Clinical trial NCT00128713: Optimal Platelet Dose Strategy for Management of Thrombocytopenia
Official title: Determination of the Optimal Prophylactic Platelet Dose Strategy to Prevent Bleeding in Thrombocytopenic Patients (A TMH CTN Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Thrombocytopenia
Keywords: Blood Transfusion
Blood Platelets
Lead sponsor: Carelon Research
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Transfusion Medicine/Hemostasis Clinical Research Network
First posted: 2005-08-10
Enrollment: 1351
Sex: ALL
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

  1. PT less than or equal to 1.3 times the upper limit of normal for the laboratory
  2. PTT less than or equal to 1.3 times the upper limit of normal for the laboratory
  3. 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

Primary outcomes:
measure: At Least One Day With Grade 2 or Higher Bleeding
timeFrame: 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 outcomes:
measure: Platelet Utilization
timeFrame: 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)
measure: Number of Platelet Transfusion Episodes
timeFrame: 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)
measure: Bleeding Severity, if a Suitable Scale is Validated and Published by the Time the Trial Ends
timeFrame: 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)
measure: Highest Grade of Bleeding While on Study
timeFrame: 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)
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Hospitals; Children's Healthcare of Atlanta
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: New Orleans
country: United States
facility: Tulane University Hospital and Clinics
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston; Beth Israel Deaconess Medical Center; Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview
state: Minnesota
city: New York
country: United States
facility: NY-Presbyterian Hosp/Weill Cornell Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospitals
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospital Cleveland
state: Ohio
city: Oklahoma City
country: United States
facility: U of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: U of Pennsylvania Health System; Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Presbyterian and Shadyside Hospital
state: Pennsylvania
city: Dallas
country: United States
facility: U of Texas SW Medical Center at Dallas
state: Texas
city: Seattle
country: United States
facility: Virginia Mason Hospital
state: Washington
city: Seattle
country: United States
facility: U of Washington Medical Center/FHCRC; Children's Hospital and Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Oncology Alliance/St. Luke's Hospital
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital
state: Wisconsin
Study officials:
affiliation: New England Research Institutes, Inc.
name: Susan F. Assmann
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina
name: Mark Brecher, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NY-Presbyterian Hosp/Weill Cornell Medical Center
name: James B. Bussel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: U of Oklahoma Health Sciences Center
name: James George, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Maryland, Baltimore
name: John R. Hess
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Christopher D. Hillyer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Barbara A. Konkle, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tulane University
name: Cindy A. Leissinger, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospitals Cleveland
name: Keith R. McCrae, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Jeffrey McCullough, MD
role: STUDY_CHAIR
affiliation: Versiti
name: Janice G. McFarland, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Paul M. Ness, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Boston Children's Hospital
name: Ellis Neufeld, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: Thomas L. Ortel, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bloodworks
name: Sherrill J. Slichter, MD
role: STUDY_CHAIR
affiliation: University of Iowa
name: Ronald G. Strauss, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh Presbyterian and Shadyside Hospital
name: Darrell J. Triulzi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Uhl L, Assmann SF, Hamza TH, Harrison RW, Gernsheimer T, Slichter SJ. Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial. Blood. 2017 Sep 7;130(10):1247-1258. doi: 10.1182/blood-2017-01-757930. Epub 2017 Jul 5.
citation: Josephson CD, Granger S, Assmann SF, Castillejo MI, Strauss RG, Slichter SJ, Steiner ME, Journeycake JM, Thornburg CD, Bussel J, Grabowski EF, Neufeld EJ, Savage W, Sloan SR. Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia. Blood. 2012 Jul 26;120(4):748-60. doi: 10.1182/blood-2011-11-389569. Epub 2012 Apr 26.
citation: Triulzi DJ, Assmann SF, Strauss RG, Ness PM, Hess JR, Kaufman RM, Granger S, Slichter SJ. The impact of platelet transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia. Blood. 2012 Jun 7;119(23):5553-62. doi: 10.1182/blood-2011-11-393165. Epub 2012 Apr 10.
citation: Slichter SJ, Kaufman RM, Assmann SF, McCullough J, Triulzi DJ, Strauss RG, Gernsheimer TB, Ness PM, Brecher ME, Josephson CD, Konkle BA, Woodson RD, Ortel TL, Hillyer CD, Skerrett DL, McCrae KR, Sloan SR, Uhl L, George JN, Aquino VM, Manno CS, McFarland JG, Hess JR, Leissinger C, Granger S. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med. 2010 Feb 18;362(7):600-13. doi: 10.1056/NEJMoa0904084.