Optimal Platelet Dose Strategy for Management of Thrombocytopenia

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to compare the three study arms of lower, medium, and higher dose platelet therapy with respect to the percentage of patients experiencing at least one episode of Grade 2 or higher bleeding as determined by the Platelet Dose Trial Bleeding Scale (Grade 2 bleeding corresponds to bleeding that is moderate, but not severe enough to warrant red blood cell transfusion). There are a number of secondary endpoints related to platelet transfusions, hemostasis, and other concerns. The four most important secondary endpoints will compare the three study arms with respect to the following outcomes: 1) platelet utilization rates (total number of platelets transfused x 10 ^11); 2) number of platelet transfusion events (frequency of transfusions); a transfusion event would be defined as each separate platelet transfusion issued by the study site's transfusion service; 3) highest category of bleeding during time of study (Platelet Dose Trial Bleeding Scale Grades less than or equal to 1, 2, 3, or 4 by arm); and 4) bleeding severity based on number of days with bleeding (total days of bleeding and bleeding/thrombocytopenic day), intensity of bleeding, and number of sites with bleeding (if such a severity score has been validated and published by the time the study is completed).

Detailed Description
-----------------
BACKGROUND: It is important to identify the safest and most cost effective strategies for providing platelet support that will achieve effective disease management without depleting platelet supplies. Informative clinical data have been provided concerning the platelet transfusion trigger. In contrast, the optimal quantity of platelets to be used per transfusion remains a highly controversial subject. No prospective platelet transfusion studies have been performed in which patients are randomized to an assigned platelet dose throughout their period of thrombocytopenia. DESIGN NARRATIVE: After obtaining consent and verifying eligibility requirements, the patients will be randomized to one of three doses for prophylactic platelet transfusions (lower, medium, or higher dose). The dosage is based on the patient's body surface area (BSA). The dose targets are as follows: 1) the lower dose is 1.1 x 10^11/m²; 2) the medium dose is 2.2 x 10^11/m²; and 3) the higher dose is 4.4 x 10^11/m². A dose within 25% of this value in either direction is considered to be in the target range. For many adult patients, the typical dose of one unit of apheresis platelets would fall in the target range for the medium dose. All prophylactic transfusions provided while the patient is in the study will be given according to the randomized target dose range. Only blood bank staff, not clinical staff, will have access to the target dose range for each patient. The patient's morning platelet count will be taken every day. If this value is less than or equal to 10,000, a prophylactic platelet transfusion will be given. Otherwise, no prophylactic platelet transfusion will be given that day. Platelet transfusions may be given at any time, and at any dose, to treat active bleeding or in association with an invasive procedure. A hemostatic assessment will be carried out every day to identify any bleeding the patient may experience. This assessment involves a patient interview, physical assessment, and a chart review. Data on all transfusions (e.g., platelets and red blood cells), all transfusion-related events, all serious adverse events, and protocol deviations will also be recorded. Patients will participate in the study either until 30 days after the initial platelet transfusion, until they have not received a platelet transfusion for 10 days after the most recent platelet transfusion, or until hospital discharge (whichever comes first). Each of the three pairwise dose comparisons is of interest. Therefore, the primary and secondary endpoints will be analyzed using three separate pairwise comparisons, each at the 0.017 significance level to adjust for multiple comparisons. This study has been approved by the National Heart, Lung, and Blood Institute (NHLBI)-appointed protocol review committee and data and safety monitoring board (DSMB), and each participating institution's institutional review board. An interim monitoring plan was developed by the protocol team and DSMB, and is described in the protocol. The study is being monitored in accordance with this plan.

Official Title
-----------------
Determination of the Optimal Prophylactic Platelet Dose Strategy to Prevent Bleeding in Thrombocytopenic Patients (A TMH CTN Study)

Conditions
-----------------
Thrombocytopenia

Intervention / Treatment
-----------------
* Procedure: Medium Dose Prophylactic Platelet Transfusions
* Procedure: Lower Dose Prophylactic Platelet Transfusions
* Procedure: Higher Dose Prophylactic Platelet Transfusions


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has, or is expected to have, hypoproliferative thrombocytopenia, and is expected to have a platelet count of up to 10,000 ul for at least 5 days and be in the hospital for at least 5 days Weight is between 10 and 135 kilograms PT/INR, PTT, and fibrinogen assays that are measured within 72 hours before study entry are as follows: PT less than or equal to 1.3 times the upper limit of normal for the laboratory PTT less than or equal to 1.3 times the upper limit of normal for the laboratory Fibrinogen greater than or equal to 100 mg/dl Undergoing, or has completed, hematopoietic stem cell transplantation, for any diagnosis; OR has a diagnosis of acute or chronic leukemia, non-Hodgkins or Hodgkins lymphoma, myeloma, myelodysplasia, or non-hematologic malignancy and is undergoing, or has completed, chemotherapy During this hospitalization, the patient has not yet received any platelet transfusions related to the current or planned course of therapy (individual platelet transfusions given prior to the study and unrelated to thrombocytopenia will not exclude the patient) Exclusion Criteria: Evidence of greater than or equal to Grade 2 bleeding (as determined by the Platelet Dose Trial Bleeding Scale) Receiving antithrombotic drugs Will receive bedside leuko-reduced platelet transfusions Present, or history of, platelet transfusion refractoriness within 30 days prior to study entry Pre-enrollment lymphocytotoxic antibody screen (PRA) known to be greater than or equal to 20% based on prior data Present, or history of, acute promyelocytic leukemia (APML), immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or hemolytic-uremic syndrome (HUS) Will be transfused at platelet trigger of greater than 10,000 platelets/ul Recent history of major surgery (within 2 weeks of study entry) Currently taking, or participating in a study involving, platelet substitutes, platelet growth factors, or pharmacologic agents intended to enhance or decrease platelet hemostatic function Pregnant Previously enrolled in this study

Ages Eligible for Study
-----------------
Maximum Age: 100 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Lower Dose Prophylactic Platelets | Procedure: Lower Dose Prophylactic Platelet Transfusions<br>* 1.1 x 10^11 platelets per m^2 BSA<br>|
| Active Comparator: 2<br>Medium Dose Prophylactic Platelets | Procedure: Medium Dose Prophylactic Platelet Transfusions<br>* 2.2 x 10^11 platelets per m^2 BSA<br>|
| Active Comparator: 3<br>Higher Dose Prophylactic Platelets | Procedure: Higher Dose Prophylactic Platelet Transfusions<br>* 4.4 * 10^11 platelets per m^2 BSA<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| At Least One Day With Grade 2 or Higher Bleeding | Any Grade 2 (moderate) or higher grade bleeding, as determined by daily hemostatic assessment and documentation of any red blood cell transfusions to treat bleeding | From randomization until the subject ends the study (10 days after most recent platelet transfusion, 30 days after first platelet transfusion on study, or hospital discharge, whichever occurs first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Utilization | Total number of platelets transfused, based on attempted dose, among subjects who have at least one platelet transfusion and no missing data on attempted doses. | From randomization until the subject ends the study (10 days after most recent platelet transfusion, 30 days after first platelet transfusion on study, or hospital discharge, whichever occurs first) | 
| Number of Platelet Transfusion Episodes | Number of platelet transfusion episodes among subjects who have at least one platelet transfusion and no missing data on attempted doses. | From randomization until the subject ends the study (10 days after most recent platelet transfusion, 30 days after first platelet transfusion on study, or hospital discharge, whichever occurs first) | 
| Bleeding Severity, if a Suitable Scale is Validated and Published by the Time the Trial Ends | No suitable scale was identified, so no analyses for this outcome were carried out | From randomization until the subject ends the study (10 days after most recent platelet transfusion, 30 days after first platelet transfusion on study, or hospital discharge, whichever occurs first) | 
| Highest Grade of Bleeding While on Study | Highest grade of bleeding during time on study using Platelet Dose Trial modification of World Health Organization Bleeding Scale. Grades 0-1 (no or minimal bleeding), 2 (moderate bleeding), 3 (bleeding generally requiring red cell transfusion), 4 (severe bleeding) | From randomization until the subject ends the study (10 days after most recent platelet transfusion, 30 days after first platelet transfusion on study, or hospital discharge, whichever occurs first) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Blood Transfusion, Blood Platelets