TRial to EvaluAte Tranexamic Acid Therapy in Thrombocytopenia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Hematologic Neoplasms, Hemorrhage, Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: Tranexamic acid (TXA).
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are eligible for this trial if: Aged ≥18 years of age Confirmed diagnosis of a haematological malignancy Undergoing chemotherapy, or chemotherapy is planned, or haematopoietic stem cell transplantation Anticipated to have a hypoproliferative thrombocytopenia resulting in a platelet count of ≤10x10⁹/L for ≥ 5 days 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: 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. Diagnosis of acute promyelocytic leukaemia (APML) and undergoing induction chemotherapy Patients with a diagnosis/previous history of veno-occlusive disease (also called sinusoidal obstruction syndrome) Patients with known inherited or acquired prothrombotic disorders e.g. Lupus anticoagulant Positive antiphospholipids 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 Patients receiving L-asparaginase as part of their current cycle of treatment History of immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS) Patients with overt disseminated intravascular coagulation (DIC) (See Appendix 3 in the protocol for definition) 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.) Patients with a known inherited or acquired bleeding disorder e.g. Acquired storage pool deficiency Paraproteinaemia with platelet inhibition Patients receiving anticoagulant therapy or anti-platelet therapy Patients with visible haematuria at time of randomisation Patients with anuria (defined as urine output < 10 mls/hr over 24 hours). Patients with severe renal impairment (eGFR ≤30 ml/min/1.73m²) Patients with a previous history of epilepsy, convulsions, fits or seizures Patients who are pregnant or breast-feeding Allergic to tranexamic acid. Patients enrolled in other trials involving platelet transfusions, anti-fibrinolytics, platelet growth factors or other pro-coagulant agents. Patients previously randomised into this trial at any stage of their treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Arm<br>Tranexamic acid (TXA). Dose schedule TXA 1g every eight hours IV or 1.5g every eight hours PO. | Drug: Tranexamic acid (TXA).<br>* IV or oral preparation. IV tranexamic acid or Oral tablet of tranexamic acid.<br>* Other names: Lysteda;|
| Placebo Comparator: Control Arm<br>Placebo (saline) if administration is IV. Placebo tablet matched for appearance to TXA if oral. | Drug: Placebo<br>* IV (saline) or oral placebo tablets<br>* Other names: Placebo for tranexamic acid;|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tranexamic acid, Platelet transfusion