Clinical trial NCT03997760
Conditions: Sickle Cell Disease
Sponsor: Shire
Start date: 2019-10-21; Completion date: 2022-10-26
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
TAK-755 (previously known as SHP655) is a medicine used to treat sickle cell disease (SCD). The main aim of the study is to measure the safety and tolerability of TAK-755 in SCD participants.

Study participants will receive TAK-755 or placebo on Day 1. Their SCD will be treated by their doctor according to their doctor's usual clinical practice.

During the study, participants will be asked to follow-up on 13 days following SHP655 or placebo administration for safety assessment. Maximum duration of participation is expected to be about 2 months.

Detailed description:

Arms: arm 1: Participants with SCD at their baseline health will receive a single intravenous (IV) infusion at one of the 3 dose levels of 40, 80 and 160 International units per kilogram (IU/kg) in a dose escalation manner. arm 2: Participants with SCD at their baseline health will receive placebo matched to TAK-755 of the 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg as single IV infusion.
Interventions: intervention 1: TAK-755 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive TAK-755 as a single IV infusion at one of the 3 dose levels of 40 IU/kg, 80 IU/kg, or 160 IU/kg. intervention 2: Participants will receive placebo matched to TAK-755 of the 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg as single IV infusion.

Protocol documents:
Prot_000.pdf: 
NCT Number: NCT03997760
Title: A Phase 1 randomized, double-blind, placebo-controlled, multicenter, 
ascending dose, safety and PK/PD study of SHP655 (rADAMTS13) in sickle cell 
disease at baseline health
Study Number: SHP655-101
Document Version and Date: Protocol Amendment 2.0 (Global), 12 JUL 2021
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
Clinical Study Protocol
For non-commercial use only


PROTOCOL: SHP655-101
TITLE:
A Phase 1 randomized, double-blind, placebo-controlled, 
multicenter, ascending dose, safety and PK/PD study of SHP655 
(rADAMTS13) in sickle cell disease at baseline health.
SHORT TITLE:
A Phase 1 randomized study of SHP655 (rADAMTS13) in sickle 
cell disease
STUDY PHASE:
Phase 1
ACRONYM:
RAISE (Recombinant ADAMTS13 In Sickle cell diseasE)
DRUG:
recombinant ADAMTS13 
IND NUMBER:
018839
SPONSOR:
Takeda Development Center Americas, Inc. 
95 Hayden Avenue, Lexington, MA 02421, USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Multicenter
PROTOCOL 
HISTORY:
Protocol Amendment 2.0 (Global): 12 JUL 2021
Replaces: Protocol Amendment 1.0 (Global) 17 MAY 2019
Protocol History: Original Protocol (Global) 28 MAR 2019
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Takeda.
For non-commercial use only


PROTOCOL SIGNATURE PAGE 
Sponsor's Approval 
-- --·---
Date: 
, MD 
Investigator's Acknowledgement 
I have read this protocol for Study SI-IP655-10L 
Title: A Phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending dose, 
safety and PK/PD study of SHP655 (rADAMTSI 3) in sickle cell disease at baseline. 
I have fully discussed the objective(s) of this study and the contents of th is protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be d isclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice 
(GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
CONFIDENTIAL
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SHP655-101 Protocol Amendment 2.0 (Global)
12 Jul 2021
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SHP655-101 Protocol Amendment 2.0 (Global)
12 Jul 2021
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION

Original Protocol (28 MAR 2019)

Protocol Amendment 1.0 (17 MAY 2019)

Protocol Amendment 2.0 (12 JUL 2021)
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.0
Amendment Date
12 JUL 2021
Global/Region/ 
Country/Site Specific
Global
Protocol Amendment Summary and Rationale: The primary purpose of this amendment is to remove Part B of 
the study (enrollment of subjects with acute vaso occlusive crisis [VOC]).
Description of Each Change and Rationale 
Section(s) Affected by Change
1. The description of the study as a
Phase 1/2 study was changed to
Phase 1.
To reflect the investigative 
objective of this study.
Title Page
Protocol signature page
Section 1.1, Synopsis
Section 2.2.2
Section 2.4
Section 4.1
Section 4.2
2. The Sponsor name and address
was updated to the following;
Takeda Development Center
Americas, Inc.
95 Hayden Avenue
Lexington, MA 02421
To reflect the recent legal 
entity name change and 
centralization of clinical trial 
development.
Title Page
Throughout, where appropriate
3. Emergency contact information
was updated.
To reflect current emergency 
personnel and contact 
information.
Emergency Contact Information
Remove Part B of the study that 
includes subjects with VOC.
To reflect the Sponsor decision 
to complete the Phase 1 safety 
study in subjects at baseline 
health (Part A) before 
designing the next trial in the 
clinical development program. 
Title Page
Protocol signature page
Section 1.1, Synopsis
Section 1.2
Section 1.3
Section 3.1
Section 3.2
Section 4.1
Section 4.2
Section 4.4
Section 5.1
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CONFIDENTIAL
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recombinant ADAMTS13
SHP655-101 Protocol Amendment 2.0 (Global)
12 Jul 2021
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.0
Amendment Date
12 JUL 2021
Global/Region/ 
Country/Site Specific
Global
Protocol Amendment Summary and Rationale: The primary purpose of this amendment is to remove Part B of 
the study (enrollment of subjects with acute vaso occlusive crisis [VOC]).
Description of Each Change and Rationale 
Section(s) Affected by Change
Section 5.2
Section 6.2.3, Dosing 
Section 6.2.3.3, Dose Escalation 
Committee
Section 8.1, Study Schedule
Section 8.1.1, Screening Visit
Section 8.1.2, Treatment Period
Section 8.1.4, Study 
Completion/Termination Visit
Section 8.2.2.5, Pregnancy Test
Section 8.2.3, Pharmacokinetics
Section 8.2.4, Pharmacodynamics
Section 8.2.5, Biomarkers
Section 9.2, Planned Interim Analysis
Section 9.3, Sample Size and Power 
Considerations
Section 9.6.1, Pharmacokinetic Analysis
Section 9.6.2, Pharmacodynamic 
Analysis
Section 9.6.3, Pharmacokinetic-
Pharmacodynamic Relationship 
Section 9.7, Efficacy Analysis
The product quality complaint 
email was updated to 
ctmcomplaint@takeda.com.
Updated for accuracy
Product Quality Complaints
Assessment of 
 
 
 
 
 
The assays involved with these 
biomarkers are investigative 
and under development. 
Section 1.1, Synopsis
Section 1.3 (Table 2)
Section 3.1.2
Section 3.1.3
Section 3.2
Section 8.2.4
Section 8.2.5
Throughout the document
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CONFIDENTIAL
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recombinant ADAMTS13
SHP655-101 Protocol Amendment 2.0 (Global)
12 Jul 2021
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.0
Amendment Date
12 JUL 2021
Global/Region/ 
Country/Site Specific
Global
Protocol Amendment Summary and Rationale: The primary purpose of this amendment is to remove Part B of 
the study (enrollment of subjects with acute vaso occlusive crisis [VOC]).
Description of Each Change and Rationale 
Section(s) Affected by Change
All Health Economics and 
Outcomes Research (HEOR)
objectives, endpoints, and 
assessments were removed from the 
study.
To reflect removal of 
endpoints most relevant to 
Part B.
Section 1.1, Synopsis
Section 1.2
Section 1.3
Section 3.1.3
Section 3.2
Section 8.2.1
Section 8.2.5
Section 9.8
Assessment of the effect of SHP655 
on platelet count was added as a 
secondary, pharmacodynamic 
objective, and platelet count as a 
PD endpoint. 
ADAMTS13 cleavage of VWF 
may directly result in
dissolution or prevention of 
platelet aggregates, resulting in 
an increase in the platelet 
count. 
Section 1.1, Synopsis
Section 3.1.2
Section 3.2
Section 8.2.4
Section 9.6.2
The list of exploratory markers was 
updated.
To reflect changes to the 
, 
removal of Health Economics 
and Outcomes Research
endpoints, and for consistency 
throughout the protocol
Section 1.1, Synopsis
Section 3.2
Section 8.2.5
Section 9.7
The pain score by VAS and oxygen 
use were removed as exploratory 
endpoints.
To reflect removal of all 
exploratory efficacy endpoints 
due to the change to a Phase 1 
study
Section 1.1, Synopsis
Section 1.2
Section 1.3 (Table 1)
Section 8.2.1
Section 8.2.5
Dose justification was updated and 
clarified regarding discussion of the
PK/PD modeling and the relevant 
preclinical toxicology studies in 
rats and nonhuman primates.
Updated for completeness and 
clarity, and to harmonize with
information presented in the 
IND.
Section 4.3
This study will be conducted in 
approximately 20 sites across the 
United States.
This Phase 1 study will not be 
conducted in Europe. 
Section 1.1, Synopsis
Section 4.4
The exclusion criteria were updated 
to indicate at which visit each 
criterion applies.  
Updated for clarity
Section 1.1, Synopsis
Section 5.2
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SHP655-101 Protocol Amendment 2.0 (Global)
12 Jul 2021
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.0
Amendment Date
12 JUL 2021
Global/Region/ 
Country/Site Specific
Global
Protocol Amendment Summary and Rationale: The primary purpose of this amendment is to remove Part B of 
the study (enrollment of subjects with acute vaso occlusive crisis [VOC]).
Description of Each Change and Rationale 
Section(s) Affected by Change
Exclusion criteria 5 was updated to 
include exclusionary bilirubin 
levels at the Screening Visit, 
“…direct bilirubin level >2 mg/dL, 
or indirect bilirubin level 
>5 mg/dL.” 
Due to the nature of this phase 
1 safety study, the exclusion 
criterion was clarified for 
elevated bilirubin levels. 
Exclusion criteria for indirect 
bilirubin ensures unconjugated 
bilirubin levels remain within 
the range validated for the 
ADAMTS13 activity assay. 
High direct bilirubin levels 
were excluded, which may 
indicate hepatic dysfunction.
Section 1.1, Synopsis
Section 5.2
Exclusion criteria 11 and 12 were 
deleted.
Exclusion criteria 11 and 12 
were designed for hospitalized 
subjects in Part B and are no 
longer applicable.
Section 1.1, Synopsis
Section 5.2
The Note defining menopausal was
removed from the exclusion 
criteria.
Detailed definitions of acceptable 
methods of contraception for 
female and male subjects were 
removed.
To simplify the protocol and 
improve consistency with the 
change to a US-only study. 
The FDA does not require 
these detailed definitions 
within the protocol.
Section 1.1, Synopsis
Section 5.2
Section 5.4
Appendix 4
Exclusion criteria 8 and 9 were 
simplified to exclude febrile 
subjects and those with infections 
requiring IV antibiotics.
Removal of subjects 
presenting with a VOC allows 
the criteria to be simplified to 
reduce confusion.
Section 1.1, Synopsis
Section 5.2
Exclusion criteria 14 was updated 
to exclude use of anticoagulant or 
antiplatelet therapy within the past 
3 weeks before dosing; 
crizanlizumab within the past 30 
days before dosing; and voxelotor 
within the past 14 days before 
dosing.
To specify wash-out periods 
for 1.) anticoagulant and anti-
platelet therapies, based on 
advice from the FDA that these 
should be restricted during the 
study; and 2.) recently 
approved protocol-restricted 
concomitant treatments for 
SCD. 
Section 1.1, Synopsis
Section 5.2
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Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.0
Amendment Date
12 JUL 2021
Global/Region/ 
Country/Site Specific
Global
Protocol Amendment Summary and Rationale: The primary purpose of this amendment is to remove Part B of 
the study (enrollment of subjects with acute vaso occlusive crisis [VOC]).
Description of Each Change and Rationale 
Section(s) Affected by Change
Exclusion criteria 23 was added to 
exclude subjects with active 
hepatitis B, hepatitis C, or HIV 
infections.
To clarify the exclusion 
criteria for the protocol-
specified viral serology 
assessments.
Section 1.1, Synopsis
Section 5.2
A statistical analysis description for 
PD measurements was added, and 
the statistical analysis of 
exploratory variables was updated.
To improve clarity and 
consistency throughout the 
protocol.
Section 1.1, Synopsis
Section 1.2 (Figure 1)
Section 9.6.2
Section 9.7
Details regarding exploratory 
biomarkers were removed in 
Figure 1.
To improve clarity by keeping 
focus on the most relevant 
information.
Section 1.2
The 9 h (±30 min) PK assessment 
timepoint was changed to 8 h 
(±30 min).
Subject burden may be 
reduced with an 8-hour PK 
sampling time point, as it 
limits the amount of time spent 
at the clinic. 
Section 1.3 (Table 2)
Collection of daily opioid use data 
was removed from the Schedule of 
Activities and text regarding 
collection of oral opioid use as a 
Prior Treatment was updated.
To reflect the removal of Part 
B endpoints related to opioid 
use; data on oral opioid use 
will be collected in the same 
manner as other prior and 
concomitant treatments.
Section 1.3 (Table 1)
Section 6.6.1
The introduction of this study was 
updated to reflect relevant 
background information for SCD 
subjects at baseline.
To reflect the removal of Part 
B, and to reduce excess 
information that may not 
pertain to the current study 
population.
Section 2
Following the review of unblinded 
data for a completed dose cohort by 
the DEC, and a recommendation by 
the DEC that it is safe to proceed 
with enrollment of the next dose 
cohort, the Sponsor study team will 
have access to the unblinded data 
for the completed dose cohort, with 
details to be specified in an 
unblinding plan. 
Clarify the procedure for 
Sponsor review of unblinded 
data following completion of a 
dose cohort and review of 
safety data by the DEC. 
Unblinding the Sponsor study 
team is unlikely to introduce a 
bias as efficacy is not being 
evaluated and cohorts are 
independent from each other.
Section 6.2.4
Appendix 1.4
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Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.0
Amendment Date
12 JUL 2021
Global/Region/ 
Country/Site Specific
Global
Protocol Amendment Summary and Rationale: The primary purpose of this amendment is to remove Part B of 
the study (enrollment of subjects with acute vaso occlusive crisis [VOC]).
Description of Each Change and Rationale 
Section(s) Affected by Change
Figure 2 was removed.
Due to the removal of Part B 
of the study, Figure 2 no 
longer improves the clarity of 
the study design.
Section 1.3
Glutamine was replaced with 
glutamic acid in the introduction of 
the indication.
Updated for correction.
Section 2.1
In the benefit/risk assessment 
section, the description of the 
specific criteria for Dose Escalation 
Committee activities was removed 
and references were added to the 
relevant sub-sections of
Section 6.2.3 for clarity.
For consistency with 
information provided in 
Section 6.2.3 Dosing.
Section 2.4
Stopping criteria for dose escalation 
was changed from 2 or more 
subjects receiving active drug who 
have a severe AE, to 2 or more 
subjects receiving active drug who 
have a related SAE. 
Language was changed to 
ensure subjects remain on 
treatment unless an SAE 
occurs that is related to 
treatment. 
Section 6.2.3
IV opioid use was removed as a 
permitted concomitant medication. 
To reflect removal of 
hospitalized subjects 
experiencing an acute crisis. 
Section 6.6.3
The following text was added, “The 
Sponsor recommends that subjects 
not be administered a vaccine 
against SARS-CoV2 during the 
Study Period. Should a subject 
receive such a vaccination during 
the Study Period, the Sponsor 
recommends study investigators to 
follow patients closely for vaccine-
related adverse events for 14 days 
after vaccination, in collaboration 
with the study medical monitor."
Based on safety concerns 
following the recent pause of 
the Johnson & Johnson and 
AstraZeneca COVID-19 
vaccines.
Section 6.6.3
The prohibited treatment list was 
updated to include L-glutamine, 
voxelotor, and crizanlizumab are 
restricted during the study period.
To specify that the recently 
approved therapies for sickle 
cell disease are restricted 
during the study period.
Section 1.1, Synopsis
Section 5.2
Section 6.6.4
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SHP655-101 Protocol Amendment 2.0 (Global)
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Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.0
Amendment Date
12 JUL 2021
Global/Region/ 
Country/Site Specific
Global
Protocol Amendment Summary and Rationale: The primary purpose of this amendment is to remove Part B of 
the study (enrollment of subjects with acute vaso occlusive crisis [VOC]).
Description of Each Change and Rationale 
Section(s) Affected by Change
Lack of efficacy was removed from 
the list of reasons for 
discontinuation.
Efficacy is not a main 
objective of this study.
Section 7.2
The method for selecting subject 
identifiers was updated.
To reflect the current subject 
identifier format.
Section 8
Full analysis set was removed
All efficacy analyses have 
been removed.
Section 1.1, Synopsis
Section 9.5
Section 9.7
PK Assessments, PD Assessments, 
and Immunogenicity Assessment 
sections were removed from 
Appendix 2 Clinical Laboratory 
Tests.
To clarify that these 
assessments are not part of 
‘clinical laboratory 
assessments’ per the Schedule 
of Activities.
Appendix 2
ECG was removed as a safety 
assessment.
An ECG is not a planned 
safety assessment in this study. 
Appendix 3
The definition IP was updated to, 
“Investigational Product (SHP655 
and Placebo)”.
For clarity
Appendix 4
See Appendix 5 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Shire 
Clinical Study Adverse Event Form for SAEs and Non-serious AEs as Required by Protocol” 
within 24 hours to the Takeda Global Drug Safety Department. The fax number and e-mail 
address are provided on the form (sent under separate cover). A copy of this form must also be 
sent to the contract research organization (CRO)/Takeda medical monitor using the details 
below.
For protocol- or safety-related questions or concerns during normal business hours 9:00 AM 
through 5:00 PM EST (North America), the investigator must contact the IQVIA and Takeda 
medical monitors:
IQVIA medical monitor
, MD
Mobile: 
 
E-mail: 
Takeda Medical Monitor
, MD, ScD
Mobile: 
E-mail: 
For protocol- or safety-related questions or concerns outside of normal business hours, the 
investigator must contact the 24-hour hotline:
For 24-hr urgent medical contact: contact on mobile phone, or at the following numbers:
US primary +1 512 652 0191
US alternate +1 512 652 0864
EU +33 186 990 019
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Takeda within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
This includes any instances wherein the quality or performance of a Takeda product (marketed or 
investigational) does not meet expectations (e.g., inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (e.g., wrong product such that the label and contents are different products); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following:
A failure of a product to exhibit its expected pharmacological activity and/or design function, 
e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product causing it to 
malfunction or to present a hazard or fail to meet label claims
For instructions on reporting AEs related to product complaints, see Appendix 1, Appendix 3.4.
Please use the information below as applicable to report the Product Quality Complaint or 
Non-Medical Complaint:
Origin of Product Quality Complaint
E-mail Address: ctmcomplaint@takeda.com
Telephone number (provided for reference if needed):
Takeda, Cambridge, MA (USA)
1-800-828-2088
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE..............................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION...........................3
EMERGENCY CONTACT INFORMATION .........................................................................10
PRODUCT QUALITY COMPLAINTS....................................................................................11
TABLE OF CONTENTS ............................................................................................................12
LIST OF IN-TEXT TABLES .....................................................................................................15
LIST OF IN-TEXT FIGURES ...................................................................................................15
LIST OF APPENDICES .............................................................................................................15
1. PROTOCOL SUMMARY ......................................................................................................16
1.1 Synopsis..............................................................................................................................16
1.2 Schema ...............................................................................................................................21
1.3 Schedule of Activities........................................................................................................22
2. INTRODUCTION....................................................................................................................24
2.1 Indication and Current Treatment Options...................................................................24
2.2 Product Background and Clinical Information .............................................................25
2.2.1 Nonclinical studies......................................................................................................26
2.2.2 Clinical studies............................................................................................................28
2.3 Study Rationale .................................................................................................................28
2.4 Benefit/Risk Assessment...................................................................................................28
2.5 Compliance Statement......................................................................................................29
3. OBJECTIVES AND ENDPOINTS ........................................................................................30
3.1 Study Objectives................................................................................................................30
3.1.1 Primary Objective ......................................................................................................30
3.1.2 Secondary Objectives .................................................................................................30
3.1.3 Exploratory Objective................................................................................................30
3.2 Study Endpoints ................................................................................................................31
4. STUDY DESIGN......................................................................................................................32
4.1 Overall Design ...................................................................................................................32
4.2 Scientific Rationale for Study Design..............................................................................32
4.3 Justification for Dose ........................................................................................................33
4.4 Duration of Subject Participation and Study Completion Definition..........................33
5. STUDY POPULATION ..........................................................................................................35
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5.1 Inclusion Criteria ..............................................................................................................35
5.2 Exclusion Criteria .............................................................................................................35
5.3 Restrictions ........................................................................................................................37
5.4 Reproductive Potential .....................................................................................................37
5.4.1 Female Contraception................................................................................................37
5.4.2 Male Contraception....................................................................................................37
6. STUDY INTERVENTION......................................................................................................38
6.1 Investigational Product.....................................................................................................38
6.1.1 Identity of Investigational Product ...........................................................................38
6.1.2 Blinding the Treatment Assignment.........................................................................38
6.2 Administration of Investigational Product.....................................................................38
6.2.1 Interactive Response Technology for Investigational Product Management.......39
6.2.2 Allocation of Subjects to Treatment .........................................................................39
6.2.3 Dosing ..........................................................................................................................39
6.2.3.1 Stopping Criteria for Dose Escalation ...............................................................40
6.2.3.2 Dose Limiting Toxicities......................................................................................40
6.2.3.3 Dose Escalation Committee.................................................................................41
6.2.4 Unblinding the Treatment Assignment ....................................................................42
6.2.5 Dose Modification.......................................................................................................42
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product....................43
6.3.1 Labeling.......................................................................................................................43
6.3.2 Packaging ....................................................................................................................43
6.3.3 Storage.........................................................................................................................44
6.3.4 Special Handling.........................................................................................................44
6.4 Drug Accountability..........................................................................................................45
6.5 Subject Compliance ..........................................................................................................46
6.6 Prior and Concomitant Therapy .....................................................................................46
6.6.1 Prior Treatment..........................................................................................................46
6.6.2 Concomitant Treatment.............................................................................................46
6.6.3 Permitted Treatment..................................................................................................47
6.6.4 Prohibited Treatment.................................................................................................47
6.7 Adverse event management..............................................................................................47
7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .............................................................................49
7.1 Discontinuation of Study Treatment...............................................................................49
7.2 Reasons for Discontinuation ............................................................................................49
7.3 Withdrawal from the Study .............................................................................................49
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..................................49
8. STUDY ASSESSMENTS AND PROCEDURES..................................................................51
8.1 Study Schedule ..................................................................................................................51
8.1.1 Screening Visit ............................................................................................................51
8.1.2 Treatment Period........................................................................................................51
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8.1.3 Follow-up Period ........................................................................................................52
8.1.4 Study Completion/Termination Visit .......................................................................52
8.1.5 Additional Care of Subjects after the Study............................................................52
8.2 Study Assessments.............................................................................................................52
8.2.1 Demographic and Other Baseline Characteristics ..................................................52
8.2.2 Safety ...........................................................................................................................52
8.2.2.1 Physical Examination ..........................................................................................52
8.2.2.2 Adverse Events.....................................................................................................53
8.2.2.3 Vital Signs.............................................................................................................53
8.2.2.4 Clinical Laboratory Tests....................................................................................54
8.2.2.5 Pregnancy Test.....................................................................................................54
8.2.3 Pharmacokinetics .......................................................................................................54
8.2.4 Pharmacodynamics ....................................................................................................54
8.2.5 Additional Exploratory Biomarkers.........................................................................54
8.2.6 Retention of Study Samples.......................................................................................55
9. STATISTICAL CONSIDERATIONS ...................................................................................56
9.1 Statistical Analysis Process...............................................................................................56
9.2 Planned Interim Analysis, Adaptive Design, and Data Escalation Committee...........56
9.3 Sample Size and Power Considerations..........................................................................56
9.4 Statistical Analysis Set(s)..................................................................................................57
9.5 Safety Analyses..................................................................................................................57
9.5.1 Primary Safety Endpoint...........................................................................................57
9.5.2 Statistical Analysis of Safety Parameters.................................................................57
9.6 Pharmacokinetic and Pharmacodynamic Analyses.......................................................58
9.6.1 Pharmacokinetic Analysis..........................................................................................58
9.6.2 Pharmacodynamic Analysis ......................................................................................59
9.6.3 Pharmacokinetic-Pharmacodynamic Relationship.................................................59
9.7 Efficacy Analyses...............................................................................................................59
9.8 Exploratory Analyses........................................................................................................60
10. REFERENCES.......................................................................................................................61
11. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...63
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LIST OF IN-TEXT TABLES
Table 1. Schedule of Study Procedures and Assessments ........................................................22
Table 2. Schedule of Laboratory Assessments ..........................................................................23
Table 3. Objectives and Endpoints.............................................................................................31
LIST OF IN-TEXT FIGURES
Figure 1. Study Schematic...........................................................................................................21
LIST OF APPENDICES
Appendix 1 Regulatory, Ethical, and Study Oversight Considerations .................................63
Appendix 2 Clinical Laboratory Tests.......................................................................................71
Appendix 3 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting......................................................................................................72
Appendix 4 Abbreviations...........................................................................................................81
Appendix 5 Protocol History.......................................................................................................84
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1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: SHP655-101
Drug: recombinant ADAMTS13 
Title of the study: A Phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending dose, safety 
and PK/PD study of SHP655 (rADAMTS13) in sickle cell disease at baseline health
Short title: A Phase 1 study of SHP655 (rADAMTS13) in sickle cell disease
Study phase: Phase 1
Number of subjects (total and per treatment arm):
A total of approximately 20 subjects will be randomized to IP or placebo as follows: Four evaluable subjects 
(3 active:1 placebo) at the 40 IU/kg dose cohort to be increased to 8 evaluable subjects per dose cohort 
(6 active:2 placebo) in the 80 IU/kg and 160 IU/kg dose cohorts.
Investigator(s): Multicenter study
Site(s) and Region(s): 
The study will be conducted approximately at 20 sites in the United States
Study period (planned): 2019-2022
Clinical phase:
1
Objectives:
Primary: 
•
Assess safety, tolerability, and immunogenicity of SHP655 in subjects with SCD at baseline health.
Secondary:
Pharmacokinetic
•
Assess the single dose pharmacokinetics (PK) of SHP655 at 3 dose levels in subjects with SCD.
Pharmacodynamic
•
Assess the effect of SHP655 on von Willebrand factor (VWF) and platelets. Study the correlation of plasma 
free hemoglobin and thrombospondin on SHP655 activity and VWF. 
Exploratory:
•
Assess additional exploratory biomarkers,
 
.
Rationale:
This study will assess safety (including immunogenicity), tolerability, PK, and pharmacodynamics (PD) of 
ascending doses of SHP655 in SCD. It is expected that SHP655 (rADAMTS13) activity will be inhibited by 
plasma free hemoglobin and thrombospondin-1 to variable degrees across subjects. Additionally, dosing of 
SHP655 to supraphysiologic levels has not been characterized clinically. Understanding the relationships among 
PK, PD, biomarkers, and their clinical correlates can guide the design of the adaptive Phase 2/3 study.
Investigational product, dose, and mode of administration:
Investigational product: SHP655 (rADAMTS13)
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Mode of Administration: Single intravenous (IV) infusion.
Dose:
SHP655 will be administered at 3 dose levels of 40, 80, and 160 IU/kg. 
Placebo will be administered in an equivalent volume of the 3 dose levels of 40, 80, and 160 IU/kg as single IV 
infusion.
Methodology:
This is a Phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending dose study evaluating 
safety, tolerability, and immunogenicity of SHP655 (rADAMTS13) in 12- to 65-year-old subjects with SCD. 
This study will characterize the PK and PD profile of SHP655.
Approximately 20 subjects with baseline SCD will be randomized in a 3:1 ratio to receive either SHP655 or 
placebo as a single IV infusion at one of the 3 dose levels of 40, 80, or 160 IU/kg. The dose cohorts will be 
opened sequentially, after safety data up to the Day 13 visit of the last subject in the previous dose cohort has 
been reviewed by the Dose Escalation Committee. 
The first 3 subjects will be dosed a minimum of 14 days apart to observe and interpret reactions and adverse 
events in order to ensure that no SAE requiring a pause or stop of the clinical trial (see Section 6.2.3.1 and 
Section 6.2.3.2) has occurred in the most recently treated subject.
Enrollment and escalation to the next dose cohort will be paused for review if anaphylaxis, neutralizing antibody, 
or death is reported.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
1.
Age 18 to 65 years at the time of signing the informed consent.
2.
An understanding, ability, and willingness to fully comply with study procedures and requirements.
3.
Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized 
representative) informed consent to participate in the study.
4.
Male or female with a documented history of HbSS or HbSβo thalassemia (based on clinical record of 
genetic, electrophoresis, or high-performance liquid chromatography testing).
5.
Subject currently taking hydroxyurea must be on a stable dosing for 3 months at screening.
Exclusion Criteria:
1.
The subject was diagnosed with acute VOC in the 21 days before dosing on Day 1.
2.
The subject has undergone blood transfusion within the last 30 days or blood transfusion on 
≥2 occasions in the last 90 days, at Screening Visit.
3.
The subject has a history of acquired or congenital thrombotic thrombocytopenic purpura.
4.
The subject has serum creatinine level >1.2 mg/dL at the Screening Visit 
5.
The subject has alanine transaminase >3×upper limit of normal (based on clinical laboratory normal 
range), direct bilirubin level >2 mg/dL, or indirect bilirubin level >5 mg/dL at the Screening Visit.
6.
The subject has a hemoglobin level <5 g/dL at the Screening Visit.
7.
The subject has a platelet count of <100 000/mm3 at the Screening Visit.
8.
Signs or symptoms of infection requiring treatment with IV antibiotics during the Screening Period.
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9.
The subject has fever with body temperature of ≥38.5ºC (101.3ºF) at the Screening Visit or before 
dosing on Day 1.
10. The subject has acute chest syndrome (ACS), diagnosed or strongly suspected, as evidenced by a new 
infiltrate on chest radiograph, and one or more of the following criteria:

Fever with body temperature >39°C (102.2°F)

Hypoxia (confirmed by arterial blood gases with PaO2 <70 mmHg)

Chest pain

Suspicious findings on physical examination (tachypnea, intercostal retraction, wheezing, and/or 
rales).
11. The subject has recently (within the past 28 days, from Screening Visit) undergone major surgery, 
requires hospitalization, documented serious bacterial infection requiring antibiotic treatment, or 
significant bleeding.
12. The subject has had a recent (within the past 90 days, from Screening Visit) episode of stroke, transient 
ischemic attack, symptomatic pulmonary hypertension, or seizure.
13. Any history of hemorrhagic stroke or bleeding diathesis.
14. The subject has received any of the following protocol-restricted medicines: a) systemic steroid therapy 
within 48 hours before dosing, or there is the expectation that such therapy may be given during the 
study (inhaled or topical steroids are allowed); b) Anticoagulant or antiplatelet therapy within the past 
3 weeks before dosing; c) crizanlizumab within the past 30 days before dosing; d) voxelotor within the 
past 14 days before dosing.
15. For subjects receiving chronic or long-acting opioids, a change in dose or pain requiring medical 
attention in the past 14 days before dosing.
16. The subject has a medical or psychiatric condition that, in the opinion of the investigator, may pose a 
risk to the subject for participation or interfere with the conduct or results of the study.
17. The subject has received or plans to receive any other investigational agent within the 4 weeks prior to 
the study Screening Visit or during the course of the study.
18. There is the expectation that the subject will not be able to be followed for the duration of the study.
19. The subject is i) pregnant, or ii) lactating, or iii) either a female of childbearing potential or a male 
who is unable or unwilling to comply with birth control methods or abstinence until the end of study 
visit. 
20. The subject with active use of illicit drugs (excluding marijuana) and/or alcohol dependence, as 
determined by the investigator.
21. The subject has been administered SHP655 previously.
22. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule 
ADAMTS-13, hamster protein, or other constituents of SHP655.
23. The subject has a positive test result for hepatitis B surface antigen, or hepatitis C antibody, or HIV 
antigen/antibody, at the Screening Visit. However, a subject with a hepatitis C antibody and a negative 
hepatitis C virus RNA polymerase chain reaction test is not excluded.
Maximum duration of subject participation in the study:
The planned duration of participation is 2 months.
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Endpoints: 
Primary:
Serious adverse events (SAEs)/adverse events (AEs), adverse changes in vital signs and laboratory 
parameters, and incidence of binding and inhibitory antibodies to SHP655 occurring up to 28±3 days after 
SHP655 infusion.
Secondary:
Pharmacokinetic
Area under the concentration-time curve (AUC) from zero (predose) to 72 hours postdose (AUC0-72), AUC from 
zero (predose) extrapolated to infinite time (AUC0-inf), AUC from zero (predose) to time of last quantifiable 
concentration (AUC0-last), terminal half-life (t1/2), systemic clearance (CL), mean residence time (MRT) from zero 
(predose) to 72 hours postdose (MRT0-72), MRT from zero (predose) extrapolated to infinite time (MRT0-inf), 
volume of distribution at steady state (Vss), observed maximum concentration (Cmax), time to reach Cmax (tmax), 
and incremental recovery (IR) will be estimated for ADAMTS13 activity and ADAMTS13 antigen 
(ADAMTS13Ag).
Pharmacodynamic
•
VWF:antigen (VWF:Ag), and VWF:Ristocetin cofactor activity (VWF:RCo).
•
Plasma free hemoglobin and plasma thrombospondin levels.
•
Platelet count
Exploratory:
.
Statistical analysis:
Safety Analysis Set: all subjects randomized and who received any dose of IP.
PK Analysis Set: all subjects who receive at least 1 complete dose of SHP655 or placebo and provide at least 
1 concentration measured at a scheduled time post start of infusion for at least 1 of the PK analytes and have no 
major protocol deviations or events that may affect the integrity of the PK data.
PD Analysis Set: all subjects who receive at least 1 complete dose of SHP655 or placebo and provide at least 
1 valid data point postdose of the respective infusion for at least 1 PD measurement for any of the PD outcome 
measures and have no major protocol deviations or events that may affect the integrity of the PD data.
Safety, including immunogenicity data, will be summarized descriptively by dose cohort. 
Adverse events and SAEs will be tabulated and summarized according to the Medical Dictionary for 
Regulatory Activities, in total, by treatment and by dose level. Individual and summary vital signs and clinical 
laboratory data will be presented in tabular form with mean, standard deviation, quartiles, and range as 
appropriate.
For laboratory safety data, out of range values will be flagged in the data listings and a list of clinically significant 
abnormal values will be presented.
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Pharmacokinetic parameters for ADAMTS13 activity and ADAMTS13:Ag following SHP655 or placebo 
infusion will be derived using non-compartmental methods, including but not limited to, where applicable and 
estimable: Incremental recovery, Cmax, tmax, t1/2, mean residence time from zero (predose) extrapolated to infinite 
time, mean residence time from zero (predose) to 72 hours postdose, area under the concentration-time curve 
from zero (predose) to time of last quantifiable concentration (AUC0-last), area under the concentration-time curve 
from zero (predose) extrapolated to infinite time (AUC0-inf), area under the concentration-time curve from zero 
(predose) to 72 hours postdose, CL, and Vss.
PK concentrations and PK parameters will be listed and summarized by dose level (and by scheduled time as 
applicable). Figures of concentration-time profiles and exposure PK parameters versus dose level will be 
presented.
The observed PD measurements of plasma VWF:Ag, VWF:RCo, plasma free hemoglobin, plasma 
thrombospondin, and platelet count will be listed and summarized by treatment, dose level, and scheduled time. 
Ratio to baseline values will be calculated for VWF:Ag, VWF:RCo, and platelet count. Individual and mean PD 
profiles over time will be presented. The correlation of plasma free hemoglobin and thrombospondin with 
ADAMTS13 activity and VWF will be assessed.
The exploratory variables of 
 
 will be listed and 
summarized by treatment, dose level, and scheduled time. 
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1.2 Schema
Figure 1. Study Schematic
ADAMTS13=A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; AEs=Adverse 
events; PD=Pharmacodynamics; PK=Pharmacokinetics; SCD=Sickle cell disease; TSP1=Thrombospondin 1; 
VVF:Ag=von Willebrand factor antigen; VWF:RCo=von Willebrand factor:Ristocetin cofactor.
Baseline SCD
40 IU/kg×1
(n=4)
Randomize 3:1 (SHP655:Placebo)
80 IU/kg×1
(n=8)

Safety: Follow 28 days for AEs, immunogenicity

PK: ADAMTS13 activity and antigen

PD: VWF:Ag, VWF:RCo, plasma free Hgb, TSP1, platelet count
160 IU/kg×1
(n=8)
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1.3 Schedule of Activities
Table 1. Schedule of Study Procedures and Assessments
Procedures/Assessments
Screening
Randomization/ 
PK Baseline Visit
PK 
Assessments
Follow-Up
Study 
Completion/
Termination
Visita
Day -28 
to 0
Day 1
Day 1, 2, 4, 
6, 8, and 10
Day 13
±2 days
Day 28
±3 days
Informed Consentb
X
Eligibility Criteria
X
X
Demographics and Medical 
History
X
Prior and Concomitant 
Medications
X
X
X
X
X
Non-drug Therapies
X
X
X
X
X
Physical Examination
X
X
X
X
Adverse Events
X
X
X
X
X
Laboratory testingc
X
X
X
X
X
Vital Signsd,e
X
Xe
X
X
X
Height/weight
X
X
IP infusion
X
Peripheral O2 saturationf
X
X
X
X
IP=Investigational product; O2=Oxygen; PK=Pharmacokinetic; SOP=Standard operating procedure; VAS=Visual 
analog scale
a.
Including for subjects who withdraw or discontinue.
b.
Occurs at enrollment (before screening and prior to any study-specific procedure).
c.
Laboratory assessments are listed in Table 2.
d.
Vital signs include: pulse rate, respiratory rate, body temperature, and blood pressure. 
e.
Vital signs should be recorded within 5 minutes before the 15 minutes and 1-hour PK samplings, and within 
30 minutes before all other PK samplings.
f.
Peripheral oxygen saturation will be assessed as per local nursing SOP.
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Table 2. Schedule of Laboratory Assessments
Assessment
Screening
PK 
Baseline 
Visit
PK Assessments
Follow-Up
Study 
Completion/ 
Termination
Visit
Day -28 
to 0
Within 
1 hour 
prior to 
IP 
infusion
15 min (±5min), 1 h (±5 min), 
3 h (±30 min), 8 h (±30 min), 
24 h (±2 h), 72 h (±4 h), 120 h 
(±24 h), 168 h (±24 h), 216 h 
(±24 h), and 288 h (±24 h)
Day 13
±2 days
Day 28
±3 days
PK/PD assessmentsa
C
C
C
Complete Blood Countb
L
L
Lf
L
L
Plasma free hemoglobin,
c
C
Cf
C
C
Thrombospondind
C
Cf
C
C
Clinical Chemistrye
L
L
Lf
L
L
Immunogenicityg
C
C
C
Viral serologyh
C
Blood groupi
L
Urine pregnancy testj
L
L
ADAMTS13=A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; 
anti-HBc=Hepatitis B-core total antibodies; C=Testing at central/specialty laboratory; HCV=Hepatitis C virus; 
HBsAg=Hepatitis B surface antigen; h=Hour; HIV=Human immunodeficiency virus; 
 
; IP=Investigational product; L=Testing at local laboratory; min=Minute; 
PD=Pharmacodynamic; PK=Pharmacokinetic; VWF=von Willebrand factor; VWF:Ag=von Willebrand factor 
antigen; VWF:RCo=von Willebrand factor:Ristocetin cofactor activity.
a.
ADAMTS13 activity, ADAMTS13 antigen, VWF:RCo, VWF:Ag, 
 
.
b.
Complete blood count with platelets and leukocyte differential.
c.
Plasma free hemoglobin requires separation of platelet-poor plasma within 2 hours of collection.
d.
Requires special handling (See Laboratory Manual).
e.
Clinical chemistry assessments: Sodium, potassium, chloride, bicarbonate, albumin, alanine 
aminotransferase, aspartate aminotransferase, 
, bilirubin (total, 
), alkaline 
phosphatase, blood urea nitrogen, creatinine, and glucose.
f.
To be performed at the following time points only: 3 h, 9 h, 24 h, 72 h, 120 h, 168 h.
g.
Immunogenicity assessments: Anti-ADAMTS13 antibody (binding and neutralizing).
h.
Viral serology: Anti-HIV 1/2, HBsAg, anti-HBc, anti-HBsAg, anti-HCV.
i.
Only if not available in subject’s medical history.
j.
For females of childbearing potential. To be performed if pregnancy is suspected during study period, or on 
withdrawal of the subject from the study.
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2. INTRODUCTION
2.1 Indication and Current Treatment Options 
Sickle cell disease (SCD) is a common genetic disorder affecting millions of people globally and 
decreasing life expectancy by 25 to 30 years (U.S. Preventive Services Task Force, 1996). 
In 2006, the World Health Organization (WHO) recognized SCD as a global public health 
problem (World Health Organization., 2006). Sickle cell disease is caused by a single base 
substitution of valine for a glutamic acid at the sixth amino acid of the gene coding for the 
hemoglobin (Hgb) β chain. This leads to sickle beta globin, which when deoxygenated forms 
chains of hemoglobin polymers that cause rigid and deformed (sickle-shaped) red blood cells. 
These sickle red cells are adhesive to endothelium and often unable to traverse the 
microcirculation. Damaged endothelium promotes white blood cell and platelet activations and 
adhesion, which in conjunction with sickled red cells, form blockages (vaso-occlusion) that 
cause decreased oxygen supply to tissues. The resulting ischemic blockages in the 
microvasculature cause severe hypoxia in tissues throughout the body, which can cause 
excruciating pain - often in multiple sites simultaneously - and additional debilitating 
comorbidities. Protracted and repeated exposure to these hypoxic crises can cause broad-ranging 
tissue injury, potentially leading to organ failure and even death.
Management of SCD has evolved slowly. Currently, the only curative therapy for SCD is bone 
marrow transplant but the use of this procedure is limited because of a lack of related or 
well-matched stem cell donors and risk for mortality and complications such as graft versus host 
disease (Bolaños-Meade and Brodsky, 2014). Chronic red cell transfusion therapy can reduce 
symptoms and complications of SCD but comes with a risk of infection, allo-immunization and 
significant iron overload. The primary pharmacotherapy approved for SCD is hydroxyurea. 
Hydroxyurea has been shown to reduce, but not eliminate VOCs requiring medical care and 
reduce the need for blood transfusions. Hydroxyurea continues to have a relatively low rate of 
use, especially in adults, partly because of its side effect profile, need for monitoring and 
concerns of toxicity. L-glutamine was recently approved by the food and drug administration for 
the reduction of VOCs as well, but there has yet to be widespread use of this agent partly 
because of a modest effect in clinical studies. Currently there are no agents approved for the 
amelioration of vaso-occlusive painful episodes once they occur (Kato et al., 2018). Despite 
these therapeutic options, patients with SCD continue to suffer significant morbidity and 
mortality, and there is an imperative to identify and evaluate new treatments.
There has been increasing evidence to suggest that an elevated level of von Willebrand factor 
(VWF) antigen and the accumulation of larger VWF multimers in circulation are associated with 
the development of vaso-occlusion and thrombotic complications in patients with SCD 
(Zhou et al., 2009). 
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The existence of hyper-adhesive ultralarge VWF (ULVWF) multimers in plasma and on vascular 
endothelium indicates that the activity of metalloprotease ADAMTS13, which cleaves ULVWF 
multimers to reduce their adhesiveness, is probably impaired in these patients with SCD. This 
impairment may come from biochemical inhibitors of ADAMTS13 (free hemoglobin and 
thrombospondin-1) and/or by the relative deficiency of ADAMTS13 that occurs as the 
concentrations of ULVWF increase without a concomitant increase in ADAMTS13 
concentration (Bonnefoy et al., 2006; Novelli et al., 2013; Zhou et al., 2011).
Ultralarge VWF additionally promotes the aggregation of other processes that lead to 
vaso-occlusion in SCD (see Figure 2 in Zhou et al., 2011). As VWF binds endothelium and 
activated platelets, blood flow decreases. Decreased blood flow promotes white blood cell 
adherence to endothelium, decreases red cell transit time to promote increased deoxygenation 
and further sickling and hemolysis, which in turn releases free hemoglobin that impairs 
ADAMTS13 function.
The pathophysiologic role of VWF is thought to be common to all VOCs, and therefore 
treatment with rADAMTS13 may be relevant for all VOCs. As therapeutic concentrations of 
ADAMTS13 are achieved, ULVWF is cleaved into lower molecular weight forms that are less 
adhesive and less able to trap cells in low blood flow areas. Therapeutic levels of ADAMTS13 is 
hypothesized to increase blood flow and lead to faster resolution of VOC pain that is caused by 
ischemia.
There may be multiple reasons for the acquired ADAMTS13 deficiency associated with SCD, all 
affecting the synthesis and activity of the metalloprotease. The proinflammatory cytokines such 
as tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 have been shown to stimulate the 
secretion of ULVWF from inflamed endothelial cells, and IL-6 has been shown to inhibit 
ADAMTS13. It was also observed that the VWF cleavage activity of plasma ADAMTS13 is 
about 35% lower in patients with SCD than in normal individuals, even though the antigen level 
of the metalloprotease was normal. Similarly, others have reported that the ADAMTS13 
activity/VWF antigen ratio is lower in patients with SCD. These observations support the view 
that there is acquired ADAMTS13 deficiency associated with SCD.
2.2 Product Background and Clinical Information
Takeda has developed a recombinant ADAMTS13 (rADAMTS13) named SHP655 (previously 
known as BAX 930) which is synthesized by a genetically engineered Chinese hamster ovary 
(CHO) cell line that expresses the human ADAMTS13 complementary DNA (cDNA). To 
address concerns regarding the risk of transmission of blood-borne pathogens that may be 
introduced by human plasma, no exogenously added raw materials of human or animal origin are 
employed in the cell culture, purification, or formulation of the final product. 
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A plasma-protein-free method and 2 virus inactivation steps are used in this process. This 
process virtually eliminates any risk of transmission of human blood-borne viruses or other 
adventitious agents that could, in theory, be introduced by the use of animal- or human-derived 
raw materials. The only proteins present in the final product other than SHP655 are trace 
quantities of host cell (i.e., CHO) protein.
SHP655 is a composition of the fully glycosylated recombinant human ADAMTS13 protein and 
a fully glycosylated recombinant human ADAMTS13 protein variant. Testing of the SHP655 
cell bank in 2017 revealed a single nucleotide exchange (A to G) in the catalytic domain 
resulting in amino acid change Glutamine “Q” to Arginine “R” at position 97 at the protein level 
(described as “Q97R variant”). Further investigation revealed that the Q97R variant was 
consistent throughout product development, was a rare naturally occurring variant in humans and 
did not appear to increase immunogenicity. No differences in the structure/function relationship 
of native and variant protein in the composition was observed and no safety concerns have been 
identified.  Variant protein constitutes between 52%-72% of the product.
SHP655 is a lyophilized formulation for intravenous (IV) injection. SHP655 is a composition of 
the fully glycosylated recombinant human ADAMTS13 protein and a fully glycosylated 
recombinant human ADAMTS13 protein variant that appears to be benign in nature.
See Section 6.1 for further information on the investigational product (IP) and its usage in this 
study. A detailed description of SHP655 is also provided in the investigator’s brochure (IB).
2.2.1 Nonclinical studies
Nonclinical studies have been performed in vitro and in vivo to characterize the safety, efficacy, 
pharmacokinetic (PK), and toxicity of SHP655 (Denorme et al., 2016; Denorme et al., 2015; 
Höllriegl et al., 2013; Kopic et al., 2016; Plaimauer and Scheiflinger, 2004).
The SHP655 nonclinical development program to support the planned Phase 1 trial in patients 
with sickle cell disease is based on the nonclinical program conducted with SHP655 for the 
indication of congenital TTP (cTTP). It includes in vivo testing for efficacy, safety 
pharmacology, pharmacokinetics (PK), and toxicity in several rodent and nonrodent species, 
including non-human primates.
In addition to the nonclinical efficacy studies already submitted in support of TTP, which are 
considered supportive for the SCD indication, because the underlying proposed mechanism of 
action is the same, the sponsor completed specific in vitro and in vivo efficacy studies with 
SHP655 to support the use in the indication of SCD.
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In an in vitro pharmacology proof-of-concept study, the inhibitory effect of hemoglobin on 
ADAMTS13-mediated VWF multimer cleavage and whether ADAMTS13 can prevent or 
override this inhibitory effect of hemoglobin were evaluated. Results confirmed the inhibitory 
effect of hemoglobin at concentrations approximating those in patients during acute VOC and 
showed that this effect can be prevented by appropriate concentrations of rADAMTS13.
In an in vivo pharmacology proof-of-concept study, a transgenic mouse model for human SCD 
(Tim Townes mouse), was used to assess the effects of SHP655 administration on hypoxia 
induced SCD-related acute VOC. Mice were studied under two forms of hypoxia, a severe form 
to study the survival and more mild version to study the effect on blood and tissue parameters. 
Under the severe hypoxic conditions, SS mice treated with SHP655 survived, while all 
vehicle-treated SS animals were sacrificed in extremis. Under the milder hypoxic conditions, 
SHP655 reduced the hypoxia-induced systemic inflammation and hemolysis, pulmonary vascular 
leakage, vaso-constriction, inflammatory vasculopathy, formation of cell inflammatory infiltrate, 
and thrombi in lung and kidney.
General safety pharmacology evaluations did not find deleterious effects of SHP655 on 
cardiovascular and respiratory functions in cynomolgus monkeys. Pharmacokinetic evaluations 
demonstrated similar PK profiles for SHP655 in rats and cynomolgus monkeys. 
Overall, the completed nonclinical toxicity studies with SHP655 support the following 
conclusions:

SHP655 did not cause any adverse effects on respiratory and cardiovascular function in 
cynomolgus monkeys at a dose up to 400 IU/kg, which was the highest dose tested.

In a 4-week repeat dose toxicity study in rats the no-observed-adverse-effect-level 
(NOAEL) was 1820 IU/kg/day, the highest dose tested in this study and the maximum 
feasible dose.

In a long-term toxicity study in rats, there was no evidence of toxicity after IV injection of 
400 IU/kg every 3 days for 26 weeks. Based on these results, the NOAEL was considered 
to be at 400 IU/kg, which was the highest dose tested.

Administration of 80, 200, or 400 IU/kg SHP655 once a week for 29 days in cynomolgus 
monkeys did not cause any adverse clinical symptoms, target organ pathologies, or other 
adverse findings directly attributable to the test item. The NOAEL was the highest dose 
tested, 400 IU/kg.

SHP655 was well tolerated after IV (intended clinical administration route) (5 mL), 
intra-arterial (5 mL), and paravenous (0.5 mL) administration in a local tolerance study in 
New Zealand white rabbits.
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
In female fertility and embryo-fetal development and pre and postnatal development 
studies in rats, no reproductive toxicity was observed at doses up to 400 IU/kg, which was 
the highest dose tested. A human placenta transfer study demonstrated that there is no 
biologically relevant transfer of SHP655 from the maternal blood circulation to the 
embryo.
Please see Section 4 of the IB for further details on nonclinical studies of SHP655.
2.2.2 Clinical studies
The use of SHP655 has not yet been examined in patients with SCD. In the completed first in 
human Phase 1 Study 281101 in patients with congenital thrombotic thrombocytopenic purpura, 
SHP655 was active in vivo, including effects on VWF multimers and platelet counts. 
Please refer to Section 5 of the IB for further details on effects of SHP655.
2.3 Study Rationale
Sickle cell disease patients have a higher ratio of ULVWF:ADAMTS13 activity compared to 
that found in the healthy population. By increasing the concentration of plasma ADAMTS13 
with SHP655, a more physiologic balance of ULVWF:ADAMTS13 ratio may be restored 
(Schnog et al., 2006; Sins et al., 2017). Dosing to achieve a meaningful increase over normal 
activity (i.e., supraphysiologic) levels is anticipated to be necessary to achieve a therapeutic 
effect in the presence of biochemical inhibitors (i.e., plasma free hemoglobin and 
thrombospondin-1) to ADAMTS13 and relatively high concentrations of ULVWF.
This study will assess safety (including immunogenicity), tolerability, PK and 
pharmacodynamics (PD) of SHP655 in SCD. Understanding the relationships among PK, PD, 
biomarkers, and their clinical correlates can guide the design of the subsequent studies. 
2.4 Benefit/Risk Assessment
The benefit-risk relationship was carefully considered in the planning of this study. Based on the 
nonclinical data available from the IB to date, the conduct of this study is considered justifiable 
using the dose(s) and dosage regimen(s) of SHP655 as specified in this clinical study protocol. A 
direct benefit is considered unlikely for participants in this Phase 1 study. The sample size of the 
dose cohorts was chosen to provide descriptive statistics to further explore the safety, PK, PD, 
and immunogenicity of SHP655 in the specific indication. Participation in this study may help 
develop important scientific knowledge that should contribute to the development of better 
comprehensive treatment of subjects with SCD. A Dose Escalation Committee is planned for 
ongoing safety review during the study. 
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The Dose Escalation Committee may stop enrollment and/or escalation to the next dose cohort 
based on the criteria outlined in Section 6.2.3.1 and Section 6.2.3.2. A list of dose-limiting 
toxicities can be found in Section 6.2.3.2.
In summary, it needs to be determined that the benefits of conducting the study outweigh the 
potential risks of SHP655 administration at this stage of product development. The key societal 
benefit is a better understanding of treatment options for patients with SCD.
Currently, the highest dose planned for this study is 160 IU/kg, allowing a 2.5-fold safety margin 
from the lowest NOAEL in the 6-month toxicity study (400 IU/kg). Data from the most recent 
repeat dose toxicity study in rat, with daily administration of 800 and 1820 IU/kg/day for 30 days 
even allow 5-fold and 11-fold, based on exposure and dose respectively, safety margin for the 
highest dose planned for this study of 160 IU/kg.
Always refer to the latest version of the SHP655 IB for the overall benefit/risk assessment and 
the most accurate and current information regarding drug metabolism, pharmacokinetics, 
efficacy, and safety of SHP655. 
2.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; E6 R2, 2017), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
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3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Primary Objective
Assess safety, tolerability, and immunogenicity of SHP655 in subjects with SCD at baseline 
health 
3.1.2 Secondary Objectives
Pharmacokinetic Objective: 

Assess the single dose PK of SHP655 at 3 dose levels in subjects with SCD.
Pharmacodynamic Objectives:

Assess the effect of SHP655 on VWF and platelets

Study the correlation of plasma free hemoglobin and thrombospondin on SHP655 activity 
and VWF.
3.1.3 Exploratory Objective

Assess additional exploratory biomarkers, 
 
 
.
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3.2 Study Endpoints
Table 3. Objectives and Endpoints
Objective
Endpoint(s)
Primary
Assess safety, tolerability, and 
immunogenicity of SHP655 in subjects 
with SCD subjects at baseline health 

SAEs/AEs, adverse changes in vital signs and laboratory 
parameters, and incidence of binding and inhibitory antibodies 
to SHP655 occurring up to 28±3 days after SHP655 infusion.
Secondary
Assess the PK of SHP655 at 3 dose levels 
in subjects with SCD

Including but not limited to: IR, Cmax, tmax, t1/2, MRT0-inf, 
MRT0-72, AUC0-last, AUC0-inf, AUC0-72, CL, and Vss will be 
estimated for ADAMTS13 activity and ADAMTS13 antigen.
Assess the effect of SHP655 on von 
Willebrand factor (VWF) and platelet 
count.

VWF:antigen (VWF:Ag), VWF:Ristocetin cofactor activity 
(VWF:RCo), and platelet count.
Study the correlation of plasma free 
hemoglobin and thrombospondin on 
SHP655 activity 
Plasma free hemoglobin and plasma thrombospondin levels
Exploratory
Assess additional exploratory biomarkers, 
 
 
.
ADAMTS13=A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13; AE=Adverse 
event; AUC0-72=Area under the concentration-time curve from zero (predose) to 72 hours postdose; 
AUC0-inf=Area under the concentration-time curve from zero (predose) extrapolated to infinite time, 
AUC0-last=Area under the concentration-time curve from zero (predose) to time of last quantifiable concentration; 
CL=Systemic clearance; Cmax=Observed maximum concentration; 
; IR=Incremental 
recovery; 
; MRT0-72=Mean residence time from zero (predose) to 72 hours postdose; 
MRT0-inf=Mean residence time from zero (predose) extrapolated to infinite time; PK=Pharmacokinetic; 
SAE=Serious adverse event; SCD=Sickle cell disease; t1/2=Terminal half-life; tmax=Time to reach Cmax; 
Vss=Volume of distribution at steady state; VWF=von Willebrand factor.
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4. STUDY DESIGN
4.1 Overall Design 
This is a Phase 1, randomized, double-blind, placebo-controlled, multicenter ascending dose 
study evaluating the safety, tolerability, and immunogenicity of SHP655 (rADAMTS13) in 18 to 
65-year-old subjects with SCD. This study will also characterize the PK and assess the PD of 
SHP655 and its effect on biomarkers.
Dose escalation
Approximately 20 subjects with baseline SCD will be randomized in a 3:1 ratio to receive either 
SHP655 or placebo as single IV infusion at 3 dose levels: 40 IU/kg (n=4), 80 IU/kg (n=8), or 
160 IU/kg (n=8). The dose cohorts will be opened sequentially, after safety data up to the Day 13 
visit of the last subject in the previous dose cohort has been reviewed by the Dose Escalation 
Committee. The number of subjects will be increased to 8 subjects per dose cohort 
(6 active:2 placebo) in the 80 IU/kg and 160 IU/kg dose cohorts for more robust PK, PD, 
clinical, and biomarker assessments.
There will be a 14-day interval between dosing for the first 3 subjects in any dose cohort. The 
higher dose cohorts will be opened only after safety data from up to Day 13 post-infusion from 
all subjects at the corresponding dose have been evaluated by the Dose Escalation Committee. 
Enrollment and escalation to next dose cohort will be paused for review if anaphylaxis, 
neutralizing antibody, or death is reported.
4.2 Scientific Rationale for Study Design
The ratio of ULVWF:ADAMTS13 activity is higher in subjects with SCD than in healthy 
people. Hence, the study population selected for this study includes subjects with SCD. 
Additionally, dosing of SHP655 to supraphysiologic levels has not been characterized clinically. 
In this Phase 1, dose escalation study, SHP655 or placebo will be administered as single dose 
IV infusion at 3 dose levels (40, 80, and 160 IU/kg) to evaluate PK, PD, clinical, and biomarker 
assessments.
Using a placebo improves the integrity of the study in several ways. Placebo provides a 
comparison group for evaluation of safety in a study population that is anticipated to have 
comorbidities that are reported as AEs. Obtaining PK/PD assessments on subjects receiving 
placebo serves as a control group for PK/PD and biomarker assessments.
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Blinding IP treatment removes bias from the study design. Knowledge of active versus placebo 
treatment can influence reporting of safety events, perception and reporting of pain, and affect 
clinical management decisions that can influence study outcomes. Similarly, randomization
reduces bias by ensuring that a relationship between baseline characteristics and outcomes is due 
to chance, and not by confounding traits (e.g., disease severity).
A Dose Escalation Committee is included in the study design to provide ongoing monitoring of 
safety and study progress. At each dose level, a decision must be made about the safety of 
increasing to a higher dose level. The Dose Escalation Committee may recommend that the 
number of subjects at a dose level be changed to obtain additional safety information, cap 
enrollment at a dose level, or modify a dose at a subsequent dose level, taking into consideration 
data that are observed in other cohorts.
4.3 Justification for Dose
Dosing to achieve a meaningful increase over normal activity (i.e., supraphysiologic) levels is 
anticipated to be needed for a therapeutic effect in the presence of biochemical inhibitors to 
ADAMTS13 and relatively high concentrations of ULVWF. Doses are escalated to evaluate
safety prior to higher dose exposure. Single dose exposure to 40 IU/kg has been found to be safe 
and well tolerated in subjects with congenital thrombotic thrombocytopenia purpura and was 
selected as the starting dose for this study. 
A mechanistic PK/PD modeling study guided dosing of SHP655 by providing a quantitative 
relationship between dose level and VWF activity. Based on the clinical goal of reducing the 
VWF activity level in SCD patients with a VOC to a normal level, the model indicates that this 
can be achieved with a single dose of approximately 120 U/kg. The low exposures of SHP655 in 
the monkey study were attributed to neutralizing antibodies and are not considered to be 
predictive of antibody formation in humans, therefore the rat data is more relevant for deriving 
safety margins. The NOAEL (1820 U/kg) observed in the 30-day daily administration study in 
rats represents a 10.8X safety margin to the starting dose (40 U/kg) and a 5.6X safety margin to 
the highest proposed clinical dose 160 U/kg in the initial Phase 1 clinical trial based upon 
predicted clinical exposure. Thus, the dose levels selected in this study were 40, 80, and 
160 IU/kg.
4.4 Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 2 months. The 
study will be completed in approximately 2 years. 
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The study completion date is defined as the date on which the last subject in the study completes 
the final protocol-defined assessment(s). This includes the End of Study Visit or Termination 
Visit, whichever is later (refer to Section 8.1.3).
Sites and Regions
The study will be conducted at approximately 20 sites in the United States.
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5. STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
5.1 Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Age 18 to 65 years at the time of signing the informed consent.
2. An understanding, ability, and willingness to fully comply with study procedures and 
requirements.
3. Ability to voluntarily provide written, signed, and dated (personally or via a legally 
authorized representative) informed consent to participate in the study.
4. Male or female with a documented history of HbSS or HbSβo thalassemia (based on clinical 
record of genetic, electrophoresis, or high-performance liquid chromatography testing).
5. Subject currently taking hydroxyurea must be on a stable dosing for 3 months at screening.
5.2 Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met.
1. The subject was diagnosed with acute VOC in the 21 days before dosing on Day 1
2. The subject has undergone blood transfusion within the last 30 days or blood transfusion on 
≥2 occasions in the last 90 days, at Screening Visit.
3. The subject has a history of acquired or congenital thrombotic thrombocytopenic purpura.
4. The subject has serum creatinine level >1.2 mg/dL at the Screening Visit 
5. The subject has alanine transaminase >3×upper limit of normal (based on clinical laboratory 
normal range), direct bilirubin level > 2 mg/dL, or indirect bilirubin level >5 mg/dL at the 
Screening Visit.
6. The subject has a hemoglobin level <5 g/dL at the Screening Visit.
7. The subject has a platelet count of <100 000/mm3 at the Screening Visit.
8. Signs or symptoms of infection requiring treatment with IV antibiotics during the Screening 
Period.
9. The subject has fever with body temperature of ≥38.5ºC (101.3ºF) at the Screening Visit or 
before dosing on Day 1.
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10. The subject has acute chest syndrome (ACS), diagnosed or strongly suspected, as evidenced 
by a new infiltrate on chest radiograph, and one or more of the following criteria:

Fever with body temperature >39°C (102.2°F)

Hypoxia (confirmed by arterial blood gases with PaO2 <70 mmHg)

Chest pain

Suspicious findings on physical examination (tachypnea, intercostal retraction, wheezing, 
and/or rales).
11. The subject has recently (within the past 28 days, from Screening Visit) undergone major 
surgery, requires hospitalization, documented serious bacterial infection requiring antibiotic 
treatment, or significant bleeding.
12. The subject has had a recent (within the past 90 days, from Screening Visit) episode of 
stroke, transient ischemic attack, symptomatic pulmonary hypertension, or seizure.
13. Any history of hemorrhagic stroke or bleeding diathesis.
14. The subject has received any of the following protocol-restricted medicines: a) systemic 
steroid therapy within 48 hours before dosing, or there is the expectation that such therapy 
may be given during the study (inhaled or topical steroids are allowed); b) Anticoagulant or 
antiplatelet therapy within the past 3 weeks before dosing; c) crizanlizumab within the past 
30 days before dosing; d) voxelotor within the past 14 days before dosing.
15. For subjects receiving chronic or long-acting opioids, a change in dose or pain requiring 
medical attention in the past 14 days before dosing.
16. The subject has a medical or psychiatric condition that, in the opinion of the investigator, 
may pose a risk to the subject for participation or interfere with the conduct or results of the 
study.
17. The subject has received or plans to receive any other investigational agent within the 
4 weeks prior to the study Screening Visit or during the course of the study.
18. There is the expectation that the subject will not be able to be followed for the duration of the 
study.
19. The subject is pregnant or lactating or a female of childbearing potential or male unable or 
unwilling to comply with birth control methods or abstinence until the end of study visit.
20. The subject with active use of illicit drugs (excluding marijuana) and/or alcohol dependence, 
as determined by the investigator.
21. The subject has been administered SHP655 previously.
22. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent 
molecule ADAMTS-13, hamster protein, or other constituents of SHP655.
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23. The subject has a positive test result for hepatitis B surface antigen, or hepatitis C antibody, 
or HIV antigen/antibody, at the Screening Visit. However, a subject with a hepatitis C 
antibody and a negative hepatitis C virus RNA polymerase chain reaction test is not 
excluded.
5.3 Restrictions
No dietary or activity restrictions are associated with this study.
5.4 Reproductive Potential
5.4.1 Female Contraception
Sexually active females of childbearing potential should use a highly effective or acceptable 
method of contraception. Females of childbearing potential must be advised to use these 
contraceptive methods throughout the study period.
Female subjects should be either:

Postmenopausal 

Surgically sterile, or

Of childbearing potential with a negative urine and/or serum beta-human chorionic 
gonadotropin (β-hCG) pregnancy test at Screening Visit.
5.4.2 Male Contraception
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to 1 of the following: 

Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent during the 
study period.

Agree to use a male condom when having penile-vaginal intercourse with a partner of 
childbearing potential who is not currently pregnant during the study period.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
SHP655 and placebo (0.9% saline)
Dosage form:
Lyophilized formulation in capacity of 2 dosing solutions (100 and 300 IU/mL).
Dosage frequency:
One dose is administered per subject. 
Mode of Administration: 
Intravenous
SHP655 (rADAMTS13), a recombinant ADAMTS13, which is synthesized by a genetically 
engineered CHO cell line that expresses the human ADAMTS13 cDNA. It will be provided in 
lyophilized formulation together with sterile water for reconstitution for IV administration. 
Additional information is provided in the current SHP655 IB.
The reference/comparator product is placebo (0.9% saline).
6.1.2 Blinding the Treatment Assignment
This is a randomized, double-blind, placebo-controlled study with limited access to the 
randomization code. SHP655 and placebo will be prepared by an unblinded pharmacist and will 
be provided to the investigator or designee in a blinded manner after reconstitution. Investigators 
do not have access to the randomization (treatment) code except under circumstances described 
in Section 6.2.4.
6.2 Administration of Investigational Product
The reconstituted solution of SHP655 should be inspected for particulate matter and 
discoloration prior to administration. The solution should be clear and colorless in appearance. If 
not, do not administer the product. SHP655 should be administered at room temperature and 
within 3 hours of reconstitution. Prior to administration, ensure that venous access via an 
IV cannula is available. However, for IP infusion, the butterfly needle may be inserted 
immediately prior to the infusion.
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6.2.1 Interactive Response Technology for Investigational Product Management
An IRT system will be used for screening and randomizing subjects, recording subject visits, IP 
supply dispensation and management, inventory management and supply ordering, IP expiration 
tracking and management, IP return, and emergency unblinding. Please refer to the Study 
Manual for additional details regarding the IRT system.
6.2.2 Allocation of Subjects to Treatment 
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation.
The randomization number represents a unique number corresponding to IP allocated to the 
subject, once eligibility has been determined.
Individual subject treatment is automatically assigned by the IRT following a 3:1 ratio between 
SHP655 vs. placebo within each dose cohort.
Once a randomization number/unique identifier has been assigned, that number must not be used 
again if, for example, a subject is withdrawn from the study. If a randomization number/unique 
identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor must be 
notified as soon as the error is discovered.
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same IP packing identification number may not be 
assigned to more than one subject.
6.2.3 Dosing
The IP will be administered intravenously.
SHP655/placebo will be administered as a single IV infusion at 3 dose levels: 40 IU/kg (n=4), 
80 IU/kg (n=8), and 160 IU/kg (n=8).
The IP will be infused at 4 mL/min, to achieve an infusion rate of 1200 IU/min with 300 IU/vial 
preparation.
Note: For 100 kg person at 160 IU/kg = 16 000 IU/1200 IU/min = 13 minutes.
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The first 3 subjects in each dose cohort will be dosed a minimum of 14 days apart to observe and 
interpret reactions and adverse events in order to ensure that no related SAE requiring a pause or 
stop of the clinical trial (see Section 6.2.3.1 and Section 6.2.3.2) has occurred in the most 
recently treated subject.
In the event that DLT criteria are met (see Section 6.2.3.2), either revision of the dose to a lower, 
intermediate level or augmented enrollment of the previous dose level will be considered.
6.2.3.1 Stopping Criteria for Dose Escalation 
1. If 2 or more subjects in a given cohort receiving active drug have a related SAE in any vital 
organ or body system, no further subjects will be enrolled or dosed until further evaluation of 
the available data is made by the medical monitor and investigator to determine whether to 
stop or proceed with the study. Following a safety review of the event, study enrollment or 
dosing of currently enrolled subjects may be restarted if the Dose Escalation Committee 
determines that it is safe to proceed with the study.
2. Any neutralizing antibody to SHP655 that develops after administration.
3. Any death that is possibly related to SHP655 administration.
4. If any other drug-related event occurs in subjects receiving active drug and is deemed to pose 
an unacceptable risk to subjects by the investigator or medical monitor after further 
evaluation, no further subjects will be enrolled or dosed until further evaluation of the 
available data is made by the Dose Escalation Committee to determine whether to proceed 
with the study. Following a safety review of the event, study enrollment or dosing of 
currently enrolled subjects may be restarted if the medical monitor and the investigator 
determine that it is safe to proceed with the study.
6.2.3.2 Dose Limiting Toxicities
DLT are defined according to Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0. 
DLT are defined as two events of any of the following AEs at least possibly related to SHP655 
within a dose cohort:

Purpura Grade 2

Gastrointestinal hemorrhage Grade 1 (lower gastrointestinal, oral, esophageal, gastric, 
duodenal, ileal, cecal, or colonic hemorrhage)

Epistaxis Grade 2 
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
Menorrhagia Grade 2

Hematuria Grade 1
In the event that 2 DLTs are observed within a dose cohort, a Dose Escalation Committee 
meeting will be convened to review the treatment assignment of the subjects experiencing the 
toxicities to determine if DLT criteria have been met. 
The following are DLTs if observed in one SHP655 treated subject:

Purpura Grade 3 or higher

Gastrointestinal hemorrhage Grade 2 or higher (lower gastrointestinal, oral, esophageal, 
gastric, duodenal, ileal, cecal, or colonic hemorrhage)

Epistaxis Grade 3 or higher

Menorrhagia Grade 3 or higher

Hematuria Grade 2 or higher

Stroke Grade 2 or higher

Intracranial hemorrhage Grade 1 or higher

Any Grade 4 AE at least possibly related to SHP655 exposure.
DLTs are not to be AEs assessed by the investigator as disease related. 
6.2.3.3 Dose Escalation Committee 
Throughout the study, dose escalation meetings will commence at regular time points to review 
safety data and authorize progression into the next cohort. The Dose Escalation Committee may 
recommend continuing the study, stop dose escalation, expand a dose cohort to obtain more 
safety data, modify or add a dose escalation in between planned dose cohorts (e.g., 120 IU/kg 
after the 80 IU/kg dose cohort is evaluated), and add a dose to a treatment regimen within a dose 
cohort. The following arrangement is planned for the Dose Escalation Committee to help 
maintain study integrity.
The Dose Escalation Committee will convene at least after every dose cohort has been enrolled 
and completed up to the 2 week Follow-Up Visit. 
If AEs are observed within a dose cohort that could meet DLT criteria, the Dose Escalation 
Committee will review treatment assignments to determine whether the DLT has been reached.
The Dose Escalation Committee will recommend whether:
1. It is safe to proceed to the next dose cohort
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2. A dose level may be modified, reduced, or repeated, depending on the outcome of the safety 
data review
3. A dose level should be added or eliminated
4. Protocol modifications regarding dosing are needed
Dose escalation committee review meetings will be held after SAE and immunogenicity data are 
available up to Day 13 of the last subject in the dose cohort. This dose cohort will be opened for 
Dose Escalation Committee review. Enrollment will be paused for review for any case of 
anaphylaxis, neutralizing antibody, life-threatening condition, or death.
The Dose Escalation Committee will have a charter that defines roles, responsibilities, and 
procedures.
6.2.4 Unblinding the Treatment Assignment
The treatment assignment must not be unblinded to the investigator during the study except in 
emergency situations where identification of the IP is required for medical management of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
treatment code has been broken and the investigator is unblinded. 
In the event that the treatment assignment code is broken, the date and the signature of the person 
who broke the code are recorded on the IRT and in the source documents, as applicable. The 
reason for breaking the code will be recorded in the source documents, as appropriate, based on 
safety or deviation reporting. Upon breaking the blind, the subject will be withdrawn from the 
study, but should be followed up for safety purposes. Any code-breaks that occur must be 
reported to IQVIA and Takeda. For blinded studies, there will be a provision for unblinding to 
ensure adequate management of the subject in the case of an emergency.
Following the review of unblinded data for a completed dose cohort by the DEC, and a 
recommendation by the DEC that it is safe to proceed with enrollment of the next dose cohort, 
the Sponsor study team will have access to the unblinded data for the completed dose cohort, 
with details to be specified in an unblinding plan. 
6.2.5 Dose Modification
The decision to proceed to the next dose cohort will be made by the Dose Escalation Committee 
based on safety, tolerability, and preliminary PK and/or pharmacodynamic data. Enrollment will 
be paused for review for any case of anaphylaxis, neutralizing antibody, or death.
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The Dose Escalation Committee will monitor the safety of the study and will have standing to 
stop dose escalation, expand a dose cohort to obtain more safety data, modify or add a dose 
escalation in between planned dose cohort, and add a dose to a treatment regimen within a dose 
cohort.
In the event that DLT criteria are met (see Section 6.2.3.2), either revision of the dose to a lower, 
intermediate level or augmented enrollment of the previous dose level will be considered.
The IP will be permanently discontinued or temporarily discontinued based on Dose Escalation
Committee’s decision or after discussion with sponsor.
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1 Labeling
Labels containing study information and pack identification are applied to the IP (s) container.
All IP(s) is labeled with a minimum of the following: Protocol number, dosage form (including 
product name and quantity in pack), directions for use, storage conditions, expiry date, batch 
number and/or packaging reference, the statements “For clinical study use only” and/or 
“CAUTION: New Drug – Limited by Federal (or US) Law to Investigational Use”.
Space is allocated on the label so that the site representative can record a unique subject 
identifier.
Additional labels (e.g., those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the IP in order to satisfy local or institutional requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.

Break the study blind
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2 Packaging
Details are provided in Section 6.1.1.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
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6.3.3 Storage
The investigator has overall responsibility for ensuring that IP is stored in a secure, limited 
access location. Limited responsibility may be delegated to the pharmacy or member of the study 
team, but this delegation must be documented. Investigational products are administered by 
qualified study personnel or designee. The pharmacist/nominated team member will enter the 
unique subject identifier on the IP bottle/carton labels as they are distributed. Unblinded 
pharmacists will have access to IP supplied by the sponsor. Other study staff should only have 
access to IP in blinded syringes with the appropriate label.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the IP is maintained 
within an established temperature range. The investigator is responsible for ensuring that the 
temperature is monitored throughout the duration of the study and that records are maintained; 
the temperature should be monitored continuously by using either an in-house system, a 
mechanical recording device such as a calibrated chart recorder, or by manual means, such that 
both minimum and maximum thermometric values over a specific time period can be recorded 
and retrieved as required.
Such a device (i.e., certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the IP and will 
provide supportive documentation as necessary. Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the IP 
that could affect the integrity of the product(s), e.g., fumigation of a storage room.
All controlled-substance IP for the sponsor’s studies must be stored in a securely locked, 
substantially constructed room or cabinet according to all applicable local, state, and/or national 
laws. Limited, controlled access to these IP(s) must be maintained, as well as chain of custody, 
for all IP movement.
6.3.4 Special Handling
SHP655 must not be used beyond the expiration date printed on the vial. Freezing should be 
avoided at all times to prevent damage to the diluent vial. Before administration, the 
reconstituted product has to be brought to room temperature. Storage of SHP655 
post-reconstitution should be limited to 3 hours at room temperature. 
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In case large volumes of SHP655 are required, it is possible to pool multiple vials of SHP655 
together. The contents of each reconstituted product can be drawn in a single syringe. The 
recommended storage condition for SHP655 is 2 to 8°C. The expiration date for SHP655 is 
included on the IP label. The stability of the clinical lots will be monitored throughout the period 
of use in clinical studies.
For additional information please refer to the SHP655 IB and/or other specific instructions 
provided by the sponsor. Changes to sponsor-supplied packaging prior to dosing may not occur 
without full agreement in advance by the sponsor. 
6.4 Drug Accountability
Investigators will be provided with sufficient amounts of the IP to carry out this protocol 
for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the IP, documenting shipment content and condition. Accurate records of all 
IP dispensed, used, returned, and/or destroyed must be maintained as detailed further in this 
section.
The investigator has overall responsibility for administering/dispensing IP. Where permissible, 
tasks may be delegated to a qualified designee (e.g., a pharmacist) who is adequately trained in 
the protocol and who works under the direct supervision of the investigator. This delegation must 
be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the IP only to subjects included in this study 
following the procedures set out in the study protocol. Each subject will be given only the IP 
carrying his/her treatment assignment. All administered medication will be documented in the 
subject’s source and/or other IP record.
No IP stock or returned inventory from a Takeda-sponsored study may be removed from the site 
where originally shipped without prior knowledge and consent by the sponsor. If such transfer is 
authorized by the sponsor, all applicable local, state, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, and empty/used IP 
packaging are to be sent to a nominated contractor on behalf of the sponsor. Investigational 
products being returned to the sponsor’s designated contractors must be counted and verified by 
clinical site personnel and the sponsor (or designated CRO). 
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For unused supplies where the original supplied tamper-evident feature is verified as intact, the 
tamper-evident feature must not be broken and the labeled amount is to be documented in lieu of 
counting. Shipment return forms, when used, must be signed prior to shipment from the site. 
Validated electronic return systems (i.e., IRT) do not require a shipment form. Returned 
IP (s)must be packed in a tamper-evident manner to ensure product integrity. Contact the sponsor 
for authorization to return any IP prior to shipment. Shipment of all returned IP must comply 
with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile IPs 
delivered with those used and returned. All IP(s) must be accounted for and all discrepancies 
investigated and documented to the sponsor’s satisfaction.
6.5 Subject Compliance
The IP will be administered in the study center by the authorized study center staff. The 
investigator or designee will record the correct dose, date, and time of administration on the 
Drug Accountability Record.
6.6 Prior and Concomitant Therapy
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to the Screening Visit (Visit 1) (or pharmacokinetic equivalent of 
5 half-lives, whichever is longer) and through the final study contact (including protocol defined 
follow-up period) must be recorded in the subject’s source document. 
6.6.1 Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
non-pharmacological treatment such as psychotherapy as appropriate) received within 30 days of 
the date of screening. Prior blood transfusion history will be collected for 90 days prior to 
screening. Prior treatment information must be recorded in the subject’s source document, 
including use of oral opioids.
6.6.2 Concomitant Treatment 
Concomitant treatment refers to all treatment taken between screening and the study 
completion/termination visit, inclusive. Concomitant treatment information must be recorded in 
the subject’s source document.
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6.6.3 Permitted Treatment
Use of stable dose of hydroxyurea for 3 months prior to Screening Visit, and steroid for 
inhalation or topical application are permitted during the study. Females of childbearing potential 
are to continue using their hormonal contraceptives and postmenopausal women are allowed to 
use hormone replacement therapy.
The investigator must record the use of all concomitant medications, both prescribed and 
over-the-counter, into the electronic case report form (eCRF) and subject’s medical records. This 
includes medications used on both a regular and an as needed basis.
Subjects should be discouraged from starting any new medication, both prescribed and 
over-the-counter, without consulting the investigator, unless the new medication is required for 
emergency use or has been prescribed for clinical need.
The Sponsor recommends that subjects not be administered a vaccine against SARS-CoV2 
during the Study Period. Should a subject receive such a vaccination during the Study Period, the 
Sponsor recommends study investigators to follow patients closely for vaccine-related adverse 
events for 14 days after vaccination, in collaboration with the study medical monitor.
6.6.4 Prohibited Treatment

Systemic steroids within 48 hours prior to randomization

L-glutamine, voxelotor, and crizanlizumab are restricted during the study period

Anticoagulant or anti-platelet medications

Illicit drugs are prohibited during the study treatment 

Coagulation factor concentrates 

Administration of another investigational drug or device 
A subject who has taken any of these medications or received any of these non-drug therapies 
during the study may be withdrawn from the study at the discretion of the sponsor.
6.7 Adverse event management
The mechanism of action of SHP655 reduces high molecular weight von Willebrand factor. 
SHP655 dosing theoretically could induce a von Willebrand disease phenotype. In the event of 
hemorrhage after SHP655 dosing consistent with DLT criteria in Section 6.2.3.2, treatment that 
replenishes von Willebrand factor may be indicated. 
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Immunogenicity to SHP655 theoretically could result in a TTP-like syndrome. In case of 
evolving thrombocytopenia, neurologic changes, or thrombotic microangiopathy that emerges 
after IP dosing, ADAMTS13 activity should be tested. Treatment of an immunogenicity-induced 
TTP event with standard TTP treatment would be expected to be beneficial.
SHP655 should not be administered in patients with known hypersensitivity to any of the 
components of rADAMTS13. As with any i.v. protein product, allergic-type hypersensitivity 
reactions are possible. Subjects must be closely monitored for any symptoms throughout the 
infusion period. Subjects should be informed of the early signs of hypersensitivity reactions 
including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and 
anaphylaxis. If these symptoms occur, the administration should be discontinued immediately. In 
case of shock, standard medical treatment for shock should be implemented.
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7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL
7.1 Discontinuation of Study Treatment
If IP is discontinued, regardless of the reason, the evaluations listed for study completion visit 
will be performed as completely as possible. Whenever possible, all discontinued subjects should 
also undergo the protocol-specified evaluations at termination visit. Comments (spontaneous or 
elicited) or complaints made by the subject regarding discontinuation must be recorded in the 
source documents. The reason for discontinuation, date of discontinuation of the IP, and the total 
amount of IP administered must be recorded in the source documents.
Subjects may be replaced at the same dose cohort for drop out prior to the Day 13 
immunogenicity sampling.
7.2 Reasons for Discontinuation 
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document. If a subject is discontinued for more than one reason, each 
reason should be documented in the source and the most clinically relevant reason should be 
indicated. 
Reasons for discontinuation include, but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow-up

Other (e.g., pregnancy)
7.3 Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (e.g., in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or telephone contact). 
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At least 1 of these documented attempts must include a written communication sent to the 
subject’s last known address via courier or mail (with an acknowledgment of receipt request) 
asking that the subject return to the site for final safety evaluations.
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8. STUDY ASSESSMENTS AND PROCEDURES
Prior to performing any study assessments that are not part of routine medical care for 
the subject, the investigator will obtain written informed consent as described in Appendix 1.5. 
Any subject who is randomized is considered a subject enrolled in the study.
The following series of numbers will comprise the subject identifier: The last three digits of 
the protocol identifier (i.e., 101), a 3-digit study site number (e.g., 002), and 4-digit subject 
number (e.g., 0003) assigned by the IRT system and reflecting the order of enrollment 
(i.e., signing the ICF). For example, the third subject who signed an ICF at study site 002 will 
be identified as Subject 101-002-0003. All study documents (e.g., case report forms [CRFs], 
clinical documentation, sample containers, drug accountability logs, etc.) will include the 
subject identifier. Subjects who fail to meet eligibility criteria may be re-screened during the 
open screening period of the study. A different subject identifier will be issued to all such 
subjects.
8.1 Study Schedule
The overall study design is illustrated in Figure 1. Details on the assessments to be performed at 
each study visit, including screening, are provided in Table 1. Study assessments are detailed in 
Section 8.2.
8.1.1 Screening Visit
All screening procedures and confirmation of eligibility shall take place within 28 days prior to 
the first infusion of IP. If the IP is not infused within 28 days, all screening assessments must be 
repeated to reconfirm eligibility.
The study site is responsible for maintaining a screening and enrollment log that includes all 
subjects who provided informed consent. The log also will serve to document the reason for 
screening failure.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered IP. A 
complete or partial re-screen may also become necessary at the discretion of the investigator or 
sponsor.
8.1.2 Treatment Period 
On Day 1, the subjects will be randomized to receive either SHP655 or placebo in a 3:1 ratio. 
Additional Day 1 procedures will be carried out in accordance with the Schedule of Assessment
in Table 1. 
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Subjects with any ongoing AEs or SAEs at the time of scheduled discharge from the study center 
should remain at the study center until the investigator has determined that these events have 
been resolved or deemed as not clinically significant by the investigator.
The Treatment Period consists of the Day 1 IP infusion through the last planned PK/PD 
assessment.
8.1.3 Follow-up Period
The follow-up period for this protocol is 13 days. At the end of this period there will be 
a Follow-Up Visit query for SAEs, AEs, and concomitant treatments. All AEs and SAEs that are 
not resolved at the time of this contact will be followed to closure (see Appendix 3.2).
8.1.4 Study Completion/Termination Visit
After the follow-up period, all subjects will return to the study center for the EOS Visit. The 
EOS will be on Day 28 following IP infusion. Subjects who discontinue the study early will be 
asked to return to the study center for the termination visit. 
Different procedures will be carried out in accordance with the Schedule of Assessments in 
Table 1.
8.1.5 Additional Care of Subjects after the Study
No aftercare is planned for this study.
8.2 Study Assessments 
8.2.1 Demographic and Other Baseline Characteristics
Subject demographic information and other baseline characteristics including gender, age, and 
race, vital signs, physical examination, height/weight, medical history, prior medications, AE, 
etc. will be collected prior to the subject receiving the first dose of IP.
8.2.2 Safety
8.2.2.1 Physical Examination
At screening and subsequent study visits (refer to Section 1.3), a physical examination will be 
performed by the investigator. A complete physical examination includes, general appearance, 
eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, liver/gastrointestinal, 
extremities/musculoskeletal, skin/dermatological, neck/thyroid, lymph nodes, 
psychiatric/neurological systems.
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Abnormalities identified at the Screening Visit and at subsequent study visits will be recorded in 
the subject’s source documents. At study visits, if a new abnormal or worsened abnormal 
pre-existing condition is detected, the condition will be described on the AE CRF. If the 
abnormal value was not deemed an AE because it was due to an error, due to a preexisting 
disease not clinically significant, a symptom of a new/worsened condition already recorded as an 
AE, or due to another issue that will be specified, the investigator will record the justification on 
the source record.
8.2.2.2 Adverse Events
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (e.g., “Have you had any health problems since your last 
visit?”). Adverse events are collected from the time informed consent is signed. Refer to 
Appendix 3 for AE definitions, assessment, collection time frame, and reporting procedures. 
8.2.2.3 Vital Signs
Vital signs will be assessed pre- and post-infusion at each visit, if not stated otherwise:

Height (cm) and weight (kg).

Systolic/diastolic blood pressure (mmHg) baseline measurements will be measured after a 
10-minute rest in the supine/semi-recumbent position.

Pulse (beats/min) will be measured at the distal radial arteries under the same conditions as 
above.

Respiratory rate (breaths/min) will be measured over a period of 1 minute under the same 
conditions as above.

Body temperature (ºC or ºF) may be determined by oral, rectal, axillary, temporal, or 
tympanic measurement at the discretion of the investigator. However, the same method 
should be used for all measurements in 1 subject.
Vital signs, excluding height and weight, will be measured at screening and within 5 minutes
before the 15-minutes and 1-hour PK samplings, and within 30 minutes before all other PK 
samplings and at each study visit, and at study completion/termination. Blood pressure will be 
measured when subjects are in the supine/semi-recumbent position.
The investigator will assess whether a change from the Baseline Visit in vital signs may be 
deemed clinically significant and whether the change should be considered and recorded as an 
AE. If assessed as an AE, the medical diagnosis (preferably), symptom, or sign, will be recorded 
on the AE eCRF. Additional tests and other evaluations required to establish the significance or 
etiology of an abnormal value, or to monitor the course of an AE should be obtained when 
clinically indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
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8.2.2.4 Clinical Laboratory Tests
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out of range changes which may be associated with, or constitute, an AE. The 
investigator should assess out of range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
A complete list of the clinical laboratory tests to be performed is provided in Appendix 2.
8.2.2.5 Pregnancy Test
A urine or serum pregnancy test will be performed on all females of childbearing potential at the 
screening visit (Visit 1) and Baseline Visit; if pregnancy is suspected; or on withdrawal of the 
subject from the study.
8.2.3 Pharmacokinetics
Blood samples will be assessed to determine ADAMTS13 activity and ADAMTS13 antigen 
according to Schedule of Assessment presented in Table 1 as per the timepoints mentioned 
in Table 2. The actual date and time of dosing and of the blood sample collection will be 
recorded in the subject’s eCRF. The details of blood sample collection, sample tube labeling, 
sample preparation, storage, and shipping procedures will be described in a separate laboratory 
manual.
8.2.4 Pharmacodynamics
PD effects will be assessed by measuring VWF:Ag, VWF:RCo, and platelets, as specified in 
Table 2. The impact of plasma free hemoglobin and plasma thrombospondin levels will also be 
assessed. 
The actual date and time of the sample collection will be recorded in the subject’s eCRF. 
The details of blood sample collection, sample tube labeling, sample preparation, 
storage, and shipping procedures will be described in a separate laboratory manual. The 
analytical methods used to measure these PD endpoints will be described in a separate 
bioanalytical report.
8.2.5 Additional Exploratory Biomarkers
Biomarkers of SCD severity and additional PD readouts that may be impacted by SHP655 will 
be assessed. 
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These evaluations may include, but are not limited to,
 
 
 
.
The actual date and time of the sample collection or observation will be recorded in the subject’s 
eCRF. The details of blood sample collection, sample tube labeling, sample preparation, storage, 
and shipping procedures will be described in a separate laboratory manual.
8.2.6 Retention of Study Samples
Biologic samples will be retained in biostorage for up to 4 years after study completion. Consent 
will be obtained for any testing of these samples that are outside the objectives of this study.
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9. STATISTICAL CONSIDERATIONS
9.1 Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the safety, pharmacokinetic, and pharmacodynamic data, as well as describe the 
approaches to be taken for summarizing other study information such as subject disposition, 
demographics and baseline characteristics, IP exposure, and both prior and concomitant 
medications. It will also provide the preparation of tables, listings, and figure details.
The SAP will be finalized prior to final unblinding to preserve the integrity of the statistical 
analysis and study conclusions. Data handling approaches, including imputation of missing 
values, will be provided in the SAP.
Data will be summarized by dose level. The placebo group will be pooled for the presentation.
All statistical analyses will be performed using statistical analysis system (SAS) (SAS Institute, 
Cary, NC 27513) Version 9.4 or above.
9.2 Planned Interim Analysis, Adaptive Design, and Data Escalation Committee
Although no formal DMC will be involved in the management of this study, safety will be 
monitored by a Takeda Dose Escalation Committee. Please refer to Section 6.2.3.2 for more 
details.
9.3 Sample Size and Power Considerations
Four evaluable subjects (3 active:1 placebo) will be the first to be enrolled at the 40 IU/kg dose 
cohort in baseline health in order to obtain initial safety and PK data. The number of subjects 
will be increased to 8 evaluable per dose cohort (6 active:2 placebo) in the 80 and 160 IU/kg 
dose cohorts for more robust PK, PD, clinical and biomarker assessments. 
Sample size: 
40 IU/kg
(n=3)
80 IU/kg
(n=6)
160 IU/kg
(n=6)
Placebo
(n=5)
Sample size is not selected by a power calculation. It is chosen to provide descriptive statistics 
for safety, tolerability, immunogenicity and PK data following administration of SHP655.
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Subjects may be replaced at the same dose cohort for drop out prior to the Day 13 
immunogenicity sampling.
9.4 Statistical Analysis Set(s)
Classification into all Analysis Sets, except for PK and PD Analysis Sets, will be conducted prior 
to database lock. The PK and PD Analysis Sets will be concluded after database lock using final 
data from the database and final concentrations in accordance to the criteria specified below.
The Safety Analysis Set will consist of all subjects randomized and who received any dose of IP.
The PK Analysis Set will contain all subjects who receive at least one complete dose of SHP655 
or placebo and provide at least 1 concentration measured at a scheduled time post start of 
infusion for at least 1 of the PK analytes and have no major protocol deviations or events that 
may affect the integrity of the PK data. Subjects in this population will be used for all PK 
summaries.
The PD Analysis Set will contain all subjects who receive at least one complete dose of SHP655 
or placebo and provide at least 1 valid data point postdose of the respective infusion for at least 
1 PD measurement for any of the PD outcome measures, and have no major protocol deviations 
or events that may affect the integrity of the PD data. Subjects in this population will be used for 
all PD summaries.
9.5 Safety Analyses
All safety analyses (including the primary analysis and exploratory analyses) will be performed 
on the Safety Analysis Set.
9.5.1 Primary Safety Endpoint
The safety endpoints will include SAEs and AEs, adverse changes in vital signs and laboratory 
parameters, and incidence of binding and inhibitory antibodies to SHP655 occurring up to 
28±3 days after SHP655 infusion.
9.5.2 Statistical Analysis of Safety Parameters
Safety, including immunogenicity data, will be assessed using descriptive summaries by dose 
cohort appropriate for the measure (e.g., number and percent for categorical measures and mean, 
standard deviation, quartiles, and range as appropriate for continuous measures).
For each measure, baseline is the last non-missing value reported prior to the first infusion of IP.
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Treatment-emergent adverse events (TEAEs) are defined as AEs that started or worsened in 
severity on or after the infusion of IP. 
The number of events, incidence, and percentage of TEAEs will be calculated overall, by system 
organ class, by preferred term, and by treatment cohort. Treatment-emergent adverse events will 
be further summarized by severity and relationship to IP. Adverse events related to IP, AEs 
leading to withdrawal, SAEs, and deaths will be similarly summarized/listed. AEs and SAEs will 
be tabulated and summarized according to the Medical Dictionary for Regulatory Activities.
Individual and summary vital signs and clinical laboratory data will be presented in tabular form. 
For laboratory safety data, out of range values will be flagged in the data listings and a list of 
clinically significant abnormal values will be presented. 
The number and proportion of subjects will be summarized by dose for incidence of binding and 
inhibitory antibodies to SHP655.
9.6 Pharmacokinetic and Pharmacodynamic Analyses
The PK, PD, and PK/PD analyses are described below. Additional details will be provided in the 
SAP.
9.6.1 Pharmacokinetic Analysis
Pharmacokinetic parameters for ADAMTS13 activity and ADAMTS13: Ag following SHP655 
or placebo infusion will be derived using non-compartmental methods, including but not limited 
to, where applicable and estimable:

Incremental recovery

Observed maximum concentration (Cmax)

Time to reach Cmax (tmax)

Terminal half-life (t1/2)

Mean residence time from zero (predose) extrapolated to infinite time (MRT0-inf) and 
from zero (predose) to 72 hours postdose (MRT0-72)

Area under the concentration-time curve from zero (predose) to time of last quantifiable 
concentration (AUC0-last)

Area under the concentration-time curve from zero (predose) to 72 hours postdose 
(AUC0-72) and/or partial AUC over other time intervals may be calculated as appropriate

Area under the concentration-time curve from zero (predose) extrapolated to infinite time 
(AUC0-inf)
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
Systemic clearance (CL)

Volume of distribution at steady state (Vss)
Weight measured at the PK Baseline Visit on the IP infusion day will be used to calculate total 
dose. ADAMTS13 activity and ADAMTS13:Ag in SHP655 dosing solutions will be used to 
derive actual dose amount for calculating IR, CL, and Vss.
Area under the curves will be calculated using linear up/log down trapezoidal summation.
For PK parameter calculations, should the measurement at pre-infusion of the respective PK 
infusion be above the lower limit of quantitation, baseline may be subtracted from post-infusion 
measurements, or used as a covariate as applicable if other analysis methods are employed.
PK concentrations and PK parameters will be listed and summarized by treatment and dose 
cohorts (and by scheduled time for PK concentrations). Individual and mean PK 
concentration-time profiles over time will be presented. Scatter plots of individual and geometric 
mean PK exposure parameters (Cmax, AUC0-last, and AUC0-inf) versus dose level will be presented 
for dose proportionality assessment. Additional figures may be generated as applicable.
9.6.2 Pharmacodynamic Analysis
The observed PD measurements of plasma VWF:Ag, VWF:RCo, plasma free hemoglobin, 
plasma thrombospondin, and platelet count will be listed and summarized by treatment, dose 
level, and scheduled time. Ratio to baseline values will be calculated for VWF:Ag, VWF:RCo, 
and platelet count. Individual and mean PD profiles over time will be presented. The correlation 
of plasma free hemoglobin and thrombospondin with ADAMTS13 activity and VWF will be 
assessed.
9.6.3 Pharmacokinetic-Pharmacodynamic Relationship
The PK/PD assessments will be performed to evaluate the correlation of plasma free hemoglobin 
and thrombospondin with ADAMTS13 activity and VWF.
Graphical assessments of plasma free hemoglobin and thrombospondin versus ADAMTS13 
activity and VWF activity will be generated.
Other assessments may be performed to evaluate the PK/PD relationships.
9.7 Efficacy Analyses
No efficacy analyses are planned.
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9.8 Exploratory Analyses
The exploratory variables, including but not limited to 
 
 
 will be listed and summarized by treatment, dose level, and 
scheduled time.
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10. REFERENCES
Bolaños-Meade, J. & Brodsky, R. A. 2014. Blood and marrow transplantation for sickle cell 
disease: Is less more? Blood Reviews, 28, 243-248.
Bonnefoy, A., Daenens, K., Feys, H. B., de Vos, R., Vandervoort, P., Vermylen, J., et al. 2006. 
Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in 
mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13. Blood, 107,
955-964.
Denorme, F., Langhauser, F., Desender, L., Vandenbulcke, A., Rottensteiner, H., Plaimauer, B., 
et al. 2016. ADAMTS13-mediated thrombolysis of t-PA-resistant occlusions in ischemic 
stroke in mice. Blood, 127, 2337-2345.
Denorme, F., Langhauser, F., Rottensteiner, H., Plaimauer, B., Scheiflinger, F., Kleinschnitz, C., 
et al. 2015. ADAMTS13 destabilizes thrombi in a mouse model of thrombotic focal 
cerebral ischemia. J Thromb Haemost, 13 Suppl 2, 694-695.
Höllriegl, W., Schiviz, A., Höbarth, G., Kubik, S., Plaimauer, B., Scheiflinger, F., et al. 2013. 
Pharmacokinetics of a recombinant ADAMTS13 in mice, rats and macaques. J Thromb 
Haemost, 11 Supp 2, 789-789.
Kato, G. J., Piel, F. B., Reid, C. D., Gaston, M. H., Ohene-Frempong, K., Krishnamurti, L., et al. 
2018. Sickle cell disease. Nature Reviews Disease Primers, 4, 18010.
Kopic, A., Benamara, K., Piskernik, C., Plaimauer, B., Horling, F., Hobarth, G., et al. 2016. 
Preclinical assessment of a new recombinant ADAMTS-13 drug product (BAX930) for 
the treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost, 14, 1410-
1419.
Novelli, E. M., Kato, G. J., Hildesheim, M. E., Barge, S., Meyer, M. P., Lozier, J., et al. 2013. 
Thrombospondin-1 inhibits ADAMTS13 activity in sickle cell disease. Haematologica,
98, e132-e134.
Plaimauer, B. & Scheiflinger, F. 2004. Expression and characterization of recombinant human 
ADAMTS-13. Semin. Hematol, 41, 24-33.
Schnog, J. J. B., Kremer Hovinga, J. A., Krieg, S., Akin, S., Lämmle, B., Brandjes, D. P. M., et 
al. 2006. ADAMTS13 activity in sickle cell disease. Am. J. Hematol, 81, 492-498.
Sins, J. W. R., Schimmel, M., Luken, B. M., Nur, E., Zeerleder, S. S., van Tuijn, C. F. J., et al. 
2017. Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso
occlusive crisis and steady state. Journal of Thrombosis and Haemostasis, 15, 1392-
1402.
U.S. Preventive Services Task Force 1996. Screening for Hemoglobinopathies. Guide to Clinical 
Preventive Services, 2nd edition. Alexandria, VA: International Medical Publishing: 485-
94.
World Health Organization. 2006. Fifty-ninth World Health Assembly, Geneva, 22-27 May
2006: resolutions and decisions: annexes. WHA59/2006/REC/1.
For non-commercial use only
., Sch
, Sc
mice, rats
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Zhou, Z., Behymer, M. & Guchhait, P. 2011. Role of extracellular hemoglobin in thrombosis and 
vascular occlusion in patients with sickle cell anemia. Anemia, 2011, 918916.
Zhou, Z., Han, H., Cruz, M. A., Lopez, J. A., Dong, J. F. & Guchhait, P. 2009. Haemoglobin 
blocks von Willebrand factor proteolysis by ADAMTS-13: a mechanism associated with 
sickle cell disease. Thromb. Haemost, 101, 1070-1077.
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11. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
Appendix 1 Regulatory, Ethical, and Study Oversight Considerations
Appendix 1.1 Regulatory and Ethical Considerations
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
Appendix 1.2 Sponsor’s Responsibilities
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP Guidelines, as well as all applicable national 
and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
Indemnity/Liability and Insurance
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO and investigator as necessary.
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Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements.
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance.
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
Appendix 1.3 Investigator’s Responsibilities
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
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If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995).
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
Documentation and Retention of Records
Case Report Forms
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
The CRFs should be approved by the investigator per study specifications and the sponsor’s data 
delivery requirements.
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Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, original clinical laboratory reports, and histology and pathology reports.
All key data must be recorded in the subject’s source documents.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
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Appendix 1.4 Data Management Considerations
Data Collection
The investigators’ authorized site personnel must enter the information required by the study 
CRF Completion Guidelines or similar for all data requiring transcription of the source. A study 
monitor will visit each site in accordance with the monitoring plan and review the CRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered on the CRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting. 
Data Management
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring 
clarification are to be communicated to the site for resolution. Only authorized personnel 
will make corrections to the clinical database, and all corrections are documented in an 
auditable manner.
Data Handling
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to SHP655, and investigational product preparation/accountability 
data) will be handled with special care during the data cleaning and review process. These 
data will be handled in such a way that, prior to unblinding, any data that may unblind study 
team personnel will be presented as blinded information or otherwise will not be made 
available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits. Following the review 
of unblinded data for a completed dose cohort by the DEC, and a recommendation by the
DEC that it is safe to proceed with enrollment of the next dose cohort, Sponsor study team 
will have access to the unblinded data for the completed dose cohort, as specified in the 
unblinding plan.  
Appendix 1.5 Ethical Considerations
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. 
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Each subject or the subject’s legally authorized representative, as applicable, is requested to sign 
and date the subject ICF or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the Sponsor with a copy of the consent form where 
applicable that was reviewed by the IRB/EC and received their favorable opinion/approval. A 
copy of the IRB/EC’s written favorable opinion/approval of these documents must be provided 
to the sponsor prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or coordinating principal investigator) is responsible for this action. Additionally, if the 
IRB/EC requires modification of the sample subject information and consent document 
provided by the Sponsor, the documentation supporting this requirement must be provided to 
the Sponsor.
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
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For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol at least annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. This can be the responsibility of the sponsor or investigator for sites within the EU, or 
for multicenter studies, the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant AEs as 
required by IRB/EC procedures.
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP655; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities. Subjects are assigned a unique 
identifying number; however, their initials and date of birth may also be collected, if permitted 
under local laws governing privacy.
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
Study Results/Publication Policy
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet 
posting, presentation slides, abstract, outline, video, instructional material, presentation (in 
the form of a written summary), or other public disclosure of the study results, in printed, 
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The parties understand and agree that participation in the study may involve a commitment to 
publish the data from all sites participating in the study in a cooperative publication with other 
investigators prior to publication or oral presentations of the study results on an individual basis. 
The site agrees not to publish or present the site’s study results until such time as either the 
aggregate multi-site study results are published in a cooperative publication or for a period of 
1 year after termination or completion of the study at all participating sites, whichever shall first 
occur. After that time, the site may publish the site’s study results in scientific journals or present 
the study results at symposia or other professional meetings in accordance with the following 
provisions:
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Takeda is committed to transparent dissemination of all scientific, technical, and medical 
manuscripts generated from Takeda-supported research. Therefore, after 01 Jan 2018, Takeda 
will require the submission of all Takeda-supported research manuscripts to journals that offer 
public availability via Open Access (including publisher platforms/repositories and 
self-archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
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Appendix 2 Clinical Laboratory Tests
The following clinical laboratory assessments will be performed:
Chemistry
Creatinine
Alanine aminotransfarase (ALT)
Aspartate aminotransferase (AST)
Alkaline phosphatase (ALP)
Albumin
Total bilirubin (TBL)
Blood Urea Nitrogen 
Glucose
Sodium
Potassium
Chloride
Bicarbonate
Hematology
Erythrocytes (Red Blood Cell [RBC])
Leukocytes (White Blood Cell [WBC])
Hemoglobin 
Hematocrit
Blood Group
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC)
WBC Differential count (Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils)
Platelet
Viral Serology
Anti-Human immunodeficiency virus (HIV) 1/2,
Anti-Hepatitis C virus (HCV)
Hepatitis B surface antigen (HbsAg)
Anti-Hepatitis B-core total (HBc)
Anti- Hepatitis B surface antigen (HbsAg)
Pregnancy Test
Urine human chorionic gonadotropin (HCG)a
1. Only women with childbearing potential (excluding menopausal women or women with surgical 
contraception) will receive the urine HCG test at Screening Period and, if necessary, during the study.
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Appendix 3 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting
Appendix 3.1 Adverse Event Definitions
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this investigational product or medicinal product. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
causality is suspected (ICH Guidance E2A 1995).
Treatment-emergent Adverse Event
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product.
Serious Adverse Event
A serious adverse event (SAE) is any untoward clinical manifestation of signs, symptoms, or 
outcomes (whether considered related to investigational product or not and at any dose):

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of hospitalization. Note: Hospitalizations 
that are the result of elective or previously scheduled investigations procedures or surgery 
for pre-existing conditions and have not worsened after initiation of treatment should not 
be classified as SAEs. 

For example, an admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE; however, complication(s) resulting from a hospitalization for an 
elective or previously scheduled surgery that meet(s) serious criteria must be reported as 
SAE(s).

Results in persistent or significant disability/incapacity

Results in a congenital abnormality/birth defect
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
Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of 
such medical events include:

Bronchospasm associated with anaphylaxis requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.

Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E 
virus (HEV), or parvovirus B19 (B19V)
Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the product but are not 
specifically mentioned as occurring with the particular product under investigation.
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. 
This determination will include considerations such as the number of AEs previously observed, 
but not on the basis of what might be anticipated form the pharmacological properties of a 
product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
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Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected disease progression and are part of the efficacy or 
effectiveness data collected in the study. Significant worsening of symptoms should be recorded 
as an AE.
When there is an increase in the severity of a pre-existing condition, duration or frequency of a 
preexisting condition, the event must be described on the AE CRF.
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory parameter, or vital sign measure can represent an 
AE if the change is clinically relevant or if, during administration of investigational product, a 
shift of a parameter is observed from a value in the normative range to a value that is outside the 
normal range and considered clinically significant, or a further waning of an already clinically 
significant value. When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing administration or 
after the end of administration with the investigational product, and the range of variation of the 
respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), or vital sign values, which were not present at the 
pretreatment evaluation observed closest to the start of study treatment, further investigations 
should be performed until the values return to within the reference range or until a plausible 
explanation (eg, concomitant disease or expected disease evolution) is found for the abnormal 
values.
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, or vital sign is clinically significant and 
represents an AE.
Appendix 3.2 Collection of Adverse Events 
All AEs/SAEs are collected from the time the informed consent document is signed until the 
defined follow-up period stated in Section 8.1.3. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. 
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All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained.
Appendix 3.3 Assessment of Adverse Events
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity is captured as a new event. 
Worsening medical conditions, signs or symptoms present prior to initiation of investigational 
product, must be recorded as new AEs.
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
investigational product, and the dyspepsia becomes severe and more frequent after first dose a 
new AE of severe dyspepsia (with the appropriate date of onset) should be documented in the 
source.
The medical assessment of severity is determined by using the following definitions:

Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living.

Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject.

Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source.
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The following additional guidance may be helpful:
Table A1
Adverse Event Relationship Categorization
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling enough and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the subject’s 
medical condition, other therapies, or accident.
Not related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
Outcome Categorization
The outcome of AEs must be documented in the source during the course of the study. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae

Recovering/Resolving

Unknown
If applicable, action taken (ie, dose increased, dose not changed, dose reduced, drug interrupted, 
drug withdrawn, not applicable, or unknown) will also be recorded on the AE CRF.
Appendix 3.4 Safety Reporting
Reference Safety Information
The RSI for this study is the IB which the sponsor has provided under separate cover to all 
investigators.
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Takeda Global 
Drug Safety Department and the CRO/Takeda medical monitor within 24 hours of becoming 
aware of the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors (see Appendix 3.9) unless they result in an 
SAE.
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The investigator must complete, sign, and date the Takeda “Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol”, 
verify the accuracy of the information recorded on the form with the corresponding source 
documents (Note: Source documents are not to be sent unless requested), and fax or e-mail 
the form to the Takeda Global Drug Safety Department. A copy of the Takeda Clinical Study 
Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required 
by Protocol (and any applicable follow-up reports) must also be sent to the CRO/Takeda 
medical monitor using the details specified in the emergency contact information section of the 
protocol.
Appendix 3.5 Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined EOS Visit stated in Section 8.1.3 and must 
be reported to the Takeda Global Drug Safety Department and the CRO/Takeda medical monitor 
within 24 hours of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Takeda 
Global Drug Safety Department within 24 hours of the reported first becoming aware of the 
event.
Appendix 3.6 Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms reported by the subject after signing the ICF or leading up to 
the onset date of the SAE, or following the resolution date of the SAE, must be recorded as an 
AE, if appropriate.
Appendix 3.7 Fatal Outcome
Any SAE that results in the subject’s death (eg, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
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For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death.
Appendix 3.8 Pregnancy
All pregnancies are reported from the time informed consent is signed until the defined EOS 
Visit stated in Section 8.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Takeda Global Drug Safety Department using the Takeda Investigational and Marketed Products 
Pregnancy Report Form.
A copy of the Shire Investigational and Marketed Products Pregnancy Report Form (and any 
applicable follow-up reports) must also be sent to the CRO/Takeda medical monitor using the 
details specified in the emergency contact information section of the protocol. The pregnant 
female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome 
and condition of the infant. It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
post-partum.
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion or 
congenital abnormality are considered SAEs and must be reported using the Takeda Clinical 
Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form.
A pregnancy that occurs in the partner of a study subject during the study must be reported and 
recorded on the appropriate CRF.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Takeda Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Takeda Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
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Appendix 3.9 Abuse, Misuse, Overdose and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Appendix 3.9.
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than one category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
Appendix 3.10 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical study from immediate harm, these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator, and may include any of the following:

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical study or studies

Any other immediate action taken in order to protect clinical study participants from 
immediate hazard to their health and safety
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The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
Appendix 3.11 Regulatory Agency, Institutional Review Board, Ethics Committee and Site 
Reporting
The sponsor and the CRO are responsible for notifying the relevant regulatory authorities: US 
central IRBs/ECs of related, unexpected SAEs.
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP655 program.
The investigator is responsible for notifying the local IRB/EC of SAEs or significant safety 
findings that occur at his or her site as required by IRB/EC procedures (see Appendix 1.5).
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Appendix 4 Abbreviations
Abbreviation
Definition
ACS
Acute chest syndrome
ADAMTS13
A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B-core total antibodies
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-∞
Area under the curve from time 0 to infinity
AUC0-last
Area under the curve from time 0 to the time of last concentration measured
hCG
Beta-human chorionic gonadotropin
CBC
Complete blood count
cDNA
Complementary deoxyribose nucleic acid
CHO
Chinese hamster ovary
CL
Systemic clearance
Cmax
Observed maximum concentration
CRA
Clinical research associate
CRF
Case report form
CRO
Contract research organization
DMC
Data Monitoring Committee
eCRF
Electronic case report form
EOS
End of study
GCP
Good Clinical Practice
HBV
Hepatitis B virus 
HCV
Hepatitis C virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HMW
High molecular weight
IB
Investigator’s Brochure
ICF
Informed consent form
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Abbreviation
Definition
ICH
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICU
Intensive care unit
IL
Interleukin
IP
Investigational product (SHP655 or Placebo)
IR
Incremental recovery
IRT
Interactive response technology
IV
Intravenous (ly)
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MRT
Mean residence time
MRT0-inf
Mean residence time from zero (predose) extrapolated to infinite time
n
Number of subjects
NOAEL
No-observed-adverse-effect-level
O2
Oxygen
PD
Pharmacodynamic (s)
PK
Pharmacokinetic(s)
q4h
Every 4 hours
rADAMTS13
Recombinant a disintegrin and metalloproteinase with thrombospondin type 1 motif, 
member 13
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis system
SCD
Sickle cell disease
SIC
Subject identification code
t1/2
Terminal half-life
TEAEs
Treatment-emergent adverse events
Tmax
Time to reach maximum concentration
TNF
Tumor necrosis factor
TSP1
Thrombospondin 1
ULVWF
Ultralarge von Willebrand factor
US
United States
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Abbreviation
Definition
VOC
Vaso-occlusive crisis
Vss
Apparent steady state volume of distribution
VWF
von Willebrand factor
VWF:Ag
VWF:antigen
VWF:RCo
VWF:Ristocetin cofactor activity
WBC
White blood cell
WHO
World Health Organization
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Appendix 5 Protocol History
Document
Date
Global/Country/Site Specific
Protocol Amendment 2.0
12 JUL 2021
Global
Protocol Amendment 1.0
17 MAY 2019
Global
Original Protocol
28 MAR 2019
Global
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17 MAY 2019
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION

Original Protocol (28 MAR 2019)

Protocol Amendment 1.0 (17 MAY 2019)
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1.0
Amendment Date
17 MAY 2019
Global/Region/
Country/Site Specific
Global
Protocol Amendment Summary and Rationale:
Changes were made in response to regulatory authority request.
Description of Each Change and Rationale 
Section(s) Affected by Change

In Parts A and B of the study, the first 3 patients in 
each dose cohort will be dosed a minimum of 14 
days apart to observe and interpret reactions and 
adverse events in order to ensure that no SAE 
requiring a pause or stop of the clinical trial has 
occurred in the most recently treated subject.

The booster dose was removed from the protocol.
Request by FDA.
Synopsis, 
Section 1.3, 
Section 4.1,
Section 6.1.1, 
Section 6.2.3, 
Section 9.6.1

Subjects 12-17 years old were removed from 
inclusion criteria; only adults aged 18 to 65 years 
old will be included in the study.

Specific criteria for organ dysfunction was added 
to inclusion criteria as follows:
The subject must have uncomplicated acute VOC 
(no significant organ dysfunction [ALT>3xULN of 
local lab; creatinine >2; symptomatic cardiac 
decompensation, no new neurologic symptoms] or 
signs or symptoms of systemic infection, or fever 
with body temperature ≥39ºC). 

The specific genotypes of sickle and beta 
thalassemia were added to the inclusion criteria.

Inclusion criteria #12 stated that if subject has 
uncomplicated UTI, body temperature < 38.5°C or 
costovertebral angle tenderness; or if subject had 
suspected minor viral syndromes, the subject had 
no symptoms suggestive of bacterial infection 
other than uncomplicated otitis media or 
uncomplicated streptococcal pharyngitis.  This 
inclusion criteria was removed. In the exclusion 
criteria, the following was added: 
Minor infection that does not meet the following 
criteria: uncomplicated urinary tract infection 
Request by FDA.
Synopsis, 
Section 5.1, 
Section 5.2, 
Section 8.2.7,
Appendix 3.9, 
Appendix 5
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17 MAY 2019
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1.0
Amendment Date
17 MAY 2019
Global/Region/
Country/Site Specific
Global
Protocol Amendment Summary and Rationale:
Changes were made in response to regulatory authority request.
Description of Each Change and Rationale 
Section(s) Affected by Change
with body temperature <38.5°C (101.3°F) and no 
costovertebral angle tenderness; or 
uncomplicated otitis media; or uncomplicated 
streptococcal pharyngitis.

The following exclusion criteria was added:
Any history of hemorrhagic stroke or bleeding 
diathesis.
Under pharmacodynamic endpoints, 
 
 was removed.
No longer 
considered a 
necessary test.
Synopsis, 
Section 1.2, 
Section 1.3,
Section 3.2, 
Section 8.2.4, 
Section 9.6.2, 
Appendix 2
Health-related Quality of Life will not be assessed at 
screening.
Baseline 
assessments are 
sufficiently close 
to screening 
assessments, so 
redundancy 
removed.
Section 1.3
Added to the schedule of activities:
VAS is assessed at all PK sampling time points when 
awake and every 4 hours while awake during 
hospitalization.
Clarification
Section 1.3
Information on the Q97R variant was added to the 
protocol.  
Request by FDA
Section 2.2
The following text was added to section 2.4:
Enrollment will be stopped for any case of 
anaphylaxis, neutralizing antibody, life-threating 
condition, or death (see Section 9.2.1).
Also, Section 6.2.1 (Hypersensitivity of SHP655) was 
removed.
Clarification
Section 2.4, (6.2.1)
Parts A and B will be conducted at approximately 20 
(instead of 3) sites in the United States and Europe.
Clarification
Section 4.5
Contraception methods of females were adjusted to 
Clarification
Section 5.4.1, 
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17 MAY 2019
Protocol Amendment
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1.0
Amendment Date
17 MAY 2019
Global/Region/
Country/Site Specific
Global
Protocol Amendment Summary and Rationale:
Changes were made in response to regulatory authority request.
Description of Each Change and Rationale 
Section(s) Affected by Change
include highly effective or acceptable methods of 
contraception.  These are listed in Appendix 4, and are 
described in this section.
Section 6.2.3, 
Appendix 4
Stopping criteria were adjusted to define a study stop 
if a) 2 or more subjects in a given cohort receiving 
active drug have a severe AE in any vital organ or 
body system or b) any neutralizing antibody to 
SHP655 that develops after IP administration or c) 
any death occurs that is possibly related to SHP655 
administration.
Request by FDA
Section 6.2.3.1
Section 6.2.3.2 Dose Limiting Toxicities was added.  
Section 6.2.5 was adjusted accordingly.
Request by FDA
Section 6.2.3.2.
Section 6.2.5
The following text was added:  
If AEs are observed within a dose cohort (Part A 
or Part B) that could meet DLT criteria, the Dose 
Escalation Committee will review treatment 
assignments to determine whether the DLT has 
been reached.
Section 6.2.5 was also adjusted accordingly.
Request by FDA
Section 6.2.3.3
Anticoagulant or anti-platelet medications were added 
to prohibited treatment.
Request by FDA
Section 6.6.4
Section 6.7 Adverse Event Management was added.
Request by FDA
Section 6.7
Efficacy assessments in pain score (VAS) were 
adjusted to use a consistent VAS scale.  The first 
measure of time to discharge readiness was changed 
to:  
1.
A sustained 15 point decrease in on a linear 
100 point VAS pain scale from baseline ore from 
baseline and transition to oral analgesia;
Request by FDA
Section 8.2.6
See Appendix 7 for protocol history, including all amendments.
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SAP_001.pdf: 
NCT Number: NCT03997760
Title: A Phase 1 randomized, double-blind, placebo-controlled, multicenter, 
ascending dose, safety and PK/PD study of SHP655 (rADAMTS13) in sickle cell 
disease at baseline health
Study Number: SHP655-101
Document Version and Date: Version 1.0, 04 JUL 2022
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information.
Statistical Analysis Plan
For non-commercial use only


 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PRODUCT: Recombinant ADAMTS13  
 
 
A Phase 1 randomized, double-blind, placebo-controlled, multicenter, ascending 
dose, safety and PK/PD study of SHP655 (rADAMTS13) in sickle cell disease at 
baseline health 
 
 
PROTOCOL IDENTIFIER: SHP655-101 
 
 
 
Study Sponsor(s): 
Takeda Development Center 
Americas, Inc. 
95 Hayden Avenue, Lexington, 
MA 02421, USA 
 
 
Authors: 
  
 
Protocol: 
Amendment 2.0 12 JUL 2021 
 
Amendment 1.0 17 MAY 2019 
 
 
SAP Version:   1.0 
 
SAP Date: 
2022 JUL 04 
 
Status: 
 Final 
 
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided and 
should not be copied, shared with, or disclosed to any third party without the express written consent of Takeda.  
Confidential – Restricted: Do NOT distribute without prior approval 
 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
REVISION HISTORY 
 
Version  
Issue Date 
Summary of Changes 
0 
2020 Mar 25 
First draft document 
1.0 
2022 Jul 04 
Update according to Protocol Amendment 2.0 
 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
TABLE OF CONTENTS 
REVISION HISTORY................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................ 3 
ABBREVIATIONS ..................................................................................................... 6 
1. 
INTRODUCTION ........................................................................................... 9 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS ...................................... 9 
2.1 
Objectives..................................................................................................... 9 
2.1.1 Primary Objective .................................................................................. 9 
2.1.2 Secondary Objective(s)........................................................................... 9 
2.1.3 Exploratory Objective ............................................................................ 9 
2.2 
Endpoints ................................................................................................... 10 
2.2.1 Primary Endpoint(s) ............................................................................. 10 
2.2.2 Secondary Endpoint(s) ......................................................................... 10 
2.2.3 Exploratory Endpoint(s) ....................................................................... 10 
3. 
STUDY DESIGN ........................................................................................... 10 
3.1 
General Description .................................................................................... 10 
3.2 
Randomization............................................................................................ 11 
3.3 
Blinding ..................................................................................................... 12 
3.4 
Sample Size and Power Considerations........................................................ 12 
4. 
STATISTICAL ANALYSIS SETS ................................................................ 13 
4.1 
Screened Set ............................................................................................... 13 
4.2 
Enrolled Set ................................................................................................ 13 
4.3 
Safety Analysis Set ..................................................................................... 13 
4.4 
Completers Set............................................................................................ 13 
4.5 
Pharmacokinetic Analysis Set...................................................................... 13 
4.6 
Pharmacodynamic Analysis Set ................................................................... 14 
5. 
STUDY SUBJECTS....................................................................................... 14 
5.1 
Disposition of Subjects................................................................................ 14 
5.2 
Demographic and Other Baseline Characteristics ......................................... 14 
5.3 
Medical History .......................................................................................... 15 
5.4 
Prior Medications, Therapies and Procedures ............................................... 15 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
5.5 
Concomitant Medications, Therapies, and Procedures .................................. 15 
5.6 
Exposure to Investigational Product ............................................................. 16 
5.7 
IP Infusion .................................................................................................. 16 
5.8 
Protocol Deviations..................................................................................... 16 
6. 
EFFICACY ANALYSIS ................................................................................ 16 
6.1 
Analyses of Primary Safety Endpoint(s)....................................................... 17 
6.2 
Analyses Secondary Endpoint(s) ................................................................. 17 
6.3 
Analyses of Exploratory Endpoint(s) ........................................................... 17 
7. 
SAFETY ANALYSIS .................................................................................... 17 
7.1 
Adverse Events ........................................................................................... 17 
7.2 
Clinical Laboratory Data ............................................................................. 19 
7.3 
Vital Signs .................................................................................................. 19 
7.4 
Other Safety Data........................................................................................ 20 
8. 
PHARMACOKINETIC ANALYSIS ............................................................ 21 
8.1 
Pharmacokinetic Analyses in Support of Data Review by the Dose 
Escalation Committee ................................................................................. 21 
8.2 
Relationships of Immunogenicity Results with Pharmacokinetics ................. 21 
9. 
PHARMACODYNAMIC ANALYSIS .......................................................... 21 
9.1 
Pharmacodynamic Data............................................................................... 21 
9.1.1 Primary Pharmacodynamic Endpoint and Analysis ................................ 21 
9.1.2 Secondary Pharmacodynamic Endpoints and Analysis........................... 22 
9.1.3 Analyses of Pharmacokinetic/Pharmacodynamic Relationships.............. 22 
9.2 
Relationships of Immunogenicity Results with Pharmacodynamics............... 22 
10. 
HEALTH ECONOMICS AND OUTCOMES RESEARCH (HEOR) 
ENDPOINTS ................................................................................................. 22 
11. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) 
COMMITTEE ............................................................................................... 23 
12. 
DATA HANDLING CONVENTIONS .......................................................... 23 
12.1 
General Data Reporting Conventions ........................................................... 23 
12.2 
Definition of Baseline ................................................................................. 24 
12.3 
Repeated or Unscheduled Assessments of Safety Parameters ........................ 24 
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Statistical Analysis Plan v1.0  
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12.4 
Handling of Missing, Unused, and Spurious Data......................................... 24 
12.4.1 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures/Opioids/Transfusions)........................................ 24 
12.4.1.1 Incomplete Start Date ............................................................. 25 
12.4.1.2 Incomplete Stop Date.............................................................. 25 
12.4.2 Missing Date Information for Adverse Events ....................................... 26 
12.4.2.1 Incomplete Start Date ............................................................. 26 
12.4.2.2 Incomplete Stop Date.............................................................. 27 
12.4.3 Missing Severity Assessment for Adverse Events .................................. 27 
12.4.4 Missing Relationship to Investigational Product for Adverse Events ...... 27 
12.4.5 Character Values of Clinical Laboratory Variables ................................ 27 
13. 
ANALYSIS SOFTWARE .............................................................................. 27 
14. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL .......................... 27 
15. 
REFERENCES .............................................................................................. 27 
 
 
 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
ABBREVIATIONS 
 
ADAMTS13 
A Disintegrin and Metalloproteinase with Thrombospondin Type 1 Motif, 
Member 13 
ADAMTS13ag 
ADAMTS13 Antigen 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ASCQ-Me 
Adult Sickle Cell Quality of Life Measurement Information System 
AUC 
Area Under the Concentration-Time Curve 
AUC(0-72) 
AUC from Zero (predose) to 72 hours Postdose 
AUC(0-inf) 
AUC from Zero (predose) Extrapolated to Infinite Time 
AUC(0-last) 
AUC from Zero (predose) to Time of Last Quantifiable Concentration 
AUMC 
Area Under the Moment Curve 
AUMC(0-72) 
AUMC from Zero (predose) to 72 hours Postdose 
AUMC(0-inf) 
AUMC from Zero (predose) Extrapolated to Infinite Time 
BLQ 
Below the Limit of Quantitation 
BMI 
Body Mass Index 
BPI 
Brief Pain Inventory 
CBC 
Complete Blood Count 
CL 
Systemic Clearance 
cm 
Centimeter 
Cmax 
Observed Maximum Concentration 
CRA 
Clinical Research Associate 
 
 
DEC 
Dose Escalation Committee 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
HBc 
Anti-Hepatitis B-core Total 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Anti-Hepatitis C Virus 
HEOR 
Health Economics and Outcomes Research 
Hgb 
Hemoglobin 
HIV 
Anti-Human Immunodeficiency Virus 
HRQoL 
Health-Related Quality of Life 
IP 
Investigational Product 
IR 
Incremental Recovery 
IRT 
Interactive Response Technology 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
IU 
International Units 
IV 
Intravenous 
kg 
Kilogram 
 
 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantitation 
ml 
Milliliter 
mmHg 
Millimeters of Mercury 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
MRT(0-72) 
MRT from Zero (Predose) to 72 Hours Postdose 
MRT(0-inf) 
MRT from Zero (Predose) Extrapolated to Infinite Time 
n 
Number 
PCS 
Potentially Clinically Significant  
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
Preferred Term 
rADAMTS13 
Recombinant ADAMTS13 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SCD 
Sickle Cell Disease 
SI 
Système International 
SOC 
System Organ Class 
t1/2 
Terminal Half-Life 
TBL 
Total Bilirubin 
TEAE   
Treatment-Emergent Adverse Event 
TFL 
Table/Figure/Listing 
tmax 
Time to Reach Cmax 
TSP1 
Thrombospondin 1 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper Limit of Normal 
Vss 
Volume of Distribution at Steady State 
VWF 
Von Willebrand Factor 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
VWF:Ag 
VWF:Antigen 
VWF:RCo 
VWF:Ristocetin Cofactor Activity 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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Page 9 of 27 
Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
1. 
INTRODUCTION  
This study will assess safety (including immunogenicity), tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) of ascending doses of SHP655 in sickle cell disease 
(SCD). It is expected that SHP655 (recombinant - a disintegrin and metalloproteinase with 
thrombospondin type 1 motif, member 13 [rADAMTS13]) activity will be inhibited by 
plasma free hemoglobin and thrombospondin-1 to variable degrees across subjects.  
Additionally, dosing of SHP655 to supraphysiologic levels has not been characterized 
clinically.  Understanding the relationships among PK, PD, biomarkers, and their clinical 
correlates can guide the design of the adaptive Phase 2/3 study. 
 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of exploratory and safety data. PK/PD data analyses will be provided in 
the Clinical Pharmacology Analysis Plan (CPAP). Specifications for tables, figures, and 
listings are contained in a separate document. 
 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
Assess safety, tolerability, and immunogenicity of SHP655 in subjects with SCD at 
baseline health. 
2.1.2 
Secondary Objective(s) 
Pharmacokinetic Objective: 
o Assess the single dose PK of SHP655 at 3 dose levels in subjects with SCD. 
 
Pharmacodynamic Objectives: 
o Assess the effect of SHP655 on von Willebrand factor (VWF) and platelets. 
o Study the correlation of plasma free hemoglobin and thrombospondin on SHP655 
activity and VWF. 
 
2.1.3 
Exploratory Objective 
o Assess additional exploratory biomarkers, 
 
 
. 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
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2.2 
Endpoints 
2.2.1 
Primary Endpoint(s) 
Serious adverse events (SAEs)/adverse events (AEs), adverse changes in vital signs and 
laboratory parameters, and incidence of binding and inhibitory antibodies to SHP655 
occurring up to 28±3 days after SHP655 infusion, are the primary endpoints on this study. 
2.2.2 
Secondary Endpoint(s)  
Pharmacokinetic 
Area under the concentration-time curve (AUC) from zero (predose) to 72 hours postdose 
(AUC(0-72)), AUC from zero (predose) extrapolated to infinite time (AUC(0-inf)), AUC from 
zero (predose) to time of last quantifiable concentration (AUC(0-last)), terminal half-life 
(t1/2), systemic clearance (CL), mean residence time (MRT) from zero (predose) to 72 hours 
postdose (MRT(0-72)), MRT from zero (predose) extrapolated to infinite time (MRT(0-inf)), 
volume of distribution at steady state (Vss), observed maximum concentration (Cmax), time 
to reach Cmax (tmax), and incremental recovery (IR) will be estimated for ADAMTS13 
activity and ADAMTS13 antigen (ADAMTS13Ag). This will be further discussed in the 
CPAP. 
 
Pharmacodynamic 
o VWF:antigen (VWF:Ag), VWF:Ristocetin cofactor activity (VWF:RCo) and 
platelet count. 
o Plasma free hemoglobin and plasma thrombospondin levels. 
2.2.3 
Exploratory Endpoint(s) 
 
 
 
 
 
 
 
 
 
 
 
3. 
STUDY DESIGN 
3.1 
General Description 
This is a Phase 1 randomized, double-blind, placebo-controlled, multicenter ascending 
dose study evaluating the safety, tolerability, and immunogenicity of SHP655 
(rADAMTS13) in 18 to 65-year-old subjects with SCD. This study will also characterize 
the PK and assess the PD of SHP655 and its effect on biomarkers. 
 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
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Dose escalation 
Approximately 20 subjects with baseline SCD will be randomized in a 3:1 ratio to receive 
either SHP655 or placebo as single IV infusion at 3 dose levels: 40 IU/kg (n=4), 80 IU/kg 
(n=8), or 160 IU/kg (n=8). The dose cohorts will be opened sequentially, after safety data 
up to the Day 13 visit of the last subject in the previous dose cohort has been reviewed by 
the Dose Escalation Committee. The number of subjects will be increased to 8 subjects per 
dose cohort (6 active:2 placebo) in the 80 IU/kg and 160 IU/kg dose cohorts for more robust 
PK, PD, clinical, and biomarker assessments. 
 
The study schematic diagram from the protocol is presented below in  
 
Figure 1. 
 
Figure 1: Study Schematic 
 
 
Abbreviations: ADAMTS13=A disintegrin and metalloproteinase with thrombospondin type 1 motif, 
member 13; AEs=Adverse events; PD=Pharmacodynamics; PK=Pharmacokinetics; SCD=Sickle cell 
disease; TSP1=Thrombospondin 1; VVF:Ag=von Willebrand factor antigen; VWF:RCo=von Willebrand 
factor:Ristocetin cofactor. 
3.2 
Randomization 
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule. 
Baseline SCD 
40 IU/kg×1 
(n=4) 
Randomize 3:1 (SHP655:Placebo) 
80 IU/kg×1 
(n=8) 

Safety: Follow 28 days for AEs, immunogenicity 

PK: ADAMTS13 activity and antigen 
•
PD: VWF:Ag, VWF:RCo, plasma free Hgb, TSP1, platelet count 
160 IU/kg×1 
(n=8) 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
 
Subject numbers are assigned to all subjects as they consent to take part in the study.  
Within each site (numbered uniquely within a protocol), the subject number is assigned to 
subjects according to the sequence of presentation for study participation. 
 
The randomization number represents a unique number corresponding to IP allocated to 
the subject, once eligibility has been determined. 
 
Individual subject treatment is automatically assigned by the interactive response 
technology (IRT) following a 3:1 ratio between SHP655 vs. placebo within each dose 
cohort. 
 
Once a randomization number/unique identifier has been assigned, that number must not 
be used again if, for example, a subject is withdrawn from the study. If a randomization 
number/unique identifier is allocated incorrectly, the clinical research associate 
(CRA)/study monitor must be notified as soon as the error is discovered. 
 
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment 
assignment as dictated by the study. In these cases, the same IP packing identification 
number may not be assigned to more than one subject. 
3.3 
Blinding  
This is a randomized, double-blind, placebo-controlled study with limited access to the 
randomization code. SHP655 and placebo will be prepared by an unblinded pharmacist and 
will be provided to the investigator or designee in a blinded manner after reconstitution.  
Investigators do not have access to the randomization (treatment) code except under 
circumstances described in Section 6.2.4 of the protocol. 
3.4 
Sample Size and Power Considerations 
Four evaluable subjects (3 active:1 placebo) will be the first to be enrolled at the 40 IU/kg 
dose cohort in baseline health in order to obtain initial safety and PK data. The number of 
subjects will be increased to 8 evaluable per dose cohort (6 active:2 placebo) in the 80 and 
160 IU/kg dose cohorts for more robust PK, PD, clinical and biomarker assessments. 
 
Sample size: 
40 IU/kg 
(n=3) 
80 IU/kg 
(n=6) 
160 IU/kg 
(n=6) 
Placebo 
(n=5) 
 
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Statistical Analysis Plan v1.0  
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04JUL2022 
Confidential – Restricted: Do NOT distribute without prior approval 
Sample size is not selected by a power calculation. It is chosen to provide descriptive 
statistics for safety, tolerability, immunogenicity and PK data following administration of 
SHP655. 
 
Subjects may be replaced at the same dose cohort for drop out prior to the Day 13 
immunogenicity sampling. 
 
4. 
STATISTICAL ANALYSIS SETS 
Classification into all Analysis Sets, except for PK and PD Analysis Sets, will be conducted 
prior to database lock. The PK and PD Analysis Sets will be concluded after database lock 
using final data from the database and final concentrations in accordance to the criteria 
specified below. The placebo group will be pooled for the presentations. Where applicable, 
the total column will pool only the SHP655 treatment groups.  
4.1 
Screened Set  
The Screened Set will consist of all subjects who have signed informed consent. 
4.2 
Enrolled Set 
Enrolled Set consists of all subjects who have signed informed consent and also passed 
inclusion/exclusion criteria. 
4.3 
Safety Analysis Set   
The Safety Analysis Set will consist of all subjects randomized and who received any dose 
of IP.  Analysis will be performed according to the treatment regimen actually received 
regardless of the randomized treatment regimen. 
4.4 
Completers Set  
The Completers Set will consist of all subjects in the Safety Analysis Set who have 
completed the study completion/termination visit. 
4.5 
Pharmacokinetic Analysis Set  
The PK Analysis Set will consist of all subjects who receive at least 1 complete dose of 
SHP655 or placebo and provide at least 1 concentration measured at a scheduled time post 
start of infusion for at least 1 of the PK analytes and have no major protocol deviations or 
events that may affect the integrity of the PK data. Subjects in this population will be 
included for all PK summaries. See CPAP for further details. 
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Statistical Analysis Plan v1.0  
Protocol Number: SHP655-101 
04JUL2022 
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4.6 
Pharmacodynamic Analysis Set  
The PD Analysis Set will consist of all subjects who receive at least 1 complete dose of 
SHP655 or placebo and provide at least 1 valid data point postdose of the respective 
infusion for at least 1 PD measurement for any of the PD outcome measures and have no 
major protocol deviations or events that may affect the integrity of the PD data. Subjects 
in this population will be included for all PD summaries. See CPAP for further details. 
 
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
A listing of all Screen Failures (i.e., subjects who were screened but not randomized) will 
be presented along with reasons for screen fail and details of any AEs.   
 
The number and percentage of subjects who were included in each defined analysis set in 
section 4 will be summarized by treatment group and overall. 
 
The number and percentage of subjects who completed and prematurely discontinued will 
be presented for each treatment group and overall. Reasons for premature discontinuation 
as recorded on the study completion / early termination page of the electronic case report 
form (eCRF) will be summarized (number and percentage) by treatment group and overall. 
All subjects who prematurely discontinued will be listed. 
 
The number of subjects enrolled, randomized and completed will be tabulated by site and 
country.  In addition, the duration of enrollment, in days, will be summarized for each site, 
country, and overall.  Duration of enrollment will be calculated as (last date of contact for 
any subject at that site - the first date of informed consent for any subject at that site + 1). 
 
A listing for subject disposition, subjects randomized, deviations from inclusion/exclusion 
criteria, study analysis set classification, subjects who terminated from the study, as well 
as study lot numbers, will be presented. 
5.2 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the Safety Analysis Set. 
 
The following demographic characteristics will be summarized, in the following order in 
the table, age (years), sex, ethnicity, and race, at screening. A baseline characteristics table 
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Statistical Analysis Plan v1.0  
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summarizing weight (kg) & height (cm), body mass index (BMI) (kg/m2) will be presented.  
Listings will be presented. 
5.3 
Medical History 
Medical history will be collected at the Screening Visit (Day -28 to 0) and will be coded 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). 
 
The medical history will be summarized, presenting frequency counts, by system organ 
class (SOC) and preferred term (PT), for each treatment group and overall, for the Safety 
Analysis Set. A listing will also be presented. 
5.4 
Prior Medications, Therapies and Procedures 
Prior medications/therapies will be coded using the latest version of the World Health 
Organization Drug Dictionary (WHO-DD). Prior procedures will be coded using the latest 
version of MedDRA. 
 
Prior medications (therapies/procedures) are defined as any medications, therapies or 
procedures with an end date within 30 days prior to the date of treatment (IP infusion). 
Prior blood transfusion history will be collected for 90 days prior to screening. Prior 
treatment information must be recorded in the subject’s source document including use of 
oral opioids. 
 
The prior therapies, procedures and medication usage will be summarized by the number 
and proportion of subjects in each treatment group and in overall subjects within each 
therapeutic class / system organ class, and preferred term, for the Safety Analysis Set. 
Multiple medications (therapies/procedures) used by a subject in the same category will be 
counted only once. 
 
All prior therapies, procedures and medications will be listed for the Safety Analysis Set. 
5.5 
Concomitant Medications, Therapies, and Procedures 
Concomitant medications/therapies will be coded using the latest version of WHO-DD. 
Concomitant procedures will be coded using the latest version of MedDRA. 
 
Concomitant medication (therapy) is defined as any medication (therapy) with a start date 
prior to the date of IP infusion and continuing after IP infusion or with a start date between 
the dates of IP infusion and completion/termination visit, inclusive. Concomitant procedure 
is defined as any procedure with a start date between the dates of IP infusion and 
completion/termination visit, inclusive. Any medication (therapy/procedure) with a start 
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Statistical Analysis Plan v1.0  
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date after the completion/termination visit date will not be considered a concomitant 
medication (therapy/procedure). 
 
The concomitant therapies, procedures and medications used will be summarized by the 
number and proportion of subjects in each treatment group and in overall subjects within 
each therapeutic class / system organ class, and preferred term, for the Safety Analysis Set.  
Multiple medications (therapies/procedures) used by a subject in the same category will be 
counted only once. 
 
All concomitant therapies, procedures and medications will be listed for the Safety 
Analysis Set. 
5.6 
Exposure to Investigational Product 
A listing will be created by subject number presenting all the IP infusion data collected, for 
the Safety Analysis Set. 
5.7 
IP Infusion 
Infusion duration (min), planned dose volume (mL), given dose volume (mL), and the 
difference between planned and given dose volume (mL), as well as the location, saline 
flush, and if the infusion was interrupted or not, duration of interruption (min), will be 
summarized by treatment group and overall, and listed, for the Safety Analysis Set. 
5.8 
Protocol Deviations 
Protocol deviations will be recorded by the site separately from the clinical database. The 
study team will classify major and minor protocol deviations per the agreed protocol 
deviation management plan. The sponsor study team will review the protocol deviations 
and their classification throughout the study and before treatment unblinding and database 
lock. 
 
Protocol deviations will be presented in a listing. 
 
6. 
EFFICACY ANALYSIS 
There are no efficacy endpoints for this study. This study is focused on safety; thus, the 
primary safety analysis and exploratory analyses are defined below. The primary and 
exploratory analyses will be performed on the Safety Analysis Set. 
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Statistical Analysis Plan v1.0  
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6.1 
Analyses of Primary Safety Endpoint(s) 
The primary safety endpoints will include SAEs and AEs, adverse changes in vital signs 
and laboratory parameters, and incidence of binding and inhibitory antibodies to SHP655 
occurring up to 28±3 days after SHP655 infusion. 
 
Analyses of these parameters are described in section 7. 
6.2 
Analyses Secondary Endpoint(s) 
The secondary endpoints for this study are related to PK/PD, and PK analysis will be 
further discussed in the CPAP. 
6.3 
Analyses of Exploratory Endpoint(s) 
The exploratory variables, include but are not limited to 
 
 
 
 plasma free hemoglobin. 
 
The exploratory endpoints will be listed and summarized  by treatment group, dose level 
and overall, by visit. Summaries will include descriptive statistics for exploratory variables 
and changes from baseline at each assessment time point. Change from baseline will only 
be presented if both baseline and post baseline assessments exist.  
 
7. 
SAFETY ANALYSIS 
All safety analyses (including the primary analysis) will be performed on the Safety 
Analysis Set. 
 
Safety variables include AEs, clinical laboratory variables, vital signs, and immunogenicity 
data and will be assessed using descriptive summaries by treatment group, dose level and 
overall, by visit. The placebo group will be pooled for the presentations. The total column 
will pool the SHP655 treatment groups. 
 
All safety analyses will be conducted according to the treatment the subject actually 
received. 
7.1 
Adverse Events  
Adverse events will be coded using the latest version of MedDRA. 
 
An AE that starts or worsens in severity on or after the infusion of IP will be considered a 
treatment emergent adverse event (TEAE).  
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Statistical Analysis Plan v1.0  
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An overall summary of the number of subjects with TEAEs as well as the number of events 
will be presented, by treatment group, dose level and overall, including the number and 
percentage of subjects with any TEAEs, serious TEAEs, TEAEs related to IP, TEAEs 
leading to study termination, and TEAEs leading to deaths. 
 
The number and percentage of subjects reporting TEAEs, as well as the number of events, 
in each treatment group, dose level and overall will be tabulated by system organ class 
(SOC) and preferred term.  A summary will also be presented by SOC, preferred term, and 
maximum severity.  
 
TEAEs considered related to investigational product will also be summarized by SOC and 
preferred term. If more than 1 AE occurs with the same preferred term for the same subject, 
then the subject will be counted only once for that preferred term using the most severe 
and most related occurrence for the summarization by severity and by relationship to 
investigational product. Serious TEAEs related to IP will be summarized. TEAEs related 
to IP will be summarized by maximum severity. 
 
Presentation by SOC and preferred term will display SOC by descending incidence and 
preferred term within SOC by descending incidence of study drug events (across all 
treatment groups), and then alphabetically for equal frequencies. 
 
TEAEs leading to study termination, TEAEs leading to death, TEAEs related to IP, serious 
TEAEs, and non-serious TEAEs will be summarized similarly, by SOC, preferred term and 
treatment group. 
 
The following will also be summarized, frequently occurring (≥10%) serious TEAEs and 
frequently occurring (≥10%) non-serious TEAEs, by preferred term and treatment group. 
 
Listings of all AEs, AEs related to IP, SAEs, AEs leading to death, and AEs leading to 
discontinuation, will be presented.  TEAEs will be flagged. 
 
AEs that occur at the time of IP infusion are of particular interest. Two additional listings 
will be presented which subset on AEs that occur on the same day as the IP infusion, 
displaying related and unrelated TEAEs. The same data will be summarized with the 
number and percentage of subjects, as well as the number of events in each treatment group, 
dose level and overall by preferred term.   
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Statistical Analysis Plan v1.0  
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7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline 
at each assessment time point as well as shift tables from baseline to each visit for 
quantitative variables will be presented by treatment group and overall, for the following 
clinical laboratory variables.  
 
Chemistry 
Alanine aminotransferase (ALT), Aspartate aminotransferase 
(AST), 
Alkaline 
phosphatase 
(ALP), 
Albumin, 
 
, Total bilirubin (TBL), 
,  
Blood Urea Nitrogen, Creatinine, Glucose, Sodium, Potassium, 
Chloride, Bicarbonate 
Hematology 
Platelets, Hemoglobin, Hematocrit, Erythrocytes (Red Blood Cell 
[RBC]), Mean corpuscular volume (MCV), Mean corpuscular 
hemoglobin (MCH), Mean corpuscular hemoglobin concentration 
(MCHC), 
, Leukocytes (White Blood Cell 
[WBC]), WBC Differential count (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils) 
Local and central clinical laboratory data will be flagged for out-of-range values and will 
be listed for the Safety Analysis Set. A list of clinically significant abnormal values will 
also be presented.  Results for blood group typing,
, viral serology 
[Anti-Human immunodeficiency virus (HIV) 1/2, Anti-Hepatitis C virus (HCV), Hepatitis 
B surface antigen (HBsAg), Anti-Hepatitis B-core total (HBc), Anti- Hepatitis B surface 
antigen], and pregnancy testing at screening and baseline will only be presented in a listing. 
7.3 
Vital Signs 
Descriptive statistics for vital signs, systolic and diastolic blood pressure, pulse rate, 
respiratory rate, body temperature, oxygen saturation, and their changes from baseline at 
each post-baseline visit and at the end of study will be presented by treatment group, dose 
level and overall. 
 
Vital sign values will be considered PCS if they meet both the observed value criteria and 
the change from baseline criteria listed in Table 1. The number and percentage of subjects 
with PCS post-baseline values will be tabulated by treatment group and overall. The 
percentages will be calculated relative to the number of subjects with baseline and at least 
1 post-baseline assessment. The numerator is the total number of subjects with at least 1 
PCS post-baseline vital sign value. A supportive listing of subjects with post-baseline PCS 
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Statistical Analysis Plan v1.0  
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values will be provided including the subject number, site, baseline, and post-baseline PCS 
values.  
 
 
 
Table 1: Criteria for Potentially Clinically Significant Vital Signs  
 
 
Vital Sign Parameter 
 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Systolic 
blood 
pressure 
(mmHg) 
High 
180 
Increase of 20 
Low 
90 
Decrease of 20 
Diastolic 
blood 
pressure 
(mmHg) 
High 
105 
Increase of 15 
Low 
50 
Decrease of 15 
Pulse rate (beats per minute) 
High 
120 
Increase of 15 
Low 
50 
Decrease of 15 
a A post-baseline value is considered as a PCS value if its meets both criteria for observed value and 
change from baseline. 
 
All vital signs data will be listed for the Safety Analysis Set. Descriptive statistics and 
listing will be presented for oxygen use. 
7.4 
Other Safety Data  
Based on the availability of immunogenicity data, as applicable, the number and proportion 
of subjects with pre-existing (baseline), treatment-induced, treatment-boosted and overall 
incidences of ADA in serum, as well as titers will be summarized by treatment group and 
overall for subjects with a non-missing baseline sample. Similar summary will be provided 
for serum neutralizing antibodies.  
• Pre-existing ADA positive is defined as a subject with positive ADA response in 
baseline sample. 
• Treatment-induced ADA positive is defined as a subject who has negative ADA in 
baseline sample and has positive ADA response in any postbaseline assessment. 
• Treatment-boosted ADA positive is defined as a subject who has positive ADA 
response in both baseline and postbaseline samples, and the maximum titer/value 
of the postbaseline ADA is ≥4 times that of the baseline titer value. 
Individual results for binding and neutralizing antibodies to SHP655 will be presented in 
listings, including results for subjects with missing baseline sample. Data allowing, the 
relationship of immunogenicity with PK/PD may be evaluated as outlined in Sections 8.1 
and 9.2. 
 
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8. 
PHARMACOKINETIC ANALYSIS 
The non-compartmental PK analysis will be conducted at IQVIA and details are provided 
in the CPAP. 
8.1 
Pharmacokinetic Analyses in Support of Data Review by the Dose Escalation 
Committee 
PK analysis using NCA method will be performed by the IQVIA Pharmacokineticist to 
support the Dose Escalation Committee (DEC). Analyses and data presentations will 
follow the conventions described in CPAP. The PK analyses in support of the DEC will be 
performed using unblinded data at the treatment/subject level and will only be shared 
according to the unblinding plan. 
8.2 
Relationships of Immunogenicity Results with Pharmacokinetics 
Data allowing, observed and baseline-adjusted concentrations, as well as available PK 
parameters (Cmax, AUC(0-last), AUC(0-inf) and CL) of ADAMTS13 activity and 
ADAMTS13:Ag in the placebo group and at each SHP655 dose level will be summarized 
by binding antibody status (positive vs. negative) and immunogenicity type (treatment-
induced vs. treatment-boosted). Similarly, summaries of above ADAMTS13 activity and 
ADAMTS13:Ag PK concentraions and parameters will be provided by neutralizing 
antibody status and immunogenicity type. 
 
Data allowing, for each SHP655 dose level, figures of arithmetic mean (SD) observed 
concentration-time data will be overlaid by binding antibody status (positive vs. negative) 
and immunogenicity type (treatment-induced vs. treatment-boosted) for each 
anti-ADAMTS13 antibody category (binding and neutralizing) and presented on linear 
scale plot.  Individual and geometric mean PK exposure parameters (Cmax, AUC(0-last), 
AUC(0-inf) and CL) will be plotted by binding antibody status (positive vs. negative) and 
immunogenicity type (treatment-induced vs. treatment-boosted) for each anti ADAMTS13 
antibody category (binding and neutralizing). 
 
9. 
PHARMACODYNAMIC ANALYSIS 
9.1 
Pharmacodynamic Data 
9.1.1 
Primary Pharmacodynamic Endpoint and Analysis 
There is no primary PD analysis due to be performed on the study. 
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9.1.2 
Secondary Pharmacodynamic Endpoints and Analysis 
Summaries, using the following descriptive statistics: n, mean, median, standard deviation, 
CV%, minimum, and maximum, for 
, VWF:Ag, VWF:RCo levels over 
time, as well as for 
, plasma free hemoglobin, and plasma 
thrombospondin level, will be provided by treatment group and overall for all SHP655 dose 
levels. Observed value, change from baseline and percent change from baseline will be 
summarized.  Listings including all the above PD parameters will be presented. 
9.1.3 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships 
For each SHP655 dose level and each PD analyte, arithmetic mean (SD) observed 
ADAMTS13 activity data will be overlaid with PD responses over time on a figure with 
two linear y-axes. PD responses will include median and arithmetic mean (SD) observed 
value and change from baseline. 
 
Scatter plots of individual PK exposure parameters (Cmax, AUC(0-last), AUC(0-inf) and CL) 
and individual PD responses will be presented for graphical assessments of exposure-
response. PD responses will include maximimum or minimum observed value and change 
from baseline, as applicable for each PD analyte. 
9.2 
Relationships of Immunogenicity Results with Pharmacodynamics 
Data allowing, figures of arithmetic mean (SD) observed value and change from baseline 
PD data over time will be overlaid by antibody status (positive vs. negative) and 
immunogenicity type (treatment-induced vs. treatment-boosted) for each anti-ADAMTS13 
antibody category (binding and neutralizing) and provided by treatment group.   
 
10. 
HEALTH ECONOMICS AND OUTCOMES RESEARCH (HEOR) 
ENDPOINTS 
The Health Economics and Outcomes Research (HEOR) outcome measures were collected 
for cohort 1 and 2, prior to Protocol Amendment 2. HEOR measures include: 
o Rate of acute VOC complications 
o Time interval between the initiation of IP infusion and discontinuation of IV 
narcotics 
o Treatment satisfaction (TSMQ-9) 
o Health-related quality of life assessments:  
o Brief Pain Inventory (BPI) 
o Patient-Reported Outcomes Measurement Information System (PROMIS) 
Fatigue 
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o Adult Sickle Cell Quality of Life Measurement Information System 
(ASCQ-Me) 
o Pain score - Visual Analog Score (VAS) 
o Days of hospitalization 
o Type of transfusion 
 
The HEOR outcome measures with available data will be listed for the Safety Analysis 
Set.  
 
11. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE  
Although no formal data monitoring committee (DMC) will be involved in the 
management of this study, safety will be monitored by a Takeda Dose Escalation 
Committee. See Section 6.2.3.3 of the protocol for more details. 
 
12. 
DATA HANDLING CONVENTIONS  
12.1 
General Data Reporting Conventions  
Continuous variables will be summarized using the following descriptive statistics:  n, 
mean, median, standard deviation, minimum, maximum, 1st and 3rd quartiles. Categorical 
and count variables will be summarized by the number of subjects (n) and the percent of 
subjects in each category.  
 
If the original data has N decimal places (as derived from the raw data) (i.e., decimal 
precision [N]) then the summary statistics will contain the following decimal places (with 
a maximum of 3 decimals): 
• 
Minimum and maximum: N decimals 
• 
Mean, median, and quartiles: N + 1 decimals 
• 
Standard deviation: N + 2 decimals 
For qualitative variables the number (n) and percentage (%) of subjects in each category 
will be the default summary presentation. Unless otherwise specified percentages will be 
calculated relative to the total number of subjects in the relevant analysis set with data 
available as described in the latest version of the Output Templates. 
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All values will be rounded using the SAS® function ROUND. All computed percentages 
will be presented using 1 decimal place, except for 100% which will be presented with no 
decimals. 
12.2 
Definition of Baseline 
For each measure, safety and exploratory data, baseline will be defined as the last non-
missing measurement obtained prior to the first dose date and time.  
 
The last post-baseline assessment will be used as the end of study assessment. 
For quantitative measurements where change from baseline (CFB) is presented, CFB will 
be derived as: 
𝐶𝐹𝐵= (𝑉𝑎𝑙𝑢𝑒 𝑎𝑡 𝑇𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡 𝑋) −(𝑉𝑎𝑙𝑢𝑒 𝑎𝑡 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒). 
12.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the 
results from the final assessment made prior to the start of investigational product will be 
used as baseline. If end of study assessments are repeated, the last post-baseline assessment 
will be used as the end of study assessment for generating descriptive statistics. However, 
all post-baseline assessments will be used for PCS value determination.  
 
In the case of retests or repeated assessments, the last available measurement for that visit 
will be used for by-visit summaries.  
 
Unscheduled results will not be included in summaries. All results (scheduled and 
unscheduled; original and repeated) will be presented in the listings. 
12.4 
Handling of Missing, Unused, and Spurious Data 
12.4.1 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures/Opioids/Transfusions) 
For prior or concomitant medications (and/or therapies/procedures), including rescue 
medications, incomplete (i.e., partially missing) start date and/or stop date will be imputed.  
When the start date and the stop date are both incomplete for a subject, impute the start 
date first. 
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12.4.1.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date 
is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. 
12.4.1.1.1 Missing Day and Month 
o If the year of the incomplete start date is the same as the year of the date of the dose of 
investigational product, then the day and month of the date of the dose of 
investigational product will be assigned to the missing fields. 
o If the year of the incomplete start date is before the year of the date of the dose of 
investigational product, then December 31 will be assigned to the missing fields. 
o If the year of the incomplete start date is after the year of the date of the dose of 
investigational product, then 01 January will be assigned to the missing fields. 
12.4.1.1.2 Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
12.4.1.1.3 Missing Day Only 
o If the month and year of the incomplete start date are the same as the month and year 
of the date of the dose of investigational product, then the day of the date of the dose 
of investigational product will be assigned to the missing day. 
o If either the year is before the year of the date of the dose of investigational product or 
if both years are the same, but the month is before the month of the date of the dose of 
investigational product, then the last day of the month will be assigned to the missing 
day. 
o If either the year is after the year of the date of the dose of investigational product or if 
both years are the same, but the month is after the month of the date of the dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
12.4.1.2 
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields.  If the date of 
the study completion/termination visit is missing, then replace it with the Day 13 follow-
up visit date.  If the imputed stop date is before the start date (imputed or non-imputed start 
date), then the imputed stop date will be equal to the start date. 
12.4.1.2.1 Missing Day and Month 
o If the year of the incomplete stop date is the same as the year of the date of the study 
completion/termination visit, then the day and month of the date of the study 
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completion/termination visit will be assigned to the missing fields. 
o If the year of the incomplete stop date is before the year of the date of the study 
completion/termination visit, then 31 December will be assigned to the missing fields. 
o If the year of the incomplete stop date is after the year of the date of the study 
completion/termination visit, then 01 January will be assigned to the missing fields. 
12.4.1.2.2 Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
12.4.1.2.3 Missing Day Only 
o If the month and year of the incomplete stop date are the same as the month and year 
of the date of the study completion/termination visit, then the day of the date of the  
study completion/termination visit will be assigned to the missing day 
o If either the year is before the year of the date of the study completion/termination visit 
or if both years are the same, but the month is before the month of the date of the study 
completion/termination visit, then the last day of the month will be assigned to the 
missing day 
o If either the year is after the year of the study completion/termination visit or if both 
years are the same, but the month is after the month of the date of the study 
completion/termination visit, then the first day of the month will be assigned to the 
missing day. 
12.4.2 Missing Date Information for Adverse Events  
For AEs with partial start dates, non-missing date parts will be used to determine if the AE 
is treatment-emergent or not.  If a determination cannot be made using the non-missing 
date parts as to when the AE occurred relative to study drug administration, e.g., AE start 
year and month are the same as the year and month of the dose of investigational product, 
then the AE will be classified as treatment emergent.  To facilitate categorization of AEs 
as treatment emergent, imputation of dates can be used.   
 
For AEs, the default is to only impute incomplete (i.e., partially missing) start dates. 
Incomplete stop dates may also be imputed when calculation of the duration of an AE is 
required per the protocol. If imputation of an incomplete stop date is required, and both the 
start date and the stop date are incomplete for a subject, impute the start date first. 
12.4.2.1 
Incomplete Start Date  
Follow the same rules as in Section 11.4.1.1. 
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12.4.2.2 
Incomplete Stop Date  
Follow the same rules as in Section 11.4.1.2. 
12.4.3 Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE 
starting on or after the date of the dose of investigational product, then a severity of 
“Severe” will be assigned.  The imputed values for severity assessment will be used for 
incidence summaries. 
12.4.4 Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the 
date of the dose of investigational product, a causality of “Related” will be assigned.  The 
imputed values for relationship to double-blind investigational product will be used for 
incidence summaries. 
12.4.5 Character Values of Clinical Laboratory Variables 
For the quantitative laboratory measurements reported as “<X”, i.e., below the limit of 
quantification (BLQ), or “>X”, i.e., above the upper limit of quantification (ALQ), these 
are to be presented in listings as “<X” or “>X” and summarized as “X” for “<X” or “>X”.  
 
13. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 of SAS on a suitably qualified 
environment. 
 
14. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
Not applicable.  
 
15. 
REFERENCES 
None 
 
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