STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis

Study Overview
=================
Brief Summary
-----------------
Patients with cancer are prone to have blood clots, which are usually treated with blood thinners. The main complication of blood thinners is bleeding. This is especially a concern when the number of platelets in the blood is lower than 50,000 per microliter. The role of platelets is to stop bleeding, so when the number of platelets is low, patients are at a higher risk of bleeding. Cancer patients are prone to have lower platelet numbers due to cancer therapies and/or cancer itself. It is not clear what the best treatment is for cancer patients who need blood thinners for a blood clot but have low platelet counts. The investigators plan to do a small study called a pilot study to help plan for a larger study in such patients. In the pilot study, investigators will include 50 patients with cancer, low platelet counts, and a blood clot diagnosed within 4 weeks. Patients will be randomly assigned to one of the two treatment strategies: the full dose of blood thinners along with platelet transfusion or a reduced dose of blood thinners without platelet transfusion. The investigators will follow all patients for 90 days. If this pilot study is successful, it will help lead to a much larger trial, which will provide important information on the best treatment strategy in these patients.

Detailed Description
-----------------
The current proposal is for the pilot trial to assess feasibility of a full-scale RCT. To determine feasibility, the pilot and the full-scale trials will use the same recruitment strategy, inclusion/exclusion criteria, interventions, follow up duration, and measurement/adjudication of clinical outcomes. If the pilot trial finds that the full-scale trial is feasible, and no changes to the study design are indicated, the data from the pilot trial will be included in the full-scale trial, which will be efficient and reduce the recruitment time and costs of the full-scale trial. The START trial is a multi-centre RCT with prospective, open-label, blind-evaluator (PROBE) design. Adult patients with acute cancer-associated thrombosis (diagnosed within 14 days) and thrombocytopenia (platelet count < 50,000/µL) secondary to cancer therapy or cancer itself will be randomized 1:1 to modified dose LMWH or higher dose LMWH with platelet transfusion support, to evaluate the superiority of a modified dose LMWH strategy in reducing clinically relevant bleeding events compared to full dose LMWH with platelet transfusion. The PROBE design is an efficient use of research funds while maintaining the benefits of randomization and blinded evaluation of endpoints.

Official Title
-----------------
STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis

Conditions
-----------------
Thrombocytopenia, Cancer-associated Thrombosis

Intervention / Treatment
-----------------
* Biological: Enoxaparin
* Biological: Dalteparin
* Biological: Tinzaparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients (age ≥ 18) with active malignancy (malignancy diagnosed or treated within the previous 6 months, or progressive/relapsed); Objectively confirmed VTE within last 14 days for which therapeutic anticoagulation is planned; Thrombocytopenia with a platelet count < 50,000/uL from cancer therapy or malignancy itself; Able to provide written informed consent Exclusion Criteria: Receipt of anticoagulant for index VTE with platelet count < 50,000/uL for > 72 hours; Superficial vein thrombosis only; Life expectancy < 1 month (as judged by the treating physicians); Creatinine clearance < 30 ml/min; Contraindication to LMWH such as a history of heparin induced thrombocytopenia; Thrombocytopenia from other causes, such as thrombotic microangiopathy, immune thrombocytopenia, disseminated intravascular coagulation; Previously documented history of refractoriness to platelet transfusion secondary to HLA antibodies; Refusal of blood products; Anticoagulation at any dose is deemed unsafe (i.e. active bleeding or bleeding disorders)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Modified dose LMWH without platelet transfusion support<br>Patients will be given modified dose LMWH as below based on the first platelet count of the day (daily in admitted patients or at least 2 times a week in outpatients), without empiric platelet transfusion: I. Platelet count 25-50,000/µL: 50% dose LMWH II. Platelet count < 25,000/µL: hold anticoagulation | Biological: Enoxaparin<br>* I. Platelet count 25-50,000/µL: 0.5mg/kg subcutaneously twice daily II. Platelet count < 25,000/µL: hold anticoagulation<br>* Other names: Lovenox;Biological: Dalteparin<br>* I. Platelet count 25-50,000/µL: 100 IU/kg subcutaneously daily for the first month of an acute VTE then 75 U/kg II. Platelet count < 25,000/µL: hold anticoagulation<br>* Other names: Fragmin;Biological: Tinzaparin<br>* I. Platelet count 25-50,000/µL: 87.5 units/kg subcutaneously daily II. Platelet count < 25,000/µL: hold anticoagulation<br>* Other names: Innohep;|
| Active Comparator: Higher dose LMWH with platelet transfusion support<br>Patients assigned to higher dose LMWH (see below) will be given transfusion for 14 days when the first platelet count of the day falls below 50,000/uL (daily inpatient or at least 2 times a week in outpatients). Post-transfusion counts will not be routinely obtained unless clinically indicated I. Platelet count 25-50,000/µL: platelet transfusion + 100% dose LMWH II. Platelet count < 25,000/µL: platelet transfusion + 50% dose LMWH After Day 14, patients will be transitioned to modified dose LMWH as the other arm without platelet transfusion. LMWH can include enoxaparin, dalteparin, or tinzaparin, with 100% as: Enoxaparin - 1mg/kg subcutaneously twice daily Dalteparin - 200 IU/kg subcutaneously daily for 1 month then 150 U/kg daily Tinzaparin - 175 units/kg subcutaneously daily | Biological: Enoxaparin<br>* I. Platelet count 25-50,000/µL: 0.5mg/kg subcutaneously twice daily II. Platelet count < 25,000/µL: hold anticoagulation<br>* Other names: Lovenox;Biological: Dalteparin<br>* I. Platelet count 25-50,000/µL: 100 IU/kg subcutaneously daily for the first month of an acute VTE then 75 U/kg II. Platelet count < 25,000/µL: hold anticoagulation<br>* Other names: Fragmin;Biological: Tinzaparin<br>* I. Platelet count 25-50,000/µL: 87.5 units/kg subcutaneously daily II. Platelet count < 25,000/µL: hold anticoagulation<br>* Other names: Innohep;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility - The average number of patients recruited per month | The average number of patients recruited per month | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility - Proportion of eligible patients who provide consent | Number of consenting participants from the number of eligible patients | 18 months | 
| Feasibility - Reasons for non-participation in eligible patients | Reasons for non-participation in eligible patients | 18 months | 
| Feasibility - Number of patients who complete study procedures by adhering to protocol | Number of participants adhering to the protocol (such as anticoagulation, transfusion, platelet count monitoring according to the protocol) | 18 months | 
| Feasibility - Rates of withdrawal | Number of participants withdrawing from study | 18 months | 
| Feasibility - Loss to follow-up | Number of participants lost to follow-up | 18 months | 
| Feasibility - Crossover between treatment arms | Number of participants crossing over between treatment arms | 18 months | 
| Clinical Outcome - Rate of clinically relevant bleeding (composite of major bleeding and clinically relevant non-major bleeding events) | Rate of clinically relevant bleeding (composite of major bleeding and clinically relevant non-major bleeding events) | 18 months | 
| Clinical Outcome - Rate of symptomatic or incidentally detected recurrent or new major VTE | Rate of symptomatic or incidentally detected recurrent or new major VTE | 18 months | 
| Clinical Outcome - PE-related death | PE-related death | 18 months | 
| Clinical Outcome - Composite of recurrent VTE and major bleeding events | Composite of recurrent VTE and major bleeding events | 18 months | 
| Clinical Outcome - Non-major VTE (distal upper or lower extremity DVT, superficial upper or lower extremity vein thrombosis) | Number of non-major VTE (distal upper or lower extremity DVT, superficial upper or lower extremity vein thrombosis) | 18 months | 
| Clinical Outcome - Duration of thrombocytopenia (days of platelet count < 50,000/uL) per patient | Duration of thrombocytopenia (days of platelet count < 50,000/uL) per patient | 18 months | 
| Clinical Outcome - Number of transfused units and adverse platelet transfusion reactions | Number of transfused units and adverse platelet transfusion reactions | 18 months | 
| Clinical Outcome - Overall mortality | Overall mortality | 18 months | 
| Clinical Outcome - Health-related quality of life using EuroQoL-EQ-5D-5L questionnaire | Health-related quality of life using EuroQoL-EQ-5D-5L questionnaire | 18 months |