard procedures, as required under the regulations of the 
EU Blood Directive. Unexpected adverse reactions should also be reported via the Yellow 
card system. Staffs at the institution are also responsible for notifying their local R&D 
department of SAEs (as per the institutions standard local procedure).  
 
 

 
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10. 
Quality Assurance and Control 
10.1. 
Risk Assessment 
A Risk assessment has been conducted which acknowledges the potential risks to the trial. 
This section provides an overview of the Quality Assurance (QA) and Quality Control (QC) 
measures that will be put in place to ensure the trial is performed and data generated and 
recorded in accordance with the principles of ICH GCP.  
10.2. 
Central Monitoring at CTU 
The CTU data managers will review all data received for errors and missing data points. 
Central monitoring procedures for data verification and issue and resolution of queries raised 
will be detailed in a separate data management plan. 
10.3. 
 On-Site Monitoring 
The frequency, type and intensity for routine monitoring and the requirements for “for cause” 
monitoring will be detailed in a separate monitoring plan.  
10.3.1. Direct access to patient records 
Participating investigators should agree to allow trial-related monitoring, including audits, 
ethics committee review and regulatory inspections by providing direct access to source 
data and documents as required. Patient consent must be obtained for this.  
10.3.2. Confidentiality 
The data will be handled in accordance with the principles of the UK Data Protection Act. 
10.4. 
Auditing 
In addition to potential audits by the MHRA or the local R&D department, NHSBT reserves 
the right to conduct site audits, either as part of its on-going audit programme, or in response 
to adverse observations during monitoring visits.  
 
11. 
Statistical Considerations 
11.1. 
Method of Generating Allocation Sequence 
Participants will be randomised to antifibrinolytic therapy or placebo in a 1:1 fashion, 
stratified by site. Randomisation will further be balanced within blocks of varying, 
undisclosed sizes. 
 
 
 
 
NOTIFICATION OF SAEs 
 
 
Within twenty-four hours of becoming aware of an event, 
please send a completed SAE form to the NHSBT Clinical 
Trials Unit, unless SAE has been excluded from expedited 
reporting 
Email to: serious_adverse_events@nhsbt.nhs.uk 
 
 
 
 
 
 
 
 
 

 
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11.2. 
Outcome Measures 
See section 7. 
11.3. 
Sample size 
11.3.1. Minimal Clinically Important Difference (MCID)  
Based on the experience of similar patients in the TOPPS trial, in the absence of 
antifibrinolytic therapy, it is anticipated that 43% of eligible patients would experience death 
or WHO Grade 2 bleeding or higher within the first 30 days. In such a background setting of 
bleeding, the trial investigators anticipate less than a 10% relative reduction in bleeding rates 
would not be sufficient to substantially change clinical practice, because the absolute risk 
reduction of 4.3% would mean that it would be necessary to treat approximately 23.3 
patients in order for the treatment to have an impact on 1 patient (“Number Needed to Treat” 
(NNT) = 23.3). 
 
As much as a 26% relative reduction in bleeding rates would likely be judged sufficient to 
change clinical practice, because the associated NNT = 8.9 patients might be acceptable, 
provided no new safety issues related to anti-fibrinolysis in the thrombocytopenic population 
are uncovered. 
 
We thus evaluate the planned sample size of the trial relative to these hypothesised effects 
as a reference. 
11.3.2. Primary efficacy outcomes  
616 participants will be accrued to the UK/Australian clinical trial.  
The participants will be randomised in a double blind fashion to receive TXA or a matching 
placebo.  
 
The clinical trial will be conducted with the primary endpoint of decreased proportion of death 
or WHO Grade 2 or higher bleeding among all patients receiving TXA versus placebo over 
30 days. The type 1 error will be controlled at a two-sided level of 0.05. The primary endpoint 
will be analysed using the Kaplan-Meier (KM) method to estimate the probability of bleeding 
or death within 30 days in the analysis populations.  Power and sample size calculations are 
based on a log-rank test for comparing two survival curves, as described in Collett (40). 
 
It is anticipated that the UK and Australia will be able to recruit 616 participants for this trial.  
Under the assumption that anti-fibrinolysis results in a decrease of death or WHO Grade 2 
bleeding from 43% to 32%, the 616 participants will provide 80% power to detect an 
observed absolute decrease in bleeding rates of 11% (a relative reduction of 26% with a 
NNT of 8.9) and will be judged statistically significant at the two-sided 0.05 level. The 
planned trial size of 616 subjects includes an additional 5% of participants above the 
required sample size of 586. This 5% figure is more than the proportion of participants within 
TOPPS (4%) that dropped their platelet count below 50 x 109/L but did not drop their platelet 
below 30 x109/L. This therefore accounts for the number of participants within the trial who 
are randomised but never receive the trial treatment. 
 
We do not expect there to be a problem with the assessment of the primary outcome of 
bleeding over the 30 day trial period, starting from the first day of administration of trial 
treatment.,   
 In the recent TOPPS trial, completeness of bleeding outcome documentation was excellent. 
A bleeding assessment was completed on 93% (8405/9030) of days for patients in the no-
prophylaxis group, and 97% (8733/8970) of days in the prophylaxis group. The majority of 
patients in both arms had bleeding information completed on each trial day (median no-

 
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prophylaxis 30 days (IQR 29 to 30); median prophylaxis 30 days (IQR 30 to 30)). There were 
also only 6 deaths (1% of patients) while on the trial. 
 
11.3.3. Safety outcomes 
This trial is not powered to definitively establish the safety of the treatment with respect to 
the frequency of VTE. However, with the planned enrolment of 616 patients, an observed 
difference in frequency of VTE of 3.6% on the placebo arm and 5% or less on the TXA arm 
would result in a 95% confidence interval that excluded a relative risk of 3.5.   
11.3.4. Health economic evaluation 
The cost-effectiveness analysis will be performed based upon the data from the patients 
recruited to the UK component of TREATT. Although the trial is necessarily powered for the 
primary clinical endpoint of proportion of patients who die or have WHO Grade 2 or above 
bleeding over 30 days, we are confident that a reliable estimate of the cost-effectiveness of 
TXA for this patient group can be generated. 
11.4. 
Interim Monitoring and Analyses 
TREATT proposes to investigate the efficacy and safety of anti-fibrinolytic therapy in 
thrombocytopenic patients. In order to better address the often urgent nature of treatment 
administration, patients will be randomised earlier (when the platelet count is less than 
50x109/L) than when the trial treatment is administered (when the platelet count is less than 
30x109/L). The TREATT investigators have thus identified separate analysis populations to 
test the trial hypotheses. 
 
 
Analysis Populations 
 
 
Efficacy population 
The population used for efficacy analyses will be a modified intent to treat population (mITT) 
including all eligible randomised patients whose platelet count falls to 30x109/L or below. 
Data gathered for 30 days from the time the first dose of trial treatment is administered, or 
is planned to be administered for those participants who did not receive treatment. .  
Randomised participants whose platelet counts do not fall to 30x109/L or below will be 
excluded from the analysis, as will participants who develop exclusion criteria prior to their 
count falling to 30x109/L or below.  These exclusions are deemed appropriate as the early 
randomisation is for pragmatic reasons only. Characteristics of all randomised patients will 
be compared to the mITT population to ensure that excluded participants are similar across 
the arms. 
 
Unless otherwise specified, all analyses will be by this mITT. All subjects who fulfil the mITT 
requirements will be included in the analyses, in the treatment group to which they were 
randomly assigned.  Subjects who were prescribed trial treatment will be included in the 
analyses, even if they stop trial treatment “early”, or receive prophylactic transfusions not in 
accordance with the protocol. 
 
Rationale: Owing to the emergent nature of treatment of thrombocytopenic patients, 
participants are randomised in a double blind fashion to the treatment arms when platelet 
levels drop below 50x109/L. This will allow time for the pharmacy to prepare the trial 
treatment, and for the trial treatment to be available when the platelet count falls to 30x109/L 
or below. This has been instituted for pragmatic reasons and will guard against delays in the 
availability of the trial treatment. 
 

 
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The main primary outcome analysis will be based on the mITT population.  However, a per-
protocol analysis of the primary outcome will also be performed.  This per-protocol analysis 
will exclude all participants who were randomised in error and all participants who did not 
adhere to a set of minimum compliance criteria during the first 30 days of the trial.  The 
criteria are: 
 
 The participant commenced trial treatment within 72 hours of the first recorded platelet 
count ≤ 30 x 109/L, OR if the participant was admitted with a platelet count already below 
30 x 109/L within 72 hours after the start of chemotherapy or conditioning for a stem cell 
transplant.   
 
The participant received trial treatment and only received the trial treatment prescribed 
to them and did not receive open label tranexamic acid, other antifibrinolytic agent or 
procoagulant drug  
 
The participant only received the correct dose of the trial treatment prescribed to them  
 
 
The participant did not receive trial treatment after the point at which discontinuation of 
trial treatment should have occurred 
 
Participants who did not meet all the eligibility criteria and/or met at least one of the exclusion 
criteria will be considered as randomised in error.  
 
 
Safety population (apart from thrombotic events) 
The population used for safety analyses will be all participants who receive any amount of 
trial treatment, using data gathered from first administration of trial treatment until up to 120 
days after first administration of trial treatment.  
 
 
Thrombotic Event Safety population 
The population used for safety analyses of thrombotic events will be all participants who 
receive any amount of trial treatment, using data gathered from time of randomisation until 
120 days after first administration of trial treatment. 
 
 
Stopping rules 
Owing to the need to establish both the efficacy and safety of anti-fibrinolytic therapy, the 
intention is that TREATT will not stop randomising participants if anti-fibrinolytic therapy 
appears to show effectiveness in an interim analysis. This is because the trial will need to 
collect additional information on safety endpoints. This is judged important due to the low 
power the trial has to detect increased rates of thromboembolic events. Because TXA is 
currently being used off-label in thrombocytopenic patients, it is similarly judged important 
that any deleterious effect of anti-fibrinolytic therapy with respect to bleeding in 
thrombocytopenic patients be documented at a level that would be clinically and statistically 
credible. An interim analysis will be performed after 300 participants have been in the trial 
for 30 days. The independent DMC will have overall oversight and can recommend 
terminating the trial early for these or any other safety concerns.  A summary of SAEs, UARs, 
thrombotic events and veno-occlusive disease will be provided to the DMC.  In addition, a 
multivariate test for heterogeneity of UK and Australian baseline patient characteristics will 
be performed.  Sex, diagnosis, (acute leukaemia or not),  treatment plan (autograft or not) 
and haemoglobin at randomisation will be compared using Hotelling’s T-squared test.  
Sample proportions for categorical variables will be considered to be approximately normally 
distributed for the purposes of the multivariate test.  Only strong evidence of a difference 
between UK and Australian participants will be considered as evidence of heterogeneity.  If 
evidence of heterogeneity between UK and Australian participants is identified in the interim 
analysis, subgroup analysis by country of participant will be performed for the primary 
outcome in the main analysis,  
 

 
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11.5. 
Analysis Plan (Brief) 
11.5.1. Analysis of primary and secondary outcomes 
The analyses will be described in detail in a full Statistical Analysis Plan. This section 
summarises the main issues.  A full statistical analysis plan will be drawn up prior to closure 
of the trial database.  All analyses will be adjusted for the stratification variable (recruitment 
site).   
 
Primary efficacy analysis 
The proportion of participants who die or have bleeding of grade 2 or above by WHO criteria 
during the first 30 days from the first dose of trial treatment, or planned first dose for those 
participants who did not receive treatment,, will be estimated by the Kaplan-Meier method 
and compared using Cox regression analysis.  All participants whose platelet count dropped 
to 30x109/L or below, regardless of length of follow-up will be included. 
 
Secondary efficacy outcomes  
 
Proportion of days with bleeding up to study day 30; this will be compared using 
logistic regression.  Nesting at participant level will be accounted for by including 
a random participant effect.   
 
Time to first episode of bleeding of WHO grade 2 or greater up to study day 30 
will be estimated using the cumulative incidence function, with the competing risk 
of death prior to bleeding of WHO grade 2 or greater.  Cox regression analysis 
will be used to compare the two treatment groups. Participants who have not 
experienced bleeding of WHO grade 2 or greater will be censored at day 30 or at 
the point of last contact, whichever is first.  Participants who died prior to study 
day 30 and did not experience bleeding of WHO grade 2 or greater will be 
censored at the time of death. 
 
Highest grade of bleeding a participant experiences up to study day 30; this will 
be modelled using an ordinal logistic regression model, modelling grade as an 
ordinal categorical outcome. 
 
Number of platelet transfusions/participant up to study day 30 will be compared 
using a negative binomial model.  The model will include an offset to account for 
the number of days the participant spent in hospital, up to 30 days.. 
 
Number of red cell transfusions/participant up to study day 30 will be compared 
using a negative binomial model.  The model will include an offset to account 
for the number of days the participant spent in hospital, up to 30 days. 
 
Proportion of participants surviving at least 30 days without a platelet 
transfusion will be estimated by the Kaplan-Meier method and compared using 
Cox regression analysis. The event of interest is time to first platelet transfusion 
or death.  
 
Proportion of participants surviving at least 30 days without a red cell 
transfusion will be estimated by the Kaplan-Meier method and compared using 
Cox regression analysis.  The event of interest is time to first red cell 
transfusion or death. 
 
Safety outcomes 
 
Number of thrombotic events from first administration of trial treatment up to and 
including 120 days after the first dose of trial treatment is received, per day at risk 
will be described by arm. 
 
Number of participants developing Veno-occlusive Disease (VOD; Sinusoidal 
obstructive syndrome, SOS) within 60 days of first administration of trial treatment 
will be described by arm. 

 
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 
All-cause mortality during the first 30 days and 120 days after the first dose of trial 
treatment is administered will be will be estimated by the Kaplan-Meier method and 
compared using Cox regression analysis.. 
 
Death due to thrombosis during the first 120 days after the first dose of trial treatment 
is administered will be estimated using the cumulative incidence function, with the 
competing risk of death due to other causes.  Cox regression analysis will be used 
to compare death due to thrombosis between treatment arms. Participants who have 
not died will be censored at day 120 or at the point of last contact, whichever is first.  
Participants who died prior to day 120 from causes other than thrombosis will be 
censored at the time of death.  If numbers of deaths due to thrombosis are very 
small, the number of deaths will simply be described by arm.    
 
Death due to bleeding during the first 30 days after the first administration of trial 
treatment is received will be estimated using the cumulative incidence function, 
with the competing risk of death due to other causes.  Cox regression analysis will 
be used to compare death due to bleeding between treatment arms.   
 
Number of serious adverse events from first administration of trial treatment until 
60 days after the first dose of trial treatment is administered, per day at risk, will be 
summarised by arm, including number of symptomatic thrombotic events (venous 
thromboembolisms and arterial ischaemic events), veno-occlusive disease, sepsis, 
organ failure and death. 
 
Other outcomes 
 
Proportion of days with thrombocytopenia (<10x109/L, <30x109/L, <50x109/L) will be 
analysed using logistic regression. 
 
Proportion of days with fever (highest daily temperature ≥ 38.1°C) of days spent in 
hospital, up to study day 30, will be analysed using logistic regression. 
 
Reasons for platelet and red cell transfusions; the reasons will be described by arm. 
11.5.2. Other Analyses 
Analyses for the sub-studies will be specified in separate analysis plans. 
11.5.3. Sub-group Analyses 
Subgroup analyses will be performed for the primary outcome in the main analysis by 
including an interaction term.  Analysis will be performed using the same methods as for the 
primary outcome, except a treatment-covariate interaction will be included in the model for 
each of the following variables in turn:   
 
 
Country of participant (UK vs. Australia), if evidence of heterogeneity between UK 
and Australian participants is identified in the interim analysis  
 
Platelet count at consent (≤30x109/L vs. > 30x109/L) 
 
Treatment compliance during first 30 days of the trial (withdrawal of consent for trial 
treatment vs. no withdrawal of consent)  
 
11.5.4. Analysis Population and Missing Data 
For pragmatic reasons participants discharged from the hospital prior to 30 days post first 
dose of trial treatment will not have as intense surveillance for trial events as will those who 
remained in the hospital. They will complete a daily bleeding diary and be contacted to 
determine any clinically important bleeding events. If a participant reports no bleeding on 
their bleeding diary this will be recorded as a WHO grade 0 bleed. If the participant does 
report bleeding they are asked to consult with their haematology care team. If this team 
considers the bleeding to be clinically significant then the participant should be reviewed and 

 
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a bleeding assessment conducted by a member of the research team. If the haematology 
team consider the bleeding to be clinically insignificant, then this will be recorded as WHO 
grade 1.  
 
TREATT is to be conducted in patients who are undergoing intensive chemotherapy or stem 
cell transplantation, and thus we do anticipate that some participants may die due to their 
underlying disease, overwhelming infection, or other complications of their therapy.  
 
Some participants may also withdraw consent or be withdrawn during the conduct of the 
trial. In either of these cases, it is impossible to know whether such participants are either 
less or more likely to experience bleeding had they not experienced early censoring. 
Sensitivity analyses will be performed to account for this. 
 
12. 
Ancillary Studies 
12.1. 
Fibrinolysis Study  
A laboratory study to understand the mechanisms of action of TXA will be built into the 
proposal at selected centres. The specific tests for laboratory assessment of fibrinolysis will 
depend upon the results of analysis of samples from 50 patients collected within a pilot 
prospective observational cohort study (ATHENA)(41). This is an optional sub-study and the 
results of the tests for fibrinolysis will be for research purposes only. Samples will be frozen 
and analysed in batches. The results of these tests will have no impact on the day to day 
management of trial participants. 
12.2. 
Health Economic Evaluation 
A health economic evaluation for UK participants will form an integral part of this trial, and 
will ascertain whether from the perspective of the health care provider, prophylactic use of 
TXA is likely to constitute a cost-effective use of scarce resources. 
 
Detailed data will be collected on the resources consumed by each participant during their 
hospital inpatient stay, including information on TXA given, transfusions of platelets, red 
blood cells and FFP, treatment for major bleeds, thromboembolic events, time in ITU, and 
on wards.  Following hospital discharge, participants will be followed up by research nurse 
at 30 days and 120 days after starting the  study drug, and asked about health care contacts 
including hospital re-admissions, day hospital attendances, outpatient clinic attendances 
and  A&E visits,.  These data will be costed using national average unit costs from 
established sources. 
 
Participants will be asked to complete the EuroQol EQ-5D-5L questionnaire (a generic 
measure of health related quality of life routinely used in cost-effectiveness studies) at 
baseline, and at 10-14 days, 30 days, and 120 days post-start of study drug.   Responses 
will be converted into a single index score using the UK social tariff and used to weight 
patient survival and facilitate the calculation of quality adjusted life years (QALYs) for each 
patient. 
 
 
Costs and effects in each arm of the trial will be compared. Cost-effectiveness will be 
expressed using a number of metrics, including cost per bleed averted, and cost per QALY. 
Uncertainty around the study results will be explored using one-way, and probabilistic 
sensitivity analysis.  Cost-effectiveness acceptability curves will be used to determine the 
probability that TXA is cost-effective at various thresholds of willingness to pay for health 
gain.  
 

 
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Quality of Life Study 
A quality of life study will also be performed. Quality of life will be assessed at baseline, and 
at 10 to 14 days, 30 days, and 120 days after start of the trial treatment   using the EuroQol 
EQ-5D-5L questionnaire (a generic measure of health related quality of life routinely used in 
cost-effectiveness studies – see section immediately above).The FACT-Th questionnaire (a 
measure of health related quality of life that has been specifically designed for 
thrombocytopenic cancer patients (42)) will be administered at baseline, and at 10-14 days 
and 30 days after start of the trial treatment. 
For those participants who have been randomised, but then did not start treatment QoL will 
be measured up to 30 days only. 
13. 
Ethical and Regulatory Issues 
13.1. 
Compliance 
This trial complies with the Declaration of Helsinki [2013 Declaration of Helsinki] (45). 
It will also be conducted in compliance with the approved protocol, the principles of Good 
Clinical Practice (GCP), the UK Data Protection Act and the UK Policy Framework for Health 
and Social Care Research  
13.1.1. Site Compliance 
The site will comply with the above. An agreement will be in place between the site and 
CTU, setting out respective roles and responsibilities. 
 
The site will inform the CTU as soon as they are aware of a possible serious breach of 
compliance, so the CTU can report the breach if necessary, within 7 days as per the UK 
regulatory requirements. For the purposes of this regulation, a serious breach is one that is 
likely to affect to a significant degree: 
The safety or physical or mental integrity of the subjects in the trial, or 
The scientific value of the trial.  
13.1.2. Data Collection and retention 
The Principal Investigator has overall responsibility for data collection at Sites. Participant 
data will be entered onto the trial database designed and administered by the NHSBT CTU 
data management team using MACRO-v4.2.3.3850, a commercially available FDA 21 CRF 
Part 11 compliant clinical trial database system produced by InferMed. Following completion 
of analysis, the trial database will be archived in accordance with NHSBT’s policies. 
 
The sites must keep the signed Informed Consent forms, all trial documentation and source 
documents collected during the trial in a secure location (e.g. locked filing cabinets in a room 
with restricted access). All data must be accessible to the competent authorities and the 
Sponsor with suitable notice for inspection. All trial documentation must be retained for at 
least 5 years after trial completion or termination. In addition, the Investigator must not 
discard or destroy any trial specific materials unless otherwise instructed by NHSBT.  
13.1.3. Access to Data 
The CTU will oversee any data sharing process, with input from the TSC. 
13.2. 
Ethical Conduct of the Trial 
This trial has been designed as a placebo controlled trial, to provide the most robust 
evidence for the effectiveness and safety of prophylactic tranexamic acid in patients with 
haematological malignancies. Tranexamic acid is not used in routine practice for this 
indication.  

 
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13.3. 
Ethical Considerations 
Issues relevant to ethical considerations are described fully in the Participant Information 
Sheet. The right of the patient to refuse to participate in the trial without giving reasons will 
be respected.  
 
After the patient has entered the trial, the clinician is free to give alternative treatment to that 
specified in the protocol at any stage if he/she feels it to be in the participant’s best interest, 
and the reason for doing so should be recorded. Similarly, the participant must remain free 
to withdraw at any time from protocol treatment without giving reasons and without 
prejudicing any further treatment. All participants who come off protocol therapy for whatever 
reason will still need to remain within the trial for the purposes of follow-up and data analysis. 
 
In the UK, research ethics approval will be required. A copy of a centre’s R&D approval must 
be lodged with the Trial Office before entry of patients can commence at that centre. Centres 
are required to go through a registration process with the Trial Office before recruitment is 
started. The institution’s Research and Development Office must complete the site 
agreement with the sponsor. 
 
In Australia, this protocol will be submitted to a Human Research and Ethics Committee 
(HREC) according to the NHMRC National Statement on Ethical Conduct in Research 
Involving Humans for each institution. Approval of the protocol and related documents will 
be obtained prior to the start of the study at each site. It is the principal investigator’s 
responsibility to ensure that all conditions for approval of the study are met and that 
amendments to the protocol or serious adverse events are also reported to the HREC as 
required by that committee. No subject will be enrolled into the trial until The Therapeutic 
Goods Administration (TGA) has been notified. Copies of all submissions to and 
correspondence (approvals and disapprovals) from the HREC must be maintained on file at 
the trial site. 
 
Before initiation of the trial at each clinical site, the protocol, all informed consent forms and 
any information to be provided to the prospective participant will be submitted to a Research 
Ethics Committee for ethical approval.  Any subsequent amendments will be submitted and 
approved by the same Research Ethics Committee. 
13.4. 
Consent 
 
Main Trial 
Informed consent will be sought by the Principal Investigators or appropriately trained 
delegate. At this point the patient will receive a written information sheet (Participant 
Information Sheet) about the study, to keep, as well as a further verbal explanation to 
address any questions they may have.   
 
Each patient will be asked to sign the consent form before study participation. Patients will 
not be allowed to take part in the study unless fully-informed consent has been obtained. 
 
 The patients will also be informed that they have the right to withdraw from the study at any 
time and this will not affect their future treatment in any way. Any blood samples collected 
up until the time of withdrawal will be retained and included in the analysis. 
 
Ancillary Studies 
At centres participating in the fibrinolysis sub-study the consent form will specifically ask 
about whether the patient agrees to having additional blood samples taken. Blood samples 
will only be taken if the participant has given informed consent for this to occur.  
 

 
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The participants will also be informed that they have the right to withdraw from additional 
blood sampling at any time and this will not affect their future treatment in any way. Blood 
samples collected up until the time of withdrawal of consent will be retained and included in 
the analysis. 
 
13.5. 
Confidentiality 
The study will comply with the Data Protection Act which requires data to be anonymised as 
soon as it is practical to do so.  
Blood samples collected as part of the fibrinolysis sub-study will be stored in a secure facility 
that can only be accessed by authorised researchers. Samples will be code-labelled and the 
code-index will not be divulged to any parties outside of the local research group.  
 
14. 
Indemnity 
 
The NHS indemnity scheme applies to this trial when it is being conducted in the UK. Section 
4 of the non-commercial clinical trial agreement 2008 describes the indemnity arrangements 
as follows: 
 
As both sponsor and site are NHS bodies, i.e. NHS bodies / NHS Foundation Trusts in 
England, Wales or Northern Ireland and are indemnified by the same Indemnity Scheme 
(being one of the NHS Litigation Authority clinical negligence or the Welsh Risk Pool or the 
Clinical Negligence Fund in Northern Ireland) and the Party incurring any loss can recover 
such loss under one of the Indemnity Schemes, then such Party shall rely on the cover 
provided by the Indemnity Scheme and not seek to recover the Loss from the other 
Party(ies).  Where the other Party (ies) caused or contributed to the Loss, it undertakes to 
notify the relevant Indemnity Scheme(s) to take this into account in determining the future 
levies of all Parties in respect of the indemnity schemes. 
If: 
The Parties are members of the same Indemnity Scheme in England, Wales or Northern 
Ireland and the Party incurring the Loss is not indemnified for that Loss by its Indemnity 
Schemes; or 
All Parties are NHS bodies in Scotland; or 
The Parties are NHS bodies/Foundation Trusts established in different jurisdictions within 
the United Kingdom; 
 
Then the Parties shall apportion such Loss between themselves according to their 
respective responsibility for such Loss. Should the Parties be unable to agree the 
apportionment the matter shall be resolved in accordance with clause 16.5. 
If one or more Parties are NHS Foundation Trusts and the Party incurring the Loss is not 
responsible for all or part of the Loss and is not indemnified in respect of the Loss by one of 
the Indemnity Schemes, then the Party incurring the Loss shall be entitled to recover the 
Loss from the other Party (ies) pursuant to the provisions of this Agreement. 
 
15. 
Finance 
15.1. 
Funding 
Funding arrangements will be provided in the Trust agreement with the Sponsor. 
This trial is funded in the UK by a grant from the NHSBT R&D Committee; Grant number 12-
01-CSU.  

 
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15.2. 
Declaration of interests 
None of the individuals named in this protocol have any competing interests to declare. The 
NHSBT CTU requires serving members of all Oversight Committees to sign a declaration of 
interests form on appointment and to declare any competing interests which may develop 
during the conduct of the trial to be declared at the start of every meeting 
 
16. 
Oversight and Trial Committees 
There are a number of committees involved with the oversight of the trial. These committees 
are detailed below. 
 
16.1. 
Trial Management group (TMG) 
A Trial Management Group (TMG) comprising the Chief Investigator, other lead investigators 
and members of the CTU. The TMG will be responsible for the day to day running and 
management of the trial. It will meet at least four times a year, more often during set up and 
close down phases of the trial. At least one face to face meeting will be held each year.  
 
In the UK members include the CI, PIs from representative centres (UK), the Trial Manager, 
and a NHSBT CTU Clinical Operations Manager.  
 
TMG (UK) Members: 
 
Dr Lise Estcourt 
 
Chief Investigator 
 
Dr Simon Stanworth  
Co-Chief Investigator 
 
Ms Gillian Powter 
 
Trial Manager 
 
Mrs Claire Dyer 
 
Clinical Operations Manager 
 
Ms Elinor Curnow 
 
Trial Statistician 
 
Ms Siobhan Martin 
 
Trial Data Manager 
 
Ms Katie Keen 
 
Senior TREATT Data Manager 
 
Ms Alison Deary 
 
Head of Clinical Operations 
 
Dr Graham Collins  
 
Clinical Advisor 
 
Dr Gail Jones  
 
Clinical Advisor 
 
 
In Australia, the TMG members include the CI, local lead investigators, the local Trial Co-
ordinator and PIs from local centres (Australia). 
 
TMG (Australia) Members: 
 
Dr Erica Wood 
 
Lead Australian investigator 
 
Dr Simon Stanworth  
Chief Investigator 
 
Dr Zoe McQuilten 
 
Co-lead Australian investigator 
 
Ms Amber Degelia 
 
Australian Trial co-ordinator 
 
Ms Sharon Erb 
 
Australian Trial co-ordinator 
 
16.2. 
Trial Steering Committee (TSC) 
The Trial Steering Committee (TSC) has membership from the TMG and independent 
members, including the Chair. The role of the TSC is to provide overall supervision for the 

 
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trial and provide advice through its’ independent chair. The ultimate decision on continuation 
of the trial lies with the TSC. 
 
This trial protocol has been designed and developed in collaboration with international 
partners Dr Erica Wood (Australia) and Drs Terry Gernsheimer and Sherrill Slichter (US). 
With Australia joining the trial, the composition of the TSC has been adjusted. Should the 
US or other partners join this trial, the composition of the TSC may be further adjusted to 
reflect international recruitment. 
 
TSC Members:  
 
Dr Ian Franklin 
 
Independent Chair 
 
A/Prof Jake Shortt 
 
Independent Member 
 
Dr Dan Hart 
 
 
Independent Member 
 
Dr Lise Estcourt 
 
Chief Investigator 
 
Dr Simon Stanworth  
Co-Chief Investigator 
 
Ms Elinor Curnow 
 
Trial Statistician 
 
Mr Cliff Gorton 
 
Patient Representative 
 
Dr Charles van Heyningen 
Patient Representative 
 
R&D Office 
 
 
Sponsor Representative 
 
Dr Erica Wood 
 
Lead Australian Investigator 
 
16.3. 
Data Monitoring Committee (DMC) 
The CTU has a core Data Monitoring Committee (DMC) for all of its trials, currently chaired 
by Professor Adrian Newland, Professor of Haematology at Barts and the London School of 
Medicine and a Consultant Haematologist at the Royal London. The group will act as DMC 
to this trial, provide advice to the Chair of the TSC and can recommend premature closure 
of the trial.  
 
The conduct of the trial and the safety of patients accrued to the trial will be monitored by 
the DMC. The DMC will be guided by a DMC Charter that delineates the roles and 
responsibilities of the DMC, including delineation of the lines of communication between trial 
clinical investigators, trial data coordinating centre, and NHSBT.  
 
The DMC will meet approximately every 6 months to review trial progress (recruitment, 
adherence to protocol) and safety data, including (serious) adverse events, bleeding events, 
and mortality. After an initial face-to-face meeting, meetings are envisioned to generally be 
by teleconference, though the DMC may request a face-to-face meeting as indicated. The 
DMC may also request more frequent meetings as necessary to protect trial integrity and 
trial safety. 
16.4. 
Role of Trial Sponsor 
The trial sponsor will have ultimate authority over the study design; collection, management, 
analysis, and interpretation of data; writing of the report; or the decision to submit the report 
for publication. The trial sponsor will have a representative on the TSC. See section (16.2) 
for membership of the TSC.  
16.5. 
Role of Trial Funder(s) 
In the UK the trial sponsor and the trial funder are the same entity. The Australian funder, 
the National Health and Medical Research Council, has had no role in the design of the 
study and will not have any role during its execution, analyses, interpretation of the data, or 
decision to submit results. 

 
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17. 
Publication 
17.1. 
Dissemination 
The results from different centres will be analysed together and published as soon as 
possible. Individual Clinicians must not publish data concerning their patients that are 
directly relevant to questions posed by the trial until the Trial Management Group has 
published its report. The Trial Management Group will form the basis of the Writing 
Committee and will advise on the nature of publications. 
17.2. 
Authorship 
Authorship of all publications associated with this trial will be compliant with the International 
Committee of Medical Journal Editors criteria for authorship. 
17.3. 
Approvals 
The TSC will see and approve the final trial publication.  The CIs will see and approve any 
supplementary publications, e.g. from a sub-study.  
17.4. 
Identification 
A trial identifier will be included on all presentations and publications (e.g. the ISCRTN)  
17.5. 
Timing 
No data may be made public before publication and never without agreement from the CIs. 
17.6. 
Acknowledgements 
All professionals who have participated in the TREATT trial for a minimum of one year will 
be listed in the acknowledgements section of the final trial report. 
 
18. 
Protocol Amendments 
 
Any modifications of the protocol which may impact on the conduct of the study, potential 
benefit of the participant or may affect participant safety, including changes of study 
objectives, study design, patient population, sample sizes, study procedures, or significant 
administrative aspects will require a formal amendment to the protocol. Such amendments 
will be agreed upon by the TREATT TSC, TMG, and NHSBT, and approved by the Ethics 
Committee and the Competent Regulatory Authority prior to implementation. 
 
Administrative changes of the protocol are minor amendments that have no effect on the 
way that the study is conducted. These administrative changes will be agreed by the 
TREATT TMG and the Ethics Committee will be informed of the minor amendment. 
 
 
 
 
 
Revision History: 
Version  
Author 
Date 
Reason for revision 
1.0 
Various. 
10th 
September 
2014 
Version submitted to REC for ethical approval. 

 
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1.1 
Various. 
24th October 
2014 
Responding to the REC comments and to provide 
greater clarity. 
1.2 
Various 
8th January 
2015 
Responding to the MHRA comments and to 
provide greater clarity 
1.3 
Various 
13th  
February 
2015 
Minor changes following provisional approval 
from MHRA and to provide greater clarity. 
Additions with respect to the trial in Australia. 
1.4 
Various 
5th 
June 
2015  
Minor textual amendments and changes to Trial 
team personnel.  Amendment of dose adjustment 
table to bring it in line with Investigator Brochure. 
2.0 
Various 
27 
August 
2015 
 
Trial Summary – Recruitment status 
updated: now open 
 
Section 4.2 (and summary) Reordering of 
exclusion criteria and Clarification of Exclusion 
Criterion 9 (previously 12) 
 
Sections 5.5 and 6.2.4 – Addition with 
regard to (potential) participants admitted to 
hospital with platelet counts ≤ 30 x 109/L. or ≤ 50 
x 109/L. 
 
Section 7 Proportion of participants 
changed to estimated proportion 
 
Section 11.4 – Stopping Rules: Change to 
wording for clarification 
 
11.5 – Analysis Plan: proportion changed 
to Estimated proportion 
 
Section 16.1 – Change in name of 
Australian Trial Coordinator 
 
16.3 – Reference to co-opted member of 
DMC removed as not relevant 
2.1 
Various 
09 
December 
2015 
 
Amendment to ‘Administration of Trial 
Treatment’  (in summary and section 6.1)   to 
allow for patients admitted with  platelet 
counts already below 30 x 109/L 
 
Clarification of definition of Day 1 with 
respect to Primary and Secondary Outcomes 
(In Summary and section 7) 
 
Clarification of Day 1 with respect to Day 
1 for Data Collection (In Summary and 
section 7 ) 
 
Time boundaries added to define period 
when trial treatment can be started ( 6.2.4) 
 
Typographical amendments to Trial 
Schema Flow Chart 
 
Further detail added with respect to the 
daily bleeding assessment (section 8) 
 
Additional analysis:  A per-protocol 
analysis of the primary outcome which will 
exclude patients who did not follow the 
protocol (e.g. did not receive the trial 
treatment) section 11.4 
 
A secondary analysis of  bleeding of grade 
2 or above or death for the 30 days after 
treatment started (or when it should have 

 
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started for patients that did not receive the 
treatment). (Section 11.5) 
 
Clarification re bleeding grades in section 
11.5.3 
 
Additional note re QoL questionnaires for 
participants who did not start treatment 
(Section 12.2) 
 
Professor Stephen Morris added as Co-
Investigator 
 
3.0 
Various 
09 May 
2018 
 
Changes/ updates to trial team, TMG and 
TSC personnel 
 
Some laboratory values removed from 
the Schedule of Investigations 
 
Post hospital discharge visits (GP and 
District nurse) removed from Health 
Economic analysis  
 
Additions to the glossary 
 
Total sample size revised to 616 and 
consequent changes to text relating to 
sample size in section 11.3 
 
Removal of anomalies, so that there is 
consistent reference to trial ‘participants’ 
rather than ‘patients’. 
 
Clarification that Day 1 is the first day of 
administration of trial treatment, albeit this 
may be a maximum of 72 hours from the first 
recorded platelet count of ≤ 30, or for patients 
admitted with a count already ≤ 30 a 
maximum of 72 hours from them starting 
treatment with chemotherapy. 
 
Consequent to this changes to text in 
Section 7, (Trial Outcomes), 11.4 (Interim 
analysis), 11.5 (Analysis Plan) 
 
Clarification of the methodology for the 
interim and main analyses in Section 7 (Trial 
Outcomes), Section 11.4 (Interim analysis), 
11.5 (Analysis Plan) 
 
Additional text section 6.2.4 re 
administration of IMP and dosing guidelines 
where participants have raised creatinine 
levels 
 
Addition to section 6.2.2 on the nature of 
the oral IMP (tablets instead of capsules) 
 
Addition to section 6.2.4 to note change 
of label on TREATT IMP 
 
Expansion of text for exclusion criterion 
No 20 re PMH convulsions 
 
Removal of footnotes to SAE table 9a as 
these contradict parts of text in this section 
 
Addition of a new reference (validation of 
bleeding assessment tool) 

 
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3.1 
Following 
comments 
from 
MHRA 
30 July 
2018 
 
Clarification that bilirubin & albumin 
required if VOD suspected or reported 
 
Additional text to section 9.2.1 –
Expectedness 
 to clarify the Reference Safety Information 

 
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20. 
Appendices 
20.1. 
Adverse Reactions 
20.1.1. Toxicities associated with Tranexamic Acid (TA) 
Please refer to the Investigator Brochure Section 7 for a list of expected adverse 
reactions to the intravenous trial treatment, and to Section 4.8 of the Summary of 
Product Characteristics (found in Section 15 of the Investigator Brochure) for a list 
of expected adverse reactions to the oral trial treatment. 
20.1.2. Toxicities Related to Platelet Transfusion 
 
 
Viral Infections:  
With the transfusion of any blood product, a virus may be transmitted. All donor blood is 
routinely screened for the presence of hepatitis B and C, the AIDS virus (HIV 1 & 2), the 
HTLV viruses (1 & 2), West Nile virus (in the UK), and, on occasion, for cytomegalovirus. In 
spite of testing, infections with these or other viruses may rarely still result from a transfusion.  
 
 
Bacterial Infections:  
Because platelets must be stored at room temperature and not in a refrigerator, overgrowth 
of bacteria may occur if there has been a break in the sterility of the system. This could result 
in a serious infection.   
 
 
Transfusion Reactions:  
There also may be reactions to transfusion of any blood product such as chills, fever, drop 
in blood pressure, shortness of breath, and, very rarely, shock. On rare occasions, 
transfusions may be associated with a severe reaction that could result in lung injury, kidney 
failure, or heart failure. There may also be allergic reactions such as hives, rashes, or very 
rarely, a severe reaction that could result in death.  
20.1.3. Additional access to central venous catheters 
Administration of the trial treatment may lead to the central venous catheter being accessed 
more frequently. This may lead to a slight increase in the risk of infection. This will be 
minimised by staff trained in the use of the line minimising the number of times the line is 
accessed and using aseptic technique at all times. 
20.1.4. Discomfort Related to Venesection 
There may be some discomfort to subjects associated with the withdrawal of blood samples. 
Occasionally there may be soreness, bruise, light-headedness, and on rare occasions, 
infection or scarring damage to a vein. 
 
 
 
 
 
 
 
 

 
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20.2. 
WHO Grading System 
 
General Definitions of WHO Grades 
 
Grade 4  
 
Any bleeding that is: 
 
Fatal 
 
Life-threatening. For example: 
° 
Bleeding that requires transfer to intensive care/treatment unit 
° 
Bleeding that is associated with haemodynamic instability and causes 
inadequate tissue perfusion 
 
Evidence of inadequate tissue perfusion could include: 
° 
Hypotension  
° 
Systolic blood pressure (BP) < 90mmHg 
° 
>40mmHg fall in systolic BP 
° 
Mean arterial pressure (MAP) <65mmHg 
 
In absence of hypotension, markers of inadequate tissue perfusion include increased 
blood lactate, increased base deficit, perfusion-related low pH (if other causes of 
metabolic acidosis (e.g. sepsis) are not present) 
(Please also see organ-specific definitions) 
 
Grade 3 
 
Any bleeding that does not fulfil the criteria for grade 4 bleeding (general or organ-specific) 
BUT requires: 
 
Red cell transfusion specifically related to treatment of bleeding within 24 hours of 
onset of bleeding, for example: 
° 
Required to treat fall in haemoglobin of at least 2g/dl within preceding 24 hours 
without evidence of haemolysis 
° 
No haemoglobin increment within 24 hours of at least a 2 unit red cell transfusion 
without evidence of haemolysis 
 
A significant intervention, for example: 
° 
Endoscopy to treat the bleeding 
° 
Interventional radiography to treat the bleeding 
° 
Transfer to the operating theatre/room for treatment of bleeding 
(Please also see organ-specific definitions) 
 
Grade 2 
 
Any bleeding that does not fulfil the requirements for grade 3 bleeding (general or organ-
specific) BUT requires an intervention or treatment: 
 
Examples of Interventions 
° 
Nasal Packing 
° 
Bladder irrigation 
 
Examples of treatments 
° 
Platelet transfusion given to treat active bleeding and NOT given only because 
the platelet count is below the prophylactic platelet transfusion trigger 
° 
Medications prescribed to treat bleeding  
(Please also see organ-specific definitions) 
 
Grade 1 
 
Any bleeding that does not fulfil the requirements for grade 2 bleeding (general or organ-
specific). For examples of grade 1 bleeding please see the organ-specific definitions. 

 
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Organ-specific definitions of WHO Grades 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
General 
Bleeding that does not 
fulfil the requirements for 
grade 2 bleeding. Please 
see examples in organ-
specific categories below. 
Any bleeding that does not 
fulfil the requirements for 
grade 3 bleeding BUT 
requires an  
intervention or treatment: 
Examples of Interventions 
- Nasal Packing 
- Bladder irrigation 
Examples of treatments 
- Platelet transfusion given 
to treat active bleeding 
and NOT given only 
because the platelet 
count is below the 
prophylactic platelet 
transfusion trigger 
- Medications prescribed to 
treat bleeding 
Any bleeding that does 
not fulfil the criteria for 
grade 4 bleeding  
BUT requires: 
Red cell transfusion 
specifically related to 
treatment of bleeding 
within 24 hours of onset 
of bleeding. 
OR 
A significant intervention, 
for example: 
- Endoscopy to treat the 
bleeding 
- Interventional 
radiography to treat the 
bleeding 
- Transfer to the 
operating theatre/ room 
for treatment of bleeding 
Any bleeding that is fatal 
or life threatening. For 
example:  
 
- Bleeding that requires 
transfer to intensive 
care/treatment unit 
- Bleeding that is 
associated with 
haemodynamic 
instability and causes 
inadequate tissue 
perfusion 
(for further clarification 
see general guideline 
above). 
 
Oral and nasal† 
Spontaneous 
oropharyngeal bleeding - 
total duration of all 
episodes in previous 24 
hours < 30 minutes* 
 
Traumatic oropharyngeal 
bleeding e.g. after bites 
to lips and tongue lasting 
> 10 minutes or 
interfering with daily 
activities 
 
Epistaxis - total duration 
of all episodes in 
previous 24 hours < 30 
minutes* 
Oropharyngeal bleeding – 
total duration of all 
episodes in previous 24 
hours > 30 minutes* 
 
 
 
 
 
 
 
 
 
Epistaxis – total duration of 
all episodes in previous 24 
hours > 30 minutes* 
 
 
Any bleeding that 
requires intubation to 
protect the airway 

 
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Petechiae of oral mucosa 
≤ 25% 
 
 
Petechiae of oral mucosa > 
25% 
 
 
 
Skin† 
Petechiae (< 3mm 
diameter), purpura (3mm 
to 10mm diameter) or 
bruising covering ≤ 25% 
of skin (1 arm = 9%; 1 leg 
= 18%; trunk = 36%; 
head = 9%; genitalia 1%) 
Petechiae, purpura (3mm 
to 10mm diameter) or 
bruising covering > 25% of 
skin ((1 arm = 9%; 1 leg = 
18%; trunk = 36%; head = 
9%; genitalia 1%) 
 
 
Soft-tissue and 
musculoskeletal 
Asymptomatic 
spontaneous soft-tissue 
haematoma less than 
10cm in diameter. 
 
Traumatic haematoma of 
any size  
 
 
Traumatic joint bleeding 
(confirmed by aspiration, 
imaging study or other 
accepted technique) 
Asymptomatic 
spontaneous soft-tissue 
haematoma greater than 
10cm in diameter. 
 
Symptomatic soft-tissue 
haematoma (e.g. causing 
pain or discomfort). 
 
Spontaneous joint bleeding 
(confirmed by aspiration, 
imaging study or other 
accepted technique) 
 
Any bleeding that causes 
compartment syndrome. 
 
Gastrointestinal 
Faecal occult blood 
 
Rectorrhagia- visible red 
blood on tissue paper/not 
mixed with stool 
Melaena 
 
Hematochezia – visible red 
blood mixed in stool, not 
requiring a transfusion 
 
Haematemesis – Grossly 
visible blood in emesis 
(vomit) or in nasogastric 
drainage tube (not related 
or 
secondary to swallowed 
blood) 
 
 

 
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Genitourinary 
Abnormal vaginal 
bleeding (Unexpected 
bleeding out of normal 
cycle OR Bleeding 
heavier than normal OR 
Breakthrough bleeding 
(patient on hormonal 
therapy to prevent 
bleeding)) with spotting 
 
Microscopic haematuria/ 
dipstick positive 
haematuria 
Abnormal vaginal bleeding 
(Unexpected bleeding out 
of normal cycle OR 
Bleeding heavier than 
normal OR Breakthrough 
bleeding (patient on 
hormonal therapy to 
prevent bleeding)) more 
than spotting 
 
Gross/visible haematuria  
 
 
 
Any bleeding that causes: 
increase ≥1.5 X reference 
serum creatinineǂ 
or 
Serum creatinine rises by 
≥ 26µmol/L (0.3mg/dl) 
within 48 hours 
or 
Urine output <0.5 
mL/kg/hr for > 6 
consecutive hrs 
Any bleeding that causes: 
increase ≥3 X reference 
serum creatinineǂ 
or  
Serum creatinine rises by 
≥354 μmol/L (4.0 mg/dl) 
or  
Commenced on renal 
replacement therapy  
or  
Urine output <0.3 mL/kg/ 
hr for > 24 hrs  
or  
Anuria for at least 12 hrs 
Pulmonary 
 
Haemoptysis – Visible 
blood 
 
Blood in broncho-
pulmonary lavage, or blood 
tinged sputum 
(excluding those with nose 
or oropharyngeal bleeding 
or mucositis). 
Any bleeding requiring 
supplemental oxygen to 
maintain oxygen 
saturation above 93%. 
 
Any bleeding requiring 
respiratory support 
(includes non-invasive 
(CPAP, BiPAP), or 
invasive ventilation) 
Body cavity 
 
Visible blood in body cavity 
fluid (e.g. red cells 
apparent in fluid aspirate) 
short of criteria for Grade 3 
or 4 
Grossly visible blood in 
body cavity fluids AND 
organ dysfunction with 
symptoms, AND/OR need 
to intervene (e.g. to 
aspirate). 
 
Eye† 
Sub-conjunctival 
haemorrhage  
 
Traumatic retinal 
bleeding without visual 
impairment 
 
Traumatic vitreous 
bleeding without visual 
impairment 
Diffuse sub-conjunctival 
haemorrhage in both eyes 
 
Spontaneous retinal 
bleeding without visual 
impairment 
 
Spontaneous vitreous 
bleeding without visual 
impairment 
 
 
Retinal bleeding with 
temporary visual 
impairment ** (present for 
≤ 7 days) 
 
Vitreous bleeding with 
temporary visual 
 
 
Retinal bleeding with 
permanent visual 
impairment ** (present for 
> 7 days) 
 
Vitreous bleeding with 
permanent visual 

 
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impairment *** (present 
for ≤ 7 days) 
impairment ** (present for 
> 7 days) 
Central nervous 
system 
 
Lumbar puncture with 
blood (>5 RBC/μL in CSF 
on microscopic analysis 
and non-traumatic tap), 
no neurological symptoms 
and no  visible red colour 
 
Traumatic CNS bleeding 
on imaging study without 
neurological dysfunction 
Lumbar puncture with 
visible red colour in 
absence of neurological 
symptoms, and non-
traumatic tap 
 
 
Spontaneous CNS 
bleeding on imaging 
study without neurological 
dysfunction 
CNS symptoms with non-
traumatic bloody lumbar 
puncture 
 
 
 
 
CNS bleeding on imaging 
study with neurological 
dysfunction 
Invasive sites 
Bleeding at invasive sites 
or sites of minor trauma 
(e.g. venepuncture sites, 
intravenous lines or 
catheter exit sites): active 
oozing at site for > 10 
minutes 
Bleeding at invasive sites 
(venepuncture sites, 
intravenous lines or 
catheter exit sites): active 
oozing at site for a 
cumulative total of > 1 hour 
in the previous 24 hours. 
 
 
 
*Count actual bleeding (i.e. “running out” or need for basin, tissue, towel, etc.) not minor bleeding 
**Visual impairment is defined as a field deficit, and patients with suspected visual impairment require an ophthalmological consultation 
*** Visual impairment confirmed by ophthalmological consultation 
† Petechiae of oral mucosa and skin, Subconjunctival haemorrhage, Haemorrhagic bullae/blisters in mouth, Purpura and ecchymoses 
These are all documented as bleeding on the 1st day they are seen and any subsequent day that the bleeding is worse than the preceding day. If the bruising / petechiae is the same as or not as 
severe as the previous day, it will not be counted as bleeding [For discussion]. ǂ Reference serum creatinine is the baseline serum creatinine result taken on entry into the study 
 
20.3. 
Definitions of Bleeding Signs 
 
Definition of bleeding signs based on physical examination 
Site of bleeding 
Sign 
Definition 
Skin (epidermis and dermis) 
 
 
        
Petechiae 
Red (recent) or purplish (a few days old) spot 
discoloration in the skin with a diameter between 0.5 

 
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mm to < 3 mm, not blanching  with pressure and not 
palpable 
 
Purpuric macule 
(purpura) 
Differentiated from petechiae only for their larger size 
between 3 to 10 mm.  
 
Ecchymosis 
(bruise or 
contusion) 
Larger than 10mm in size. Flat, rounded or irregular, 
red, blue, purplish or yellowish green patches, larger 
than a petechia or purpura. If elevated they represent 
superficial spreading of an underlying hematoma 
Skin (subcutaneous tissue) 
 
 
 
Haematoma 
Bulging localized accumulation of blood often with 
discoloration of overlying skin 
Visible mucous membranes 
 
 
 
Petechia, 
purpuric  
macules and 
ecchymoses 
As for skin 
 
Bulla/vescicle 
(Blister) 
Visible raised, thin-walled, circumscribed lesions  
containing blood.  
Bullae (≥ 5mm) are larger than vescicles (< 5 mm).  
They should be counted together as bullae 
 
Epistaxis 
Any bleeding from the nose, may be anterior or 
posterior and unilateral or bilateral 
 
Gingival bleeding 
Any bleeding from the gingival margins 
 
Subconjunctival 
haemorrhage 
Bright red discoloration underneath the conjunctiva at 
onset then same colour changes as ecchymoses 
Muscles and soft tissues 
 
 
 
Haematoma 
Any localised collection of blood visible, or palpable or 
revealed by imaging. May be dissecting when 
spreading along fascial spaces 
 
 

 
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20.4. 
Other Definitions 
 
20.4.1. Definition of DIC (ISTH) (43) 
 
Score 
Prolonged PT 
Fibrinogen g/l 
Platelet count 
Elevated fibrin 
marker 
0 
< 3 s 
> 1 
> 100 
Not ↑ 
1 
> 3s  but  < 6s 
< 1 
< 100 
 
2 
> 6s 
- 
< 50 
↑ 
3 
- 
- 
- 
↑↑ 
Score greater than or equal to 5 is compatible with overt DIC 
 
20.5.1 Definition of deep vein thrombosis 
Diagnosis of deep-vein thrombosis (DVT) should follow the American Association of Chest 
Physician (ACCP) guidelines for diagnosis and treatment of DVT(57) 
 
Confirmed Episodes 
In patients with suspected first lower extremity DVT: 
 
Compression ultrasound of the proximal veins of the leg is positive for DVT 
 
Compression ultrasound of the whole leg is positive for DVT 
 
Venography2 (including CT, MRI, or MR direct thrombus imaging) is positive for DVT 
 
In patients with suspected recurrent lower extremity DVT: 
 
Compression ultrasound (CUS) of the proximal veins of the leg shows a new non- 
compressible segment in the common femoral or popliteal vein, (a ≥ 4-mm increase 
in venous diameter during compression compared with that in the same venous 
segment on a previous result) 
 
Venography (including CT, MRI, or MR direct thrombus imaging) is positive for DVT 
 
In patients with suspected upper extremity DVT: 
 
Combined modality ultrasound (compression with either Doppler or colour Doppler) 
is positive for DVT 
 
Venography (including CT, MRI, or MR direct thrombus imaging) is positive for DVT 
 
Suspected Episodes 
In patients with suspected first lower extremity DVT: 
 
Patients with negative scan results and a moderate or high pre-test probability of 
thrombosis should have additional testing with a highly sensitive D-dimer, whole-leg 
US or repeat proximal CUS in 1 week 
 
Patients with haematological malignancies are likely to have positive D-dimers for 
other reasons e.g. sepsis. Therefore, patients with a single negative proximal CUS 
and positive D-dimer should undergo whole-leg US or repeat proximal CUS in 1 
week 
 
ACCP recommend venography when ultrasound is impractical (e.g. when leg casting or 
excessive subcutaneous tissue or fluid prevent adequate assessment of compressibility) or 
nondiagnostic. 
 
In patients with suspected recurrent lower extremity DVT: 
 
Compression ultrasound of the proximal veins of the lower leg shows a new non-
compressible segment in the common femoral or popliteal vein, (<4 but ≥ 2-mm 

 
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increase in venous diameter during compression compared with that in the same 
venous segment on a previous result) should have additional testing with 
venography, if available, serial proximal CUS or testing with a moderately or highly 
sensitive D-dimer and serial proximal CUS if the test is positive. 
 
If no previous scan is available further testing with venography or a highly sensitive 
D-dimer is required. 
 
In patients with suspected upper extremity DVT: 
 
Combined modality ultrasound (compression with either Doppler or colour Doppler) 
is negative or there is less than a complete evaluation and D-dimer is positive should 
undergo venography 
 
DVT Excluded 
 
Negative serial proximal CUS 
 
Negative single proximal CUS and negative highly sensitive D-dimer 
 
Negative whole-leg US 
 
Negative venography 
 
Low or moderate pre-test probability of DVT and negative highly sensitive D-dimer 
 
Previous ipsilateral DVT, an abnormal US and negative highly sensitive D-dimer 
 
Negative combined-modality US and negative moderate or highly sensitive D-dimer 
 
Negative combined-modality US and negative CT or MRI venography 
 
 
Pre-test Probability (PTP) (Well’s Score) for DVT 
Variable 
Points 
Active cancer (treatment on-going or within previous 6 
months or palliative) 
1 
Paralysis or plaster cast 
1 
Bed > 3 days or surgery within 4 weeks 
1 
Tenderness along veins 
1 
Entire leg swollen 
1 
Calf swollen > 3cm 
1 
Pitting oedema 
1 
Collateral veins 
1 
Alternative diagnosis 
-2 
Add up points 
Low risk 
0 
Moderate risk 
1 to 2 
High risk 
> 2 
 
 
 

 
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20.5.2 Definition of pulmonary embolism 
Diagnosis of pulmonary embolism (PE) should follow the European Society of Cardiology 
(ESC) Guidelines on the diagnosis and management of acute pulmonary embolism(44). 
 
Confirmed Cases 
In patients with suspected high-risk pulmonary embolus (i.e. with shock or hypotension) 
 
Echocardiography shows RV overload and patient unstable or no other tests 
available 
 
A CT angiography showing a segmental or more proximal thrombus 
 
In patients with suspected non-high-risk pulmonary embolus (i.e. without shock or 
hypotension) 
 
Pulmonary angiography showing PE 
 
A CT angiography showing a segmental or more proximal thrombus 
 
Compression ultrasound of the proximal veins of the lower leg is positive for DVT 
 
Moderate or high clinical probability of PE and high probability ventilation-perfusion 
lung scintigraphy (V/Q scan) 
 
PE Excluded 
 
Normal pulmonary angiogram 
 
Normal V/Q scan 
 
Low or moderate clinical probability of PE and negative highly sensitive D-dimer 
 
Low or moderate clinical probability of PE and negative proximal leg CUS (+/- non-
diagnostic V/Q scan; +/- negative single-detector CT angiography) 
 
Low or moderate clinical probability of PE and negative multi-detector CT 
angiography 
 

 
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Clinical Prediction Rules for PE  
 
(Well’s Score)  
Variable 
Points 
Previous DVT or PE 
1.5 
Cancer 
1 
Bed > 3 days or surgery within 4 weeks 
1.5 
Haemoptysis 
1 
Heart rate > 100 beats/min 
1.5 
Clinical signs of DVT 
3 
Alternative diagnosis less likely than PE 
3 
Add up points 
Low risk 
0 to 1 
Moderate risk 
2 to 6 
High risk 
> 6 
 
 
(Geneva Score) 
Variable 
Points 
Previous DVT or PE 
3 
Active malignancy 
2 
Surgery or fracture within 4 weeks 
2 
Age > 65yrs 
1 
Haemoptysis 
2 
Unilateral lower limb pain 
3 
Heart rate 75 to 94 beats/min 
3 
Heart rate ≥ 95 beats/min 
5 
Pain on lower limb deep vein at palpation and unilateral 
oedema 
4 
Add up points 
Low risk 
0 to 3 
Moderate risk 
4 to 10 
High risk 
> 10