Clinical Effectiveness of Conventional Versus Mirasol-treated Apheresis Platelets in Patients With Hypoproliferative Thrombocytopenia
Phase: NA
Conditions: Hematologic Malignancies, Hypoproliferative Thrombocytopenia
Sponsor: Terumo BCTbio

 
Terumo BCT, Inc. 
Terumo BCT Europe N.V. 
Terumo BCT (Asia Pacific) Ltd. 
Terumo BCT Latin America S.A. 
Terumo BCT Japan, Inc. 
10811 West Collins Ave. 
Europe, Middle East and Africa 
Room 3903-3903A, 39/F 
La Pampa 1517 – 12th Floor 
20-14, 3-chome 
Lakewood, Colorado 80215-4440 
Ikaroslaan 41 
ACE Tower, Windsor House 
C1428DZE 
Higashi Gotanda, Shinagawa-ku 
USA 
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311 Gloucester Road 
Buenos Aires 
Tokyo 141-0022 
USA Phone: 1.877.339.4228    
Belgium 
Causeway Bay, Hong Kong 
Argentina 
Japan 
Phone: +1.303.231.4357     
Phone: +32.2.715.05.90 
Phone: +852.2283.0700 
Phone: +54.11.5530.5200 
Phone: +81.3.6743.7890 
Fax: +1.303.542.5215     
Fax: +32.2.721.07.70 
Fax: +852.2576.1311 
Fax: +54.11.5530.5201 
Fax: +81.3.6743.9800 
 
UNLOCKING POTENTIAL| TERUMOBCT.COM 
 
 
 
 
 
 
 
Cover Page for Clinical Trials Results Document Upload  
 
Trial Name: Efficacy of Mirasol-treated Apheresis Platelets in Patients With Hypoproliferative 
Thrombocytopenia (MIPLATE)  
 
Trial ID: CTS-5030 
 
NCT Number: NCT02964325 
 
Document Name: Statistical Analysis Plan  
 
Document Date: 02 SEP 2020, Version 3.0 
 
 
 

 
 
Statistical Analysis Plan 
 
 
Protocol Title: 
Clinical Effectiveness of Conventional Versus 
Mirasol-treated Apheresis Platelets in Patients 
with Hypoproliferative Thrombocytopenia 
(MIPLATE) 
 
Sponsor: 
Terumo BCT Biotechnologies, LLC 
 
1215 Quail Street 
 
Lakewood, CO 80215; USA 
 
Phone: 1 (877) 339-4228 
 
Protocol Number: 
CTS-5030 
 
Protocol Version Number: Version 9.0 
 
Protocol Date: 
30 JAN 2019 
 
Version Number: 
Version 3.00  
 
Version Date: 
02 SEP 2020 
 
Prepared by: 
CPC Clinical Research 
 
2115 N. Scranton St., Suite 2040 
 
Aurora, CO 80045 
 
 

 
 
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2. 
APPROVALS 
 
Author 
 
Director, Biostatistics and 
Programming Biostatistician 
 
 
 
 
 
 
 
Robin White, MS 
 
 
 
 
 
____________  
Date 
 
 
CPC Approval 
 
 
Medical Safety Officer 
 
 
 
 
 
 
 
Cecilia C. Low Wang, MD 
 
 
 
 
 
_____________  
Date 
 
 
Sponsor Approval 
 
 
Senior Manager, Global Clinical
Affairs 
 
 
 
 
 
 
Christopher Graybill, PhD
 
 
 
 
_____________  
Date
 
 
Clinical Research Manager 
 
 
 
 
 
 
Bethany Brown, PhD, MSCS
 
 
 
 
_____________  
Date
 
 
Clinical Affairs Manager 
 
 
 
 
 
 
Chriss Stanford, MA 
 
 
 
 
_____________  
Date 
 
 

 
 
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Appendix II Approval 
 
 
BSRI Statistician 
 
 
 
 
 
 
Brian Custer, PhD 
 
 
 
 
_____________  
Date 
 
Sponsor Statistical Representative Approval 
 
 
Consultant Statistician 
 
 
 
 
 
 
Richard Cook, PhD 
 
 
 
 
_____________  
Date 
 

 
 
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3. 
TABLE OF CONTENTS 
2. ........ APPROVALS .................................................................................................................................. 2 
3. ........ TABLE OF CONTENTS ................................................................................................................. 4 
4. ........ LIST OF ACRONYMS ................................................................................................................... 6 
5. ........ PREFACE ........................................................................................................................................ 9 
5.1. 
CPC Clinical Research Representative ............................................................................... 9 
5.2. 
Statistical Analysis Plan Drafts and Approval Process ....................................................... 9 
6. ........ INTRODUCTION ........................................................................................................................... 9 
6.1. 
Study Design ....................................................................................................................... 9 
6.2. 
Subject Selection ............................................................................................................... 10 
6.3. 
Study Objectives ............................................................................................................... 10 
6.3.1. 
Primary Endpoint ............................................................................................ 11 
6.3.2. 
Secondary, Exploratory, and Safety Endpoints .............................................. 11 
6.3.3. 
Sample Size..................................................................................................... 12 
7. ........ DATABASE DESCRIPTION ....................................................................................................... 12 
7.1. 
Creating Analysis Data Sets.............................................................................................. 12 
7.2. 
Validation of Data and Analysis Programs ....................................................................... 12 
7.3. 
Archiving Data and SAS® Files ....................................................................................... 12 
7.4. 
Analysis Conventions ....................................................................................................... 13 
7.4.1. 
Dropouts and Missing Data ............................................................................ 14 
7.4.2. 
Adjustments for Covariates............................................................................. 14 
7.4.3. 
Multi-center studies ........................................................................................ 14 
7.4.4. 
Multiplicity Issues ........................................................................................... 14 
7.5. 
Analysis Populations ......................................................................................................... 14 
7.5.1. 
Full Analysis Set ............................................................................................. 14 
7.5.2. 
Modified Intent-to-Treat Analysis Set ............................................................ 14 
7.5.3. 
Safety Set ........................................................................................................ 14 
7.5.4. 
Per Protocol Set .............................................................................................. 14 
7.6. 
Definition of Baseline Value ............................................................................................ 15 
7.7. 
Calculation of Study Day and Treatment Period .............................................................. 15 
7.8. 
Definition of Visit or Windows ........................................................................................ 15 
7.9. 
Display of Treatment Groups............................................................................................ 15 
7.10. 
Subject Demographics and Baseline Characteristics ........................................................ 15 
7.11. 
Concomitant Medication, Medical History and other Baseline Data ............................... 16 
7.12. 
Protocol Deviations ........................................................................................................... 16 
7.13. 
Treatment Exposure .......................................................................................................... 16 
7.14. 
On- Off-Protocol Transfusions ......................................................................................... 16 
7.15. 
Subject Disposition ........................................................................................................... 17 

 
 
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8......... EFFICACY ANALYSIS ...............................................................................................................17
8.1. 
Primary Endpoint .............................................................................................................. 17 
8.1.1. 
Primary Analysis ............................................................................................. 18 
8.1.2. 
Secondary Analyses ........................................................................................ 19 
8.1.3. 
Assessment of Non-Inferiority and Superiority .............................................. 20 
8.1.4. 
Supporting Analyses ....................................................................................... 21 
8.1.5. 
Subgroup Analyses ......................................................................................... 21 
8.2. 
Secondary Endpoints ........................................................................................................ 22 
8.2.1. 
Key Secondary Endpoint ................................................................................ 22 
8.2.2. 
Additional Secondary Endpoints .................................................................... 22 
8.3. 
Exploratory Endpoints ...................................................................................................... 25 
8.4. 
Safety Endpoints ............................................................................................................... 26 
8.4.1. 
Physical Examinations .................................................................................... 26 
8.4.2. 
Vital signs ....................................................................................................... 26 
8.4.3. 
Clinical Laboratory Values ............................................................................. 26 
8.4.4. 
Treatment Emergent Adverse Events ............................................................. 27 
8.5. 
Tertiary Analyses .............................................................................................................. 28 
8.5.1. 
Irradiation of Platelets ..................................................................................... 28 
8.5.2. 
Washed Platelets ............................................................................................. 29 
8.5.3. 
Age of Platelets ............................................................................................... 29 
8.6. 
Interim Analysis ................................................................................................................ 29 
9. ........ REFERENCES .............................................................................................................................. 31 
10. ...... APPENDIX I, ANNOTATED WHO GRADING SCALE ........................................................... 32 
11. ...... APPENDIX II, ANALYSIS OF THE KEY SECONDARY ENDPOINT .................................... 36 
11.1. 
Introduction ....................................................................................................................... 36 
11.2. 
Data Sources ..................................................................................................................... 36 
11.3. 
HLA Antibody Testing ..................................................................................................... 36 
11.4. 
Analysis Objectives .......................................................................................................... 37 
11.5. 
Populations........................................................................................................................ 37 
11.6. 
Endpoints and Covariates ................................................................................................. 37 
11.7. 
Handling of Missing Values and Other Data Conventions ............................................... 37 
11.8. 
Statistical Procedures ........................................................................................................ 37 
11.9. 
Approaches to Adjust for Multiplicity, Confounders, Heterogeneity ............................... 38 
11.10. Programming Plans ........................................................................................................... 38 
11.11. REFERENCES ................................................................................................................. 38 

 
 
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4. 
 LIST OF ACRONYMS  
ABO 
AE 
Blood Type 
Adverse Event 
Aph 
Apheresis 
aPTT 
Activated Partial Thromboplastin time 
BDRC 
Blinded Data Review Committee 
BSA 
Body Surface Area 
BSRI 
Blood Systems Research Institute 
BP 
Blood Pressure 
CCI 
Corrected Count Increment 
CI 
Confidence Interval 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CMV 
Cytomegalovirus 
CPC 
CPC Clinical Research 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
HLA 
Human Leukocyte Antigen 
HR 
Heart Rate 
IA 
Interim Analysis 
IgG 
Immunoglobulin G 
INR 
International Normalized Ratio 
ISBT 
International Standard for the Transfer of Information Associated with 
Tissue Transplantation, Cellular Therapy and Blood Transfusion 

 
 
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ln 
Natural Logarithm 
KM 
Kaplan-Meier 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MIR 
Mirasol 
mmHG 
Millimeters of Mercury 
NGB 
Normalized Background 
NI 
Non-Inferiority 
PLT 
Platelet 
PPS 
Per Protocol Set 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Cell 
REF 
Reference 
Rh 
Rhesus factor 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
SMQ 
Standard Operating Procedure 
Standard Medical Query 
SpO2 
Blood Oxygen Saturation 
SS 
Safety Set 
TEAE 
TESAE 
Treatment-Emergent Adverse Event 
Treatment Emergent Serious Adverse Event 
TFL 
Tables Figures and Listings 
UADE 
Unanticipated Adverse Device Effects 

 
 
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WHO 
World Health Organization 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 

 
 
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5. 
PREFACE 
5.1. CPC Clinical Research Representative 
Data analysis will be performed by CPC Clinical Research (CPC). Responsibility for overall data analysis 
will be held by the Head of Biostatistics and Programming. Questions regarding data analysis or 
statistical resources should be directed to: 
Head of Biostatistics and Programming 
CPC Clinical Research 
2115 N. Scranton St., Suite 2040 
Aurora, CO 80045 
Telephone: (303) 860-9900 
Facsimile: (303) 860-1288  
5.2. Statistical Analysis Plan Drafts and Approval Process 
This Statistical Analysis Plan (SAP) and any subsequent versions (e.g. amendments) will be developed, 
reviewed and approved in accordance with 
 Standard Operating Procedures (SOPs). The SAP will 
be version controlled. 
When departures from conventions described in CPC SOPs occur, the rules set forth in this SAP take 
precedence over the general conventions. 
All approved original versions of the SAP (e.g., implemented over the course of the project) will be 
retained by CPC until the Clinical Investigation Report (CIR) has been signed, at which time files will be 
transferred to Terumo BCT Biotechnologies, LLC. 
 
6. 
INTRODUCTION 
This SAP is designed to provide a comprehensive understanding of the statistical analyses utilized in 
describing/assessing all study primary, secondary, and exploratory endpoints as well as analyses related to 
safety and the interim analysis (IA) identified in the MIPLATE Clinical Investigation Plan (CIP) version 
9.0. 
The key secondary study endpoint will be analyzed separately by Blood Systems Research Institute 
(BSRI), now Vitalant Research Institute. Blood Systems Research Institute will be wholly responsible for 
all analyses related to the key secondary study endpoint. The details of these analyses are provided in 
Appendix II of this document.  
6.1. Study Design 
This is a prospective, multi-center, controlled, randomized study in which a non-inferiority (NI) design 
will be employed to evaluate the clinical effectiveness of Mirasol (MIR)-treated versus Conventional 
(CONTROL) apheresis (Aph) platelets (PLTs) in subjects with hematologic malignancies with 
hypoproliferative thrombocytopenia expected to have PLT count(s)  10,000/µL and requiring  2 PLT 
transfusions. Subjects will be randomized by a ratio of 1:1 (MIRASOL vs CONTROL group) using a 
permuted-block schedule stratified by investigational site and type of treatment (allogeneic transplant vs 
autologous transplant vs chemotherapy). Randomization will occur as close to the initiation of the first 
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Subject participation will be for up to eighty-one 81 days; a 14-day screening period, a 28-day treatment 
period, and a 28-day follow-up period. Study Day (also referred to in this document as 
 0 of the 
treatment period is defined as the day of the first study transfusion following randomization. The primary, 
secondary, and exploratory endpoints will be based on data captured during the treatment period (Day 0 
to transfusion independence or Day 28, whichever comes first). Transfusion independence is defined as 
ten (10) days without a PLT transfusion prior to date of last contact or Day 28 whichever is earlier. The 
date of transfusion independence will be the 10th day without a PLT transfusion. 
Daily bleeding assessments assess bleeding for the previous day. The first bleeding assessment to be used 
for analysis of primary and secondary endpoints etc., will be collected on Study Day 1 which assesses 
bleeding at Study Day 0.  Bleeding assessments are planned to occur on Study Days 0-27 and at the post 
transfusion follow-up visit. Consequently, there will be a maximum of 28 bleeding assessment days used 
for analysis. The bleeding assessments to be included in analysis are greyed out the in schematic below.  
 
Study Day 
0 (first transfusion
day)* 
1 
2 
3 
4 
5 
6 
27 Post transfusion/ 
Follow-up (in some 
cases Study Day 28) 
Day bleeding 
assessed (24 hours
previous to Study 
Day) 
-1 
0 
1 
2 
3 
4 
5 
26 27 
+ 2-day window 
allowed for visit 
 
*The day the subject receives their first post-randomization PLT transfusion will be considered Day 0. If 
the 
 PLT transfusion episode spans two (2) calendar days, the day the transfusion started will be 
considered Day 0. 
A single IA will be conducted after approximately 279 randomized individuals satisfying the inclusion 
criteria for the modified intent to treat (mITT) analysis have completed the Post-transfusion period 
Follow-up/Early Termination visit. 
6.2. Subject Selection 
Subject study selection is governed by the inclusion/exclusion criteria defined in the CIP. Subjects that 
meet all inclusion criteria and no exclusion criteria and who have signed an informed consent form will 
be eligible for enrollment. 
6.3. Study Objectives 
The primary study objective is to determine if the hemostatic efficacy of MIR-treated plasma stored 
Trima Accel® Aph PLTs (MIRASOL) is non-inferior to Conventional plasma stored Aph PLTs 
(CONTROL) in subjects with hypoproliferative thrombocytopenia requiring PLT transfusions. 
The secondary study objectives include comparing other efficacy and safety endpoints between the 
MIRASOL and CONTROL groups. 
Unless otherwise specified, comparisons of each endpoint will be presented as (MIRASOL vs 
CONTROL). The primary analyses will be based on the observed data in the mITT set. The secondary 
and exploratory endpoints are summarized below. An in-depth discussion of the analysis of these 

 
 
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endpoints is provided in Sections 8.1 to 8.3, respectively. The safety endpoints are also summarized 
below and are discussed in detail in Section 8.4 
6.3.1. Primary Endpoint 
The primary study objective will be assessed through examination of the Primary Efficacy Endpoint 
where clinical effectiveness will be measured by comparing the days of grade 2 or higher bleeding over 
the treatment period between the MIRASOL and CONTROL groups.  Specifically, this study will 
investigate whether MIR-treated Aph PLTs (MIRASOL) are non-inferior to conventional PLTs 
(CONTROL) by testing the null hypothesis that the MIRASOL arm is inferior to the CONTROL arm. 
The null hypothesis will be tested using a one-sided alpha level of 0.025.  If NI is established, superiority 
of MIR-treated Aph PLTs vs Conventional PLTs will be tested using a one-sided alpha level of 0.025 by 
employing a closed gate 
 multiple testing strategy. An in-depth discussion of the analysis of the 
primary efficacy endpoint is provided in Section 8.1 of this document. 
6.3.2. Secondary, Exploratory, and Safety Endpoints 
The Key Secondary Endpoint is human leukocyte antigen (HLA) alloimmunization defined as a binary 
response indicating the occurrence of alloimmunization. 
Additional Secondary Endpoints: 
1. Occurrence of World Health Organization (WHO)  grade 2 bleeding 
2. Time to first day of WHO  grade 2 bleeding 
3. Occurrence of WHO  grade 3 bleeding 
4. Occurrence of PLT refractoriness defined as 2 sequential transfusion episodes, each with corrected 
count increments (CCIs) < 5000 measured 1-hour post-transfusion  
5. Occurrence of PLT refractoriness as defined above and with a positive antibody test within 14 days 
before or after the onset of PLT refractoriness 
6. Number of PLT transfusion episodes per subject, i.e., frequency of transfusion 
7. Days of PLT support; the number of days from the first to the last PLT transfusion 
8. PLT utilization (average number of PLTs transfused) 
9. CCIs at 1 hour and  18 but < 30 hours post-PLT transfusion(s) 
10. Total number of red blood cells (RBC) transfusions (number of units)/subject 
Exploratory Endpoints: 
1. Total number of units of PLTs transfused/day of PLT support 
2. Total number of PLTs (PLT dose) transfused/body surface area (BSA)/day of PLT support 
3. Interval between PLT transfusion episodes (days) 
4. PLT refractoriness defined as 2 sequential transfusion episodes, each with CCIs < 7500 measured 1-
hour post-transfusion 
Safety Endpoints 
1.   Treatment-emergent adverse events (TEAEs) 
2. Transfusion-related adverse events (AEs) 
3. Serious adverse events (SAEs) 
4. Unanticipated adverse device effects (UADEs) 
5. Pulmonary events 
a. Subjects on assisted ventilation 
6. All-cause mortality 
7. Death due to bleeding as the primary or contributory cause of mortality 
 

 
 
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6.3.3. Sample Size 
A total of approximately 558 mITT subjects will be randomized in a 1:1 fashion to 
MIRASOL:CONTROL. This sample size estimate accounts for 10% of subjects who are randomized but 
will never receive an on-study transfusion and thus, will not be included in the mITT analysis set and, 
therefore, the primary analysis. A total of 558 mITT subjects in MIRASOL versus CONTROL will 
provide approximately 85% power for establishing non-inferiority at the 1-tailed 0.025 level of 
significance (using a 2-sided 95% CI) accommodating a 10% relative increase in the mean rate of WHO 
grade 2 or higher bleeding (i.e. µT / µC = 1.1). 
7. 
Database Description 
A comprehensive database description can be found by referencing the Terumo BCT CTS-5030 Data 
Management Plan (DMP). Two data sources will be used for study analysis, a clinical study database and 
a central laboratory database.  
The clinical study database will be populated by an Electronic Data Capture (EDC) system which is 
developed and hosted by IBM Clinical Development using the 
 software platform. Data 
integrity will be maintained by conducting both internal and external data checks as described in the 
DMP. The clinical database will be used to create tables, figures, and listings (TFLs) for both the interim 
and final analyses. 
Additionally, HLA antibody results are maintained exclusively by BSRI. Blood System Research Institute 
will be responsible for analyzing all data related to HLA and alloimmunization. Details of this analysis 
are provided in Appendix II of this SAP. 
7.1. Creating Analysis Data Sets 
To enable analysis of study data, it will be necessary to derive analysis datasets from raw variables in the 
clinical study database. All data and processing will be completed using SAS® version 9.4 or higher. 
7.2. Validation of Data and Analysis Programs 
All programs created by CPC to create analysis datasets, produce TFLs, or to perform statistical analysis 
will be generated according to CPC SOP-BDM-C-002: Developing Data Analysis Programs. 
Additionally, all datasets, output, and statistical analysis produced by CPC will be validated according to 
CPC SOP-BDM-C-003: Statistical Validation. 
7.3. Archiving Data and SAS® Files 
Following database lock, the SAS® programs used to analyze data for the final CIR will be executed and 
archived according to CPC SOP-BDM-C-002: Developing Data Analysis Programs. 
The final analyses will be conducted on locked clinical study data using SAS® version 9.4 or higher. 
Unless specified otherwise, all analyses related to the primary, secondary and exploratory endpoints will 
involve the direct comparison of the MIRASOL and CONTROL arms.  
To ensure integrity and internal consistency of all data points used for the IA, the biostatistics group will 
define data elements needed for the IA and work with the clinical data manager to determine which 
electronic case report forms (eCRFs) need to be cleaned. The identified data elements and timing of the 
IA will then be communicated to the appropriate study team members to facilitate timely collection and 
cleaning in preparation for the IA. All efforts will be made to fully monitor and resolve critical queries on 
the IA data elements. At the time of the data cut for the IA, all data in the clinical database will be used. 
As this is an ongoing study, outstanding queries may remain, and/or some data entered at the time of the 
data cut may not have been monitored. 

 
 
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7.4. Analysis Conventions 
The following general conventions will be used for conducting all statistical analyses, where, departures 
from these conventions are defined in a more precise manner in specific sections of this SAP. In these 
instances, rules established in the specific sections take precedence over the general convention. 
 
Formal hypothesis testing will be performed on the primary outcome using a closed testing procedure 
with a first test of non-inferiority followed by a test of superiority if non-inferiority is demonstrated. 
 
Key secondary and secondary efficacy outcomes will be tested but viewed as supportive and 
exploratory. 
 
The distribution of continuous variables will be summarized using means, standard deviations (SD) 
and/or standard errors, medians, minimums (or 25th percentile), and maximums (or 75th percentile) 
and the number of subjects with non-missing data. 
 
Mean/median/quartiles are presented to one decimal more than the measured value.  
Minimum/Maximum are reported to the same number of decimals as the measured value. Standard 
deviation is presented to two decimals more than the measured value. 
 
Summary of discrete variables will consist of the number and percent of responses in each category. 
All percentages will be rounded to one decimal place. The count and percentage of responses will be 
presented in the form of 
 (XX.X%
 where the percentage is in parentheses. If the count is 
 
then the percentage may not be presented to draw attention to the non-zero count cells. If zero 
percentages are displayed these will be shown as 
 If the percentage is 
 the decimal 
place may be dropped. In addition, the decimal place may also be dropped due to space constraints 
within a table where this does not impact the interpretation of results. 
 
All Medical History and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 19.1. 
 
All medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHO DDE) version dated 01Sep2016. 
 
Uncoded AE terms will be included with a System Organ Class (SOC) and Preferred Term (PT) of 
  
 
Leading zeros will be used for decimal values less than one. For example, 
 will be used rather 
than 
 
 
All tables will clearly indicate the sample sizes contributing to the summary data in the column 
heading and labeled as Treatment 
 For example, if a table reports data for the Full Analysis 
Set (FAS) population, N would represent all subjects in the FAS. If a table reports data for the Safety 
Set (SS), N would represent all subjects in the SS. Within the table the small 
 will represent the 
number of subjects within the population of interest who have non-missing data or data otherwise 
available for the summary measures of interest (i.e. the denominator for a subset of the overall 
population being presented in the summary). If no data are available for a TFL, the output will be 
produced with 
 data to 
 Footnotes which are data driven may be applied to the TFLs as 
needed. These changes will not necessarily be made to the mock TFLs. 
 
Percentages are calculated out of the header N unless otherwise footnoted. 
 
Duration of periods of time will be calculated in days as (stop date  start date + 1) in order to include 
both the starting day and final day of the periods of time. Conversions to weeks, months, or years will 
be calculated as days/7, days/30.4375, or days/365.25, respectively. 
 
In general, missing values will be handled as follows: for continuous variables at baseline, missing 
values will be excluded from calculation of summary statistics and the n of subjects reporting will be 
reported. For categorical values at baseline, the number and percent of subjects with missing values 
will be displayed. Handling of missing postbaseline values will depend on the analysis. 

 
 
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7.4.1. Dropouts and Missing Data 
Handling of subject dropouts and other forms of missing data with regard to the primary endpoint will be 
discussed in Section 8.1. Handling of subject dropouts and other forms of missing data with regard to key 
secondary endpoints is the responsibility of BSRI. No imputation of missing data will be applied to 
secondary, exploratory or safety endpoints unless otherwise specified. 
7.4.2. Adjustments for Covariates 
Covariate adjustment will be utilized in both supporting and subgroup analysis of the primary endpoint 
and is discussed in Section 8. 
7.4.3. Multi-center studies 
Data from each of the study sites will be pooled for summarization and analysis unless otherwise 
specified. 
7.4.4. Multiplicity Issues 
As described in FDA s Guidance for Industry: Non-inferiority Clinical Trials, testing for superiority after 
successfully establishing non-inferiority is possible so long as Type I error control is maintained. For this 
study, a sequential testing strategy will be employed, whereby if the primary endpoint is positive in the 
sense that non-inferiority is concluded, a test for superiority will be performed for the primary endpoint 
with the same one-sided type I error rate. 
No adjustments for multiple comparisons/testing will be performed for the key secondary, secondary or 
exploratory endpoints. 
7.5. Analysis Populations 
The study analysis populations (sets) are defined in Sections 7.5.1 thru 7.5.4. 
7.5.1. Full Analysis Set  
The FAS is defined as containing all randomized subjects, wherein subjects will be analyzed based on 
their assigned treatment group (MIRASOL or CONTROL) at the time of randomization.  
7.5.2. Modified Intent-to-Treat Analysis Set 
The mITT analysis set is defined as containing all randomized subjects who undergo at least one (1) study 
transfusion post-randomization based on the treatment group to which they were randomized. Subjects 
will be analyzed according to the treatment group (MIRASOL or CONTROL) they were assigned at 
randomization. 
7.5.3. Safety Set 
The SS is defined as containing all subjects who have been randomized and undergo at least one (1) PLT 
transfusion post-randomization, independent of the outcome or successful completion of the procedure. 
Subjects will be analyzed according to the majority treatment (transfusion type: MIRASOL or 
CONTROL) received. If there is a tie, i.e. no majority treatment exits, then the subject will be classified 
into the treatment group to which they were randomized.  
7.5.4. Per Protocol Set 
The Per Protocol Set (PPS) is defined as containing all randomized subjects who undergo at least 75% of 
post-randomization PLT transfusions as per the protocol treatment allocation and have not experienced 
any major protocol deviations (as described in Section 7.12). For instance, if a subject is randomized to 

 
 
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the MIRASOL arm and has 4 transfusions, 3 of those transfusions must contain MIR-treated Aph PLTs if 
the subject is to be included in the PPS. Similarly, if the subject had 3 transfusions, all 3 transfusions must 
contain MIR-treated Aph PLTs if the subject is to be included in the PPS. Subjects eligible for the PPS 
will be analyzed according to the treatment group to which they were assigned at randomization.  
7.6. Definition of Baseline Value 
Baseline is defined as the data point collected the closest, but prior to, the date and time when the first 
study transfusion is administered. In cases where the date is the same and the times are unknown, 
assessments taken on the same day are considered baseline. 
7.7. Calculation of Study Day and Treatment Period 
The day the subject receives their first post-randomization PLT transfusion will be considered Day 0. If 
the subj
 PLT transfusion episode spans two calendar days, the day the transfusion started will be 
considered Day 0. 
The treatment period is defined as the period of time from Day 0 through Day 27 or to the day of 
transfusion independence, defined as the last of ten (10) successive days after the last PLT transfusion 
(on- or off-protocol), whichever occurs first. Bleeding assessments are conducted at baseline and are to be 
conducted every day from Day 0 until the post-transfusion follow-up visit or early termination visit.  
7.8. Definition of Visit or Windows 
Visit labels, as collected in the database, will be used and no visit windows will be calculated. 
7.9. Display of Treatment Groups 
Unless specified otherwise, data will be summarized by study arm (MIRASOL vs CONTROL).  
Treatment groups (arms) will be displayed as follows with respect to labels and ordering.  Total columns 
may be provided for baseline assessments. 
 
Groups
Definition
MIRASOL 
Mirasol PLTs (MIR PLTs): LR-Trima Accel® Aph-pathogen 
reduced (PR)-plasma PLT 
CONTROL
Reference PLTs (REF PLTs): LR-Aph-plasma PLT 
 
7.10. Subject Demographics and Baseline Characteristics 
Subject demographics including date of birth, age (years) at informed consent, age group (Age <18, Age 
18-65, Age > 65), sex, ethnicity (Hispanic and non-Hispanic), race (American Indian or Alaska Native, 
Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, Other, and 
Multiple), height, weight, and body surface area (BSA) will be listed by subject and summarized. 
Childbearing potential/pregnancy information for females will be listed. Age will be calculated as a 
continuous variable, where, the calculated value will be used in creating the different age groups. All 
demographic and baseline characteristics will be listed, and summaries will be generated using the mITT 
set and the SS. Summary tables will be presented by treatment group.  

 
 
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7.11. Concomitant Medication, Medical History and other Baseline Data 
Concomitant medications will be listed and summarized. 
Diagnosis and treatment including treatment type strata of allogeneic transplant, autologous transplant, 
and chemotherapy will be listed and summarized. 
Medical and surgical history and history of transfusions will be listed by subject.  
Blood type (ABO), ABO incompatibility and Rhesus factor (Rh) will be listed by subject. 
7.12. Protocol Deviations 
Subjects who are randomized into the study but who do not meet all major inclusion/exclusion criteria 
will be considered as having major protocol deviations. All protocol deviations reported by hospital study 
sites will be summarized by deviation type (major/minor) the for the FAS population.  All protocol 
deviations reported by hospital study sites including non-compliant transfusions and protocol deviations 
reported by blood centers will be listed for all screened subjects. Protocol deviations due to the COVID-
19 pandemic can be identified through the standard text of 
 to COVID-
 in the text of the 
deviation. A Blinded Data Review Committee (BDRC) will be formed and will review and classify 
possible protocol deviations for all subjects in the FAS as major or minor in a blinded fashion according 
to the BDRC Charter.  
International Standard for the Transfer of Information Associated with Tissue Transplantation, Cellular 
Therapy and Blood Transfusion (ISBT) codes and corresponding definitions provided by the sponsor will 
be used in a read only manner to identify whether or not a platelet product meets the criteria either for the 
CONTROL group or the MIRASOL group transfusion per the CIP 
Non-Compliant Transfusions are platelet transfusions that do not meet the platelet product requirements 
of the CIP. For subjects randomized to MIR treatment, ISBT codes categorized as anything other than 
 or 
 
 meet this criterion. For subjects randomized to Reference (REF), ISBT 
codes categorized as anything other than 
 
 meet this criterion. Non-compliant 
transfusions are protocol deviations, but they cannot be reported as protocol deviations in the database 
because that would potentially unblind users of the database. Instead, non-compliant transfusions are 
identified through ISBT codes and will be summarized and listed as separate protocol deviations. 
7.13. Treatment Exposure 
Exposure to platelet transfusions will be conducted on the mITT set and the SS by reason for transfusion.  
One or multiple study platelet transfusions can occur anytime from Study Day 0 to Study Day 27 per 
subject. If a subject received a platelet unit within four (4) hours of completion of transfusion of the 
preceding platelet unit, these transfusions will be considered part of a single platelet transfusion episode 
in analyses. 
Additional blood products transfused will be analyzed based on the SS. The number of blood products 
transfused (other than PTLs), type of blood product transfused, and for RBC transfusions, whether the 
RBCs were leukocyte-reduced, will be summarized. 
7.14. On- Off-Protocol Transfusions 
On- and Off-Protocol Transfusion definitions are as follows: 
Off-Protocol Transfusion: any kind of PLT transfusion, other than those to which the subject was 
randomized (MIR PLTs or REF PLTs), regardless of the reason for the transfusion. For subjects 

 
 
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randomized to MIR treatment (MIRASOL), ISBT codes defined by the sponsor as 
 
 or 
 NOT 
 meet this criterion. For subjects randomized to CONTROL, ISBT codes defined 
by the sponsor as 
 or 
 Not 
 meet this criterion. 
On-Protocol Transfusion: non-MIR or MIR treated platelet product transfused according to randomization 
assignment. For subjects randomized to MIR treatment (MIRASOL), ISBT codes defined by the sponsor 
as 
 or 
 Not 
 meet this criterion. For subjects randomized to CONTROL, 
ISBT codes defined by the sponsor as 
 
 or 
 NOT 
 meet this criterion. 
On- and off-protocol platelet transfusions will be reported on the SS and summarized by treatment group 
and reason for transfusion, i.e. prophylactic, therapeutic (bleeding event), and other. The total number of 
platelet transfusions and the number of transfusions on- and off-protocol will be reported. The mean, 
median, minimum and maximum number of transfusions per subject will be reported. The number and 
percent of subjects with at least 1 on-protocol transfusion will be reported along with the median, 
minimum, and maximum duration of the transfusion period in days. The number and percent of subjects 
who had at least 75% of transfusions on-protocol (part of the PPS definition) will also be reported. 
Each 
 transfusion will be listed along with on- or off-protocol and non-compliance status 
described in Section 7.12. 
7.15. Subject Disposition 
Subject disposition will be listed and summarized. The number of subjects screened, number of subjects 
in the FAS, mITT set, PPS and SS, the 
 final study status, and the number of subjects terminating 
the study early with reasons for early termination will be summarized for all subjects.  
 
Subjects with Inclusion/Exclusion criteria deviations will be listed by subject. 
8. 
Efficacy Analysis 
A single primary efficacy endpoint will be considered and investigated using a NI design. The primary 
efficacy endpoint is defined as the number of days on which bleeding was assessed and WHO grade 2 or 
higher bleeding was evident over the treatment period. The maximum number of days with bleeding 
assessments will be twenty-eight (28) as this is the duration of the treatment period. Bleeding events are 
defined using criteria according to the WHO Grading Scale for Bleeding. Appendix I contains the WHO 
Grading Scale for Bleeding annotated with the 
 Bleeding Assessment (MIPLATE Annotated 
eCRFs) variable identifiers (Bx) and answers that correspond to the bleeding status. Subgroup analyses 
involving the primary efficacy endpoint will also be conducted. 
8.1. Primary Endpoint 
Bleeding assessments based on the WHO Grading Scale for Bleeding will be conducted at baseline to 
assess eligibility prior to randomization, as well as daily starting on Day 0 and continuing to the post-
transfusion bleeding assessment OR until transfusion independence (the last day of ten [10] consecutive 
days without a PLT transfusion). Each bleeding assessment will document the WHO Bleeding Scale 
components observed over the course of the prior calendar day, from 00:00 to 23:59. As such, the analysis 
of the Primary Endpoint, and Secondary Endpoint #2, will be based on bleeding assessments collected on 
Day 1 thru Day 28 which represent bleeds which occurred on Days 0-27.  
The total number of days with WHO grade 2 or higher bleeding is obtained by counting the total number 
of calendar days (00:00 to 23:59) on which bleeding was assessed and found to be present. For example, 
if a subject has WHO grade 2 bleeding on Day 1, grade 2 bleeding on Day 2, and grade 3 bleeding on Day 
3, this is considered 3 days of grade 2 or higher bleeding. Hematomas (bruises), petechiae, and purpura 

 
 
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(e.g., types of bleeding that occur under the skin) represent unique cases in which they are only counted 
as additional days of bleeding if they are new or manifest in another anatomical location. 
8.1.1. Primary Analysis 
The MIRASOL vs CONTROL group will be compared with respect to the number of days of WHO grade 
2 or higher bleeding. This will be carried out by fitting a negative binomial regression model with an 
offset defined as the natural logarithm (ln) of the number of days that bleeding was assessed in order to 
account for the fact that subjects may have different numbers of bleeding assessment days. As an 
example, if a subject had bleeding assessed on only 10 of 28 days, an 
 of ln(10) bleeding 
assessment days is incorporated into the linear predictor of the model. Similarly, if bleeding is assessed 
on each of the full 28 days of the planned treatment period, an offset of ln(28) bleeding assessment days is 
incorporated. Adjustment using this offset will ensure that bleeding rates are calculated and compared 
between treatment groups and that the variable number of days with bleeding assessments across 
individuals is appropriately dealt with. Subjects who obtain transfusion independence prior to Day 28 will 
be assumed to have zero bleeding days between the date of transfusion independence and Day 27 and 
treated as if they had bleeding assessed on each of those days; these days will therefore contribute to the 
total number of bleeding assessment days used to calculate the offset. Subjects who drop-out of the study 
before Day 28 for reasons other than transfusion independence will contribute bleeding data for each of 
the days bleeding was assessed prior to the time of drop-out; bleeding status will not be simulated beyond 
the time of drop-out since the use of an appropriately computed offset deals with the variable duration of 
follow-up.   
The handling of data following the administration of an off-protocol transfusion requires discussion. Here 
an off-protocol transfusion is defined as the transfusion of any kind of PLT product that differs from that 
to which the subject was randomized (i.e. MIRASOL or CONTROL). 
The timeline diagram provided below demonstrates the definition of an off-protocol window, which we 
sometimes refer to as an off-protocol interval of time. Consider an individual who was recruited and 
received on-protocol transfusions as needed from day 0 to day n-1. On Day n they received an off-
protocol transfusion and on Day m they received their first subsequent on-protocol transfusion; no off-
protocol transfusions were received beyond Day m. In order to avoid attributing bleeding outcomes to the 
randomized treatment arm when an off-protocol product is delivered we partition the full treatment period 
as follows. We define the intervals from day 0 to n-1 and m to Day 27 as on-protocol intervals, and days 
n to m-1 as an off-protocol interval. In the figure below bleeds are represented by red lines on Days 1-2 
and on Day 26 for illustration.  
 
 
To mitigate against the effect of the off-protocol transfusions in the primary endpoint analysis, bleeding 
data will be simulated for the off-protocol windows (e.g. intervals such as [n, m-1] above) using an 

 
 
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individual-specific bleeding rate estimated as follows. If individual i has any off-protocol intervals of 
time, then an individual-specific bleeding rate will be computed as rion=Bion/Nion where Bion is the number 
of on-protocol days during which this individual experienced, and had documented, at least WHO grade 2 
or higher bleeding. Nion is the number of days on which bleeding was assessed during the on-protocol 
intervals for this subject. Then a) the number of days bleeding was assessed during the off-protocol 
interval will be computed (Nioff) and b) the number of these days during which WHO  2 grade bleeding is 
present will be simulated (Bsoff) based on a right-truncated Poisson distribution using the individualized 
bleeding rate (rion).  The right-truncation limit will be the total number of off-protocol days (Nioff) since 
there cannot be more bleedings days than there are days at risk. Specifically, for each individual, counts 
will be simulated from a Poission distribution using rion x Nioff as the mean.  A simple rejection sampling 
technique [1] will be used to sample from the right-truncation distribution whereby all values generated 
which exceed the right truncation limit will be ignored until one is generated that satisfies the right 
truncation condition. This value will be labelled Bioff. Then the total Bion + Bioff will be taken as the number 
of bleeds for that individual experienced over Nion+Nioff days of assessments; then ln(Nion+Nioff) will be 
used as the offset.  
If the bleeding rate estimated based on available data rion = 0 then there will be no bleeding days 
simulated for the off-protocol days (Bioff=0) and the offset will still be calculated as ln(Nion+Nioff).  Note 
that for individuals whose last transfusion is off-protocol, at most 10 days of bleeding data after the last 
transfusion will be simulated as patients going ten (10) days without a transfusion will have acquired 
transfusion independence.  
On occasions where a subject receives a mix of off-protocol and on-protocol units on the same day, they 
will be considered in an on-protocol period on that day. Transfusions can last more than one calendar day.  
The daily on- and off-protocol statuses will be assigned for the day the transfusion(s) starts. For subjects 
whose last transfusion is off-protocol, bleeding will be simulated until the subject completes the 
transfusion period or reaches transfusion independence. If the subject achieves transfusion independence 
prior to completing the transfusion period, the rules for transfusion independence will take over and 
subjects will be assumed to have zero bleeds and full follow-up from the day of transfusion independence 
until Day 27 inclusive (i.e. the remainder of the transfusion period). 
Unless otherwise stated any subsequent analysis herein referring to the primary endpoint method will 
include the individualized simulated bleeding data for the off-protocol periods of time.  This simulation 
will be done twice.  Once at the IA and once at the final analysis.  The set of simulations done for the 
primary efficacy analysis will be used for all subsequent analyses wherein off-protocol intervals are called 
to use simulated bleeding data. 
8.1.2. Secondary Analyses 
First Secondary Analysis:  Off-Protocol Intervals Included with No Adjustments 
In a secondary analysis of the primary outcome all available bleeding assessment data, whether collected 
on- or off-protocol, will be used and attributed to the randomized treatment in the spirit of an intention to 
treat analysis. No imputation will be carried out for bleeding status on days following drop-out as the 
offset deals with censoring and the resulting variation in the days at risk.  
Second Secondary Analysis: Off-Protocol Intervals Excluded 
In another secondary analysis of the primary outcome, bleeding data will be excluded during off-protocol 
intervals and the offset will be computed based on the number of on-protocol days which bleeding was 
assessed for the negative-binomial model.  Subjects who obtain transfusion independence while on-
protocol will be assumed to experience no further WHO grade 2 or higher bleeding and treated as if they 

 
 
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had bleeding assessed on each of those days.  No bleeding data will be imputed following dropout if it 
occurs and the offset will accommodate different durations of time at risk. 
First Sensitivity Analysis: Imputing Bleeding Status for Missing Data 
In the analyses discussed to this point, on-protocol days without bleeding data recorded are not counted in 
the total number of days at risk. An additional sensitivity analysis will be carried out using a negative 
binomial model for imputing bleeding status on the on-protocol days when bleeding data is missing [2]. 
First, off-protocol periods of time will use the simulated bleeding rate simulated for the primary analysis 
in Section 8.1.1. Then the imputation for missing bleeding assessment days will be carried out by fitting 
an auxiliary negative binomial imputation model to the available data including these covariates: age, sex, 
treatment arm, treatment type strata, and pre-treatment platelet count.  The imputation model will be run 
fifty (50) times and PROC MIANALYZE will be used to adjust variance estimates for multiply imputed 
data. 
Second Sensitivity Analysis: Poisson Model with Robust Variance 
In addition to fitting a negative binomial model to the data from completed and simulated observations, a 
Poisson model with robust variance estimation will be fit as a sensitivity analysis to the primary analysis. 
8.1.3. Assessment of Non-Inferiority and Superiority 
An NI analysis will be carried out to assess the primary efficacy endpoint with the null hypothesis being 
the MIRASOL arm is inferior to the CONTROL arm and the alternative hypothesis being the MIRASOL 
arm is non-inferior to the CONTROL arm. The null (
and alternative (
) hypotheses are defined as: 
 
  and  
 respectively 
 
where 
 is the mean rate of the MIRASOL group, 
 is the mean rate of the CONTROL group, and,  is 
the NI margin. To facilitate analysis, the null and alternative hypotheses are expressed on the natural 
logarithmic scale and take on the following forms. 
 
  and  
 
 
Specifically, a 95% confidence interval (CI) will be created about the point estimate (equivalent to a one-
sided CI with an alpha level of 0.025) to test the null hypothesis, where the point estimate is defined 
as
. This parameter estimate will be obtained by fitting a negative binomial regression 
model with a natural log link, the response being the total number of WHO  2 grade bleeding days, a 
single treatment covariate which is 1 for individuals assigned to the MIRASOL product and 0 for those 
assigned the CONTROL, and with an offset of the ln(number the number of days bleeding was assessed). 
If the upper bound of the 95% CI is less than
, then, NI of the MIRASOL arm relative to the 
CONTROL arm is inferred. Conversely, if the upper bound of the 95% CI is greater than or equal to 
, NI is not demonstrated. In this study, the NI margin is 1.6. Justification of the value of 1.6 for the 
NI margin is provided in the CIP.        

 
 
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If NI is demonstrated, superiority of the MIRASOL arm versus the CONTROL arm will be examined. 
Superiority of the MIRASOL arm compared to the CONTROL arm will be demonstrated if the upper 
bound of the 95% CI is less than zero (ln(1)=0). 
Results of the primary analysis will be displayed by treatment group and will include the average number 
of grade 2 or higher bleeds (including minimum and maximum), the average duration of on-protocol days 
or days of transfusion dependence (including minimum and maximum), the estimate of the mean rate, the 
natural logarithm of the estimate of the mean rate and the corresponding 95% CIs. The value of the point 
estimate, i.e. 
, and its corresponding 95% CI will also be displayed. 
An NI analysis will also be carried out to assess the secondary efficacy endpoint of proportion of subjects 
with  grade 2 bleeding (Section 8.2.2 below). We let pt and pc represent the probability of a patient 
experiencing WHO >= grade 2 or higher bleeding in the MIR or CONTROL arm, respectively. With an 
NI margin of 1.2, the null hypothesis is H0: pt/pc > 1.2 (MIR has more than a 20% higher probability of a 
patient experiencing at least one WHO  grade 2 bleed compared to CONTROL). The alternative 
hypothesis is HA: pt/pc  1.2 (MIR has no more than a 20% higher relative bleeding rate compared to 
CONTROL).  The risk difference will be calculated using the Wald Test. 
8.1.4. Supporting Analyses 
First Supporting Analysis: Study Site and Type of Treatment Included as Covariates  
Supporting analysis will be conducted with regard to the Primary Efficacy Endpoint although no 
statistical inferences will be made regarding these analyses, i.e. p-values calculated will be considered 
descriptive only. A supporting analysis will be conducted by including the study site and type of 
treatment (allogeneic transplant vs autologous transplant vs chemotherapy) variables in the model. 
Treatment group by site and type of treatment interactions will be reported where other interaction terms 
may also be considered. To facilitate interpretation, exponentiated results will be provided.  
Second Supporting Analysis:  Analysis of Per Protocol Population  
Additionally, in a supporting sensitivity analysis, a repeat of the process used to analyze the Primary 
Endpoint will be conducted based on the PPS.  
Third Supporting Analysis:  Analysis excluding data from a single site 
In another supporting sensitivity analysis, data from 
 Hopkins University will be excluded to assess 
the impact of data from this site. This sensitivity analysis of the primary endpoint is to assess the impact 
of data from this site due to non-compliance findings that have been audited and resolved.   
8.1.5. Subgroup Analyses 
After all primary, secondary, and supporting analyses are completed; a subgroup analysis of the primary 
endpoint will be conducted. All subgroup analyses will follow approaches for handling off-protocol 
intervals performed on the first analysis of the primary endpoint and described in Section 8.1.1. The 
following analyses, however, will include an interaction term between subgroup and treatment.  The 
interaction p-value will be presented for each subgroup in summary table.  The full model will be 
summarized for interactions significant at the 0.05 alpha level. 
1. Age <18, 18-65, and >65 years) 
2. Sex (Male/Female) 
3. Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Other, and Multiple). 
4. Ethnicity (Hispanic and non-Hispanic) 

 
 
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NOTE:  Groups may be collapsed if an individual group represents <10% of the study population.  
8.2. Secondary Endpoints 
8.2.1. Key Secondary Endpoint 
The Key Secondary Endpoint of HLA alloimmunization will be compared between the two groups using 
 exact test with a 2-sided test at the 0.05 level of significance. Blood System Research Institute 
will assume all analytic responsibilities of the Key Secondary Efficacy Endpoint for safety, interim and 
final analysis and details of this analysis are provided in Appendix II generated by BSRI. 
8.2.2. Additional Secondary Endpoints 
The additional secondary study endpoints and their corresponding analyses are discussed in detail below. 
All Secondary Endpoints will be compared based on study arm, (MIRASOL vs CONTROL), using the 
mITT set. Each of the ten additional Secondary Endpoints, as well as their respective analytic approaches 
is discussed as follows: 
1. Proportion of subjects with  grade 2 bleeding. 
For each study arm, the proportion of subjects with at least 1 day of grade 2 or higher bleeding Day 0 
through Day 27 (or until transfusion independence is achieved) will be calculated, where, pt  denotes the 
proportion of the MIRASOL group and pc denotes the proportion for the CONTROL group. pt and pc will 
be calculated using the equations below: 
 
 
The difference between the MIRASOL and CONTROL arms (
- 
) will be reported along with the 
95% CI about this difference. The 95% CI and the corresponding p-value will be generated using 
 
exact test to test the superiority null hypothesis of pt/pc=1. Negative values of the reported difference 
favor the MIRASOL group. 
2. Time to first grade 2 or higher bleed 
The time to first grade 2 or higher bleeding will be analyzed using a log rank test comparing survival 
curves stratified by treatment group. The timeframe under consideration is defined from the day of the 
 first post randomization PLT transfusion to the day the subject experiences their first grade 2 or 
higher bleed. Subjects that do not experience a grade 2 or higher bleed will be censored at Day 27 or at 
date of transfusion independence (10th day without a PLT transfusion prior last follow-up day or Day 27 
whichever is earlier), where appropriate. Subjects that do not complete the study or are lost to follow-up 
will be censored on the date of their last study visit in the treatment period. A Kaplan-Meier (KM) plot 
contrasting the two study arms will also be generated to provide a visual representation of probability of 
remaining free of a WHO grade 2 or higher bleed as a function of time since first post-randomization 
transfusion. 
3. Proportion of subjects with  grade 3 bleeding 

 
 
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This analysis will be identical to that conducted for Secondary Endpoint number 1 except proportions for 
each study arm will be calculated based on the number of subjects with grade 3 or higher bleeding. 
4. Proportion of subjects with PLT refractoriness defined as 2 sequential transfusion episodes, 
each with CCIs < 5000 measured 1 hour post-transfusion.  
PLT refractoriness is defined as 2 sequential transfusion episodes with CCIs < 5000 measured 1 hour 
post-transfusion for the transfusion episode. The count increment (CI) is calculated as follows: CI =(Post-
transfusion[1 hour] PLT (PLTs/µL)  Pre-transfusion PLT (PLTs/µL)).  
Typically, the platelet count is expressed in platelets/µl. 
The CCI is calculated using the following equation considering a single transfusion episode at a time: 
 
CCI =(Post-transfusion[1 hour] PLT (PLTs/µL)  Pre-transfusion PLT (PLTs/µL)) × BSA (m2) 
Number of PLTs in component (PLTs) (× 1011) 
 
where, BSA (m2) = 0.007184 × Height (cm)0.725× Weight (kg)0.425 
 
where, Number of PLTs in component (PLTs)(x1011)=Platelet yield 
 
and where, Platelet yield = [Platelet Concentration (106/µL) x Platelet Unit Volume (mL)]/100 
If the full transfusion volume was not transfused the partial volume transfused will be use in this 
calculation.  The platelet concentration remains unchanged, regardless of volume transfused. 
The value for the number of platelets transfused (infused dose) is always expressed in multiples of 1011.   
If two successive CCIs < 5000 measures are not observed, then PLT refractoriness is not attained. Based 
on these criteria among the patients in the mITT population, the proportion of subjects who experience 
PLT refractoriness for the MIRASOL (
 and CONTROL (
 groups are defined as: 
 
 
 
The difference between the MIRASOL and CONTROL arms (
- 
) will be reported along with the 
95% CI about this difference. Negative values of the reported difference favor the MIRASOL group. A 
test of the null hypothesis that this difference is zero will be carried out by 
 exact test.  
NOTE: The pre-transfusion episode platelet count closest and prior to the transfusion episode should be 
used for all CCI calculations. The pre-transfusion episode platelet count should be collected within 24 
hours of the start of the transfusion episode to be clinically meaningful in relation to the effect of the 

 
 
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transfusion on the post-transfusion platelet count. The post transfusion platelet count to calculate the 1-
hour CCI is measured by a platelet count between 10 minutes and < 4 hours post-transfusion episode. The 
post transfusion platelet count to calculate the 24-hour CCI 
 18 but < 30 hours post-transfusion episode) 
is measured by a platelet count within the defined window post-transfusion episode.  
 
5. Immune PLT refractoriness will be subjects with PLT refractoriness as defined above and who 
also have a positive antibody test within 14 days before or after the onset of PLT refractoriness 
Blood System Research Institute will assume all analytic responsibilities for this analysis. Details are 
provided in Appendix II. 
6. Number of PLT transfusion episodes per subject, i.e., frequency of transfusion 
The analytic approach used to investigate secondary endpoint # 6 will be based on a negative binomial 
model. The total number of PLT transfusion episodes (regardless of whether or not the transfusion is 
determined to be 
-
 will be calculated for each subject, and the negative binomial model will 
include only the covariate for treatment group which will give a regression coefficient; the exponentiated 
regression coefficient is an estimate of the ratio of the transfusion rate for the treatment groups. The offset 
in the negative binomial model will be the natural log of time in days from Day 0 to transfusion 
independence, study dropout or end of the 28-day treatment period for each subject.    
7. Days of PLT support; the number of days from the first to the last PLT transfusion 
The number of days from the first to the last PLT transfusion will be analyzed using a Cox regression 
model with the treatment group serving as the lone covariate.  Subjects will be censored at Day 27 or on 
their last study visit in the treatment period.  Reported results will consist of the hazard ratio along with 
the corresponding 95% CI and p-value. A hazard ratio greater than 1 will favor the MIRASOL group 
because it will correspond to a shorter duration of platelet support. A KM plot contrasting the two study 
arms will also be generated to provide a visual representation of survival probability as a function of 
study duration.  
8. Platelet utilization rates (average number of PLTs transfused) 
The platelet utilization rate will be calculated for each individual by adding the number of platelets 
transfused (1011) during the treatment period divided by the total number of transfusion units for each 
individual. The number of PLTs transfused will be included regardless of whether or not the transfusion is 
determined to be off-protocol  
The difference between the platelet utilization rate received in the MIRASOL 
 and CONTROL 
 
groups will then be estimated as 
, and a test of equality will be carried out using a pooled t-test. A 
95% CI for 
will also be reported; negative values of 
 favor the MIRASOL group in the 
sense that it reflects a lower average number of platelets required in support of care. 
9.  CCIs at 1 hour and  18 but < 30 hours post-PLT transfusions 
A linear mixed-effect model [3] will be fitted with a single covariate indicating the randomized treatment 
assignment and a subject-level random effect introduced to model the between-subject heterogeneity and 
accommodate a within-subject dependence in CCI values. The coefficient of the binary treatment 
covariate will be estimated and a 95% confidence interval for it will be computed along with a p-value for 
the test of no effect. These results will be supplemented by an estimate of the group means based on the 
linear mixed-effect model.  

 
 
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As per the CIP, collection of subject PLT count  18 but < 30 hours post-PLT transfusion episode is not 
mandatory. As a result, there may be limited amount of data available to fit the model proposed. If the 
model will not converge due to lack of data, the CCI data will be summarized at the subject level. That is, 
if the subject has only one transfusion episode, the single CCI value will be used; and for subjects who 
have multiple transfusion episodes, the average CCI across their transfusions will be used as their subject-
specific number. These subject-specific (mean) CCI values will then be used to calculate group mean CCI 
values for both MIRASOL and CONTROL groups at both one (1) hour (measured between 
 minutes 
and <4 hours) at 24 hours (measured between 
 and < 30 hours). The mean subject-specific CCI 
estimate for each treatment group at each of these time points will be presented along with differences in 
means for the pairwise comparison (MIRASOL vs CONTROL). 
10. Total number of Red Blood Cell transfusions (number of units)/subject 
The analysis of this secondary endpoint, the total number of RBC transfusions (units), will be analyzed 
using the negative binomial regression model, mirroring the approach outlined for secondary endpoint #6. 
The only difference being that here, instead of the number of PLT transfusion episodes, the number of 
RBC transfusion units will be counted for each subject. Consequently, mean rate for the MIRASOL 
group
, and, mean rate for the CONTROL group 
 will be based on the average number of RBC 
transfusion units. The offset in the negative binomial model will be the natural log of time in days from 
Day 0 to date of their last study visit in the treatment period completed. The natural log of the mean rate 
of the MIRASOL group minus the natural log of the mean rate of the CONTROL group, i.e. 
, will be used to compare study arms. The corresponding 95% CI and p-value will be displayed 
such that negative values of difference between  
 and 
 favor the MIRASOL group by 
reflecting lower utilization.  
8.3. Exploratory Endpoints 
Four Exploratory Endpoints will be considered in this study, and, results of all analyses will be 
descriptive in nature. Each Exploratory Endpoint, as well as its corresponding analytic approach, is 
detailed below. All analyses will be based on the mITT population.  
1. Total number of units of PLTs transfused/day of PLT support 
For each subject, the number of units (a PLT unit is defined as one [1] single PLT bag) will be totaled and 
divided by that 
 number of days of PLT support. Consequently, each subject will have a value for 
the total number of PLT transfusion units started per day of PLT support. A day of PLT support is defined 
as any day in which a study PLT transfusion was started. Transfusions lasting more than twenty-four (24) 
hours will be counted as multiple days of PLT support. These values will then be averaged across subjects 
and will be displayed for each treatment group (MIRASOL vs CONTROL). 
2. Total number of PLTs (PLT dose) transfused/Body Surface Area/day of PLT support 
For each subject and transfusion episode, the PLT dose, i.e. the number of PLTs in a component (as 
defined in the denominator of the CCI equation), will be divided by the 
 baseline BSA which is 
calculated using the following equation: 
BSA (m2) = 0.007184 × Height (cm)0.725× Weight (kg)0.425 
Similar to the analysis of the First Exploratory Endpoint, this value will be divided by the number of days 
that subject received PLT support. These values will then be averaged across subjects and displayed for 
each treatment group (MIRASOL vs CONTROL). 
3. Interval between PLT transfusion episodes (days) 

 
 
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Only subjects with two or more transfusion episodes will be considered in this descriptive analysis. 
Additionally, if a subject has more than one transfusion episode in a day, this will be counted as a single 
transfusion episode for the purposes of this analysis. For each subject, the interval(s) between transfusion 
episodes will be recorded in days. If a subject has two transfusion episodes, the interval between PLT 
transfusion episodes will begin on the day after the initial transfusion episode ends and will end on the 
day prior to the start of the subsequent transfusion episode. For instance, if a subject has a transfusion 
episode on study Day 5, and then another transfusion episode on study Day 6, the interval is zero days. 
Likewise, if a subject has a transfusion episode on study Day 5, and then another transfusion episode on 
study Day 7, the interval will be 1 day. If a subject has three transfusion episodes, the two intervals 
between the three transfusion episodes will be determined using the same process described for a subject 
with two transfusion episodes, and the average length of the two intervals will then be calculated, i.e. 
(length of interval 1 + length of interval 2)/2. This average will be used in calculating the overall average. 
This pattern will be repeated for subjects with four transfusion episodes where the three intervals will be 
averaged, and so on for individuals with greater numbers of transfusions. The overall average number of 
days between PLT transfusion episodes will be summarized by averaging these subject-specific averages 
overall and for each treatment type (strata) by treatment group (MIRASOL vs CONTROL).  
4. Platelet refractoriness defined as 2 sequential transfusion episodes, each with CCIs < 7500 
measured 1 hour post-transfusion 
This analysis will mirror the analysis performed on Secondary Endpoint # 4. The only difference being, 
PLT refractoriness is defined as 2 sequential transfusion episodes each with CCIs < 7500 measured 1-
hour post-transfusion. 
8.4. Safety Endpoints 
All Safety Endpoints will be analyzed using the SS. Safety will be evaluated by assessment of physical 
examinations, vital signs, clinical laboratory values, and TEAEs. 
8.4.1. Physical Examinations 
Physical examinations are conducted at baseline and will be listed along with Medical and Surgical 
History. Results from physical examinations conducted through the course of bleeding assessments are 
reported as a part of the bleeding outcome. 
8.4.2. Vital signs 
Available data on vital signs (e.g., temperature [F ]), heart rate [HR] [beats/min], respiratory rate 
[breaths/min], systolic blood pressure (BP) (mmHg), diastolic BP [mmHg], SpO2 [%], and position 
[sitting, standing, supine]) will be reported utilizing appropriate thresholds by age group for each of the 
pre-, during, post- timeframes for each 
 transfusion. Data will be listed by treatment group and 
subject. See the CIP for information on the collection of vital signs. 
8.4.3. Clinical Laboratory Values 
All laboratory values will be reported in International System of Units. 
Hematology is collected at baseline, Day 0 and daily when hospitalized and for clinical visits days. 
Hematology results include white blood cells (103/µL), RBCs (106/µL), hemoglobin (g/dL), hematocrit 
(%), and platelets (103/µL), and will be summarized by study day. Hematology data will be listed by 
treatment group and subject.  Neutrophils and lymphocytes will only be included in the listing. 
Coagulation laboratory tests (prothrombin time (seconds), International Normalized Ratio (INR), 
Activated Partial Thromboplastin time (aPTT) (seconds), and fibrinogen (mg/L)) are collected at baseline 

 
 
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and, if available, as part of routine care in follow-up. These labs will be summarized by study day. 
Coagulation laboratory tests will be listed by treatment group and subject. 
Screening and Post-transfusion period Follow-up/Early Termination Cytomegolovirus (CMV) testing will 
be performed using an Immunoglobulin G (IgG) test. The results will be listed and summarized by study 
day. 
8.4.4. Treatment Emergent Adverse Events 
 
The following will be displayed.  
 
 
Overall TEAEs 
 
Platelet Transfusion Related TEAEs 
 
Medical Device Related TEAEs 
 
TEAEs by maximum severity 
 
SAEs 
 
UADEs 
 
Pulmonary events 
o Subjects on assisted ventilation 
 
TEAEs causing discontinuation from the study 
 
All-cause mortality 
 
Death due to bleeding as the primary or contributory cause of mortality 
 
All TEAEs/SAEs identified during the reporting period (i.e. from initial post randomization platelet 
transfusion through seventy-two (72) hours following the transfusion end time of the last on-protocol PLT 
transfusion; for deaths including deaths due to bleeding through thirty (30) days following the transfusion 
end time of the last on-protocol PLT transfusion) will be followed until resolution, stabilization, or the 
end of 
 study participation, whichever is first. 
Treatment Emergent Adverse Events are defined as those that occur during or following the first post-
randomization PLT transfusion. The AE start date and time and transfusion start date and time of the first 
study transfusion will be used to identify TEAEs. The transfusion end time of the 
 final study 
transfusion will be used to identify the end of the 72-hour reporting period (or 30 days for deaths). AEs 
with missing/impartial start date and or time will be considered to be treatment emergent. 
Treatment Emergent Serious Adverse Events (TESAEs) are defined as TEAEs marked serious by the 
investigator. Transfusion-related TEAEs are described through the reporting of TEAEs identified as 
related to the study treatment or those related to the medical device.  
Unanticipated Adverse Device Effects are any serious adverse effect on health or safety or any life 
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the investigational plan or 
application, or any other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects 
Unanticipated Adverse Device Effects will be identified as treatment emergent adverse events reported by 
the investigator as serious, unanticipated, at least possibly related to study device or at least possibly 
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Medical Dictionary for Regulatory Activities preferred terms in the associated SOC and Standard Medical 
Queries (SMQs) will be used to categorize TEAEs of 
 
 and additionally those 
pulmonary events requiring assisted ventilation as defined by the investigator.   
Subject related TEAE counts will be summarized using frequencies and percentages. A subject will only 
be counted once per category of summarization (i.e. if a subject has multiple TEAEs, the subject will only 
be counted once in the overall 
 
 row but will be counted in each row for specific TEAEs). 
Event counts will be summarized using frequencies of events by treatment group. 
A summary of TEAEs will be generated summarizing the number of TEAEs, TESAEs, unanticipated 
TESAEs, and UADEs. The number and percent of subjects with at least one TEAE, TESAE, TEAE 
related to study treatment, TEAE related to medical device(s), and TEAEs of pulmonary events and 
additionally those requiring assisted ventilation will also be included. The number of TEAEs by severity, 
relationship to study treatment (platelet transfusion) and relationship to the medical device, will be 
included. 
Summary tables by SOC and PT will be reported for TEAEs, TESAEs, unanticipated TESAEs, UADEs, 
and Pulmonary related TEAEs as well as those pulmonary events requiring assisted ventilation. The 
number and percent of subjects with at least one event will be presented overall and, at most, once per 
SOC and PT. 
All TEAEs will be listed by treatment group and subject. There will be a separate listing of TESAEs by 
treatment group and subject. 
The timeframe for reporting death as part of AEs and death as a safety endpoint are different. The 
timeframe for reporting death as an AE is from randomization through thirty (30) days following the last 
per protocol PLT transfusion, where the timeframe for reporting death as a safety endpoint of death is 
through Day 56. The number of deaths through thirty (30) days following the last on-protocol PLT 
transfusion will be summarized by relationship to study treatment (PLT transfusion) and by relationship 
to medical device(s). The total number of deaths through Day 56 will be reported. 
All deaths will be listed by treatment group and subject. This listing will include the investigator 
assessment of cause of death. 
Deaths due to bleeding will be defined by the applicable bleeding grade and reported in the clinical study 
report.  No listings or summaries will be produced as part of this reporting effort. 
8.5. Tertiary Analyses  
After all primary, secondary, supporting and exploratory analyses are completed; the following tertiary 
analyses of the primary endpoint will be conducted. All analyses will be performed at a group level with 
respect to the following subsets of such analyses will be considered exploratory. Due to their exploratory 
nature these analyses will be viewed as descriptive, hypothesis generating, and will not involve formal 
hypothesis testing. 
8.5.1. Irradiation of Platelets 
This exploratory analysis will summarize number and percent of irradiated PLTs transfused between 
arms.  This may inform the effect of treatment with MIR PLTS versus Conventional PLTS that were 
irradiated between arms. 

 
 
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8.5.2. Washed Platelets 
This exploratory analysis will summarize number and percent of washed PLTs transfused between arm.   
This may inform the effect of treatment with MIR PLTs versus Conventional PLTs that were washed 
between arms. 
8.5.3. Age of Platelets 
This exploratory analysis will summarize the age of PLTs transfused in days as a continuous variable 
between arms. This may inform the effect of treatment with MIR PLTs versus Conventional PLTs if there 
is a difference in the age of PLT units between arms.  Platelet age is calculated as the date of the 
transfusion start recorded by the hospital site minus the Platelet Collection Date recorded by the blood 
center.  For example, a platelet collected on the 10th of the month, and transfused on the 12th of the month 
would have an age of two (2) days. 
8.6. Interim Analysis 
An IA will be conducted at the 50% information fraction, i.e. when approximately 279 randomized mITT 
subjects have completed the post-transfusion period follow-up/early termination visit. The results of the 
IA will be presented to the 
 Data Monitoring Committee (DMC). The DMC will assess efficacy, 
safety, and quality of trial conduct at the time of the IA.  
Empirical conditional power [4] will be used in the IA to assess the futility in establishing NI. This will 
be carried out as follows. 
A negative binomial model planned for the primary analysis will be fitted using unblinded data at the time 
of the IA following the convention for handling the off-protocol intervals prescribed in the primary 
analysis for each study arm.  From these intercept only models, the estimates of 
 and the variance 
parameter 
 will be obtained. For an individual to be recruited in the second half of the trial, this 
 duration of time (ti) under observation will be drawn with replacement from each study ar
 
empirical distribution from the individuals who have completed their follow-up at the time of the IA 
regardless of on- or off-protocol intervals.  The offset will be denoted as ln(ti).  Subjects whose time to 
transfusion independence is sampled and found to take place before Day 27 will be assumed to have zero 
bleeding days on the date of transfusion independence to Day 27 inclusive (which is assessed at the Post 
Transfusion follow-up visit). To simulate bleeding days over the period of transfusion dependence we 
first draw a random number Vi ==RAND('GAMMA', 1/
), then compute Ui= Vi *
 such that Ui will be 
a gamma distributed with mean 1 and variance 
 . The count response is then to be drawn from a Poisson 
distribution with mean 
. In order to simulate a count for the number of bleeding days which 
is guaranteed to be no greater than the number of bleeding assessment days for which bleeding data are 
required, a multinomial random variable will be generated with ti+1 categories and probability vector P 
calculated based on the probability mass function of a right-truncated Poisson random variable. The 
resulting count will take on values 0, 1, 2, . . ., ti while continuing to represent a realization of the 
bleeding data from the subject since it is using their estimated bleeding rate. When a cell probability for 
the multinomial is very small it will be set to 1x 10-5 so that probabilities are > 0 and to avoid 
computational errors caused by very small floating-point numbers. The count response drawn in this way 
will be a realization from the truncated negative binomial distribution.  
A completed dataset will then be available with the first half of the sample representing individuals for 
whom data are recorded and the second half of the sample representing simulated data representing 
contributions from individuals yet to be recruited. A negative binomial model will be fitted to this 
complete dataset as described for the primary analysis. A Wald-based two-sided 95% confidence interval 
will then be constructed for the regression coefficient of the treatment indicator based on this completed 
dataset. It will then be recorded whether the upper limit of this confidence interval includes the value of ln 
1.6 which defines the non-inferiority margin on the scale of the natural logarithm.  

 
 
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Ten thousand datasets will be computed in this way and the proportion of completed datasets for which 
the upper limit of a two-sided 95% confidence interval is below the value of ln 1.6 will be taken as the 
empirical conditional power. If this empirical conditional power is below 0.30 the guidance would 
suggest termination for futility, but this would not be a binding rule. Factors other than the empirical 
conditional power will be considered when weighing the futility of the study as a whole.  
The DMC will be fully unblinded in its assessment of safety and efficacy data at the time of the formal 
IA. The IA tables will be prepared semi-blinded by treatment codes (e.g. Treatment A and Treatment B) 
and the actual treatment assignments will be provided to the DMC under separate cover. 
Note that the power calculation does not consider the minor power loss due to the futility analysis. The 
study will not be stopped at the IA for a positive primary efficacy outcome (e.g. non-inferiority or 
superiority of MIRASOL). 
The DMC will receive their routine unblinded DMC report at the IA. In addition, the following data will 
be included in the IA report: 
A summary of the mean, SD, minimum and maximum days of grade 2 or higher bleeding and days of 
bleeding assessments will be included by treatment group alone and by treatment group and treatment 
type. 
For the primary outcome of days of grade 2 or higher bleeding first a basic summary table will be 
presented of the average days of grade 2 or higher bleeding, and the average days of bleeding assessments 
per treatment group. Then a summary of estimates from the negative binomial model with the natural log 
of the estimate, standard error, and 95% CI will be presented. Last, a table testing the non-inferiority 
hypothesis will be included showing the estimate of MIRASOL versus CONTROL from the model, the 
natural log of the NI margin, standard error, and 95% CI. 
The mean CCI at 1 hour (measured between 
 minutes and <4 hours) and the mean CCI at 24 hours 
(measured between 
 and < 30 hours) after the end of every transfusion episode, when possible, will be 
calculated for each subject, and the mean of each treatment group will be presented along with differences 
in means for each pairwise comparison (treatment-control) at each time point (1 hour and >18-30 hours) 
as discussed in the analysis of Secondary Endpoint # 9. This will also be presented by age group (age 
<18, 18-65 and > 65 years) and treatment type (allogeneic transplant, autologous transplant, and 
chemotherapy). 
Additionally, HLA antibody results are captured in a central laboratory database and will be maintained 
exclusively by BSRI. Blood System Research Institute will be responsible for reporting HLA results by 
treatment, age group, and treatment strata to the DMC. 

 
 
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9. 
REFERENCES 
1. Wicklin R. (2013). Simulating Data with SAS®. SAS Institute Inc., Cary, North Carolina p. 
126. 
2. Pahel B.T., Preisser J.S., Stearns S.C., Rozier R.G. (2011). Multiple Imputation of Dental 
Caries Data Using a Zero Inflated Poisson Regression Model.  Journal of Public Health 
Dentistry, 71(1): 71-78.  
3. Verbeke, G. (1997). Linear mixed models for longitudinal data. In Linear mixed models in 
practice (pp. 63-153). Springer, New York, NY. 
4. Hammersley, J. (2013).  Monte Carlo Methods. Springer Science & Business Media. 

 
 
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10. 
APPENDIX I, ANNOTATED WHO GRADING SCALE 
WHO Grading Scale for Bleeding annotated with the study s Bleeding Assessment (MIPLATE 
Annotated eCRFs) variable identifiers (Bx) and answers that correspond to the bleeding status. 
Grade 1 
Grade 2 
Grade 3 
Oral and nasal 
 Oropharyngeal bleeding  
total duration of all episodes 
in previous 24 hours < 30 
minutes* B6a = No 
 Petechiae of oral mucosa B5 =
Yes 
 Epistaxis  total duration of 
all episodes in previous 24 
hours < 30 minutes* B7a = No 
 Oropharyngeal bleeding  
total duration of all 
episodes in previous 24 
hours > 30 minutes* B6a 
= Yes or Not Assessed or 
Refused or 
 Know 
 Epistaxis  total duration 
of all episodes in 
previous 24 hours > 30 
minutes* B7a = Yes or 
Not Assessed or 
Refused or 
 
Know 
 Any bleeding requiring 
RBC transfusion over 
routine transfusion 
needs** B8 = Yes 
Skin, soft tissue, 
musculoskeletal 
 Petechiae of skin B9 = Yes 
 Purpura < 1-inch diameter B10a 
= No 
 One or more spontaneous 
hematomas in the soft 
tissue or muscle > 
1inch B11 = Yes 
 Purpura > 1-inch diameter
B10a = Yes or Not 
Assessed or Refused or 
 Know 
 1Spontaneous hematoma 
in deeper tissues B12= 
Yes 
 Joint bleeding 
(confirmed by 
aspiration, imaging 
study or other accepted 
technique) B13 = Yes 
 Any bleeding requiring 
RBC transfusion over 
routine transfusion 
needs** B14 = Yes 
Gastrointestinal 
 Positive stool occult blood 
test B15a = Yes 
 Melanotic stool B16 = Yes
 Hematochezia  visible 
red blood mixed in stool, 
not requiring a transfusion 
B17 = Yes 
 Hematemesis  Grossly 
visible blood in emesis 
or in nasogastric 
drainage tube (not 
related or secondary to 
swallowed blood) B18a 
= Yes or B19a = Yes 
 Any bleeding requiring 
RBC transfusion over 
routine transfusion 
needs** B20 = Yes 

 
 
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Genitourinary 
 Any biochemical or 
microscopic Hb/RBCs 
without red urine B21a 
= Yes 
 Abnormal vaginal bleeding 
(Unexpected bleeding out 
of normal cycle OR 
Bleeding heavier than 
normal OR Breakthrough 
bleeding (patient on 
hormonal therapy to 
prevent bleeding)) with 
spotting B23a = Yes 
Gross/visible
hematuria without 
need for transfusion 
B22 = Yes 
 Abnormal vaginal 
bleeding (Unexpected 
bleeding out of normal 
cycle OR Bleeding 
heavier than normal 
OR Breakthrough 
bleeding (patient on 
hormonal therapy to 
prevent bleeding)) 
more than spotting 
B23b = Yes 
Any bleeding requiring
RBC transfusion over 
routine transfusion 
needs** B24 = Yes 
Pulmonary 
 
 Hemoptysis  
Visible blood B25 
= Yes 
 Blood in broncho- 
pulmonary lavage, or 
blood tinged sputum 
(excluding those with 
nose or 
oropharyngeal 
bleeding) B26a = 
Yes or B27 = Yes 
 Any bleeding requiring 
RBC transfusion over 
routine transfusion 
needs** B28 = Yes 
Body Cavity 
 
 Visible blood in 
body cavity fluid 
(eg red cells 
apparent in fluid 
aspirate) short of 
criteria for grade 3 
or 4 B29a = Yes 
 Grossly bloody body 
cavity fluids and organ 
dysfunction with 
symptoms, and/or need 
to intervene (e.g. to 
aspirate), and/or need for 
transfusion B30 = Yes 

 
 
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Central Nervous 
System (CNS) 
Retinal bleeding
without visual 
impairment B31a = 
Yes 
 Lumbar puncture 
with blood (> 5 
RBC/ µL in 
CSF on microscopic 
analysis and non- 
traumatic tap), no 
symptoms and no  
      visible red color    
       B32a = Yes 
Lumbar puncture with
visible red color in 
absence of symptoms, 
and non-traumatic tap 
B32b = Yes 
Invasive Sites 
 
 Bleeding at invasive sites 
(venipuncture sites, IV 
lines or catheter exit 
sites): active oozing at 
site for a cumulative 
total of 
> 1 hour in the previous 
24 hours B34 = Yes 
 Any bleeding requiring 
RBC transfusion over 
routine transfusion 
needs** B35 = Yes 
Hemodynamic 
Instability 
 
 
 Any bleeding 
associated with 
moderate 
hemodynamic 
instability 
(hypotension; 
> 30mmHg fall or 
> 30% decrease in either 
systolic or diastolic BP) 
and requiring RBC 
transfusion over routine 
transfusion needs** B37 
= Yes 
 
 
Abbreviations: RBC = red blood cell, Hg = hemoglobin, CSF = cerebrospinal fluid, IV = intravenous, 
mmHg = millimeters of mercury, BP = blood pressure. 
*Count actual bleeding (ie. 
 
 or need for basin, Kleenex, towel, etc.) not minor bleeding. 
**Red cell transfusion must be specifically related to treatment of bleeding within 24 hours of onset 
of bleeding. 
Grade 4: 
 
Any bleeding associated with severe hemodynamic instability (hypotension; > 50mm/Hg fall or 
> 50% decrease in either systolic or diastolic BP, with associated tachycardia (HR increase of > 
20% for 20 minutes) and requiring RBC transfusion over routine transfusion needs B36 = Yes 
 
Fatal bleeding from any source B38 = Yes 
 
Retinal bleeding with visual impairment (visual impairment is defined as a field deficit, 
and patients with suspected visual impairment require an ophthalmologic consult for 

 
 
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documentation) B31b = Yes
 
Central nervous system (CNS) symptoms with non-traumatic bloody lumbar puncture B32c = 
Yes 
 
CNS bleeding on imaging study with or without dysfunction B33a = Yes 
 
Grade 4 = (B31b=Yes or B32c=Yes or B33a=Yes or B36=Yes or B38=Yes) 
Grade 3 = (B8=Yes or B14 or B20=Yes or B24=Yes or B28=Yes or B30=Yes or B32b=Yes or 
B35=Yes or B37=Yes) 
Grade 2 = (B6a=Yes or Not Assessed or Refused or 
 know or B7a=Yes or Not Assessed or 
Refused or 
 Know or B10a=Yes or Not Assessed or Refused or 
 know or B12=Yes or 
B13=Yes or B16=Yes or B17=Yes or B18a=Yes or B19a=Yes or B22=yes or B23b=Yes or B25=Yes 
or B26a=Yes or B27=Yes or B29a=Yes or B31a=Yes or B32a=Yes or B34=Yes) 
Grade 1 = (B6a=No or B5=Yes or B7a=No or B9=Yes or B10a=No or B11=Yes or B15a=Yes or 
B21a=Yes or B23a=Yes) 
The maximum grade in the 24-hour assessment period will be the bleeding grade for that day

 
 
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11. 
APPENDIX II, ANALYSIS OF THE KEY SECONDARY ENDPOINT 
11.1. Introduction 
Alloimmunization against the highly polymorphic human leukocyte antigens (HLA) has long been known 
to occur in oncology patients receiving platelet transfusions.[1,2]  A major concern with HLA 
alloimmunization is the risk of  HLA antibody formation contributing to platelet refractoriness, though it 
is known that alloimmunization is only one of many causes of platelet transfusion refractoriness.[3] The 
majority of HLA alloimmunization events following transfusion of oncology patients occurs within the 
first four weeks of induction chemotherapy.[2,4] Animal models show decreased alloimmunization in 
recipients of ultraviolet (UV) light treated platelets.[5,6] A definitive randomized control trial showed 
clear benefit of leukoreduction or UVB irradiation of platelet products in preventing both HLA 
alloimmunization and refractoriness to platelet transfusion.[4]  The primary objective of MIPLATE is to 
determine if the hemostatic efficacy of Mirasol-treated plasma stored Trima Accel® apheresis platelets are 
non-inferior to conventional plasma stored apheresis platelets in patients with hypoproliferative 
thrombocytopenia requiring platelet transfusions. Secondary objectives include comparing other efficacy 
and safety endpoints between the treatment groups. One of the key secondary endpoints in the MIPLATE 
trial is to determine if receipt of Mirasol-treated platelets alter the risk for HLA alloimmunization after 
platelet transfusion. 
11.2. Data Sources 
Data and specimens from the enrolled patients in MIPLATE will be accessed for this assessment of 
alloimmunization.  
Samples from enrolled patients will be screened for Class I and Class II antibodies at BSRI using the 
LSM12 kit manufactured by One Lambda. Samples will be tested at baseline (pre-transfusion) and on 
days 14 (± 5 days), 28 (± 7), and 56 (± 10 days). Blood System Research Institute laboratory staff will be 
blinded to MIPLATE treatment assignment. 
11.3. HLA Antibody Testing 
Test results will be reported as the normalized background (NBG) ratio for each bead in the assay, which 
corresponds to the strength of each HLA reaction. The NBG ratio and assay validity are calculated using 
the following set of abbreviations: 
S#N 
Sample-specific fluorescent value for bead #N 
SNC bead 
Sample-specific fluorescent value for Negative Control bead 
SPC bead 
Sample-specific fluorescent value for Positive Control bead 
BG#N 
 Background NC Serum fluorescent value for bead #N 
BGNC bead 
Background NC Serum fluorescent value for Negative Control bead 
NC Serum 
Negative Control Serum validated for a given lot of LABScreen® beads 
For an assay to be interpreted as valid, the following criteria will need to be met: SNC  1500, SPC  
500, and SPC  2*(SNC). 
The NBG value for each bead will be calculated as: 
NBG = (S#N - SNC bead) / (BG#N - BGNC bead) 

 
 
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If any bead for a given sample yields an NBG ratio greater than the chosen cut-off the MIRASOL will be 
interpreted as positive, meaning evidence of alloimmunization. Cutoffs will be analyzed using a sensitive 
cutoff originally suggested by the manufacturer (NBG = 2.2) and cutoffs determined through studies of 
non-transfused males, using 3X or 5X the standard deviation above the mean value in that population.[7] 
11.4. Analysis Objectives 
The objective of the study is to compare the rate of HLA alloimmunization for recipients of Mirasol-
treated platelets and recipients of conventional platelets. The treatment effect will be measured by the 
odds ratio (OR). The relative odds of alloimmunization (comparing Mirasol-treated to conventional 
platelets) will be estimated at each of the three assay cutoffs, along with associated 95% confidence 
intervals. In addition, HLA antibody data will be examined using KM plots to explore time to 
alloimmunization, with the outcome of interest being time to development of new HLA antibodies. 
Individuals not experiencing alloimmunization will have their follow-up censored. All analyses will be 
conducted both as intention to treat analysis and a per protocol analysis.  
11.5. Populations 
The two populations to be compared will be recipients of Mirasol-treated vs recipients of standard 
platelets. 
11.6. Endpoints and Covariates 
The endpoint for the HLA alloimmunization study will be development at any post-transfusion time point 
of a positive HLA antibody test at the given assay cutoff in a subject who had a negative HLA antibody 
test at that assay cutoff at baseline (pre-transfusion). 
A relevant covariate that will be analyzed in a secondary analysis is the number of platelet transfusions 
received prior to the alloimmunization event, which will allow calculation of the rate of alloimmunization 
per unit of platelets transfused.   
11.7. Handling of Missing Values and Other Data Conventions  
Enrolled participants missing a baseline sample who do not have subsequent positive HLA antibody tests 
will be termed not alloimmunized. Participants missing a baseline sample who have subsequent positive 
HLA antibody tests will be termed unevaluable and will be excluded from analyses. Enrolled participants 
who have a baseline sample and have at least one subsequent post-transfusion sample will be used in the 
analysis. 
11.8. Statistical Procedures 
Odds ratios will be calculated to compare the risk of HLA alloimmunization in recipients of Mirasol-
treated vs. conventional platelets. The exposure will be platelet type and the outcome will be development 
of a new HLA antibody. Development of HLA class I and HLA class II antibodies will be analyzed 
separately. The number of participants in each group at risk for alloimmunization will depend on the 
intention to treat and per protocol final categorization, but in general will be the number of participants 
who did not have detectable HLA antibodies at baseline at a given assay threshold.  
In secondary analyses KM curves will be calculated using the longitudinal HLA antibody data to define 
subjects who are alloimmunized at baseline and the time to development of HLA alloantibodies post-
transfusion. Development of HLA alloantibodies will be considered 
 events during model 
specification, and the two arms of the study will be compared statistically using standard non-parametric 
tests, such as the log-rank test, with a p-value less than or equal to 0.05 considered evidence for 
significant difference  

 
 
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11.9. Approaches to Adjust for Multiplicity, Confounders, Heterogeneity 
We do not plan to adjust for other potential covariates, unless evidence from the trial data suggest an 
unexpected imbalance between potential confounding factors such as the number transfused platelets or 
other patient characteristics. It is possible that platelet transfusion exposure will affect alloimmunization 
risk. In a secondary analysis, the risk of alloimmunization per platelet transfusion received prior to the 
alloimmunization event will be calculated. 
11.10. Programming Plans 
Data will be curated, cleaned, and analyzed using SAS® v9.4 software (SAS Institute Inc., Cary, NC). 
11.11. REFERENCES 
 
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1978;18:496 503.  
2. Dutcher JP, Schiffer CA, Aisner J, Wiernik PH. Long-term follow-up patients with leukemia 
receiving platelet transfusions: identification of a large group of patients who do not become 
alloimmunized. Blood. 1981;58:1007 11.  
3. Doughty HA, Murphy MF, Metcalfe P, et al. Relative importance of immune and non-immune causes 
of platelet refractoriness. Vox Sang. 1994;66:200 5.  
4. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and 
refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study 
Group. N Engl J Med. 1997;337:1861 9.  
5. Kao KJ. Effects of leukocyte depletion and UVB irradiation on alloantigenicity of major 
histocompatibility complex antigens in platelet concentrates: a comparative study. Blood. 
1992;80:2931 7.  
6. Slichter SJ, Deeg HJ, Kennedy MS. Prevention of platelet alloimmunization in dogs with systemic 
cyclosporine and by UV-irradiation or cyclosporine-loading of donor platelets. Blood. 1987;69:414
8.  
7. Triulzi DJ, Kleinman S, Kakaiya RM, et al. The effect of previous pregnancy and transfusion on HLA 
alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk 
reduction strategy. Transfusion (Paris). 2009;49:1825 35.