Clinical trial NCT03136445: TRial to EvaluAte Tranexamic Acid Therapy in Thrombocytopenia
Official title: A Double-blind, Randomised Controlled Trial Evaluating the Safety and Efficacy of Antifibrinolytics (Tranexamic Acid) in Patients With Haematological Malignancies With Severe Thrombocytopenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hematologic Neoplasms
Hemorrhage
Hematopoietic Stem Cell Transplantation
Keywords: Tranexamic acid
Platelet transfusion
Lead sponsor: NHS Blood and Transplant
Sponsor class: OTHER_GOV
Collaborators: name: National Health and Medical Research Council, Australia
name: Monash University
First posted: 2017-05-02
Enrollment: 616
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: The first 30 days from first dose of trial treatment
Secondary outcomes:
measure: Proportion of days with bleeding (WHO grade 2 or above) up to Study Day 30.
timeFrame: The first 30 days from first dose of trial treatment .
measure: Time to first episode of bleeding of WHO grade 2 or greater up to study day 30.
timeFrame: The first 30 days from first dose of trial treatment.
measure: Highest grade of bleeding a patient experiences up to study day 30.
timeFrame: The first 30 days from first dose of trial treatment.
measure: Number of platelet transfusions per patient up to study day 30.
timeFrame: The first 30 days from first dose of trial treatment.
measure: Number of red cell transfusions per patient up to study day 30.
timeFrame: The first 30 days from first dose of trial treatment.
measure: Proportion of patients surviving at least 30 days without a platelet transfusion.
timeFrame: The first 30 days from first dose of trial treatment.
measure: Proportion of patients surviving at least 30 days without a red cell transfusion.
timeFrame: The first 30 days from first dose of trial treatment.
measure: 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.
timeFrame: Up to and including 120 days from the first administration of investigational medicinal product (IMP).
measure: Number of patients developing Veno-occlusive Disease (VOD; Sinusoidal obstructive syndrome, SOS) within 60 days of first administration of trial treatment.
timeFrame: Up to and including 60 days from the first administration of IMP.
measure: 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
timeFrame: Up to and including 120 days from the first administration of IMP.
measure: Death due to thrombosis during the first 120 days after the first dose of trial treatment is administered.
timeFrame: Up to and including 120 days from the first administration of IMP.
measure: Death due to bleeding during the first 30 days after the first dose of trial treatment is administered.
timeFrame: Up to and including 30 days from the first administration of IMP.
measure: Number of serious adverse events (SAE) from first administration of trial treatment until 60 days after the first dose of trial treatment is administered.
timeFrame: Up to and including 60 days from the first administration of IMP.
Other outcomes:
measure: Proportion of days with thrombocytopenia (≤10x10⁹/L, ≤30x10⁹L, ≤50x10⁹/L).
timeFrame: Measured during first 30 days from first dose of IMP.
measure: Reasons for platelet and red cell transfusions.
timeFrame: Measured during first 30 days from first dose of IMP.
measure: Proportion of days with fever
timeFrame: Measured during first 30 days from first dose of IMP.
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Brisbane
country: Australia
facility: Royal Brisbane
city: Canberra
country: Australia
facility: Canberra Hospital
city: Geelong
country: Australia
facility: Andrew Love Cancer Centre
city: Melbourne
country: Australia
facility: Alfred Hospital
city: Melbourne
country: Australia
facility: Monash Health
city: Melbourne
country: Australia
facility: St Vincent's Hospital
city: Melbourne
country: Australia
facility: Victorian Comprehensive Cancer Centre
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
city: Sydney
country: Australia
facility: St Vincent's Hospital
city: Westmead
country: Australia
facility: Westmead Hospital
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: Heartlands Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Leeds
country: United Kingdom
facility: St James's Hospital
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: University College London Hospitals
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
Study officials:
affiliation: NHS Blood and Transplant
name: Lise J Estcourt, MBBChir MSc DPhil MRCP FRCPath
role: PRINCIPAL_INVESTIGATOR
affiliation: Monash University
name: Zoe K McQuilten, MBBS PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: NHS Blood and Transplant
name: Simon J Stanworth, DPhil FRCP FRCPath
role: PRINCIPAL_INVESTIGATOR
affiliation: Monash University
name: Erica M Wood, MB BS, FRACP, FRCPA
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.