A Phase 2, Multicenter, Randomized, Placebo-Controlled, Double-blind Study in Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP) to Evaluate the Pharmacokinetics, Safety and Efficacy of rADAMTS-13 (SHP655) Administered in Addition to Standard Of Care (SoC) Treatment
Phase: PHASE2
Conditions: Acquired Thrombotic Thrombocytopenic Purpura (aTTP)
Sponsor: Shire

CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT03922308 
Study Title: 
Study Number: 
A Phase 2, Multicenter, Randomized, Placebo-Controlled, Double-
blind Study in Patients With Acquired Thrombotic Thrombocytopenic 
Purpura (aTTP) to Evaluate the Pharmacokinetics,Safety and Efficacy 
of rADAMTS-13 (SHP655) Administered in Addition to Standard Of 
Care (SoC) Treatment
Protocol Version and Date: 
Version Original: 03-OCT-2018 
SHP655-201
For non-commercial use only

PROTOCOL: SHP655-201
TITLE:
A Phase 2, multicenter, randomized, placebo-controlled, double-
blind study in patients with acquired thrombotic thrombocytopenic 
purpura (aTTP) to evaluate the pharmacokinetics, safety, and 
efficacy of rADAMTS-13 (SHP655) administered in addition to 
standard of care (SoC) treatment
SHORT TITLE:
A Phase 2, randomized, placebo-controlled, double-blind study of 
rADAMTS-13 (SHP655) in the treatment of patients with aTTP 
STUDY PHASE:
Phase 2
ACRONYM:
SOAR-HI (Study Of ADAMTS-13, Recombinant in acquired 
tHrombocytopenIc purpura)
DRUG:
SHP655 (rADAMTS-13)
IND NUMBER:
TBD
EUDRACT NUMBER:
TBD
SPONSOR:
Baxalta US Inc.*, 300 Shire Way, Lexington, MA 02421, USA
AND
Baxalta Innovations GmbH*, Industriestrasse 67, A-1221 Vienna 
*Baxalta is now part of Shire*
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Multicenter
PROTOCOL HISTORY:
Original Protocol 1.0: 03 OCT 2018
This document contains confidential and proprietary information of Shire 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 Shire.
For non-commercial use only

Shire
CONFIDENTIAL
Page 2
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
PROTOCOL SIGNATURE PAGE
Sponsor’s (Shire) Approval
Signature:
Date:
, MD
For non-commercial use only

Shire
CONFIDENTIAL
Page 3
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Investigator’s Acknowledgement
I have read this protocol for Study SHP 655-201.
Title: A Phase 2, multicenter, randomized, placebo-controlled, double-blind study evaluating the 
safety, efficacy, and pharmacokinetics of rADAMTS-13 (SHP655) in the treatment of patients 
with acquired thrombotic thrombocytopenic purpura (aTTP) receiving standard of care (SoC) 
treatment
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative.
I understand that the information in this protocol is confidential and should not be disclosed, 
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 guidelines on Good Clinical Practice 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:
Date:
For non-commercial use only

Shire
CONFIDENTIAL
Page 4
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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 Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol” within 24 hours to the Shire 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)/Shire 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 Shire medical monitor:
Shire Medical Monitor
, MD, PhD
Direct Line:  
Mobile: 
Email: 
IQVIA medical monitor
, MD
Mobile: 
Email: 
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
For non-commercial use only

Shire
CONFIDENTIAL
Page 5
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire 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 Shire product (marketed or 
investigational) does not meet expectations (eg, inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (eg, 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, eg, reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (eg, 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.
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
North and South America
PQC@shire.com
European Union and Rest of World
PQCROW@shire.com
Telephone number (provided for reference if needed):
Shire, Lexington, MA (USA)
1-800-828-2088
For non-commercial use only

Shire
CONFIDENTIAL
Page 6
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................. 2
Sponsor’s (Shire) Approval...................................................................................................... 2
Investigator’s Acknowledgement ............................................................................................ 3
EMERGENCY CONTACT INFORMATION .......................................................................... 4
PRODUCT QUALITY COMPLAINTS..................................................................................... 5
TABLE OF CONTENTS ............................................................................................................. 6
1. PROTOCOL SUMMARY ..................................................................................................... 11
1.1 Synopsis.............................................................................................................................. 11
1.2 Schema ............................................................................................................................... 19
1.3 Schedule of Activities........................................................................................................ 20
2. INTRODUCTION................................................................................................................... 23
2.1 Indication and Current Treatment Options................................................................... 23
2.1.1 Current Standard of Care (SoC).............................................................................. 23
2.1.1.1 Plasma Exchange (PEX)..................................................................................... 24
2.1.1.2 Corticosteroids.................................................................................................... 24
2.1.1.3 Rituximab............................................................................................................ 25
2.1.1.4 Investigational Drugs.......................................................................................... 25
2.1.2 Unmet Medical Needs of Current Therapy............................................................. 26
2.2 Product Background and Clinical Information............................................................. 27
2.3 Study Rationale................................................................................................................. 27
2.4 Benefit/Risk Assessment................................................................................................... 28
2.5 Compliance Statement...................................................................................................... 28
3. OBJECTIVES AND ENDPOINTS ....................................................................................... 29
3.1 Study Objectives ............................................................................................................... 29
3.1.1 Co-Primary Objectives.............................................................................................. 29
3.1.2 Secondary Objectives ................................................................................................ 29
3.1.3 Exploratory Objectives ............................................................................................. 30
3.2 Study Endpoints................................................................................................................ 31
4. STUDY DESIGN..................................................................................................................... 35
4.1 Overall Design................................................................................................................... 35
4.2 Scientific Rationale for Study Design.............................................................................. 36
4.2.1 Rationale for control group ...................................................................................... 36
For non-commercial use only

Shire
CONFIDENTIAL
Page 7
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
4.2.2 Rationale for Primary and Key Secondary Endpoints .......................................... 36
4.2.3 Justification for the use of placebo........................................................................... 36
4.3 Justification for Dose........................................................................................................ 36
4.4 Duration of Subject Participation and Study Completion Definition.......................... 37
4.5 Sites and Regions .............................................................................................................. 37
5. STUDY POPULATION ......................................................................................................... 38
5.1 Inclusion Criteria.............................................................................................................. 38
5.2 Exclusion Criteria............................................................................................................. 38
5.2.1 Contraception............................................................................................................. 39
6. STUDY INTERVENTION..................................................................................................... 41
6.1 Investigational Product .................................................................................................... 41
6.1.1 Identity of Investigational Product .......................................................................... 41
6.1.2 Blinding the Treatment Assignment ........................................................................ 41
6.2 Administration of Investigational Product..................................................................... 41
6.2.1 Interactive Response Technology for Investigational Product Management ...... 41
6.2.2 Allocation of Subjects to Treatment ........................................................................ 42
6.2.3 Dosing.......................................................................................................................... 42
6.2.4 Unblinding the Treatment Assignment during the Placebo-Controlled Portion of 
the Study..................................................................................................................... 43
6.2.5 Dose Modification ...................................................................................................... 43
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product.................... 44
6.3.1 Labeling ...................................................................................................................... 44
6.3.2 Packaging.................................................................................................................... 44
6.3.3 Storage ........................................................................................................................ 44
6.3.4 Special Handling........................................................................................................ 45
6.4 Drug Accountability ......................................................................................................... 45
6.5 Subject Compliance.......................................................................................................... 46
6.6 Plasma Exchange (PEX)................................................................................................... 47
6.7 Immunosuppression.......................................................................................................... 48
6.8 Prior and Concomitant Therapy..................................................................................... 48
6.8.1 Prior Treatment......................................................................................................... 48
6.8.2 Concomitant Treatment............................................................................................ 48
6.8.3 Permitted Treatment................................................................................................. 48
6.8.4 Prohibited Treatment................................................................................................ 49
7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL............................................................................. 50
7.1 Discontinuation of Study Treatment............................................................................... 50
7.2 Reasons for Discontinuation ............................................................................................ 50
7.3 Withdrawal from the Study............................................................................................. 51
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit.................................. 51
For non-commercial use only

Shire
CONFIDENTIAL
Page 8
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
8. STUDY ASSESSMENTS AND PROCEDURES................................................................. 52
8.1 Study Schedule.................................................................................................................. 52
8.1.1 Screening Period ........................................................................................................ 52
8.1.1.1 Screening/Baseline Visit..................................................................................... 52
8.1.2 Treatment Period....................................................................................................... 52
8.1.2.1 Final Visit ............................................................................................................ 53
8.1.3 Follow-up Period........................................................................................................ 53
8.1.4 Additional Care of Subjects after the Study ........................................................... 53
8.2 Study Assessments ............................................................................................................ 53
8.2.1 Demographic and Other Baseline Characteristics ................................................. 53
8.2.1.1 Height and Weight.............................................................................................. 53
8.2.1.2 Medical, Medication History, and Non-drug Therapies................................. 54
8.2.2 Efficacy ....................................................................................................................... 54
8.2.3 Safety........................................................................................................................... 54
8.2.3.1 Physical Examination......................................................................................... 55
8.2.3.2 Adverse Events.................................................................................................... 55
8.2.3.3 Vital Signs............................................................................................................ 56
8.2.3.4 Clinical Laboratory Tests .................................................................................. 57
8.2.3.5 Pregnancy Test.................................................................................................... 57
8.2.4 Other ........................................................................................................................... 58
8.2.4.1 Clinical Pharmacokinetics ................................................................................. 58
8.2.4.2 Pharmacodynamics............................................................................................. 58
8.2.4.3 Genetics................................................................................................................ 58
8.2.4.4
................................................................ 58
8.2.4.5 
....................................................................... 58
8.2.4.6 
...................................................................................................... 59
8.2.4.7 
..................................................................................................... 61
8.2.5 Volume of Blood to Be Drawn from Each Subject ................................................. 61
8.2.6 Retention of Study Samples ...................................................................................... 61
9. STATISTICAL CONSIDERATIONS .................................................................................. 62
9.1 Statistical Analysis Process .............................................................................................. 62
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......... 62
9.3 Sample Size and Power Considerations.......................................................................... 63
9.4 Efficacy Analyses .............................................................................................................. 63
9.4.1 Primary Efficacy Endpoint....................................................................................... 64
9.4.2 Secondary Efficacy Endpoints.................................................................................. 64
9.4.3 Multiplicity Adjustment............................................................................................ 65
9.4.4 Control of Type I Error ............................................................................................ 65
9.4.5 Exploratory Endpoints.............................................................................................. 65
9.5 Safety Analyses.................................................................................................................. 65
9.5.1 Secondary Safety Endpoints..................................................................................... 65
9.5.2 Safety Endpoint Analyses.......................................................................................... 66
9.6 
.................................................. 66
For non-commercial use only

Shire
CONFIDENTIAL
Page 9
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
9.6.1 
......................................... 66
9.6.2 
........................... 67
9.6.3 
............................................................. 67
9.6.4 
..................................... 67
9.7 Pharmacokinetic Analyses ............................................................................................... 68
9.7.1 Secondary PK/PD Endpoints.................................................................................... 68
9.7.2 PK/PD Analyses ......................................................................................................... 68
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........ 69
APPENDIX 1  REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS.............................................................................................................. 69
Appendix 1.1  Regulatory and Ethical Considerations ....................................................... 69
Appendix 1.2  Sponsor’s Responsibilities ............................................................................. 69
Appendix 1.3  Investigator’s Responsibilities....................................................................... 70
Appendix 1.4  Data Management Considerations ............................................................... 73
Appendix 1.5  Ethical Considerations................................................................................... 74
APPENDIX 2  ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING.............................. 78
Appendix 2.1  Adverse Event Definitions............................................................................. 78
Appendix 2.2  Collection of Adverse Events......................................................................... 81
Appendix 2.3  Assessment of Adverse Events ...................................................................... 81
Appendix 2.4  Serious Adverse Event Collection Time Frame........................................... 84
Appendix 2.5  Serious Adverse Event Onset and Resolution Dates................................... 84
Appendix 2.6  Fatal Outcome ................................................................................................ 84
Appendix 2.7  Pregnancy........................................................................................................ 85
Appendix 2.8  Abuse, Misuse, Overdose and Medication Error........................................ 85
Appendix 2.9  Urgent Safety Measures................................................................................. 86
Appendix 2.10  Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting.................................................................................................................... 87
APPENDIX 3  GENETICS ........................................................................................................ 88
APPENDIX 4  DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION ........................ 90
APPENDIX 5  ABBREVIATIONS ........................................................................................... 91
APPENDIX 6  PROTOCOL HISTORY................................................................................... 95
10. REFERENCES...................................................................................................................... 96
For non-commercial use only

Shire
CONFIDENTIAL
Page 10
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Tables
Table 1. Schedule of Study Procedures and Assessments............................................................ 20
Table 2. Non-PK Laboratory Assessments in Screening and Treatment...................................... 22
Table 3. Treatment Period PK Laboratory Assessments (Randomized to Schedule A or B)  
SCHEDULE A: Days 1, 2, 3, 4, 6, 8, 11, and every 3 days thereafter  
SCHEDULE B: Days 1, 2, 3, 5, 7, 9, 12, and every 3 days thereafter ................................. 22
Table 4. Objectives and Endpoints ............................................................................................... 31
Table A1 Adverse Event Relationship Categorization
82
Figures
Figure 1. Study Schematic Diagram ............................................................................................. 19
For non-commercial use only

Shire
CONFIDENTIAL
Page 11
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: SHP655-201
Drug: SHP655 (rADAMTS-13)
Title of the study: A Phase 2, multicenter, randomized, placebo-controlled, double-blind study in patients with 
acquired thrombotic thrombocytopenic purpura (aTTP) to evaluate the pharmacokinetics, safety, and efficacy of 
rADAMTS-13 (SHP655) administered in addition to standard of care (SoC) treatment
Short title: A Phase 2, randomized, placebo-controlled, double-blind study of rADAMTS-13 (SHP655) in the 
treatment of patients with aTTP
Study phase: Phase 2  
Number of subjects (total and per treatment arm):
Approximately 30 in total and 10 per treatment arm
Investigator(s): multicenter study
Site(s) and Region(s): 
Approximately 20 sites in the US and EU are planned.
Study period (planned):
2019-2021
Clinical phase:
2
Objectives:
Co-Primary: 
1.
Assess the PK of ADAMTS-13 in aTTP subjects treated for an acute episode by daily plasma exchange 
(PEX), immunosuppressant therapy, with or without SHP655 supplementation
2.
Study the PK/PD relationship between ADAMTS-13 levels and pathophysiological biomarkers, as well as
clinical efficacy parameters
Secondary: 
PK/PD Objectives
1.
Evaluate changes in levels of ADAMTS-13 binding and inhibitory autoantibodies in response to daily PEX, 
with or without SHP655 supplementation, during the acute episode and up to 30 days after the resolution of 
the TTP episode
2.
Evaluate ADAMTS-13 activity levels in subjects up to 30 days after TTP episode remission
3.
Specify dose(s) of SHP655 needed to achieve and maintain adequate plasma levels of rADAMTS-13 in order 
to support induction of remission and to reduce the number of PEX procedures needed for the treatment of 
acute aTTP episodes
Safety/Efficacy Objectives
1.
Assess the safety and immunogenicity of two regimens of SHP655 supplementation administered during an 
acute TTP episode in subjects undergoing PEX treatment and immunosuppressant therapy as measured by 
AEs, changes in vital signs and laboratory parameters
2.
Evaluate the occurrences of aTTP related complications, (including death, stroke, MI, and organ failure), 
aTTP relapses*, exacerbations** and end-organ function improvement
For non-commercial use only

Shire
CONFIDENTIAL
Page 12
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
3.
Evaluate the time to aTTP related complications (including death, stroke, MI, and organ failure), aTTP 
relapses*, exacerbations** and end-organ function improvement
4.
Evaluate the occurrence of procedure (e.g. PEX, SHP655 infusions) related adverse events
Exploratory Objectives:
*Defined as >30 days after achieving remission
**Defined as ≤30 days after achieving remission
Rationale:
This study is needed to enable detailed assessment of ADAMTS-13 activity in aTTP subjects in the context of PEX, 
rADAMTS-13 supplementation and anti-ADAMTS-13 autoantibodies, all of which will acutely change plasma 
ADAMTS-13 activity. 
The relationship between recovery of ADAMTS-13 activity and improvement in clinical outcomes will be explored. 
PK/PD analysis will be utilized to establish an SHP655 dosing regimen that assures achievement of adequate 
ADAMTS-13 activity levels, thus enabling a reduction in the number of PEX, a hypothesis which will be tested in 
the pivotal phase 3 study.
For non-commercial use only

Shire
CONFIDENTIAL
Page 13
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Investigational product, dose, and mode of administration:

SHP655 40 IU/kg once daily, i.v. or 40IU/kg, b.i.d., i.v.

Placebo (0.9% saline)
Study Design
Subjects experiencing the onset of an acute TTP episode will receive a single PEX as part of SoC as soon as 
feasible, consent will be obtained, and subjects will undergo screening procedures. Eligible subjects will 
provisionally be randomized into one of three treatment arms, with a total enrollment of approximately 30 evaluable 
subjects. The first 2 on-study PEX (after the first SoC PEX) will be 1.5 plasma volume, followed by daily 
1.0 plasma volume exchanges. 
Arm 1 - SoC (n=10)
Subjects will receive daily PEX and will also receive placebo immediately after each PEX and at 12±1 hours after 
completion of each PEX. 
Arm 2 - SoC with Supplementation once daily (n=10)
Subjects will receive daily PEX and will also receive 40 IU/kg SHP655 immediately after each PEX and placebo at 
12±1 hours after completion of each PEX. 
Arm 3 - SoC with Supplementation twice daily (n=10)
Subjects will receive daily PEX and will also receive 40 IU/kg SHP655 immediately after each PEX and at 
12±1 hours after completion of each PEX. 
Supplementation with SHP655 or placebo as appropriate will continue until all remission criteria are met: platelet 
count ≥150,000/μL and confirmation by a second platelet count ≥150,000/μL and LDH <2 ULN 48 hours following 
initial normalization.  Furthermore, dosing will also be discontinued based on pre-PEX ADAMTS-13 activity levels 
as described later in this section.
If screening laboratory tests show:

ADAMTS-13 activity >10%; or

The absence of anti-ADAMTS-13 autoantibodies; or

The presence of a known genetic mutation on both alleles consistent with cTTP
The subject will be discontinued from the study. A follow up safety visit will be scheduled 30 ±5 days after the last 
administration of study drug, but the subject will be excluded from the PK and efficacy analyses.
An immunosuppressive regimen of 1 g methylprednisolone iv once daily for 3 consecutive days, followed by 
2.5 mg/kg/day, and 375 mg/m2 rituximab administered weekly for 4 weeks will be initiated within 2 days of 
enrollment for all subjects. Steroid tapering is permitted per local SoC. Additional immunosuppressive therapy can 
be considered after consultation with the sponsor.
Subjects in each study arm will receive a dose of IP immediately after and at 12±1 hours after each PEX. 
In all study arms, the second daily dose (SHP655 or placebo 12h after PEX) will be terminated if a local lab 
pre-PEX ADAMTS-13 activity level is >150% or above the upper limit of quantification.  
For non-commercial use only

Shire
CONFIDENTIAL
Page 14
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
If the second dose has already been suspended and a subsequent local lab pre-PEX ADAMTS-13 activity level is 
>150% or above the upper limit of quantification, the first daily dose (SHP655 or placebo immediately after PEX) 
will be terminated.
After resolution of the TTP episode, subjects will be given additional IP (placebo for Arm 1, SHP655 40 IU/kg for 
Arms 2 and 3) once weekly if weekly ADAMTS-13 activity at the local lab is <50%.
Inclusion and Exclusion Criteria:
Inclusion Criteria:
1.
Subject or legally authorized representative voluntarily signs informed consent. For subjects unable to 
provide consent, a fully recognized medical proxy may be used according to local laws.
2.
Subject is 18 to 75 years old at the time of screening.
3.
Subject has been diagnosed with primary or secondary autoimmune aTTP based on the following criteria:
a. Thrombocytopenia [drop in platelet count ≥50% or platelet count < 100,000/µL]; 

No more than 3 subjects per arm may be enrolled with a screening platelet count ≥50,000/ µL.
b. Microangiopathic hemolytic anemia [elevation of lactate dehydrogenase (LDH) >2-fold or by presence or 
increase of schistocytes in peripheral blood smear].
4.
Willingness to fully comply with study procedures and requirements, and intention to initiate plasma 
exchange (PEX). Subjects may be provisionally entered into the trial and undergo randomization pending the 
results of the ADAMTS-13 activity, anti-ADAMTS-13 antibody, and genetic testing for cTTP.
5.
If female of childbearing potential, subject presents with a negative pregnancy test and agrees to employ 
adequate birth control measures for the duration of the study.  Sexually active males must use an accepted 
and effective method of contraception during the treatment and until a minimum of 16 days after the last dose 
administered.
Exclusion Criteria:
1.
Subject has been diagnosed with congenital TTP.
2.
Subject has plasma ADAMTS-13 activity> 10% of normal.
3.
Subject has been diagnosed with another cause of thrombotic microangiopathy (TMA) including: DIC, 
disseminated malignancy, malignant hypertension, hematopoietic stem cell transplantation, shiga toxin-
related and atypical HUS, drug toxicity (e.g. gemcitabine, mitomycin C, clopidogrel) and pregnancy-related 
thrombocytopenia syndromes (e.g. HELLP, eclampsia).
4.
Subject has been exposed to another IP within 30 days prior to enrollment or is scheduled to participate in 
another clinical study involving IP or investigational device during the course of the study.
5.
Subject has received caplacizumab within 3 months of study enrollment. 
6.
Subject is human immunodeficiency virus positive (HIV+) with unstable disease or CD4+ count 
≤200 cells/mm3 within 3 months screening.
7.
Subject has had a previous aTTP event in the past 30 days.
8.
Subject has another underlying progressive fatal disease and/or life expectancy of less than 3 months. 
9.
Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 15
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
10.
Subject suffers from a mental condition rendering him/her unable to understand the nature, scope, and 
possible consequences of the study and/or evidence of an uncooperative attitude. However, a fully recognized 
medical proxy will be permitted to provide consent.
11.
If female, subject is pregnant or lactating.
12.
Subject is a family member or employee of the Sponsor or investigator.
13.
Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing information.
Maximum duration of subject participation in the study:
6 months

Planned duration of screening period: 1 day 

Planned duration of enrollment period: 1 day 

Planned duration of treatment period: up to 3 months (dependent on time to remission)

Planned duration of follow-up: 3 months
Endpoints and statistical analysis:
Analysis sets:

Full Analysis Set (FAS): all enrolled aTTP subjects who are treated with study product and have 
ADAMTS-13 activity reading from at least one post infusion sample. Randomization errors are included in 
the treatment arm they are randomized to, not in the treatment arm of the treatment they receive.

Safety Analysis Set:

Safety Analysis Set (enrolled) -- all subjects randomized and who received any dose of investigational 
product.

aTTP Safety Analysis Set -- all aTTP subjects in the Safety Analysis Set. Subjects provisionally 
randomized, and subsequently meet the non-aTTP criterion, are not part of this analysis set.

PK/PD Analysis Set: all aTTP subjects who receive study treatment and obtain at least one post-infusion 
ADAMTS-13 activity level.
Endpoints
Primary endpoints
1.
ADAMTS-13 activity levels
2.
Platelet count and LDH levels 
Secondary 
Pharmacokinetic Endpoints
1.
The PK/PD temporal relationship of efficacy parameters (e.g., platelet count, LDH levels), as a function of 
ADAMTS-13 activity
2.
The ADAMTS-13 binding and inhibitory autoantibody levels in response to daily PEX, with or without 
SHP655 supplementation, during the acute TTP episode and up to 30 days after resolution
3.
ADAMTS-13 activity levels in subjects receiving additional SHP655 for up to 30 days after the resolution of 
the TTP episode
For non-commercial use only

Shire
CONFIDENTIAL
Page 16
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
4.
The relationship between ADAMTS-13 activity and end-organ disease status (e.g., renal, neurologic, and 
cardiac) 
5.
PK parameters such as incremental recovery, area under the curve, systemic and antibody induced clearance, 
maximum ADAMTS-13 activity between PEX or SHP 655 infusions, and trough levels prior PEX
6.
Occurrence of ADAMTS-13 activity trough levels >10%
Safety and efficacy endpoints
1.
Time to normalization of platelet count, defined as platelet count ≥ 150,000/µL, which must be confirmed by 
a second normal platelet count ≥ 150,000/µL and LDH <2 ULN 48 hours following initial normalization
2.
Occurrence of remission, defined as a normal platelet count and LDH <2 ULN for at least 48 hours following 
initial normalization of platelet count (acute episode period)
3.
Time to first exacerbation (aTTP episode ≤30 days following remission)
4.
Time to relapse (aTTP episode >30 days following remission)
5.
Occurrence of exacerbation  
6.
Occurrence of relapse 
7.
Occurrence of major clinical events related to TTP including:
a. Death
b. Stroke
c. MI
d. Organ dysfunction not normalized within the 90-day observation period
i.
Chronic renal insufficiency
ii. Neurologic impairment
iii. Neurocognitive deficits.
8.
Incidence of major clinical events related to PEX, including clinically relevant bleeding (modified ITP score) 
or thrombosis at the site of line insertion, adverse reactions to plasma, including citrate reactions, allergic 
reactions, and TRALI
9.
Changes in the titer of binding and inhibitory antibodies to ADAMTS-13
10.
Occurrence of antibodies to SHP655 
11.
Incidence of AEs and SAEs, and specifically product-related AEs and SAEs 
12.
Clinically relevant changes in vital signs, clinical chemistry, and hematology
For non-commercial use only

Shire
CONFIDENTIAL
Page 17
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Exploratory Efficacy Endpoints
Statistical Methods
Statistical models used to analyze the primary endpoints: 
A non-linear mixed effects model will be used to analyze the PK of ADAMTS-13 activity over time in the presence 
of anti-ADAMTS-13 antibodies and the administration of daily PEX, during treatment of an acute TTP event with 
or without SHP 655 supplementation.
A PD/PK model will be developed to study the temporal relationship between Platelet count or LDH levels with 
respect to the changes in ADAMTS-13 activity over time.

Safety analysis
AEs and SAEs will be tabulated and summarized according to the Medical Dictionary for Regulatory 
Activities, in total, by arm, and by relatedness to product or PEX procedure. The number and proportion of 
subjects experiencing these events will be tabulated for each arm. 
Individual and summary vital signs and clinical laboratory data will be presented in tabular form with mean, 
standard deviation, quartiles, and range as appropriate, by treatment arm and time point.
For non-commercial use only

Shire
CONFIDENTIAL
Page 18
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
For the 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.

Efficacy analysis
All time to event efficacy endpoints will be analyzed by the non-parametric Kaplan Meier (KM) estimator of 
the survival curve.  Estimates of the median time to event as well as proportions of subjects with event will 
be derived, together with two-sided, 95% confidence intervals.
Summary statistics will be provided for the efficacy endpoints assessed by study arm.  For continuous 
variables these will include mean, standard deviation and 95%, two-sided confidence interval (CI).  For 
discrete variable these will include proportions, incidence, and their two-sided 95% CI.
For non-commercial use only

Shire
CONFIDENTIAL
Page 19
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
1.2 Schema
Figure 1. Study Schematic Diagram 
For non-commercial use only

Shire
CONFIDENTIAL
Page 20
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
1.3 Schedule of Activities
Table 1. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening/ 
Enrollmenta
Interval
Study Visits
Study Completion/
Termination
Visitc
(1 month ± 7 days 
following last 
interval study 
visit)
Treatment 
Period
(Daily)b
Weekly Follow Up 
Study Visitsl
(Q1Week ±3 days 
x4 weeks)
Biweekly Follow 
Up Study Visitsl
(Q2Week ±3 days 
x2 visits)
Informed Consentd
X
Eligibility Criteria
X
Pregnancy test (females)
X
Medical History
X
Demographic and 
Baseline Characteristics
X
Medications
X
X
X
X
X
Non-drug Therapies
X
X
X
X
X
Physical Examo
(including weight)
X
X
X
X
X
Adverse Events
X
X
X
X
X
Laboratoriesg
X
Xh
X
X
X
Vital Signs
X
X
X
X
X
Randomizationk
X
IP
Xe
Xf
Plasma exchange
X
X
Cognitive assessment 
tests
X
X
X
ADAMTS-13 Antigen & 
Activity
X
Xh
X
X
X
Anti-rADAMTS-13 
Binding antibodies, total 
Ig (IgG, IgA, IgM)m
X
Xh
X
X
X
Anti-rADAMTS-13 
Binding antibodies, IgE n
Anti-ADAMTS-13 
Inhibitory antibodies
(for native protein)
X
Xh
X
X
X
Anti-rADAMTS-13 
Inhibitory antibodies
X
X
For non-commercial use only

Shire
CONFIDENTIAL
Page 21
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Table 1. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening/ 
Enrollmenta
Interval
Study Visits
Study Completion/
Termination
Visitc
(1 month ± 7 days 
following last 
interval study 
visit)
Treatment 
Period
(Daily)b
Weekly Follow Up 
Study Visitsl
(Q1Week ±3 days 
x4 weeks)
Biweekly Follow 
Up Study Visitsl
(Q2Week ±3 days 
x2 visits)
VWF antigen and 
multimers
Xi
Methylprednisolone 
(tapering permitted)
X
Xb
Rituximab
Xb
Xb
a. Screening and enrollment occur at same visit.
b. Actual number of treatment dosing visits will vary.
c. Including for subjects who withdraw or discontinue.
d. Occurs at enrollment (prior to any study-specific procedure).
e. Double blind administration of placebo or SHP655 is given twice daily in all arms until remission is achieved. 
Supplementation post-remission is blinded and administered only after local ADAMTS-13 activity levels are 
<50% (measured >72 hours after last IP dose).
f.
Actual number of supplementation dosing visits and days will vary.
g. Hematology and clinical chemistry per section 8.2.3.4.  See also Table 2.
h. See Table 2 for daily laboratory assessments during daily PEX. PK sampling is randomized to Schedule A or B 
(Table 3).
i.
Weeks 1 and 4 only.
k. Randomization to study arm and independent randomization to PK sampling schedule A or B.
l.
Follow up is in reference to when remission is achieved.
m. The assay measures both anti-native ADAMTS-13 and anti-rADAMTS-13 binding antibodies.
n. IgE assessment only in case of adverse events.
o. Height will be measured at screening only. Weight will be measured at screening, weekly during the treatment 
period, and at all follow up visits.
For non-commercial use only

Shire
CONFIDENTIAL
Page 22
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Table 2. Non-PK Laboratory Assessments in Screening and Treatment
Procedure/ Assessment
Screening/
Enrollment
Within 1 h 
Pre-PEX
Within 30 min prior to daily 
post-PEX IP infusion #2
ADAMTS-13 Gene mutation
C
Blood type
L
HIV1/2, HBV, HCV
C
ADAMTS-13 Activity
L and B
L
ADAMTS-13 Antigen
B
Anti-rADAMTS-13 binding total Ig  
B
Anti-ADAMTS-13 inhibitory Ab
B
Anti-rADAMTS-13 inhibitory Ab
B
Complete blood count with platelets and 
leukocyte differential
L
L
L
LDH
L
L
L
L = local lab; C = Central (sponsor) lab; B= Bioanalytical specialty lab (sponsor)
Table 3. Treatment Period PK Laboratory Assessments (Randomized to Schedule A or B)
SCHEDULE A: Days 1, 2, 3, 4, 6, 8, 11, and every 3 days thereafter
SCHEDULE B: Days 1, 2, 3, 5, 7, 9, 12, and every 3 days thereafter
Procedure/ 
Assessment
Within 
15 min 
Pre-PEX
Within 15 
min Post-
PEX
Within 15 min 
post end of IP 
infusion #1c
0.5-3 h 
post end of 
IP infusion 
#1c
4-6 h post 
end of IP 
infusion 
#1c
Within 30 
min pre-IP 
infusion 
#2
Within 15 
min post 
end of IP 
infusion #2
0.5-3 h 
post end of 
IP infusion 
#2
ADAMTS-13 
activity
X
X
Xa
Xa
X
Xb
Xb
Xb
ADAMTS-13 
antigen
X
X
Xa
Xa
X
Xb
Xb
Xb
Anti-
rADAMTS-
13 binding Ig
X
X
X
Xb
Anti-
ADAMTS-13 
inhibitory 
antibodies
X
X
X
Xb
All labs to be performed at a bioanalytical specialty lab (sponsor)
a To be drawn if first dose of IP on study is administered prior to first PEX (see section 6.2.2).
b Do not collect if daily IP infusion #2 (dose 12h post-PEX) is discontinued (see section 6.2.5). 
c Collect these time-points in relation to the end of PEX if IP infusion #1 (dose immediately post-PEX) is 
discontinued (see section 6.2.5).
For non-commercial use only

Shire
CONFIDENTIAL
Page 23
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
2. INTRODUCTION
Baxalta US Inc. (Baxalta), now part of Shire, has developed a recombinant A Disintegrin and 
Metalloproteinase with Thrombospondin Type-1 Motifs 13 candidate (rADAMTS-13, now 
designated as SHP655; formerly designated as BAX 930) for treating subjects with thrombotic 
thrombocytopenic purpura (TTP). TTP may occur in congenital (cTTP) or acquired (aTTP) 
forms. In aTTP, autoantibodies inhibit and/or accelerate clearance of ADAMTS-13. A severe 
deficiency of ADAMTS-13 leads to an accumulation of high molecular weight von Willebrand 
Factor (VWF) and a thrombotic microangiopathy (TMA) whose hallmarks are severe 
thrombocytopenia and schistocytosis. Clinical features that accompany the TMA classically are 
described as the pentad of fever, neurologic changes, renal insufficiency, thrombocytopenia, and 
microangiopathic hemolytic anemia. Due to the lethality of untreated aTTP, treatment often
commences with suspicion of the diagnosis, prior to laboratory confirmation of ADAMTS-13
deficiency. 
The overall goal of this study is to assess ADAMTS-13 activity in aTTP subjects in the context 
of plasma exchange (PEX) treatment, supplementation with rADAMTS-13 and the presence of 
anti-ADAMTS-13 autoantibodies, all of which will acutely change plasma ADAMTS-13
activity. The relationship between recovery of ADAMTS-13 activity and improvement in clinical 
outcomes will be explored. A pharmacometric analytical approach will be utilized to establish an 
SHP655 dosing regimen that achieves efficacious ADAMTS-13 activity levels with a reduced 
number of PEX for use in future studies.
Refer to the latest version of the SHP655 investigator’s brochure (IB) for the overall risk/benefit 
assessment and the most accurate and current information regarding the pharmacokinetics, 
efficacy, and safety of SHP655.
2.1 Indication and Current Treatment Options 
2.1.1 Current Standard of Care (SoC)
Daily PEX is the cornerstone of the present standard of care (SoC) (Rock et al., 1991).
Immunomodulatory drugs, such as corticosteroids, rituximab, vincristine, cyclosporine, 
cyclophosphamide as well as splenectomy, are recommended to reduce the production of 
autoantibodies for sustained remission (Saha et al., 2017). Other novel therapeutic modalities, 
such as a nanobody (caplacizumab) targeting the interaction between platelet glycoprotein Ib
(GPIb) and VWF multimers, are in development.
For non-commercial use only

Shire
CONFIDENTIAL
Page 24
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
2.1.1.1 Plasma Exchange (PEX)
PEX became recognized as the SoC in 1991, following the publication of the landmark study of 
102 adult TTP patients, in which PEX was more effective than plasma infusion in the treatment 
of TTP (Rock et al., 1991). This study showed a response rate (defined as a platelet count of 
>150 × 109/L and no new neurological events) by day 9 of 47% for PEX versus 25% for plasma 
infusion, P = 0.025, and 6-month survival of 78% for PEX versus 63% for plasma infusion, 
respectively, P = 0.04. Since then, PEX has reduced the mortality rate from up to 95% to 
10–20% (Zheng, 2015).
As soon as a diagnosis of an acute TTP episode is established or suspected, PEX with frozen or 
solvent detergent plasma (both containing normal levels of ADAMTS-13, i.e., approximately 
1 μg/mL) should be initiated (Allford et al., 2000, Rock et al., 2006) to replenish ADAMTS-13
activity and remove anti-ADAMTS-13 auto-antibodies (Kremer Hovinga et al., 2017, 
Rock et al., 1991). 
A daily PEX at 1 to 1.5 times the patient’s predicted plasma volume is generally given until 
clinical features related to organ manifestations (e.g., neurologic symptoms, increased troponin 
level, renal failure, abdominal pain due to enteritis or pancreatitis) are resolved, the platelet count 
and LDH are normalized, and hemolysis stops (Joly et al., 2017, Knöbl, 2014). A published UK 
TTP guideline recommends that PEX should be continued for a minimum of 2 days after the 
platelet count is normalized (> 150 x 109/L) (Scully et al., 2012).
After remission, a therapeutic PEX taper is sometimes used in clinical practice. 
However, there was no statistical difference in relapse rates comparing the taper and 
non-taper sub-groups, in a retrospective analysis of 115 patients with initial presentations 
of aTTP (Bandarenko and Brecher, 1998, Zheng, 2015).
2.1.1.2 Corticosteroids
Corticosteroids have long been utilized along with PEX as frontline therapy. Importantly, 
before the widespread use of PEX, response rates of 30/54 (55%) were reported among patients 
without considerable organ damage within 48-72 hours with the use of corticosteroids alone
(Scully et al., 2012). A randomized, controlled trial comparing high-dose (10 mg/kg/d) and 
standard-dose (1 mg/kg/d) methylprednisolone as adjunct therapy to PEX in 60 newly diagnosed 
aTTP patients demonstrated 77% and 47% remission rates respectively (Balduini et al., 2010). 
The British TTP guidelines recommend the use of glucocorticoids (1 mg of oral prednisone per 
kilogram daily; or 1 g of methylprednisolone per day for three consecutive days) for all patients 
with aTTP (Scully et al., 2012).
For non-commercial use only

Shire
CONFIDENTIAL
Page 25
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
2.1.1.3 Rituximab
Rituximab (humanized anti-CD20 monoclonal antibody) was first used in patients with 
suboptimal responses to PEX (i.e., exacerbation or refractoriness), typically at a dose of 
375 mg/m2 in 4 weekly doses) with excellent (89%) remission rates (Joly et al., 2017). These 
very positive results prompted an increase in frontline use of rituximab, which results in shorter 
hospitalization and fewer relapses (Scully et al., 2011, Vazquez-Mellado et al., 2016).
Response to rituximab was associated with a decrease in the anti-ADAMTS-13 antibodies with a 
resulting increase in the ADAMTS-13 activity (Cataland and Wu, 2015). Earlier administration 
(within 3 days) was associated with faster achievement of remission (12 vs. 20 days, P < 0.001), 
fewer PEX (16 vs. 24, P = 0.03) and shorter hospital stay (16 vs. 23 days, P = 0.01)
(Westwood et al., 2013).
In addition, rituximab improved relapse-free survival when used for prophylactic treatment of 
patients with a history of aTTP and persistent ADAMTS-13 activity less than 10% in clinical 
remission (Hie et al., 2014, Westwood et al., 2013). Rituximab prophylaxis was associated with 
normalization of ADAMTS-13 levels within 3 months in all but one case, with only one acute 
relapse at follow-up (Westwood et al., 2013).
2.1.1.4 Investigational Drugs
There is ongoing clinical evaluation of caplacizumab, an anti-VWF nanobody that inhibits the 
binding between platelet GPIb receptor and ULVWF multimers, thereby preventing platelet 
aggregation in the microcirculation, with the aim of decreasing the time to normalization of 
platelet count during PEX. In the Phase 2, controlled study, 75 patients underwent randomization 
(36 were assigned to receive caplacizumab, and 39 to receive placebo). The time to a response 
was significantly reduced with caplacizumab as compared with placebo (39% reduction in 
median time, P = 0.005). Three patients in the caplacizumab group had an exacerbation, as 
compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a 
relapse in the first month after stopping the study drug, of whom 7 had ADAMTS-13 activity 
that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse 
events (AEs), most of which were mild to moderate in severity, were more common with 
caplacizumab than with placebo (54% of patients vs. 38%) (Peyvandi et al., 2016).
Although caplacizumab blocks the formation of microthrombi, it does not address the underlying 
pathophysiology, the ADAMTS-13 deficiency (Cataland and Wu, 2015). Clinical events 
including relapse, exacerbation, and organ damage may occur once it is discontinued if the 
potential to form the microthrombi remains. For instance, 22% on the caplacizumab and none on 
the placebo arms of the Phase 2 study had a recurrence during first month after discontinuing the 
therapy (Peyvandi et al., 2016).
For non-commercial use only

Shire
CONFIDENTIAL
Page 26
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
2.1.2 Unmet Medical Needs of Current Therapy
With current therapy, acute mortality rate of aTTP is still 10-20% (Alwan F et al., 2016), and in 
high-risk patients (older age, multiple organ involvement at presentation, etc.) it may reach 
30-60% (Benhamou et al., 2012).
Although PEX is the standard treatment for TTP, it is frequently associated with complications 
related to both the procedure and the large volumes of plasma to which the patient is exposed. 
These complications include catheter-related sepsis, venous thrombosis, pneumothorax, 
hemorrhage, hypotension, allergic and anaphylactic reaction, citrate intolerance, and volume 
overload (Koyfman et al., 2011, Reutter et al., 2001).
Adverse events were reported as complications in about 26% of the PEX procedures
(George, 2007). In a nine-year cohort study of 206 consecutive patients treated for TTP, five 
patients (2%) died of complications of PEX treatment; three patients died from hemorrhage 
related to the insertion of a central venous catheter and two from catheter-related sepsis. Fifty-
three other patients had major complications attributed to PEX treatment, including systemic 
infection, venous thrombosis, and hypotension that required treatment. 
Despite significant progress in plasma safety, infectious risk associated with blood-borne 
pathogens remains (Bryant and Klein, 2007, Humpe et al., 2000). Also, long-term PEX may 
become especially problematic in patients with poor venous access. Furthermore, PEX is 
associated with high healthcare resource utilization, is time consuming, specialized equipment 
and trained staff, and can be stressful for patients.  
Recurrence (reemergence of clinical and laboratory signs and symptoms of TTP after the 
remission) has been reported in 20 to 50% of cases (Peyvandi et al., 2008). Most recurrences 
occur within the first year after the acute episode and less frequently thereafter. Exacerbation 
within 30 days of remission occurs in up to 50% of aTTP patients in spite of daily PEX, and 
relapses have been reported in 20 to 40% of cases. Refractory disease occurs in up to 10% of 
aTTP patients regardless of intensive PEX (Coppo and Veyradier, 2012).
Even among patients who do not relapse, many experience a lower quality of life (QoL) 
in terms of general and mental health, and may continue to experience pain in the long run
(Lewis et al., 2009). Patients in remission may suffer from lingering neurocognitive impairment
(Han et al., 2015, Kessler et al., 2012). In one study following patients recovering from TTP for 
up to 16 years, the prevalence of hypertension, depression, and risk of death were increased
(Deford et al., 2013). These underscore not only the ongoing therapeutic challenge in the 
treatment of the initial acute event, but also the need to decrease the long-term morbidity seen 
after its resolution.
For non-commercial use only

Shire
CONFIDENTIAL
Page 27
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
2.2 Product Background and Clinical Information.
The active drug substance of SHP655, produced in a Chinese Hamster Ovary (CHO) mammalian 
expression system in a plasma-protein-free milieu, is the fully glycosylated recombinant human 
ADAMTS-13 protein that has undergone two dedicated virus reduction steps, solvent detergent 
[S/D] treatment and nanofiltration.
Preclinical studies show efficacy in aTTP. When TTP was triggered using 2000 U/kg rVWF in 
the presence of polyclonal antibody to ADAMTS-13 in SD rats, the animals displayed severe 
TTP-like symptoms, such as thrombocytopenia, hemolytic anemia, and VWF–rich thrombi in the 
kidneys and brain. Subsequent injection SHP655 prevented development of these symptoms. 
Analysis of plasma samples confirmed that SHP655 was able to override circulating anti-
ADAMTS-13 inhibitory antibodies, resulting in restoration of ADAMTS-13 activity and 
degradation of ultra-large VWF multimers (Plaimauer et al., 2011, Plaimauer et al., 2015, 
Tersteeg et al., 2015, Tersteeg et al., 2016).
Results from the Phase 1 clinical study of cTTP show that rADAMTS-13 is safe and efficacious
for cTTP. Pharmacokinetic parameters of rADAMTS-13 were comparable to those estimated in 
previous plasma infusion studies. 
Dosing of SHP655 in aTTP subjects has not been studied previously and is complicated by the 
presence of binding and inhibitory autoantibodies and the effect of daily PEX, which removes 
plasma protein and replenishes ADAMTS-13 via donor plasma. In silico modeling that 
accounted for these factors, in addition to Phase 1 PK data of ADAMTS-13 activity in congenital 
TTP patients, were used to determine dosing in this study.
No interaction studies with other medicinal products have been performed to date.
Refer to the IB for details on the background and clinical information of the investigational 
product (IP). 
2.3 Study Rationale
Despite advances in the knowledge of the pathophysiology of aTTP, the acute mortality rate has 
remained 10-20% for over twenty years (Alwan F et al., 2016). Moreover, TTP patients suffer 
from numerous devastating morbidities and decreased quality of life (Deford et al., 2013, 
Tersteeg et al., 2016). SHP655, has demonstrated efficacy of restoring VWF-cleaving activity in 
vitro in the presence of anti-ADAMTS-13 antibodies and in an animal model of aTTP. With 
sufficient rADAMTS-13 replacement, it is expected that aTTP patients can receive adequate 
therapy, leading to a reduction in the severity of TTP episodes and time to resolution.
For non-commercial use only

Shire
CONFIDENTIAL
Page 28
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Such improvements in the therapy for aTTP patients are potentially reducing short- and long-
term clinical complications including neurological impairment, renal failure, myocardial damage 
and stroke and improve quality of life.
This study is needed to assess ADAMTS-13 activity in aTTP subjects in the context of SHP655 
dosing, PEX and anti-ADAMTS-13 autoantibodies, all of which will acutely change plasma 
ADAMTS-13 activity. The relationship between recovery of ADAMTS-13 activity and 
improvement in clinical outcomes will be explored. A PK analysis will be utilized to establish an 
SHP655 dosing regimen that achieves efficacious ADAMTS-13 activity levels with a reduced 
number of PEX for use in future studies.
2.4 Benefit/Risk Assessment 
SHP655 appeared to be safe and well tolerated following a single administration over a dose 
range of 5 to 40 U/kg in cTTP patients in Study 281101, and there was no evidence of an 
immune response to SHP655. The activity PK parameters were comparable to those estimated 
from fresh frozen plasma (FFP) studies and demonstrated dose proportionality with respect to 
Cmax and AUC. Finally, there was evidence for SHP655 activity in vivo, including effects on 
VWF multimers, platelet count, and serum LDH. Overall, the data obtained in the first-in-human 
Phase 1 Study 281101 indicate that SHP655 is suitable for further clinical development and may 
have a positive benefit:risk ratio for patients with congenital TTP. Because the primary defect, 
i.e. ADAMTS-13 deficiency, is the same in congenital and acquired TTP, rADAMTS-13
replacement is anticipated to be safe and may provide benefit in acquired TTP if sufficient 
plasma concentrations of ADAMTS-13 can be achieved.
Refer to the latest version of the SHP655 investigator’s brochure (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 
Harmonization 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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 29
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Co-Primary Objectives
1.
Assess the PK of ADAMTS-13 in aTTP subjects treated for an acute episode by daily 
PEX, immunosuppressant therapy, with or without SHP655 supplementation
2.
Study the PK/PD relationship between ADAMTS-13 activity levels on pathophysiological 
biomarkers as well as clinical efficacy parameters.
3.1.2 Secondary Objectives
PK/PD Objectives

Evaluate changes in levels of ADAMTS-13 binding and inhibitory autoantibodies in 
response to daily PEX, with or without SHP655 supplementation, during the acute episode 
and up to 30 days after the resolution of the TTP episode

Evaluate ADAMTS-13 activity levels in subjects up to 30 days after TTP episode 
remission

Specify dose(s) of SHP655 needed to achieve and maintain adequate plasma levels of 
rADAMTS-13 in order to support induction of remission and to reduce the number of PEX 
procedures needed for the treatment of acute aTTP episodes.
Safety/Efficacy Objectives

Assess the safety and immunogenicity of two regimens of SHP655 supplementation 
administered during an acute TTP episode in subjects undergoing PEX treatment and 
immunosuppressant therapy as measured by AEs, changes in vital signs and laboratory 
parameters

Evaluate the occurrences of aTTP related complications, (including death, stroke, MI, and 
organ failure) aTTP relapses*, exacerbations** and end-organ function improvement.

Evaluate the time to aTTP related complications (including death, stroke, MI, and organ 
failure), aTTP relapses*, exacerbations** and end-organ function improvement

Evaluate the occurrence of procedure (e.g. PEX, SHP655 infusions) related adverse events
*Defined as >30 days after achieving remission
**Defined as ≤30 days after achieving remission
For non-commercial use only

Shire
CONFIDENTIAL
Page 30
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
3.1.3 Exploratory Objectives
For non-commercial use only

Shire
CONFIDENTIAL
Page 31
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
3.2 Study Endpoints
Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Co-Primary
•
Assess the PK of ADAMTS-13 in aTTP subjects 
treated for an acute episode by daily plasma 
exchange (PEX), immunosuppressant therapy, 
with or without SHP655 supplementation
•
Study the PK/PD relationship between 
ADAMTS-13 activity levels and 
pathophysiological biomarkers as well as clinical 
efficacy parameters.
• ADAMTS-13 activity levels
• Platelet count and LDH levels 
Secondary
PK/PD Objectives
•
Evaluate changes in levels of ADAMTS-13
binding and inhibitory autoantibodies in response 
to daily PEX, with or without SHP655
supplementation, during the acute episode and up 
to 30 days after the resolution of the TTP episode
•
Changes in the titer of binding and inhibitory antibodies 
to ADAMTS-13
•
Occurrence of antibodies to SHP655
•
PK parameters such as incremental recovery, area under 
the curve, systemic and antibody induced clearance, 
maximum ADAMTS-13 activity between PEX or SHP 
655 infusions, and trough levels prior PEX
•
The ADAMTS-13 binding and inhibitory autoantibody 
levels in response to daily PEX, with or without 
SHP655 supplementation, during the acute TTP episode 
and up to 30 days after resolution
•
Evaluate ADAMTS-13 activity levels   in subjects 
up to 30 days after TTP episode remission
•
ADAMTS-13 activity levels in subjects receiving 
additional SHP655 for up to 30 days after the resolution 
of the TTP episode
•
Specify dose(s) of SHP655 needed to achieve and 
maintain adequate plasma levels of rADAMTS-13
in order to support induction of remission and to 
reduce the number of PEX procedures needed for 
the treatment of acute aTTP episodes.
•
The PK/PD temporal relationship of efficacy 
parameters (e.g., platelet count, LDH levels), as a 
function of ADAMTS-13 activity
•
The relationship between ADAMTS-13 activity and 
end-organ disease status (e.g., renal, neurologic, and 
cardiac) 
For non-commercial use only

Shire
CONFIDENTIAL
Page 32
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Safety/Efficacy Objectives
•
Assess the safety and immunogenicity of two 
regimens of SHP655 supplementation 
administered during an acute TTP episode in 
subjects undergoing PEX treatment and 
immunosuppressant therapy as measured by AEs, 
changes in vital signs and laboratory parameters
•
Incidence of AEs and SAEs, and specifically product-
related AEs and SAEs 
•
Clinically relevant changes in vital signs, clinical 
chemistry, and hematology
•
Platelet count and LDH levels 
•
Time to normalization of platelet count, defined as 
platelet count ≥ 150,000/µL, which must be confirmed 
by a second normal platelet count ≥150,000/µL and 
LDH <2 ULN 48 hours following initial normalization
•
Occurrence of remission, defined as a normal platelet 
count and LDH <2 ULN for at least 48 hours 
following initial normalization of platelet count (acute 
episode period)
•
Evaluate the occurrences of aTTP related 
complications, (including death, stroke, MI, and 
organ failure), aTTP relapses, exacerbations and 
end-organ function improvement.
•
Occurrence of exacerbation  
•
Occurrence of relapse 
•
Occurrence of major clinical events related to TTP 
including: (entire study)
a. Death
b. Stroke
c. MI
d. Organ dysfunction not normalized within the 
90 day observation period
i. Chronic renal insufficiency
ii. Neurologic impairment
iii. Neurocognitive deficits
•
Evaluate the time to aTTP related complications 
(including death, stroke, MI, and organ failure), 
aTTP relapses*, exacerbations** and end-organ 
function improvement
• Time to first exacerbation (aTTP episode ≤30 days 
following remission)
• Time to relapse (aTTP episode >30 days following 
remission)
•
Evaluate the occurrence of procedure (e.g. PEX, 
SHP655 infusions) related adverse events
• Incidence of major clinical events related to PEX, 
including clinically relevant bleeding (modified ITP 
score) or thrombosis at the site of line insertion, adverse 
reactions to plasma, including citrate reactions, allergic 
reactions, and TRALI
For non-commercial use only

Shire
CONFIDENTIAL
Page 33
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Exploratory Objectives
For non-commercial use only

Shire
CONFIDENTIAL
Page 34
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Table 4. Objectives and Endpoints
Objective
Endpoint(s)
For non-commercial use only

Shire
CONFIDENTIAL
Page 35
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
4. STUDY DESIGN
4.1 Overall Design 
This is a randomized, parallel, placebo-controlled, double-blind Phase 2 study. Approximately 
30 evaluable subjects between the ages of 18 to 75 years experiencing an acute TTP episode will 
receive a single PEX, and be randomized 1:1:1 into one of three treatment arms:
Arm 1 – SoC plus placebo (n=10)
Subjects will receive daily PEX and placebo immediately after PEX and 12±1 hours after 
completion of PEX. 
Arm 2 – SoC with SHP655 once daily (n=10)
Subjects will receive daily PEX and 40 IU/kg SHP655 once daily immediately after PEX and 
placebo 12±1 hours after completion of PEX.
Arm 3 – SoC with SHP655 twice daily (n=10)
Subjects will receive daily plasma exchange and 40 IU/kg SHP655 twice daily immediately after 
PEX and 12±1 hours after completion of PEX.
The first SHP655 dose may be given up to 4 hours after the initial SoC PEX that occurs before 
study entry, but preferably as soon as possible after the initial PEX. 
An immunosuppressive regimen consists of methylprednisolone and rituximab: 
1 g methylprednisolone iv once daily for 3 consecutive days, followed by 2.5 mg/kg/day; and 
375 mg/m2 rituximab administered weekly for 4 weeks will be initiated within 2 days of 
enrollment for all subjects. Steroid tapering is permitted at the discretion of the investigator. 
Additional or modified immunosuppressive therapy can be considered in exceptional 
circumstances after consultation with the sponsor.
In all study Arms, the second daily IP dose (12 hours after PEX) will be terminated if the most 
recently resulted pre-PEX ADAMTS-13 activity level is >150% or above the limit of 
quantification (local lab). After the second dose has been suspended, the first daily IP dose 
(immediately after PEX) will be terminated if the most recently resulted pre-PEX ADAMTS-13
activity level is >150% or above the limit of quantification (local lab).
In all study Arms, planned modifications to the plasma volume treated with each PEX (e.g. 
1.5 or 2 plasma volumes) or the frequency of PEX (e.g. BID or every other day) require sponsor
approval. Changes in PEX treatment due to logistical or emergent issues (e.g. venous access 
problems, Aes leading to PEX discontinuation) do not require sponsor approval but must be 
documented. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 36
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
After resolution of the TTP episode, IP (placebo in Arm 1; SHP655 40 IU/kg Arms 2 and 3) will 
be administered once weekly (maximum of 4 weekly doses of 40 IU/kg) if ADAMTS-13 activity 
at the local lab is <50%. Activity must be measured at least once weekly and >72h after the last 
IP dose.
4.2 Scientific Rationale for Study Design
4.2.1 Rationale for control group
A control group of SoC alone plus placebo was chosen so that an independent effect of PEX and 
autoantibody can be modeled without the contribution from SHP655 dosing. Additional 
considerations are that use of a SoC control group will enable a comparison of efficacy endpoints 
between placebo and SHP655 dosed groups.
4.2.2 Rationale for Primary and Key Secondary Endpoints
Deficiency of ADAMTS-13 is the cause of aTTP. Thus, determining the PK of dosed 
rADAMTS-13 in the context of aTTP treatment will lead to an understanding of how to dose 
rADAMTS-13 to achieve remission, which is defined by consensus criteria as normalization of 
platelet account and LDH.
4.2.3 Justification for the use of placebo
The use of double blind placebo offers several study design advantages. First, a double blinded 
placebo minimizes bias in AE reporting that could be influenced by knowledge of treatment 
allocation. Second, it minimizes bias in treatment decisions, PK blood sampling, and other 
procedures that could be influenced by knowledge of treatment allocation.
4.3 Justification for Dose
The dosing regimen of 40 IU/kg was selected based on the Phase 1 single-dose study of SHP655 
in subjects with cTTP (Study 281101). This dose was safe and well tolerated and is further 
supported by non-clinical safety studies (see 5.3.1 Non-clinical Studies).
In the Phase 1 study the pharmacokinetics of ADAMTS-13 was characterized in cTTP patients 
with no detectable anti-ADAMTS-13 antibodies. The mean terminal half-life was 59.2 hours 
using the FRETS-VWF73 assay. The geometric mean of IR was 0.0232 (U/mL x kg/U). 
The geometric mean Cmax after a 40 U/kg infusion was 0.948 U/mL and the AUC(0-inf) was 
53.1 U∙h/mL. In an aTTP population which will have the anti-ADAMTS-13 antibodies, 
Baxalta expects the clearance to be significantly increased. There may also be a decrease in 
the incremental recovery, as noted in Phase 1 Study 281101. In addition, PEX will remove 
anti-ADAMTS-13 antibodies and SHP655. Daily dosing therefore is needed to evaluate 
PK model that can predict doses needed for efficacious ADAMTS-13 levels. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 37
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
To augment the ability of the PK model to predict the efficacious dose and to evaluate safety at 
higher doses that the PK model may predict, a second regimen will be tested at 40 IU/Kg twice 
daily.
The proposed dosing supplementation regimen of SHP655 is not predicted to yield ADAMTS-13
activity levels that will exceed a safe threshold, even in a cTTP patient mistakenly diagnosed 
with aTTP. Daily PEX with donor plasma that has a presumed ADAMTS-13 activity of 100% 
will help normalize any excessively low or high ADAMTS-13 level. 
4.4 Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 6 months, 
depending on the time needed to achieve remission plus 3 months’ follow-up.
The study will be completed in approximately 1 year. 
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 follow-up visit or contact, 
whichever is later (refer to Section 8.1.3 for the defined follow-up period for this protocol).
4.5 Sites and Regions
The study will be conducted in approximately 20 sites across North America and Europe.
For non-commercial use only

Shire
CONFIDENTIAL
Page 38
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
5. STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent 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.
Subject voluntarily signs informed consent. For subjects unable to provide consent, a fully 
recognized medical proxy may be used according to local laws.
2.
Subject is 18 to 75 years old at the time of screening.
3.
Subject has been diagnosed with primary or secondary autoimmune aTTP based on the 
following criteria:
a.
Thrombocytopenia [drop in platelet count ≥50% or platelet count < 100,000/µL]; 

No more than 3 subjects per arm may be enrolled with a screening platelet count 
≥50,000/ µL.
b.
Microangiopathic hemolytic anemia [elevation of lactate dehydrogenase (LDH) 
>2-fold or by presence or increase of schistocytes in peripheral blood smear]
4.
Willingness to fully comply with study procedures and requirements, and intention to 
initiate plasma exchange (PEX). Subjects may be provisionally entered into the trial and 
undergo randomization pending the results of the ADAMTS-13 activity, anti-ADAMTS-13
antibody, and genetic testing for cTTP
5.
If female of childbearing potential, subject presents with a negative pregnancy test and 
agrees to employ adequate birth control measures for the duration of the study.  Sexually 
active males must use an accepted and effective method of contraception during the 
treatment and until a minimum of 16 days after the last dose administered.
5.2 Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1.
Subject has been diagnosed with congenital TTP
2.
Subject has plasma ADAMTS-13 activity> 10% of normal
3.
Subject has been diagnosed with another cause of thrombotic microangiopathy (TMA) 
including: DIC, disseminated malignancy, malignant hypertension, hematopoietic stem cell 
transplantation, shiga toxin-related and atypical HUS, drug toxicity (e.g. gemcitabine, 
mitomycin C, clopidogrel) and pregnancy-related thrombocytopenia syndromes (e.g. 
HELLP, eclampsia)
For non-commercial use only

Shire
CONFIDENTIAL
Page 39
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
4.
Subject has been exposed to another IP within 30 days prior to enrollment or is scheduled 
to participate in another clinical study involving IP or investigational device during the 
course of the study
5.
Subject has received caplacizumab within 3 months of study enrollment. 
6.
Subject is human immunodeficiency virus positive (HIV+) with unstable disease or CD4+
count ≤200 cells/mm3 within 3 months of screening
7.
Subject has had a previous aTTP event in the past 30 days
8.
Subject has another underlying progressive fatal disease and/or life expectancy of less than 
3 months.
9.
Subject is identified by the investigator as being unable or unwilling to cooperate with 
study procedures. 
10. Subject suffers from a mental condition rendering him/her unable to understand the nature, 
scope, and possible consequences of the study and/or evidence of an uncooperative 
attitude. However, a fully recognized medical proxy will be permitted to provide consent.
11. If female, subject is pregnant or lactating.
12. Subject is a family member or employee of the Sponsor or investigator.
13. Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing 
information
5.2.1 Contraception
Sexually active females of childbearing potential should use an acceptable form of contraception. 
Females of childbearing potential must be advised to use acceptable contraceptives throughout 
the study period and for 30 days following the last dose of investigational product. If used, 
hormonal contraceptives should be administered according to the package insert.
Female subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and age 51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Of childbearing potential with a negative urine and/or serum -hCG pregnancy test at the 
Screening/Enrollment Visit and prior to randomization. Females of childbearing potential 
must agree to abstain from sexual activity that could result in pregnancy or agree to use 
acceptable methods of contraception.
For non-commercial use only

Shire
CONFIDENTIAL
Page 40
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Acceptable methods of contraception include the following:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms. Note: If the subject 
becomes sexually active during the study, she should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been stabilized 
for 30 days.
Sexually active males must exercise abstinence or use an accepted and effective method of 
contraception during the treatment and until a minimum of 16 days after the last dose 
administered.
For non-commercial use only

Shire
CONFIDENTIAL
Page 41
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
SHP655 and placebo (0.9% saline)
Dosage form:
Lyophilized formulation 
Dosage frequency: 
Up to twice daily during treatment period and up to once weekly for 4 weeks after remission is 
achieved.
Mode of Administration:
Intravenous (i.v.)
The investigational product is SHP655 (rADAMTS-13), a recombinant ADAMTS-13 (a 
disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which is 
synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line that expresses 
the human ADAMTS cDNA. It will be provided in lyophilized formulation together with sterile 
water for reconstitution for intravenous administration.  Additional information is provided in the
current SHP655 Investigator’s Brochure.
The reference/comparator product is placebo (0.9% saline) which will be provided in single use 
vial form.
6.1.2 Blinding the Treatment Assignment
Double blind administration of placebo or SHP655 is given twice daily in all Arms until 
remission is achieved. Supplementation with SHP655 after remission is also blinded.
6.2 Administration of Investigational Product
6.2.1 Interactive Response Technology for Investigational Product Management
An interactive response technology (IRT) system will be used for screening and randomizing 
subjects, recording subject visits, investigational product supply dispensation and management, 
inventory management and supply ordering, investigational product expiration tracking and 
management, investigational product return, and emergency unblinding. Please refer to the Study 
Manual for additional details regarding the IRT system.
For non-commercial use only

Shire
CONFIDENTIAL
Page 42
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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 investigational product 
allocated to the subject, once eligibility has been determined. 
Subjects with platelet count >50,000/µL will not be eligible for randomization to an arm already 
having 3 evaluable subjects with screening platelet count >50,000/µL.
Individual subject treatment is automatically assigned by the interactive response technology 
(IRT).
Subjects will independently be randomized to PK sampling schedule A or B, which differ in the 
sampling days starting with PEX#4 and thereafter.
If initiation of PEX is delayed for logistical reasons and a subject completes enrollment and 
randomization prior to the first PEX, the subject may receive a dose of IP prior to initiation of 
PEX, provided post-infusion PK samples according to Table 2 (footnote A) are anticipated to be 
drawn. PEX initiation should never be delayed in order to complete study enrollment or study 
procedures.
6.2.3 Dosing
SHP655 is administered by i.v. injection. The reconstituted solution of SHP655 should be clear 
and colorless in appearance. SHP655 should be administered at room temperature and within 
3 hours of reconstitution. 
Prior to administration of the IP, it should be ensured that the solution is clear and free of 
particles. In addition, it should be ensured that venous access via an i.v. cannula is available. 
A butterfly needle may be used if placed immediately prior to the IP infusion. Central venous 
catheters may be used for IP infusion.
SHP655 should be slowly infused (between 2 to 4 mL per minute). Syringes should be changed 
according to medical practice.
For non-commercial use only

Shire
CONFIDENTIAL
Page 43
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
An unblinded investigational pharmacy at each site will coordinate the administration of IP. 
Placebo (0.9% normal saline) or SHP655 will be drawn into syringe with the appropriate study 
label that does not identify the IP as active drug or placebo, and a blinded study team member 
will administer the dose.
6.2.4 Unblinding the Treatment Assignment during the Placebo-Controlled Portion of the 
Study
The treatment assignment must not be unblinded during the study except in emergency situations 
where the identification of the investigational product is required for medical management of the 
subject. The investigator should contact the Shire physician and/or assigned 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 the source documents, as applicable. The reason 
for breaking the code will be recorded in source documents, as appropriate, based on safety or 
deviation reporting. Upon breaking the blind, the subject is withdrawn from the study, but should 
be followed up for safety purposes. Any code-breaks that occur must be reported to IQVIA and 
Shire. For blinded studies, there will be a provision for unblinding to ensure adequate 
management of the subject in the case of an emergency.
6.2.5 Dose Modification
In all study arms, the second daily dose (SHP655 or placebo given 12 hours after PEX 
completion) will be terminated if the pre-PEX ADAMTS-13 activity levels are >150% (local 
lab) or above the upper limit of the local lab quantification. After the second dose has been 
suspended, the first daily dose (SHP655 or placebo given immediately after PEX) will be 
terminated if pre-PEX ADAMTS-13 activity levels are >150% or above the upper limit of the 
local lab quantification.
After resolution of the TTP episode, subjects who received SHP655 during the treatment of the 
acute episode will be given additional supplementation with blinded IP once weekly (maximum 
of 4 doses of weekly 40 IU/kg) if a weekly ADAMTS-13 activity at the local lab is <50% (drawn 
>72 hours after last IP infusion).
For non-commercial use only

Shire
CONFIDENTIAL
Page 44
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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 investigational 
product(s) container. 
The sponsor will provide the investigator with packaged investigational product labeled in 
accordance with specific country regulatory requirements. All investigational product is labeled 
with a minimum of the following: protocol number, product identification number, dosage form 
(including product name and quantity in pack), directions for use, storage conditions, expiry date 
(if applicable), batch number and/or packaging reference, the statements “For clinical trial use 
only” and/or “CAUTION: New Drug – Limited by Federal (or United States [US]) Law to 
Investigational Use,” and the sponsor’s name and address.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product 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.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2 Packaging
Investigational product is packaged in the following labeled containers:
SHP655 will be packaged in single boxes with 2 glass vials, 1 vial containing the lyophilized 
SHP655, the other containing the diluent. Further details are provided in the Pharmacy Manual.
6.3.3 Storage
The investigator has overall responsibility for ensuring that investigational product 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 
distributed by the pharmacy or nominated member of the study team. The investigator or 
designee will be blinded to the treatment and will be responsible for administering the 
investigational product.
Investigational product must be stored in accordance with labeled storage conditions. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 45
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Temperature monitoring is required at the storage location to ensure that the investigational 
product 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 (ie, 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 investigational product 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 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
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. 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 investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, 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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 46
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
medication will be documented in the subject’s source and/or other investigational product 
record. No investigational product stock or returned inventory from a Shire-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 
investigational product 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). 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 (ie, IRT) do not require a shipment form. Returned 
investigational products must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any investigational product prior to shipment. 
Shipment of all returned investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5 Subject Compliance
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, bottles, trays, 
vials) or at the individual count level for opened containers/packaging. The 
pharmacist/nominated person will record details on the drug accountability form.
For non-commercial use only

Shire
CONFIDENTIAL
Page 47
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
6.6 Plasma Exchange (PEX)
PEX procedures will be performed per the local SoC using the locally available automated 
apheresis device with citrate anticoagulant. Replacement fluid will be the plasma type(s) 
available through the local blood bank. Fresh frozen plasma, thawed plasma, solvent-detergent 
plasma, and cryoprecipitate-poor plasma are acceptable. Replacement with normal saline or 
albumin solutions are permitted per local SoC. 
The first PEX prior to IP administration will be performed according to the local SoC. 
The first two PEX procedures on study (3rd PEX overall) will be 1.5 plasma volumes (per 
Rock et al., 1991). The 3rd and subsequent on-study PEX procedures will be 1.0 plasma volume. 
Planned PEX schedules or plasma volumes different than once daily must be pre-approved by 
the sponsor. In extenuating cases, urgent, unapproved changes to the PEX regimen may be 
required for optimal patient care, e.g. emergent stroke or MI. 
The following PEX parameters will be recorded for each PEX procedure:

Calculated plasma volume according to apheresis device

Plasma volume exchanged

Volume of anticoagulant used

Volumes and types of replacement fluid(s) exchanged

Blood loss (if applicable)

Time of PEX (time connected to apheresis device)
Adverse events related to apheresis catheters, venous access, and/or PEX will be recorded as 
(S)Aes and managed per the local SoC. Citrate toxicity is recommended to be treated with 
pausing of the apheresis procedure and administration of iv calcium preparation. Low plasma 
ionized calcium concentrations are supportive evidence of citrate reactions but are not required 
for diagnosis. 
All transfusion reactions of any severity must be documented and reported to the blood bank. 
Transfusion reactions will be managed according to the local SoC. It will be recorded whether 
PEX-related Aes lead to delays in the PEX procedure, an aborted procedure, and/or additional 
procedures (e.g. central venous catheter interventions, escalation in care).
For non-commercial use only

Shire
CONFIDENTIAL
Page 48
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
6.7 Immunosuppression

Methylprednisolone: Subjects will receive methylprednisolone 1g/day iv x 3 days starting 
on the first study treatment day. On Day 4, the methylprednisolone dose is recommended 
to start at 2.5 mg/kg/day. Corticosteroids administered prior to enrollment will be recorded 
as prior therapy. Adjustments in corticosteroid regimen deemed necessary by the principal 
investigator are allowed; the justification for the modification and the alternate treatment 
regimen will be recorded. Tapering of methylprednisolone, including transition to another 
corticosteroid, is permitted at the discretion of the principal investigator. 

Rituximab: 375mg/m2 iv once weekly x 4 weeks. The first dose will be administered 
within two days of enrollment. All doses should be administered as soon after PEX as 
feasible (when applicable). 
6.8 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/enrollment 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.
6.8.1 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 14 days of 
the date of first dose of investigational product. Prior treatment information must be recorded in 
the subject’s source document. It is anticipated that subjects will have received one SoC PEX 
prior to enrollment. Plasma infusion is permitted as prior treatment. 
6.8.2 Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the subject’s source document.
6.8.3 Permitted Treatment
The following adjunctive treatments are allowed:
For PEX, antihistamines, calcium replacement, iv fluids, and albumin solution are permitted.
Aspirin and heparin formulations are permitted per the local aTTP SoC.
For non-commercial use only

Shire
CONFIDENTIAL
Page 49
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Any treatment for comorbid conditions is permitted. Red blood cell transfusion is permitted at 
the investigator discretion. Medical treatments not otherwise specified in the protocol are 
permitted. Consultation with the study medical director is advised for any questions about 
concomitant treatments. 
6.8.4 Prohibited Treatment
Caplacizumab is prohibited within 3 months prior to the study and during the study. 
Treatments for aTTP in addition to glucocorticoids and rituximab (e.g., bortezomib, 
N-acetylcysteine, cyclophosphamide, splenectomy, cyclosporine, vincristine) require prior 
approval by the sponsor.
Plasma infusion after PEX has been initiated is prohibited. Platelet transfusion and factor 
concentrates are prohibited except for instances of life-threatening hemorrhage.
For non-commercial use only

Shire
CONFIDENTIAL
Page 50
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL
7.1 Discontinuation of Study Treatment
If investigational product is discontinued, regardless of the reason (unless as specified in the 
protocol), the evaluations listed for the Completion/Termination Visit will be performed as 
completely as possible. Whenever possible, all discontinued subjects should also undergo the 
protocol-specified evaluations at (completion/termination visit). Comments (spontaneous or 
elicited) or complaints made by the subject must be recorded in the source documents. The 
reason for discontinuation, date of discontinuation of the investigational product, and the total 
amount of investigational product administered must be recorded in the source documents.
Subjects who discontinue will be replaced at the discretion of the sponsor. 
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 1 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:

Not meeting confirmatory inclusion criteria, i.e. screening ADAMTS-13 >10% at sponsor 
bioanalytic lab, no ADAMTS-13 inhibitory antibody, or genetic mutation indicating 
congenital TTP

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow-up

Sponsor withdrawal

Major surgery

Subject becomes pregnant

Other (must be specified in CRF)
For non-commercial use only

Shire
CONFIDENTIAL
Page 51
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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 (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
If 1) the subject withdraws or 2) a subject is not confirmed to be a case of aTTP because of 
ADAMTS-13 activity >10%, absence of anti-ADAMTS-13 autoantibody, or genetic 
confirmation of congenital TTP, IP administration and study procedures will stop, with the 
exception of a Termination/Completion Visit, which should occur within 1 week after the final 
dose of IP.
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). 
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 acknowledgement of receipt request) 
asking that the subject return to the site for final safety evaluations and return any unused 
investigational product.
For non-commercial use only

Shire
CONFIDENTIAL
Page 52
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
8. STUDY ASSESSMENTS AND PROCEDURES
8.1 Study Schedule
Refer to Table 1 for the schedule of study activities. Study assessments are detailed in 
Section 8.2.
8.1.1 Screening Period 
Subjects may present with an initial or relapse aTTP episode. Screening will occur as soon as 
feasible after clinical presentation. Initial aTTP management until enrollment will be performed 
according to the local SoC, including the initial PEX. Screening will utilize local labs for initial 
eligibility determination. 
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. Subjects who are screen failures may undergo a 
full re-screening with a new study identification number. 
A subject is considered enrolled once the ICF is signed. Subjects may not re-enroll if previously 
randomized in this study. 
8.1.1.1 Screening/Baseline Visit
Informed consent must be obtained by the subject or the subject’s legally authorized 
representative before subjects are asked to prepare for any screening procedures.
Because of the need for urgent treatment, there is no baseline visit. Rather, baseline 
measurements are to be collected as part of the screening procedures. Screening and baseline 
assessments should be completed prior the initial SoC PEX, but the initial SoC PEX must not be 
delayed in order to accommodate screening procedures. 
8.1.2 Treatment Period 
After screening, subjects will be randomly assigned to 1 of 3 Arms by a computer algorithm. In 
the event that enrollment in an Arm is full, subjects will be randomly assigned to the remaining 
Arm(s).
The treatment period begins after randomization with the first IP infusion up to 4 hours after the 
initial PEX, but preferably as soon as possible. For all Arms after remission is achieved, blinded 
IP supplementation is administered weekly for ADAMTS-13 activity levels <50% (measured 
>72 hours after the last dose of IP).
For non-commercial use only

Shire
CONFIDENTIAL
Page 53
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
PEX will occur once daily during the treatment period. If the principal investigator deems that 
more intensive PEX is required for patient care, it is preferred that the volume of plasma treated 
be escalated to 1.5 or 2 plasma volumes before the frequency of PEX is increased. A planned 
increase in the frequency of treatment volume of PEX requires sponsor approval. Additional 
PEX after remission is not permitted.
8.1.2.1 Final Visit 
The Final Visit is the Completion/Termination Visit.
8.1.3 Follow-up Period
The follow-up period is 3 months after remission. For subjects in Arms 2 and 3 who receive 
SHP655 supplementation after remission, follow up after the last dose of IP will be 2 months if 
supplementation is given in week 4 after remission. Subjects maybe contacted for up to 6 months 
after study completion to correct or complete study data collection.
In the event of aTTP exacerbation or relapse during the study period, the subject will not receive 
additional IP, and treatment will be determined by the PI. During the treatment of a recurrence, 
subjects will follow the bi-weekly visit schedule and study procedures per Table 1 until 
remission is achieved or 4 months after the initial remission, whichever is sooner.
At the end of this period will be the Completion/Termination Visit. All Aes and SAEs that are 
not resolved at the time of this contact will be followed for up to 30 days (see Appendix 2.2).
8.1.4 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 including gender, age, and race will be collected prior to the 
subject receiving the first dose of investigational product. 
8.2.1.1 Height and Weight
Height and weight will be measured and recorded in the subject’s source documents. Current 
hospitalization records may be used for height and weight. Weight will be recorded in kg to one 
(1) decimal.
For non-commercial use only

Shire
CONFIDENTIAL
Page 54
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
8.2.1.2 Medical, Medication History, and Non-drug Therapies
Medical, medication history, and non-drug therapies will be collected and recorded in the 
subject’s source documents at screening/enrollment. Concurrent medication and non-drug 
therapies will be collected at every visit.
8.2.2 Efficacy
The Montreal Cognitive Assessment (MoCA) and Richmond Agitation Sedation Scale (RASS) 
assessments will be performed daily while inpatient until the subject performs in the normal 
range for two consecutive days on each scale. Once the subject performs in the normal range on 
two consecutive days on a scale, the assessment scale is discontinued. Scales may be performed 
during the treatment period and for the first 4 weekly follow up visits. For the MoCA, the normal 
range is a score of 26-30. A subjects’ inability to perform the MoCA will be documented by 
study staff. For the RASS, a normal score is zero. Assessments are to be performed during the 
daytime at a similar time of day, where feasible. MoCA and RASS may be recorded directly into 
the CRF.
Occurrence of stroke, MI, neurologic deficits, cognitive deficits, and renal insufficiency will be 
documented daily as present/absent based on local laboratory results and local consultants, as 
appropriate for the local SoC. If present, 1) a narrative description will be provided at the time of 
diagnosis; 2) the status of present or absent will be documented daily.
Occurrence of exacerbation or relapse will be determined by platelet count or the occurrence 
after remission of a major clinical event (e.g. MI, stroke, death) deemed by the investigator to be 
related to aTTP. Exacerbation is defined as recurrent thrombocytopenia following a response and 
requiring a reinitiation of daily plasma exchange treatment after ≥ 1 day but ≤ 30 days of no 
plasma exchange treatment.
8.2.3 Safety
Safety will be assessed by monitoring vital signs, clinical chemistry, hematology, clinically 
relevant bleeding (modified ITP score) or thrombosis at the site of line insertion, adverse 
reactions to plasma, including citrate reactions, allergic reactions, and TRALI. Adverse Events 
(Aes) and Serious Adverse Events (SAEs) will be assessed. The modified ITP Bleeding Score 
will be assessed by the study staff daily until remission is achieved.
Central and local laboratories will be used for all laboratory values required per protocol.
The presence of inhibitors (and total binding antibodies) against rADAMTS-13 will be assessed 
for up to 28 ±3 days.
For non-commercial use only

Shire
CONFIDENTIAL
Page 55
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
The study DMC will evaluate safety as per the DMC charter. In addition, the safety will be 
monitored by the Sponsor’s Medical Director as per the safety review plan.
8.2.3.1 Physical Examination
Complete and targeted physical examinations will be performed at the time points specified in 
Table 1. Complete physical examination includes the review of the following body systems: 
general appearance; skin; head, eyes, ears, nose, and throat; heart; lungs; eyes; breast (optional); 
abdomen; external genitalia (optional); extremities; neurologic function; back; and lymph nodes. 
Weight will be measured at screening, weekly during the treatment period, and at the time points 
specified in Table 1. Height will be measured at screening (Visit 1) only.
Changes after the screening visit that are deemed clinically significant in the opinion of the 
investigator will be recorded as an AE.
Abnormalities (such as neurologic deficits, skin lesions) identified at the screening visit (Visit 1) 
and at subsequent study visits will be recorded in the subject’s source documents.
8.2.3.2 Adverse Events
An AE is defined as any untoward medical occurrence in a subject administered IP that does not 
necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom (e.g., 
rash, pain, discomfort, fever, dizziness, etc.), or disease (eg, peritonitis, bacteremia, etc.) 
temporally associated with the use of an IP, whether or not related to the IP. An AE includes any 
event, regardless of the presumed causality between the event and the IP. 
Events that do not necessarily meet the definition of Aes, regardless of causal association with 
IP, should be treated as Aes because they may be reportable to Regulatory Authorities according 
to AE reporting regulation; these include the following:

IP overdose, whether accidental or intentional

IP abuse

An event occurring from IP withdrawal

Any failure of expected pharmacological action

Exposure to IP during pregnancy

Unexpected therapeutic or clinical benefit from the IP

Medication errors (i.e., incorrect route of administration, incorrect dosage, use of incorrect 
product)
For non-commercial use only

Shire
CONFIDENTIAL
Page 56
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
For the purposes of this study, the following non-serious events experienced after the first IP 
exposure are collected under other study outcome measures and thus are not reportable on the 
AE CRF if related to a TTP event, nor will they be included in the analysis of Aes:
1.
Increase of serum creatinine 
2.
Elevation of LDH >2×ULN
3.
Neurological symptoms (e.g., confusion, visual changes, dysphonia, paresthesias, 
dysarthria, focal or general motor symptoms)
4.
Abnormal ADAMTS-13 activity
5.
Positive anti-ADAMTS-13 inhibitor
8.2.3.3 Vital Signs
Vital signs will be assessed at each visit, if not stated otherwise:

Blood pressure: Systolic/diastolic blood pressure (mmHg) baseline measurements will be 
measured after a 10-minute rest in the supine/semirecumbent position.

Pulse rate: Pulse rate (beats/min) will be measured at the distal radial arteries under the 
same conditions as above.

Respiratory rate: Respiratory rate (breaths/min) will be measured over a period of 1 minute 
under the same conditions as above.

Temperature: Body temperature (°C or °F) may be determined by oral, rectal, axillary, or 
tympanic measurement at the discretion of the investigator. However, the same method 
should be used for all measurements in 1 subject.
During the treatment period, vital signs will be assessed 30±15 minutes prior to and 
30±15 minutes after the first IP infusion on study and 30±15 minutes prior to and 
30±15 minutes after the first post-PEX IP infusion each day thereafter. 
Vital sign values are to be recorded on the vital signs CRF. For each abnormal vital sign value, 
the investigator will determine whether the value is considered an AE (see definition in 
Appendix 2.1). If assessed as an AE, the medical diagnosis (preferably), symptom, or sign, will 
be recorded 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 (described in Appendix 2.1), 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 vital signs CRF. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 57
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, 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.
8.2.3.4 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. The hematology panel consists of complete blood count 
[hemoglobin, hematocrit, erythrocytes (i.e., red blood cell count), and leukocytes (i.e., white 
blood cell count)] with differential (i.e., basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration 
(MCHC), and platelet count.
The clinical chemistry panel consists of ALT, AST, total bilirubin, alkaline phosphatase, blood 
urea nitrogen, creatinine, and glucose.
A complete list of the clinical laboratory tests to be performed is provided in Table 1 and
Table 2.
8.2.3.5 Pregnancy Test
A beta human chorionic gonadotropin (β hCG) pregnancy test will be performed on all females 
of childbearing potential at the time points specified in Table 1; if pregnancy is suspected; or 
upon withdrawal of the subject from the study. A serum pregnancy test will be performed at the 
screening visit (Visit 1); all other pregnancy tests will be urine tests.
Pregnancy tests are not required for females of non-childbearing potential who have undergone 
hysterectomy or bilateral oophorectomy, have medically confirmed ovarian failure, or are 
medically confirmed postmenopausal (cessation of regular menses for at least 12 consecutive 
months with no alternative pathological or physiological cause; postmenopausal status may be 
confirmed by FSH testing in females who have had 12 consecutive months of spontaneous 
amenorrhea and are 51 years of age or older).
For non-commercial use only

Shire
CONFIDENTIAL
Page 58
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
8.2.4 Other 
8.2.4.1 Clinical Pharmacokinetics
Pharmacokinetics (PK) will be assessed at the following time points in all patients on each of the 
pre-specified sampling days: within 15 minutes pre-PEX, within 15 minutes post end of PEX, 
within 15 minutes post end of IP or placebo infusion, 0.5-3 hours after end of IP or placebo 
infusion #1, 4-6 hours after end of IP or placebo infusion #1, within 30 minutes pre-IP or 
placebo #2, within 15 minutes post end of IP or placebo infusion #2, 0.5-3 hours post end of IP 
or placebo infusion #2.  Patients in each study arm will be separated into two groups and follow 
Sampling Schedule A or B, respectively.
SCHEDULE A: Days 1, 2, 3, 4, 6, 8, 11, and every 3 days thereafter
SCHEDULE B: Days 1, 2, 3, 5, 7, 9, 12, and every 3 days thereafter
A complete list of PK sampling schedules and timepoints is provided in Table 3.
8.2.4.2 Pharmacodynamics
Pharmacodynamics will be assessed during the treatment period with daily LDH concentration 
and platelet count. In the one month post remission (with or without supplementation), VWF 
multimer analysis will be assessed at weeks 1 and 4 post remission (Table 2).
8.2.4.3 Genetics
Genetic sequencing of the ADAMTS-13 gene will be performed to exclude subjects with 
congenital TTP and will not be used for exploratory research purposes.
8.2.4.4
 
 
 
8.2.4.5
 
 
 
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 59
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
8.2.4.6
 
For non-commercial use only

Shire
CONFIDENTIAL
Page 60
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
For non-commercial use only

Shire
CONFIDENTIAL
Page 61
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
8.2.4.7
 
 
 
 
 
 
8.2.5 Volume of Blood to Be Drawn from Each Subject
Please refer to the study lab manual for volumes of blood to be drawn. The volume of blood to 
be drawn per subject will vary by how many PEX procedures are performed, with the 
accompanying post-PEX PK sampling.
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. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 62
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
9. STATISTICAL CONSIDERATIONS
9.1 Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other study 
information such as subject disposition, demographics and baseline characteristics, 
investigational product exposure, and prior and concomitant medications. The SAP will also 
include a description of how missing, unused and spurious data will be addressed.
The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions.
All statistical analyses will be performed using SASsoftware Version 9.3 or higher (SAS 
Institute, Cary, NC 27513). 
Unless otherwise specified, summary tabulations will be presented by treatment group. All data 
listings will be sorted by treatment group, site, and subject number, and will include the subject’s 
age, sex, and race.
For categorical variables, the number and percentage of subjects within each category (with a 
category for missing data as needed) of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation, minimum, and maximum 
values will be presented. For categorical data, the number of subjects, percentage, median, 
quartiles and range will be reported.
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis or adaptive design is planned for this study. An external DMC will be 
established to review the overall safety of the study subjects on an ongoing basis.
The DMC will be responsible for the ongoing monitoring of safety of subjects enrolled in the 
study according to the DMC charter. Recommendations made by the DMC to alter the conduct 
of the study or to amend the protocol will be forwarded to Shire for review and for a final 
decision. Shire or its designee will notify investigative sites and regulatory authorities as 
appropriate, of DMC recommendations (which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints).
Further details regarding the DMC can be found in the DMC charter, which will be available 
before the administration of investigational product to any subject. Analyses of the data for 
DMC review will be conducted according to the DMC charter and DMC SAP. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 63
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Because no formal hypothesis testing for safety assessments is planned, multiplicity concerns 
regarding repeated analyses are not applicable.
9.3 Sample Size and Power Considerations
The sample size for this study is not based on a power calculation.  It is a Phase 2 study with PK 
modeling as one of the primary objectives and is being conducted in aTTP subjects which is a 
rare condition. The sample size of 10 subjects per treatment arm is selected to provide sufficient 
PK/PD data to develop the two models outlined in the co-primary objectives.
Statistical Analysis Set(s)

The screened set will consist of all subjects who have signed an informed consent 
document.

The randomized set will consist of all subjects in the screened set for whom a 
randomization number has been assigned.

The safety set will consist of all subjects who have received at least 1 dose of 
investigational product.

Full Analysis Set (FAS) will consist of all enrolled aTTP subjects who are treated with 
study product and have ADMATS13 activity reading from at least one post infusion 
sample. Randomization errors are included in the treatment arm they are randomized to, 
not in the treatment arm of the treatment they receive. The per-protocol set will consist of 
all subjects in the FAS who do not have protocol deviations that may affect the efficacy 
endpoints.

The PK set will consist of all subjects who have received at least 1 dose of investigational 
product and who have at least 1 evaluable post-dose PK concentration value.

The pharmacodynamics (PD) set will consist of all subjects who have received at least 
1 dose of investigational product and who have at least 1 evaluable post-dose PD value.
9.4 Efficacy Analyses
Unless otherwise specified, all efficacy analyses will be based on the FAS and in the main 
efficacy analysis, subjects will be analyzed according to their randomized treatment, regardless 
of the treatment they actually received. There are no statistical hypotheses formulated for this 
study and no significant tests are planned. All confidence intervals will be 2-sided 95% 
confidence intervals, unless stated otherwise.
For non-commercial use only

Shire
CONFIDENTIAL
Page 64
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
9.4.1 Primary Efficacy Endpoint
There is no Primary Efficacy Endpoint since the primary objective of the study is to assess PK of 
ADAMTS-13.  PK analysis is described in Section 9.7.
9.4.2 Secondary Efficacy Endpoints
1.
Time to normalization of platelet count, defined as platelet count ≥ 150,000/µL, which 
must be confirmed by a second normal platelet count ≥ 150,000/µL and LDH <2 ULN 
48 hours following initial normalization
2.
Occurrence of remission, defined as a normal platelet count and LDH <2 ULN for at least 
48 hours following initial normalization of platelet count (acute episode period)
3.
Time to first exacerbation (aTTP episode ≤30 days following remission)
4.
Time to relapse (aTTP episode >30 days following remission)
5.
Occurrence of exacerbation  
6.
Occurrence of relapse
7.
Occurrence of major clinical events related to TTP including:
a.
Death
b.
Stroke
c.
MI
d.
Organ dysfunction not normalized within the 90-day observation period
i.
Chronic renal insufficiency
ii.
Neurologic impairment
iii.
Neurocognitive deficits.
All time to event efficacy endpoints will be analyzed by the non-parametric Kaplan Meier (KM) 
estimator of the survival curve.  Estimates of the median time to event as well as proportions of 
subjects with event will be derived, together with two-sided, 95% confidence intervals.
Summary statistics will be provided for the secondary efficacy endpoints assessed by study arm.  
For continuous variables these will include mean, standard deviation and 95%, two-sided 
confidence interval (CI) for the mean. For discrete variable these will include proportions, 
incidence, and the two-sided 95% CI for the proportion.
For non-commercial use only

Shire
CONFIDENTIAL
Page 65
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
9.4.3 Multiplicity Adjustment
Not applicable.
9.4.4 Control of Type I Error
Not applicable.
9.4.5 Exploratory Endpoints
9.5 Safety Analyses
9.5.1 Secondary Safety Endpoints
1.
Incidence of major clinical events related to PEX, including clinically relevant bleeding 
(modified ITP score) or thrombosis at the site of line insertion, adverse reactions to plasma, 
including citrate reactions, allergic reactions, and TRALI
2.
Changes in the titer of binding and inhibitory antibodies to ADAMTS-13
3.
Occurrence of antibodies to SHP655 
4.
Incidence of AEs and SAEs, and specifically product-related AEs and SAEs 
5.
Clinically relevant changes in vital signs, clinical chemistry, and hematology
For non-commercial use only

Shire
CONFIDENTIAL
Page 66
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
9.5.2 Safety Endpoint Analyses 
AEs and SAEs will be tabulated and summarized according to the Medical Dictionary for 
Regulatory Activities, in total, by arm, and by relatedness to product or PEX procedure. The 
number and proportion of subjects experiencing these events will be tabulated for each arm.
Individual and summary vital signs and clinical laboratory data will be presented in tabular form 
with mean, standard deviation, quartiles, and range as appropriate, by treatment arm and time 
point.
For the 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.
9.6
9.6.1
For non-commercial use only

Shire
CONFIDENTIAL
Page 67
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
9.6.2
 
.
9.6.3
 
 
9.6.4
For non-commercial use only

Shire
CONFIDENTIAL
Page 68
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
9.7 Pharmacokinetic Analyses
9.7.1 Secondary PK/PD Endpoints
1.
The PK/PD temporal relationship of efficacy parameters (e.g., platelet count, LDH levels), 
as a function of ADAMTS-13 activity
2.
The ADAMTS-13 binding and inhibitory autoantibody levels in response to daily PEX, 
with or without SHP655 supplementation, during the acute TTP episode and up to 30 days 
after resolution
3.
ADAMTS-13 activity levels in subjects receiving additional SHP655 for up to 30 days 
after the resolution of the TTP episode
4.
The relationship between ADAMTS-13 activity and end-organ disease status (e.g., renal, 
neurologic, and cardiac) 
5.
PK parameters such as incremental recovery, area under the curve, systemic and antibody 
induced clearance, maximum ADAMTS-13 activity between PEX or SHP 655 infusions, 
and trough levels prior PEX
6.
Occurrence of ADAMTS-13 activity trough levels >10%
9.7.2 PK/PD Analyses
All PK/PD analyses will be performed using the PK analysis set. ADMATS-13 activity levels 
will be tabulated and plotted by arm as data permit. PK will be assessed using a population PK 
modeling framework. A structural population PK model will be developed and validated.  
Standard model diagnostics including statistical measures of fit and goodness-of-fit plots will be 
used to discriminate between models. PK parameters of interest (e.g. clearance and volume) for 
ADMATS-13 activity will be reported for each subject and summarized using descriptive 
statistics. The model will attempt to quantify the influence of PEX, SHP655 as well as inhibitory 
autoantibody on ADAMTS-13 activity clearance.  Full details will be provided in the population 
PK analysis plan.
For non-commercial use only

Shire
CONFIDENTIAL
Page 69
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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 of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 70
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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. 
The sponsor will provide the Ecs with a copy of the same summary.
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.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 © of Directive 2001/20/EC.
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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 71
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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.
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
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
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. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 72
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Case report forms must be completed by the investigator or designee as stated in the site 
delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
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.
Incorrect entries must be crossed with a single line as to not obscure the original entry. 
Corrections must be made adjacent to the item to be altered, initialed, and dated by an authorized 
investigator or designee as stated in the site delegation log. Overwriting of this information or 
use of liquid correcting fluid is not allowed.
The CRFs should be approved by the investigator per study specifications and the sponsor’s data 
delivery requirements. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
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 and original clinical laboratory 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). Non-study site personnel will not 
disclose any personal information or personal medical information.
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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 73
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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).
Compliance to all Local, State, and National Controlled-substance Biohazard and 
Infectious Disease Regulations and Legislation
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the investigator must at all times comply with all local, state, and national laws pertaining to 
registration and reporting with the appropriate regulatory body and control and handling of such 
substances.
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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 74
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Data Management
Data are to be entered into a clinical database as specified in the CRO’s CRF completion 
guidelines and data handling plan or similar. Quality control and data validation procedures are 
applied to ensure the validity and accuracy of the clinical database.
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 treatments, 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. 
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. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form 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 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 
For non-commercial use only

Shire
CONFIDENTIAL
Page 75
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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.
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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 76
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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, electronic, oral, or 
other form. 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 one (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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 77
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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.
Shire is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Shire-supported research. Therefore, after January 1, 2018, Shire 
will require the submission of all Shire-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 
authorship of publications.
For non-commercial use only

Shire
CONFIDENTIAL
Page 78
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
APPENDIX 2  ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
Appendix 2.1  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
For non-commercial use only

Shire
CONFIDENTIAL
Page 79
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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
For non-commercial use only

Shire
CONFIDENTIAL
Page 80
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
study protocol or product labeling; or any other unanticipated serious problem associated with a
device that relates to the rights, safety, or welfare of subjects.
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.
Preexisting conditions prior to randomization are described in the medical history, and those that 
manifest with the same severity, frequency, or duration after drug exposure, are  not be recorded 
as AEs. However, when there is an increase in the severity, 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, vital sign measure, or ECG assessment 
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), vital sign, or ECG 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, vital sign, or ECG parameter is clinically 
significant and represents an AE.
For non-commercial use only

Shire
CONFIDENTIAL
Page 81
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Collection of ECG parameters is suggested to be performed in triplicates and conducted by a 
central laboratory for all study subjects.
Appendix 2.2  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. 
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 2.3  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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 82
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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.
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. Safety 
Reporting
For non-commercial use only

Shire
CONFIDENTIAL
Page 83
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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 Shire Global 
Drug Safety Department and the CRO/Shire 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 2.8) unless they result in an SAE.
The investigator must complete, sign, and date the Shire “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 
Shire Global Drug Safety Department. A copy of the Shire 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/Shire medical monitor using the 
details specified in the emergency contact information section of the protocol.
Medical Device Safety Reporting
All serious injuries and UADEs must be reported to the sponsor as an SAE in the same process 
as described above. Serious injury (SI) is defined as:

Led to death;

Led to a serious deterioration in health of a patient, user, or others that

Results in a life-threatening illness or injury

Results in a permanent impairment/ damage of a body function or body structure

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in medical or surgical intervention to prevent permanent impairment/ damage to 
body function/ structure.

Led to fetal distress, fetal death or a congenital abnormality/birth defect
For non-commercial use only

Shire
CONFIDENTIAL
Page 84
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Appendix 2.4  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 follow-up period stated in Section 8.1.3 and 
must be reported to the Shire Global Drug Safety Department and the CRO/Shire 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 Shire Global 
Drug Safety Department within 24 hours of the reported first becoming aware of the event.
Appendix 2.5  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 informed consent 
form, 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 2.6  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.
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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 85
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Appendix 2.7 Pregnancy 
All pregnancies are reported from the time informed consent is signed until the defined follow-
up period stated in Section 8.1.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Drug Safety Department using 
the Shire 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/Shire 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 Shire Clinical Study 
Serious Adverse Event and Non-serious AEs Required by the Protocol Form. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire 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.
Appendix 2.8  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 2.1.
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.
For non-commercial use only

Shire
CONFIDENTIAL
Page 86
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
The categories below are not mutually exclusive; the event can meet more than 1 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.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
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.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
Appendix 2.9 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 trial 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 trial or trials

Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
For non-commercial use only

Shire
CONFIDENTIAL
Page 87
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
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 2.10  Regulatory Agency, Institutional Review Board, Ethics Committee and Site 
Reporting
The sponsor and the CRO are responsible for notifying the relevant regulatory authorities
(central IRBs/central 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).
For non-commercial use only

Shire
CONFIDENTIAL
Page 88
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
APPENDIX 3  GENETICS
Shire intends to apply genetic research across the SHP655 development program to differentiate 
participants with congenital (genetic) versus acquired TTP. Collection of appropriate samples 
from populations with well described clinical characteristics may lead to improvements in the 
design and interpretation of clinical studies, genetically guided treatment strategies, and a better 
understanding of disease etiology, which may lead to new therapeutic approaches.
Candidate genes which may be studied include those potentially related to the mechanism of 
action of SHP655 as well as those potentially responsible for absorption, disposition, 
metabolism, and excretion of SHP655. Future research may suggest other genes, gene categories, 
proteins, etc., as candidates for influencing not only response to SHP655, but also susceptibility 
to TTP for which SHP655 may be evaluated. Thus, this additional genomic research may involve 
the future study of additional unnamed genes or gene categories, but only as they relate to TTP
disease susceptibility and drug action.
A DNA sample will be drawn at screening. Samples will be collected from all subjects in order 
to meet inclusion criteria.
Samples will be labeled with the study protocol number, the subject’s study identification 
number, and information related to the sample. No personal identifiers will be recorded on the 
sample labels.
Subjects terminating early from the study due to AE, tolerability, or drug-related issues should, 
where possible, be approached for their remaining protocol-defined samples at the earliest 
possible time. Unscheduled samples should be labeled with free text capturing study protocol 
number, subject’s study identification number, and information related to the sample (RNA or 
protein, sampling date, and time). Samples will be shipped to and stored at biorepositories as 
detailed in the laboratory manual. DNA, RNA, and protein will be extracted from the samples 
only when, and if, any separate exploratory research will be undertaken. 
As an added level of security, the sample will be recoded with a new, unique number at the 
biorepository laboratory. This unique number is the only code used in any subsequent analysis 
and will be used to link a sample to a subject and to ensure that the subject’s identity remains 
confidential. 
A link file linking the first and second codes will be kept in a secure place at the sponsor, 
with restricted access. This will be in a secure environment outside of the clinical study 
database and separate to any analysis results. This file will be used to identify the relevant 
samples for analysis, facilitate correlation of any results with clinical data, allow regulatory 
audit, and trace samples for destruction in the case of withdrawal of consent. 
For non-commercial use only

Shire
CONFIDENTIAL
Page 89
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
No record of participation in this pharmacogenomics portion of the protocol, or any results 
derived from it, should be recorded in the subjects’ personal medical records. A record of 
participation in the pharmacogenomics portion of the protocol will, however, be captured in the 
study-specific source documentation records or CRF.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
sample and/or extracted material destroyed. The link will also be destroyed at the same time as 
any remaining sample(s) are destroyed. Any results already generated from the samples will not 
be removed from any analyses that have already been performed. 
Participation in this portion of the study is optional and does not impact the subject’s eligibility 
for participation in the main clinical study. Subjects may continue to participate in the primary 
study if they refuse to provide a blood sample or if they withdraw their samples. 
Results of the genetic analyses may contribute to the global understanding of TTP and its 
treatment and may be used internally to help support the design of additional clinical studies, 
form part of scientific publication, or be made known to the regulatory authorities as part of a 
new drug application. Any results generated will be for exploratory research purposes only and 
will not be made available unless required by law (ie, to regulatory authorities). Additionally, as 
any potential analysis does not form part of predefined analysis within the clinical study 
protocol, any results will be reported separately to the main clinical study report. Subjects may 
request the results of any analysis on their samples, although it will not be possible to interpret 
these.
For non-commercial use only

Shire
CONFIDENTIAL
Page 90
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
APPENDIX 4  DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION
Female participants:
Female participants of childbearing potential and sexually active males are eligible to participate 
if they agree to use a highly effective method of contraception consistently and correctly as 
described below.
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb
•
Oral 
•
Intravaginal 
•
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation
•
Oral 
•
Injectable 
Highly Effective Methods That Are User Independent a
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Vasectomy
A vasectomy in a male subject or a vasectomized partner for a female subject is a highly effective contraception 
method provided that the partner is the sole male sexual partner of the women of childbearing potential 
(WOCBP) and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be utilized 
during the treatment period and for at least 30 days after the last dose of study treatment 
For non-commercial use only

Shire
CONFIDENTIAL
Page 91
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
APPENDIX 5  ABBREVIATIONS 
Abbreviation
Definition
Ab
antibody
ADAMTS-13
a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13
AE 
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
aTTP
Acquired thrombotic thrombocytopenic purpura
AUC
area under the curve
AUC0-inf
area under the curve from time 0 to infinity
-hCG
beta-human chorionic gonadotropin
B19V
parvovirus B19
BID
twice daily
BW
body weight
C
degree Celsius
CBC
complete blood count
CD4
cluster of differentiation 4
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CI
confidence interval
CL
clearance
Cmax
maximum concentration
CRF
case report form
CRO
contract research organization
cTTP
congenital thrombotic thrombocytopenic purpura
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
EMA
European Medicines Agency
EU
European Union
EUDRACT
European Union clinical trials database
F
degree Fahrenheit
FAS
Full Analysis Set
For non-commercial use only

Shire
CONFIDENTIAL
Page 92
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Abbreviation
Definition
FDA
Food and Drug Administration 
FFP
Fresh frozen plasma
FVII
Factor VIII
GCP
Good Clinical Practice
GmbH
Gesellschaft mit beschränkter Haftung – German term for a company that does not 
trade its shares on the stock market
GPIb
glycoprotein Ib
HAV
hepatitis A virus
HBc
hepatitis B core
HBV
hepatitis B virus
HCV
hepatitis C virus
HEV
hepatitis E virus
HIV
human immunodeficiency virus
hTTP
hereditary thrombotic thrombocytopenic purpura; congenital thrombotic 
thrombocytopenic purpura
IB
Investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IP
Investigational product
ID
intradermal(ly)
IM
Intramuscular
INR
international normalized ratio
IP
intraperitoneal(ly)
IR
Incremental recovery
IRB
institutional review board
IRT
interactive response technology
IV
intravenous(ly) 
KM
Kaplan Meier
LDH
lactic dehydrogenase
Mab
monoclonal antibody
For non-commercial use only

Shire
CONFIDENTIAL
Page 93
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Abbreviation
Definition
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MoCA
Montreal Cognitive Assessment
MI
Myocardial infarction
mmHg
millimeter(s) of mercury 
NA
not applicable
NCS
not clinically significant
PEX
Plasma exchange
PD
Pharmacodynamics(s)
PK
pharmacokinetic(s)
 
Q1W
every week
Q2W
every 2 weeks
QOD
every other day
QoL
quality of life
rADAMTS-13
a recombinant human disintegrin and metalloprotease with a thrombospondin type 1 
motif, member 13
RASS
Richmond Agitation Sedation Scale
RBC
red blood cell
RCo
ristocetin cofactor activity
Rituximab
humanized anti-CD20 monoclonal antibody
RNA
ribonucleic acid
RSI
reference safety information
rVWF
Recombinant von Willebrand factor
S/D
solvent/detergent
SAE
serious adverse event 
For non-commercial use only

Shire
CONFIDENTIAL
Page 94
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Abbreviation
Definition
SAP
statistical analysis plan
SAS
statistical analysis system
SD
Sprague-Dawley
SI
serious injury
SoC
standard of care
SUSAR
suspected unexpected serious adverse reaction
t1/2
Terminal half-life
TBD
to be determined
TEAE
treatment emergent serious adverse event (s)
TMA
thrombotic microangiopathy
TRALI
Transfusion-related acute lung injury
TTP
thrombotic thrombocytopenic purpura
U
unit(s)
UADE
unanticipated adverse device effect
UK
United Kingdom
UL VWF
ultra-large von Willebrand Factor
ULN
upper limit of normal
US
United States
Vss
steady state volume of distribution
VWF
von Willebrand factor
WOCBP
women of childbearing potential
For non-commercial use only

Shire
CONFIDENTIAL
Page 95
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
APPENDIX 6  PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
03 OCT 2018
Global
For non-commercial use only

Shire
CONFIDENTIAL
Page 96
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
10. REFERENCES
Allford, S. L., Harrison, P., Lawrie, A. S., Liesner, R., Mackie, I. J. & Machin, S. J. 2000. Von 
Willebrand factor--cleaving protease activity in congenital thrombotic thrombocytopenic 
purpura. Br. J. Haematol, 111, 1215-1222.
Alwan F, Vendramin C, Langley K & Et Al. 2016. Presenting ADAMTS13 Antigen Level 
Correlates with Clinical Outcome in Acute Thrombotic Thrombocytopenic Purpura. 
Blood, 128, 1365.
Balduini, C., Gugliotta, L., Luppi, M., Laurenti, L., Klersy, C., Pieresca, C., Quintini, G., Iuliano, 
F., Re, R., Spedini, P., Vianelli, N. & Zaccari 2010. High versus standard dose 
methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic 
purpura: a randomized study. Annals of Hematology, 89, 591-596.
Bandarenko, N. & Brecher, M. E. 1998. United States thrombotic thrombocytopenic purpura 
apheresis study group (US TTP ASG): Multicenter survey and retrospective analysis of 
current efficacy of therapeutic plasma exchange. Journal of Clinical Apheresis, 13, 133-
141.
Benhamou, Y., Assié, C., Boelle, P.-Y., Buffet, M., Grillberger, R., Malot, S., Wynckel, A., 
Presne, C., Choukroun, G., Poullin, P., Provôt, F., Gruson, D., Hamidou, M., 
Bordessoule, D., Pourrat, J., Mira, J.-P., Le Guern, V., Pouteil-Noble, C., Daubin, C., 
Vanhille, P., Rondeau, E., Palcoux, J.-B., Mousson, C., Vigneau, C., Bonmarchand, G., 
Guidet, B., Galicier, L., Azoulay, E. & Rottensteiner, H. 2012. Development and 
validation of a predictive model for death in acquired severe ADAMTS13 deficiency-
associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference 
Center experience. Haematologica, 97, 1181-6.
Bryant, B. J. & Klein, H. G. 2007. Pathogen inactivation: the definitive safeguard for the blood 
supply. Archives of Pathology & Laboratory Medicine, 131, 719-33.
For non-commercial use only

Shire
CONFIDENTIAL
Page 97
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Cataland, S. R. & Wu, H. M. 2015. Acquired thrombotic thrombocytopenic purpura: New 
therapeutic options and their optimal use. J Thromb Haemost, 13 Suppl 1, s223-s229.
Coppo, P. & Veyradier, A. 2012. Current management and therapeutical perspectives in 
thrombotic thrombocytopenic purpura. Presse Med, 41, e163-e176.
Deford, C. C., Reese, J. A., Schwartz, L. H., Perdue, J. J., Kremer Hovinga, J. A., Lammle, B., 
Terrell, D. R., Vesely, S. K. & George, J. N. 2013. Multiple major morbidities and 
increased mortality during long-term follow-up after recovery from thrombotic 
thrombocytopenic purpura. Blood, 122, 2023-2029.
George, J. N. 2007. Evaluation and management of patients with thrombotic thrombocytopenic 
purpura. J. Intensive Care Med, 22, 82-91.
Han, B., Page, E. E., Stewart, L. M., Deford, C. C., Scott, J. G., Schwartz, L. H., Perdue, J. J., 
Terrell, D. R., Vesely, S. K. & George, J. N. 2015. Depression and cognitive impairment 
following recovery from thrombotic thrombocytopenic purpura. Am. J. Hematol, 90, 709-
14.
Hie, M., Gay, J., Galicier, L., Provôt, F., Presne, C., Poullin, P., Bonmarchand, G., Wynckel, A., 
Benhamou, Y., Vanhille, P., Servais, A., Bordessoule, D. & Coindre 2014. Preemptive 
rituximab infusions after remission efficiently prevent relapses in acquired thrombotic 
thrombocytopenic purpura. Blood, 124, 204-210.
Humpe, A., Legler, T. J., Nübling, C. M., Riggert, J., Unger, G., Wolf, C., Heermann, K.-H. & 
Köhler, M. 2000. Hepatitis C Virus Transmission through Quarantine Fresh-frozen 
Plasma. Thrombosis and Haemostasis, 83, 784-788.
Joly, B. S., Coppo, P. & Veyradier, A. 2017. Thrombotic thrombocytopenic purpura. Blood, 129,
2836-2846.
For non-commercial use only

Shire
CONFIDENTIAL
Page 98
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Kessler, C. S., Khan, B. A. & Lai-Miller, K. 2012. Thrombotic Thrombocytopenic Purpura: A 
Hematological Emergency. Journal of Emergency Medicine, 43, 538-544.
Knöbl, P. 2014. Inherited and acquired thrombotic thrombocytopenic purpura (TTP) in adults. 
Semin. Thromb. Hemost, 40, 493-502.
Koyfman, A., Brém, E. & Chiang, V. W. 2011. Thrombotic thrombocytopenic purpura. Pediatr. 
Emerg. Care, 27, 1085-1091.
Kremer Hovinga, J. A., Coppo, P., Lämmle, B., Moake, J. L., Miyata, T. & Vanhoorelbeke, K. 
2017. Thrombotic thrombocytopenic purpura. Nature Reviews Disease Primers, 3,
17020.
Lewis, Q. F., Lanneau, M. S., Mathias, S. D., Terrell, D. R., Vesely, S. K. & George, J. N. 2009. 
Long-term deficits in health-related quality of life after recovery from thrombotic 
thrombocytopenic purpura. Transfusion, 49, 118-124.
Peyvandi, F., Lavoretano, S., Palla, R., Feys, H. B., Vanhoorelbeke, K., Battaglioli, T., 
Valsecchi, C., Canciani, M. T., Fabris, F., Zver, S., Reti, M., Mikovic, D., Karimi, M., 
Giuffrida, G., Laurenti, L. & Mannucci, P. M. 2008. ADAMTS13 and anti-ADAMTS13 
antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura 
during remission. Haematologica, 93, 232-239.
Peyvandi, F., Scully, M. F. & Kremer Hovinga, J. A. 2016. Caplacizumab for acquired 
thrombotic thrombocytopenic purpura. N Engl J Med, 374, 511-522.
Plaimauer, B., Kremer Hovinga, J. A., Juno, C., Wolfsegger, M. J., Skalicky, S., Schmidt, M., 
Grillberger, L., Hasslacher, M., Knöbl, P., Ehrlich, H. & Scheiflinger, F. 2011. 
Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma 
of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost, 9, 936-
944.
For non-commercial use only

Shire
CONFIDENTIAL
Page 99
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Plaimauer, B., Schiviz, A., Kaufmann, S., Höllriegl, W., Rottensteiner, H. & Scheiflinger, F. 
2015. Neutralization of inhibitory antibodies and restoration of therapeutic ADAMTS13 
activity levels in inhibitor-treated rats through defined doses of recombinant 
ADAMTS13. J Thromb Haemost, 13, 2053-62.
Reutter, J. C., Sanders, K. F., Brecher, M. E., Jones, H. G. & Bandarenko, N. 2001. Incidence of 
allergic reactions with fresh frozen plasma or cryo-supernatant plasma in the treatment of 
thrombotic thrombocytopenic purpura. J. Clin. Apher, 16, 134-138.
Rock, G., Yousef, H., Neurath, D. & Lu, M. 2006. ADAMTS-13 levels in fresh, stored, and 
solvent detergent treated plasma. Transfus Apher Sci, 35, 235-238.
Rock, G. A., Shumak, K. H., Buskard, N. A., Blanchette, V. S., Kelton, J. G., Nair, R. C. &
Spasoff, R. A. 1991. Comparison of plasma exchange with plasma infusion in the 
treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N 
Engl J Med, 325, 393-397.
Saha, M., Mcdaniel, J. K. & Zheng, X. L. 2017. Thrombotic thrombocytopenic purpura: 
pathogenesis, diagnosis and potential novel therapeutics. Journal of Thrombosis and 
Haemostasis, 15, 1889-1900.
Scully, M., Hunt, B. J., Benjamin, S., Liesner, R., Rose, P., Peyvandi, F., Cheung, B., Machin, S. 
J. & Haematology, T. B. C. F. S. I. 2012. Guidelines on the diagnosis and management of 
thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br. J. 
Haematol, 158, 323-335.
Scully, M., Mcdonald, V., Cavenagh, J., Hunt, B. J., Longair, I., Cohen, H. & Machin, S. J. 
2011. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in 
acute acquired thrombotic thrombocytopenic purpura. Blood, 118, 1746-1753.
For non-commercial use only

Shire
CONFIDENTIAL
Page 100
SHP655-201 Protocol
rADAMTS-13
03 OCT 2018
Tersteeg, C., Schiviz, A., De Meyer, S. F., Plaimauer, B., Scheiflinger, F., Rottensteiner, H. & 
Vanhoorelbeke, K. 2015. Potential for recombinant ADAMTS13 as an effective therapy 
for acquired thrombotic thrombocytopenic purpura. Arterioscler Thromb Vasc Biol, 35,
2336-2342.
Tersteeg, C., Verhenne, S., Roose, E., Schelpe, A. S., Deckmyn, H., De Meyer, S. F. & 
Vanhoorelbeke, K. 2016. ADAMTS13 and anti-ADAMTS13 autoantibodies in 
thrombotic thrombocytopenic purpura - current perspectives and new treatment 
strategies. Expert Rev Hematol, 9, 209-221.
Vazquez-Mellado, A., Pequeño-Luévano, M., Cantu-Rodriguez, O. G., Villarreal-Martínez, L., 
Jaime-Pérez, J. C., Gomez-De-Leon, A., De La Garza-Salazar, F., Gonzalez-Llano, O., 
Colunga-Pedraza, P., Sotomayor-Duque, G. & Gomez-Almaguer, D. 2016. More about 
low-dose rituximab and plasma exchange as front-line therapy for patients with 
thrombotic thrombocytopenic purpura. Hematology, 21, 311-6.
Westwood, J.-P., Webster, H., Mcguckin, S., Mcdonald, V., Machin, S. J. & Scully, M. 2013. 
Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration 
during acute episodes and use of prophylaxis to prevent relapse. Journal of Thrombosis 
and Haemostasis, 11, 481-490.
Zheng, X. L. 2015. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic 
purpura. Annu. Rev. Med, 66, 211-225.
For non-commercial use only