| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Bleeding secondary to thrombocytopaenia associated to haematological malignancies. |
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| E.1.1.1 | Medical condition in easily understood language |
| Bleeding secondary to low platelet counts associated to cancers of the blood. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10005103 |
| E.1.2 | Term | Bleeding |
| E.1.2 | System Organ Class | 100000004866 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066476 |
| E.1.2 | Term | Haematological malignancy |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Is the use of tranexamic acid to prevent bleeding safe and effective in patients with blood cancers (e.g. leukaemia, lymphoma) receiving intensive chemotherapy and/or haemopoietic stem cell transplant?
This will be assessed by comparing the number of patients who experience clinically significant bleeding during the first 30 days of the trial between those patients who receive tranexamic acid and those patients who receive placebo. |
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| E.2.2 | Secondary objectives of the trial |
Secondary research questions are divided in to those used to assess whether tranexamic acid is useful and those that assess whether tranexamic acid is safe.
Outcomes to assess the effectiveness of tranexamic acid include:
1. Several different ways of measuring the patient's burden of bleeding. These are all measured during the first 30 days of the study. They include whether tranexamic acid reduces the number of days of bleeding, whether it increases the time until patients experience a bleed and whether it reduces the severity of bleeding.
2. To assess whether tranexamic acid reduces the need for patients to receive red cell or platelet transfusions during the first 30 days of the study. This will be assessed by the number of patients who can avoid receiving a red cell or platelet transfusion and also the average number of transfusions per patient.
Outcomes to assess the safety of tranexamic acid focus on whether tranexamic acid increases the risk of a blood clot, increases the ris |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study 1.
Health economic evaluation of prophylactic tranexamic acid in patients in the UK
A health economic evaluation will form an integral part of this trial, and will ascertain whether from the perspective of health care providers at institutional and government levels, prophylactic use of TXA is likely to constitute a cost-effective use of scarce resources.
Data will be collected on the resources consumed by each patient during their hospital inpatient stay, including information on TXA given, transfusion-related investigations, transfusions of platelets and red blood cells, transfusion-related reactions, any thromboembolic events, investigation of other adverse events potentially related to TXA or transfusion, and length of hospital inpatient stay by ward type. Following hospital discharge, patients will be followed up at 1 month and at 4 months and data collected on health care contacts including hospital re-admissions, outpatient clinic attendances, and GP visits. These data will be costed using national average unit costs from established sources.
Patients will be asked to complete the EuroQol EQ-5D questionnaire (a generic measure of health related quality of life routinely used in cost-effectiveness studies) at randomisation, day 12, day 30 and day 120. These data will be used to weight patient survival and facilitate the calculation of quality adjusted life years (QALYs) for each patient.
Using data from the trial, the published literature, and expert clinical opinion modelling will be used to extrapolate costs and effects out beyond the trial.
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 trial 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 as various thresholds of willingness to pay for health gain.
Sub-study 2
A quality of life study will also be performed in UK patients. Quality of life will be assessed at randomisation, 12 days after the start of the trial, 30 days after the start of the trial and 120 days after the start of the trial. Quality of life will be assessed by the EuroQol EQ-5D questionnaire (a generic measure of health related quality of life routinely used in cost-effectiveness studies) (Day R, D12, D30, D120) and FACT-Th (a measure of health related quality of life that has been specifically designed for thrombocytopenic cancer patients (Day R, D12, D30)
Sub-study 3
A laboratory study to understand the mechanisms of action of TXA will be built into the proposal at selected centres (Bristol and Oxford). The specific tests for laboratory assessment of fibrinolysis will depend upon the results of analysis of samples from up to 50 patients collected within a pilot prospective observational cohort study (ATHENA). We will measure differences in plasmin-antiplasmin (PAP) levels between patients who do and do not bleed. In patients not treated with TXA the difference between PAP levels between patients who do and do not bleed are significant with approxiamtely 50 patients. The effect that TXA will have on this is unknown. We will have 50 patients receiving TXA and 50 patients not receiving TXA.
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| E.3 | Principal inclusion criteria |
1. At least 18 years of age
2. Confirmed diagnosis of a haematological malignancy
3. Undergoing chemotherapy or haematopoietic stem cell transplantation
4. Anticipated to have a hypoproliferative thrombocytopenia resulting in a platelet count of ≤10x10 to the power of 9/L for ≥ 5 days
5. Able to comply with treatment and monitoring
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| E.4 | Principal exclusion criteria |
1. Diagnosis of acute promyelocytic leukaemia and undergoing induction chemotherapy
2. History of ITP, TTP or HUS
3. Patients receiving L-asparginase as part of their current cycle of treatment
4. 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
5. Patients with a diagnosis/previous history of veno-occlusive disease (also called sinusoidal obstruction syndrome)
6. 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
7. Known inherited or acquired bleeding disorder. E.g. acquired storage pool deficiency; paraproteinaemia with platelet inhibition; known inherited or acquired prothrombotic disorders
9. Patients receiving anticoagulant therapy or anti-platelet therapy
10. Patients with overt disseminated intravascular coagulation
11. Patints with visible haematuria at time of randomisation
12. Patients requiring a platelet transfusion threshold >10x10 to the power of 9/L at time of randomisation
13. Patients with anuria (defined as urine output < 10mls/hr over 24 hours).
14. Patients who are pregnant
15. Patients enrolled in other trials involving platelet transfusions, anti-fibrinolytics, platelet growth factors or other pro-coagulant agents.
16. Allergic to tranexamic acid or epsilon amino caproic acid
17. Previously randomised in this study at any stage of their treatment
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients who died or had bleeding of WHO grade 2 or above during the first 30 days of the study after first dose of study treatment. Day 1 being the first day the patients platelet count is ≤30x10 to the power of 9/L. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients shall have a comprehensive bleeding assessment performed to assess for signs and symptoms of bleeding for every day that they are taking the study treatment (which shall be for a maximum of 30 days but stopped prior to this if they have a platelet count of greater than 30x10 to the power of 9/L for three consecutive days unsupported (e.g. without the need for platelet transfusions to support the platelet count). Data from the bleeding assessment shall be used to generate a WHO bleeding grade. |
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| E.5.2 | Secondary end point(s) |
Secondary Safety Outcomes
• Number of thrombotic events from first administration of study treatment up to and including 120 days after the first dose of study treatment is administered, per day at risk
• Number of patients developing Veno-occlusive Disease (VOD; Sinusoidal obstructive syndrome, SOS) within 40 days of first administration of study treatment
• All-cause mortality during the first 30 days and the first 120 days after the first dose of study treatment being administered
• Death due to thrombosis during the first 120 days after the first dose of study reatment being administered
• Death due to bleeding during the first 30 days after the first dose of study treatment being administered
• Number of serious adverse events from first administration of study treatment until 60 days after the first dose of study treatment being administered
Other outcomes
(all measured during first 30 days of the study. Day 1 being the first day the patient’s platelet count ≤30x10 to the power of 9/L.)
• Number of days with thrombocytopenia (≤10x10 to the power of 9/L, ≤30x10 to the power of 9/L, ≤50x10 to the power of 9/L)
• Reasons for platelet and red cell transfusions |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Thrombosis and mortality outcomes will be assessed for 120 days
Veno-occlusive disease will be assessed for 40 days
Serious adverse events (not secondary outcomes) will be assessed for 60 days
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 16 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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