Pathogen Reduction Evaluation & Predictive Analytical Rating Score

Study Overview
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Brief Summary
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The objective of this study is to determine if pooled buffy coat-derived pathogen reduced plasma-stored platelet concentrates are non-inferior compared to plasma-stored platelet concentrates in terms of WHO bleeding complications in hemato-oncological patients with thrombocytopenia.

Detailed Description
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Currently some pathogen-reduced platelet products (PR-PCs) have passed phase III studies, are in progress or can be expected in the near future. At present some transfusion centers throughout Europe have implemented PR-PCs, but as yet PR-PCs are not formally accepted as a standard product that should be applied nation-wide. Because many uncertainties currently exist on the optimal platelet product, it is in the interest of patients, health care providers and the transfusion provider (Sanquin) to decide on evidence. With all the current safety measures remaining in place, pathogen reduction provides a safety benefit by reducing the number of transfusions of platelet concentrates contaminated with bacteria, but which were missed by the screening method. In the Dutch situation, morbidity is estimated to be 1:14,000 platelet concentrates [Te Boekhorst, Transfusion 2005]. In this publication, two cases of transmission of B. cereus by a platelet transfusion are reported, where both patients experience a life-threatening sepsis, but recover eventually. Cases of bacterial transmission however often go unnoted, so a frequency as low as 1:130,000 has been reported [Dumont, Transfusion 2010]. The same is true for mortality; this value ranges from 1:50,000 to 1:500,000. A more precautionary benefit is protection against known and unknown pathogens. It is difficult to estimate the actual risk, and consequently to estimate the benefit for the patient. While in The Netherlands no epidemics have occurred against which no screening tests could be developed, including Q-fever, there is a small but real risk that an epidemic can wipe out the blood supply in a country. This has happened in La Réunion, where an epidemic of chikungunya virus urged import of blood products from abroad, followed by rapid introduction of a pathogen reduction technology to ensure the blood supply [Rasongles, Transfusion 2009]. An outbreak of this virus in Italy resulted in suspension of blood collections in an affected area, which led to a low blood inventory as well as a reduced delivery of plasma to fractionation institutes. Appreciating the difficulties of extrapolating in vitro tests towards in vivo efficacy, platelet products should be tested in clinical trials. Of note, radiolabeling techniques in volunteers as required by the FDA, are not used in the Netherlands. For major product variations in the Netherlands, investigators depend on studies in patients. Extending storage for logistic purposes, combined with maintaining or even improving the safety of platelet products, and maintaining clinical efficacy are the main features in the development of new platelet products. In this study protocol, the aim is to investigate transfusion efficacy of two different platelet products: plasma-PCs, and pathogen-reduced (PR)-plasma-PCs, combining extended storage with or without treatment with a photochemical pathogen reduction technique. Prior to the start of the clinical study an in vitro study of the product has been performed, showing that the study product meets the current in vitro quality requirements for release for transfusion. However, on site implementation validation still has to take place. Refractoriness to platelet transfusions and bleeding complications are the main clinical problems in intensively treated hemato-oncological patients and are essential endpoints for transfusion studies as well. In this trial, bleeding will be scored according to the World Health Organization (WHO) scale as a primary endpoint. Refractoriness is defined as a 1-hour CCI <7.5 and/or a 24-hour CCI <4.5 after ABO compatible platelet transfusions on at least two successive occasions. Known causes of non-alloimmune refractoriness are included in this trial because for the purpose of generalization, relevant to develop a national product, testing transfusion efficacy of new platelet products should imply all patients in need of a preventive support with platelet transfusions. The 1- and 24-hour CCI are commonly used to evaluate platelet transfusions and, albeit not without discussion, currently the platelet count is the only parameter in trigger-based transfusion policy. The ratio of both the 1-hour and 24-hour CCI mirrors both platelet recovery immediately after transfusion as the 1-hour CCI, and platelet survival one day after transfusion as the 24-hour CCI. Other secondary clinical endpoints of the trial will be transfusion requirement (red cells and platelets), transfusion interval to next transfusion and adverse reactions.

Official Title
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Clinical Effectiveness of Standard Versus Pathogen-reduced Buffy Coat-derived Platelet Concentrates in Plasma in Hemato-oncological Patients.

Conditions
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Thrombocytopenia

Intervention / Treatment
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* Device: Pathogen reduced plasma-stored platelet concentrates
* Other: Plasma-stored platelet concentrates


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years; Expected ≥ 2 platelet transfusion requirements; Signed informed consent; Having hemato oncological disease including those who undergo myelo ablative allogeneic stem cell transplant therapy. Exclusion Criteria: Micro-angiopathic thrombocytopenia (TTP, HUS) and ITP; Bleeding > grade 2 at randomization ( after treatment, the patient can be randomized in the study after 2 or more weeks after the last transfusion that was used to stop the bleeding); Known immunological refractoriness to platelet transfusions; HLA- and/or HPA-allo immunization and/or clinical relevant auto-antibodies; Indications to use hyper-concentrated (plasma-reduced) platelet concentrates, i.e. patients with known severe allergic reactions and documented transfusion-associated circulatory overload (TACO); Pregnancy (or lactating); Prior treatment with pathogen-reduced blood products; Known allergy to riboflavin or its photoactive products.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PR-plasma-PCs<br>Pooled buffy coat-derived pathogen reduced plasma-stored platelet concentrates (PR-plasma-PCs) | Device: Pathogen reduced plasma-stored platelet concentrates<br>* Platelet concentrates treated with the Mirasol PRT system (pathogen reduction technology) and stored in plasma.<br>|
| Active Comparator: Plasma-PCs<br>Pooled buffy coat-derived plasma-stored platelet concentrates (plasma-PCs) | Other: Plasma-stored platelet concentrates<br>* Platelet concentrates stored in plasma<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with WHO grade ≥ 2 bleeding complications | Any WHO grade ≥ 2 bleeding event, as determined by daily assessment of bleeding symptoms, and documentation of any red blood cell transfusions to treat bleeding | Transfusion episode (from the day of the first on-study transfusion until study completion), an average of 20 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1 and 24 hour count increment |  | 1 and 24 hours post-transfusion | 
| 1 and 24 hour corrected count increment (CCI) |  | 1 and 24 hours post-transfusion | 
| (1+24 hour CCI)/2 |  | 1 and 24 hours post-transfusion | 
| Adverse transfusion reactions | All transfusion-associated side effects observed within 6 hours after platelet transfusion | On-study episode (from the day of randomization until study completion), an average of 25 days | 
| Total transfusion requirement of red cells and platelets | Number of occurrences of a platelet transfusion or a red cell transfusion among subjects who have had at least one platelet transfusion | Transfusion episode (from the day of the first on-study transfusion until study completion), an average of 20 days | 
| Platelet transfusion interval | Time in hours between the last and first occurrence of a platelet transfusion, divided by the number of platelet transfusion occurrences minus 1, among subjects who have had at least two platelet transfusions | Transfusion episode (from the day of the first on-study transfusion until study completion), an average of 20 days | 
| Rate of HLA allo-immunization |  | From the day of randomization until 56 days after randomization | 
| In vitro quality markers related with the 1-hour or 24-hour CCI |  | 1 and 24 hours post-transfusion | 
| Clinical factors interacting on primary endpoint, including in vivo variables of immunological responses; and of hemostasis in the recipients after transfusion as compared prior to transfusion. | Severity of the WHO bleeding grade as determined by daily assessment of bleeding symptoms, related to the level of circulating HLA allo antibodies as determined in a blood sample collected every week during the on-study episode; severity of the WHO bleeding grade as determined by daily assessment of bleeding symptoms at the day of occurrence of a platelet transfusion as compared to the day after the occurrence of a platelet transfusion | Transfusion episode (from the day of the first on-study transfusion until study completion), an average of 20 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pathogen inactivation, platelets