TRial to EvaluAte Tranexamic Acid Therapy in Thrombocytopenia (TREATT)

A Double-blind, Randomised Controlled Trial Evaluating the Safety and Efficacy of Antifibrinolytics (Tranexamic Acid) in Patients With Haematological Malignancies With Severe Thrombocytopenia

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. Patients will be randomised to receive tranexamic acid (given intravenously through a drip, or orally) or a placebo.

Study Overview

• Status: Completed
• Conditions: Hemorrhage; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Drug: Tranexamic acid (TXA).; Drug: Placebo

Detailed Description

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. Patients will be randomised to receive tranexamic acid (given intravenously through a drip, or orally) or a placebo. The investigators will measure the rates of bleeding daily using a short structured assessment of bleeding and will record the number of transfusions given to patients.

• Study Type: Interventional
• Enrollment (Actual): 616
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
  • Brisbane, Australia
    • Royal Brisbane
  • Canberra, Australia
    • Canberra Hospital
  • Geelong, Australia
    • Andrew Love Cancer Centre
  • Melbourne, Australia
    • Alfred Hospital
  • Melbourne, Australia
    • Monash Health
  • Melbourne, Australia
    • St Vincent's Hospital
  • Melbourne, Australia
    • Victorian Comprehensive Cancer Centre
  • St Leonards, Australia
    • Royal North Shore Hospital
  • Sydney, Australia
    • St Vincent's Hospital
  • Westmead, Australia
    • Westmead Hospital
• United Kingdom
  • Bath, United Kingdom
    • Royal United Hospital
  • Belfast, United Kingdom
    • Belfast City Hospital
  • Birmingham, United Kingdom
    • Queen Elizabeth Hospital
  • Birmingham, United Kingdom
    • Heartlands Hospital
  • Bristol, United Kingdom
    • Bristol Haematology and Oncology Centre
  • Coventry, United Kingdom
    • University Hospital Coventry
  • Exeter, United Kingdom
    • Royal Devon and Exeter Hospital
  • Glasgow, United Kingdom
    • Beatson West of Scotland Cancer Centre
  • Leeds, United Kingdom
    • St James's Hospital
  • Lincoln, United Kingdom
    • Lincoln County Hospital
  • London, United Kingdom
    • King's College Hospital
  • London, United Kingdom
    • University College London Hospitals
  • Newcastle, United Kingdom
    • Freeman Hospital
  • Oxford, United Kingdom
    • Churchill Hospital
  • Plymouth, United Kingdom
    • Derriford Hospital
  • Salisbury, United Kingdom
    • Salisbury District Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Exclusion Criteria:

A patient will not be eligible for this trial if he/she fulfils one or more of the following criteria:

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.

   1. Lupus anticoagulant
   2. 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 disseminated intravascular coagulation (DIC) (See Appendix 3 in the protocol for definition)
9. Patients requiring a platelet transfusion threshold >10x10/⁹L 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.

    1. Acquired storage pool deficiency
    2. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Arm; Tranexamic acid (TXA). Dose schedule TXA 1g every eight hours IV or 1.5g every eight hours PO.	Drug: Tranexamic acid (TXA).; IV or oral preparation. IV tranexamic acid or Oral tablet of tranexamic acid.; Other Names: Lysteda; Cyklokapron®; trans-4-(aminomethyl)cyclohexanecarboxylic acid
Placebo Comparator: Control Arm; Placebo (saline) if administration is IV. Placebo tablet matched for appearance to TXA if oral.	Drug: Placebo; IV (saline) or oral placebo tablets; Other Names: Placebo for tranexamic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of patients who die or have bleeding of WHO 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 do not receive treatment.	The proportion of patients who die or have bleeding of WHO 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 do not receive treatment. A time-to-event analysis will be used to determine this proportion to ensure that all patients are included in the primary outcome analysis, not just those who are followed up for the full 30 days. Any patients lost to follow-up will be included in the analysis and censored at the time that they were lost.	The first 30 days from first dose of trial treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of days with bleeding (WHO grade 2 or above) up to Study Day 30.	Number of days where WHO grade 2 or above bleeding has been recorded bleeding using WHO bleeding criteria.	The first 30 days from first dose of trial treatment .
Time to first episode of bleeding of WHO grade 2 or greater up to study day 30.	Bleeding assessed using WHO bleeding criteria.	The first 30 days from first dose of trial treatment.
Highest grade of bleeding a patient experiences up to study day 30.	Measured using WHO bleeding criteria.	The first 30 days from first dose of trial treatment.
Number of platelet transfusions per patient up to study day 30.	Measured by number of recorded platelet transfusions per patient.	The first 30 days from first dose of trial treatment.
Number of red cell transfusions per patient up to study day 30.	Measured by number of recorded red cell transfusions per patient.	The first 30 days from first dose of trial treatment.
Proportion of patients surviving at least 30 days without a platelet transfusion.	Measured by calculating number of patients surviving at least 30 days without a platelet transfusion.	The first 30 days from first dose of trial treatment.
Proportion of patients surviving at least 30 days without a red cell transfusion.	Measured by calculating the number of patients surviving at least 30 days without a red cell transfusion.	The first 30 days from first dose of trial treatment.
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.	Measured by calculating number of clinically diagnosed thrombotic events from Treatment Day 1 i.e the first day that the investigational medicinal product (IMP) is administered, up to and including the next 120 days.	Up to and including 120 days from the first administration of investigational medicinal product (IMP).
Number of patients developing Veno-occlusive Disease (VOD; Sinusoidal obstructive syndrome, SOS) within 60 days of first administration of trial treatment.	Measured by calculating number of patients developing Veno-occlusive Disease (VOD; Sinusoidal obstructive syndrome, SOS) within 60 days of Treatment Day 1 i.e the first day that the IMP is administered.	Up to and including 60 days from the first administration of IMP.
All-cause mortality during the first 30 days and 120 days after the first dose of trial treatment is administered. All-cause mortality during the first 30 days and 120 days after the first dose of trial treatment is administered	Measured by calculating number of deaths in first 30 days and 120 days after Treatment Day 1 i.e the first day that the IMP is administered.	Up to and including 120 days from the first administration of IMP.
Death due to thrombosis during the first 120 days after the first dose of trial treatment is administered.	Measured by calculating number of deaths due to thrombosis during the first 120 days after Treatment Day 1 i.e the first day that the IMP is administered.	Up to and including 120 days from the first administration of IMP.
Death due to bleeding during the first 30 days after the first dose of trial treatment is administered.	Measured by calculating number of deaths due to bleeding during the first 30 days	Up to and including 30 days from the first administration of IMP.
Number of serious adverse events (SAE) from first administration of trial treatment until 60 days after the first dose of trial treatment is administered.	Measured by calculating the total number of SAE's reported from first administration of IMP.	Up to and including 60 days from the first administration of IMP.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of days with thrombocytopenia (≤10x10⁹/L, ≤30x10⁹L, ≤50x10⁹/L).	Measured by number of days that the patient's laboratory results indicate that the patient is thrombocytopenic.	Measured during first 30 days from first dose of IMP.
Reasons for platelet and red cell transfusions.	Reasons for platelet and red cell transfusions as documented by clinician.	Measured during first 30 days from first dose of IMP.
Proportion of days with fever	Highest daily temperature ≥ 38.1°C	Measured during first 30 days from first dose of IMP.

Collaborators and Investigators

• Sponsor: NHS Blood and Transplant
• Collaborators: National Health and Medical Research Council, Australia; Monash University
• Investigators: Principal Investigator: Lise J Estcourt, MBBChir MSc DPhil MRCP FRCPath, NHS Blood and Transplant; Principal Investigator: Zoe K McQuilten, MBBS PhD, Monash University; Principal Investigator: Simon J Stanworth, DPhil FRCP FRCPath, NHS Blood and Transplant; Principal Investigator: Erica M Wood, MB BS, FRACP, FRCPA, Monash University

Publications and helpful links

General Publications

• Estcourt LJ, McQuilten Z, Powter G, Dyer C, Curnow E, Wood EM, Stanworth SJ; TREATT Trial Collaboration (provisional). The TREATT Trial (TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia): safety and efficacy of tranexamic acid in patients with haematological malignancies with severe thrombocytopenia: study protocol for a double-blind randomised controlled trial. Trials. 2019 Oct 15;20(1):592. doi: 10.1186/s13063-019-3663-2.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): February 18, 2022
• Study Completion (Actual): June 18, 2022

Study Registration Dates

• First Submitted: February 21, 2017
• First Submitted That Met QC Criteria: April 26, 2017
• First Posted (Actual): May 2, 2017

Study Record Updates

• Last Update Posted (Estimated): November 9, 2023
• Last Update Submitted That Met QC Criteria: November 7, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Tranexamic acid; Platelet transfusion
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Site; Hematologic Diseases; Blood Platelet Disorders; Hematologic Neoplasms; Hemorrhage; Thrombocytopenia; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: 12-01-CSU; 2014-001513-35 (EudraCT Number); ISRCTN73545489 (Registry Identifier: ISRCTN Registry)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The datasets generated during and/or analysed during the current study will be available upon request from the NHSBT Clinical Trials Unit after de-identification (text, tables, figures and appendices) 9 months after publication and ending 5 years following article publication.
• IPD Sharing Time Frame: 9 months after publication and ending 5 years following article publication.
• IPD Sharing Access Criteria: Data will be shared with investigators whose use of the data has been assessed and approved by an NHSBT review committee as a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Study Data/Documents

1. Study Protocol
   Information identifier: PMC6792262
   Information comments:

   The protocol was published in The Trials Journal, The TREATT Trial (TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia): safety and efficacy of tranexamic acid in patients with haematological malignancies with severe thrombocytopenia: study protocol for a double-blind randomised controlled trial.

   Trials Free Article - Estcourt LJ, McQuilten Z, Powter G, Dyer C, Curnow E, Wood EM, Stanworth SJ, TREATT Trial Collaboration (provisional).

   To request a protocol please contact the Trial Manager Gillian Powter gillian.powter@nhsbt.nhs.uk