A study protocol for a randomised controlled trial evaluating clinical effects of platelet transfusion products: the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) trial

Introduction Patients with chemotherapy-induced thrombocytopaenia frequently experience minor and sometimes severe bleeding complications. Unrestrictive availability of safe and effective blood products is presumed by treating physicians as well as patients. Pathogen reduction technology potentially offers the opportunity to enhance safety by reducing bacterial and viral contamination of platelet products along with a potential reduction of alloimmunisation in patients receiving multiple platelet transfusions. Methods and analysis To test efficacy, a randomised, single-blinded, multicentre controlled trial was designed to evaluate clinical non-inferiority of pathogen-reduced platelet concentrates treated by the Mirasol system, compared with standard plasma-stored platelet concentrates using the percentage of patients with WHO grade ≥2 bleeding complications as the primary endpoint. The upper limit of the 95% CI of the non-inferiority margin was chosen to be a ≤12.5% increase in this percentage. Bleeding symptoms are actively monitored on a daily basis. The adjudication of the bleeding grade is performed by 3 adjudicators, blinded to the platelet product randomisation as well as by an automated computer algorithm. Interim analyses evaluating bleeding complications as well as serious adverse events are performed after each batch of 60 patients. The study started in 2010 and patients will be enrolled up to a maximum of 618 patients, depending on the results of consecutive interim analyses. A flexible stopping rule was designed allowing stopping for non-inferiority or futility. Besides analysing effects of pathogen reduction on clinical efficacy, the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) is designed to answer several other pending questions and translational issues related to bleeding and alloimmunisation, formulated as secondary and tertiary endpoints. Ethics and dissemination Ethics approval was obtained in all 3 participating countries. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. Trial registration number NTR2106; Pre-results.

[1]  M. Trivella,et al.  Pathogen-reduced platelets for the prevention of bleeding. , 2017, The Cochrane database of systematic reviews.

[2]  G. Duverlie,et al.  Inactivation of viruses in platelet and plasma products using a riboflavin‐and‐UV–based photochemical treatment , 2015, Transfusion.

[3]  L. Gutiérrez,et al.  Development of blood transfusion product pathogen reduction treatments: a review of methods, current applications and demands. , 2015, Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis.

[4]  P. Morel,et al.  Bacterial contamination in platelet concentrates , 2014, Vox sanguinis.

[5]  S. Slichter,et al.  Exploratory studies of extended storage of apheresis platelets in a platelet additive solution (PAS). , 2014, Blood.

[6]  P. Ypma,et al.  Measuring clinical bleeding using a standardized daily report form and a computer algorithm for adjudication of WHO bleeding grades , 2013, Vox sanguinis.

[7]  E. Wood,et al.  The challenges of measuring bleeding outcomes in clinical trials of platelet transfusions , 2013, Transfusion.

[8]  E. Wood,et al.  A no-prophylaxis platelet-transfusion strategy for hematologic cancers. , 2013, The New England journal of medicine.

[9]  M. Trivella,et al.  Pathogen-reduced platelets for the prevention of bleeding. , 2013, The Cochrane database of systematic reviews.

[10]  M. Franchini,et al.  Bleeding Complications in Patients with Hematologic Malignancies , 2012, Seminars in Thrombosis & Hemostasis.

[11]  J. Zwaginga,et al.  The observation of bleeding complications in haemato‐oncological patients: stringent watching, relevant reporting , 2012, Transfusion medicine.

[12]  S. Slichter,et al.  Filtration Leukoreduction Followed by Pathogen-Reduction (Mirasol Treatment) Prevents Alloimmune Platelet Refractoriness in a Dog Platelet Transfusion Model , 2012 .

[13]  N. Heddle,et al.  A new tool to assess bleeding severity in patients with chemotherapy‐induced thrombocytopenia (CME) , 2012, Transfusion.

[14]  A. Ho,et al.  Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study , 2012, The Lancet.

[15]  N. Heddle,et al.  Time to rethink clinically important outcomes in platelet transfusion trials , 2011, Transfusion.

[16]  J. Efird,et al.  Blocked Randomization with Randomly Selected Block Sizes , 2010, International journal of environmental research and public health.

[17]  E. Delwart,et al.  Transfusion transmission of highly prevalent commensal human viruses , 2010, Transfusion.

[18]  S. Slichter,et al.  White blood cell inactivation after treatment with riboflavin and ultraviolet light , 2010, Transfusion.

[19]  P. Mintz,et al.  A randomized controlled clinical trial evaluating the performance and safety of platelets treated with MIRASOL pathogen reduction technology , 2010, Transfusion.

[20]  S. Kleinman,et al.  Identification of specificities of antibodies against human leukocyte antigens in blood donors , 2010, Transfusion.

[21]  D. Korte,et al.  In vitro comparison of platelet storage in plasma and in four platelet additive solutions, and the effect of pathogen reduction: a proposal for an in vitro rating system , 2010, Vox sanguinis.

[22]  Jeffrey McCullough,et al.  Dose of prophylactic platelet transfusions and prevention of hemorrhage. , 2010, The New England journal of medicine.

[23]  R. Lieshout-Krikke,et al.  Bacterial screening of platelet concentrates: results of 2 years active surveillance of transfused positive cultured units released as negative to date , 2009, Vox sanguinis.

[24]  A. Rizvi.  Cytokine Biomarkers, Endothelial Inflammation, and Atherosclerosis in the Metabolic Syndrome: Emerging Concepts , 2009, The American journal of the medical sciences.

[25]  P. Norris,et al.  IMMUNOHEMATOLOGY: Understanding loss of donor white blood cell immunogenicity after pathogen reduction: mechanisms of action in ultraviolet illumination and riboflavin treatment , 2009, Transfusion.

[26]  N. Heddle,et al.  Platelet quality measured with dynamic light scattering correlates with transfusion outcome in hematologic malignancies , 2009, Transfusion.

[27]  R. Goodrich,et al.  A laboratory comparison of pathogen reduction technology treatment and culture of platelet products for addressing bacterial contamination concerns , 2009, Transfusion.

[28]  T. Hervig,et al.  A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. , 2009, Blood.

[29]  S. Rafii,et al.  Platelets, petechiae, and preservation of the vascular wall. , 2008, The New England journal of medicine.

[30]  S. Satchell,et al.  What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? , 2008, Diabetologia.

[31]  C. Koh,et al.  Treatment With Riboflavin and Ultraviolet Light Prevents Alloimmunization to Platelet Transfusions and Cardiac Transplants , 2007, Transplantation.

[32]  Y. Romanov,et al.  Vascular endothelium: target or victim of cytostatic therapy? , 2007, Canadian journal of physiology and pharmacology.

[33]  N. Heddle,et al.  A study of the agreement between patient self‐assessment and study personnel assessment of bleeding symptoms , 2006, Transfusion.

[34]  E. Vamvakas,et al.  The continuing risk of transfusion-transmitted infections. , 2006, New England Journal of Medicine.

[35]  J. Roodt,et al.  Correlation of in vitro platelet quality measurements with in vivo platelet viability in human subjects , 2006, Vox sanguinis.

[36]  R. Goodrich,et al.  Functional inactivation of white blood cells by Mirasol treatment , 2006, Transfusion.

[37]  R. K. Salyer,et al.  Cytosine Arabinoside Induces Programmed Endothelial Cell Death Through the Caspase-3 Pathway , 2006, Biological research for nursing.

[38]  R. Strauss,et al.  Platelet dose consistency and its effect on the number of platelet transfusions for support of thrombocytopenia: an analysis of the SPRINT trial of platelets photochemically treated with amotosalen HCl and ultraviolet A light , 2006, Transfusion.

[39]  E. D. de Vries,et al.  Endothelial cell effects of cytotoxics: balance between desired and unwanted effects. , 2004, Cancer treatment reviews.

[40]  J. Freedman,et al.  Role of platelet surface glycoprotein Ibα and P‐selectin in the clearance of transfused platelet concentrates , 2004, Transfusion.

[41]  J. Fridey,et al.  Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial. , 2004, Blood.

[42]  J. Li,et al.  Pathogen reduction of buffy coat platelet concentrates using riboflavin and light: comparisons with pathogen‐reduction technology‐treated apheresis platelet products , 2004, Vox sanguinis.

[43]  S. Slichter.  Relationship between platelet count and bleeding risk in thrombocytopenic patients. , 2004, Transfusion medicine reviews.

[44]  R. Goodrich,et al.  Photochemical inactivation of selected viruses and bacteria in platelet concentrates using riboflavin and light , 2004, Transfusion.

[45]  Hong Wang,et al.  Procoagulant surface exposure and apoptosis in rabbit platelets: association with shortened survival and steady‐state senescence , 2004, Journal of thrombosis and haemostasis : JTH.

[46]  R. Yomtovian.  Bacterial contamination of blood: lessons from the past and road map for the future , 2004, Transfusion.

[47]  P. Huijgens,et al.  In vivo PLT increments after transfusions of WBC‐reduced PLT concentrates stored for up to 7 days , 2004, Transfusion.

[48]  J. AuBuchon,et al.  Seven‐day storage of single‐donor platelets: recovery and survival in an autologous transfusion study , 2002, Transfusion.

[49]  I. Palomo,et al.  Platelet Aging In Vivo Is Associated with Activation of Apoptotic Pathways: Studies in a Model of Suppressed Thrombopoiesis in Dogs , 2002, Thrombosis and Haemostasis.

[50]  J. Barbara,et al.  Evaluation of the BacT/Alert automated blood culture system for detecting bacteria and measuring their growth kinetics in leucodepleted and non‐leucodepleted platelet concentrates , 2001, Vox sanguinis.

[51]  H. Baum,et al.  Decreased Pasteur effect in platelets of aged individuals , 2001, Mechanisms of Ageing and Development.

[52]  James M. Robins,et al.  Semiparametric Efficiency and its Implication on the Design and Analysis of Group-Sequential Studies , 1997 .

[53]  J. Loscalzo,et al.  In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Rebulla,et al.  Role of Lactate in Platelet Storage Lesion , 1993, Vox sanguinis.

[55]  R. Hillman,et al.  Progressive platelet activation with storage: evidence for shortened survival of activated platelets after transfusion , 1991, Transfusion.

[56]  U. Sugg.  [Transfusion-transmitted infections]. , 1991, Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS.

[57]  P. Rebulla,et al.  The risk of bleeding in thrombocytopenic patients with acute myeloid leukemia. , 2006, Haematologica.

[58]  H. Lehmann,et al.  Do basic laboratory tests or clinical observations predict bleeding in thrombocytopenic oncology patients? A reevaluation of prophylactic platelet transfusions. , 2002, Transfusion medicine reviews.

[59]  D. Wagner,et al.  P-Selectin and platelet clearance. , 1998, Blood.

[60]  Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. , 1997, The New England journal of medicine.

[61]  S. Hanson,et al.  Platelet kinetics in patients with bone marrow hypoplasia: evidence for a fixed platelet requirement. , 1985, Blood.