Conditions: Acquired Thrombotic Thrombocytopenic Purpura (aTTP)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics, safety, and efficacy of rADAMTS-13 (SHP655) administered in addition to standard of care (SoC) treatment of acquired thrombotic thrombocytopenic purpura (aTTP) participants.

Detailed description:

Arms:
arm 1: Participants received SoC daily PEX followed by placebo immediately and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months). arm 2: Participants received SoC daily PEX and SHP655 40 +/- 4 international units per kilogram (IU/kg), IV injection, QD, immediately after PEX and placebo 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months). arm 3: Participants received SoC daily PEX and SHP655 40 +/- 4 IU/kg, IV injection, BID, immediately after PEX and 12 +/- 1 hours after completion of PEX until remission was achieved (up to approximately 6 months).

Interventions: intervention 1: Placebo intervention 2: SHP655 intervention 3: Standard of Care
Intervention descriptions: intervention 1: Participants will receive injection of placebo matched to SHP655. intervention 2: Participants will receive injection of SHP655. intervention 3: Participants will receive PEX as Standard of Care (SOC).

Protocol document:
Prot_003.pdf: 
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: 
Protocol Amendment 3.0 : 08-JUN-2020
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: 
018577 
EUDRACT NUMBER: 
2018-003775-35 
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: Protocol Amendment 3.0: 08 JUN 2020 
Replaces:  Protocol Amendment 2.1: 23 SEP 2019 
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. 
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PROTOCOL SIGNATURE PAGE 
Sponsor’s (Shire) Approval 
Signature: 
Date: 
, MD 
 
 
Investigator’s Acknowledgement 
I have read this protocol for Study SHP 655-201. 
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 
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: 
 
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SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION 
Protocol Amendment 3.0  
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3.0 
Amendment Date 
08 JUN 2020 
Country Specific 
Protocol Amendment Summary and Rationale: 
Added rescue therapy for subjects not adequately responding to treatment after 4 days.   
Description of Each Change and Rationale 
Section(s) Affected by Change 
Made terms consistent, improved 
grammar and syntax throughout 
document. 
Clarity. 
Throughout document. 
Updated dosing to allow for 10% buffer 
in calculation 
Provided reasonable dosing buffer 
Synopsis; Section 4.1;  
Section 4.3 
Rewording of safety and efficacy 
endpoints in SOC 
General clarification 
Synopsis; Section 3.2;  
Section 9.5.2; Section 9.6.1 
Added exclusion criterion precluding 
participation for subjects with conditions 
of severe immunodeficiency. 
Clarification 
Synopsis and Section 5.2 
Added text stipulating that if the 
ADAMTS-13 levels (based on local 
labs) are <50% between discharge and 
first weekly follow-up visit then the 
investigator may treat the patient with 
the IP prior to the scheduled visit. 
Clarification 
Synopsis and Section 6.2.6 
Clarified prior treatment must be 
documented for past 30 days 
Consistency with rest of protocol 
Section 6.8.1 
Added interim analysis after 18 subjects 
have achieved remission and when 
approximately 50% of the planned 
sample size has been enrolled and treated 
in the three arms. 
Allow for internal analysis and 
review of initial study results 
Synopsis, Section 9.2,  
Section 9.5.2, Section 6.2.5 
Clarified that the final study visit should 
be 3 months after remission 
General clarification 
Schedule of study activities 
Added evaluation of schistocytes to 
screening criteria 
Aligned inclusion criteria with 
schedule of study procedures 
Schedule of study activities 
Follow-up visits can be completed by a 
home healthcare provider/healthcare 
professional 
Ensure accurate data collection 
Schedule of study activities 
Section 8.1.3 
Clarified that local ADAMTS13 could 
be used to determine eligibility 
General clarification. It is not 
always logistically feasible to 
collect central lab screening 
samples prior to the initiation of 
PEX 
Synopsis (Exclusion Criteria); 
Section 5.2 
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Protocol Amendment 3.0  
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
3.0 
Amendment Date 
08 JUN 2020 
Country Specific 
Protocol Amendment Summary and Rationale: 
Added rescue therapy for subjects not adequately responding to treatment after 4 days.   
Description of Each Change and Rationale 
Section(s) Affected by Change 
Clarified the possibilities for 
administering the first PEX and IP 
General clarification 
Section 4.1 
Removed references to ECG 
General clarification; ECGs never 
included in study 
Appendix 2.1 
Added urine-albumin-creatinine ratio 
assessment 
Increased monitoring for immune 
complexes and vasculitis 
Schedule of activities; 
Section 8.2.3.4; Appendix 2.7 
Removed physical exam from daily 
treatment period 
Patients closely monitored as part 
of standard of care 
Schedule of activities 
Removed references to urine pregnancy 
tests 
Serum β-hCG pregnancy test to be 
administered during screening 
Section 5.2.1; Section 8.2.3.5 
Changed timeframe at which 
Caplacizumab is exclusionary 
Drug expected to be cleared within 
1 month of last dosing 
Section 6.8.4; Section 5.2; 
Section 1.1 Synopsis 
Provided web-based data collection 
access 
Ensure accuracy and completeness 
of data 
Section 8.2.4.7 
Specified which non-serious adverse 
events should be reported as study 
outcomes 
Data captured as a study outcome 
Section 8.2.3.2 
 
See Appendix 6 for protocol history, including all amendments. 
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EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Shire 
Clinical Study Adverse Event Form for 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  
Direct Line:  
 
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 
 
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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 (e.g., inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (e.g., wrong product such that the label and contents are different products); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following: 
• 
A failure of a product to exhibit its expected pharmacological activity and/or design 
function, e.g., reconstitution difficulty 
• 
Missing components 
• 
Damage to the product or unit carton 
• 
A mislabeled product (e.g., potential counterfeiting/tampering) 
• 
A bacteriological, chemical, or physical change or deterioration of the product causing it to 
malfunction or to present a hazard or fail to meet label claims 
 
For instructions on reporting AEs related to product complaints, see Appendix 1. 
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 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ............................................................................................. 2 
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION .......................... 3 
EMERGENCY CONTACT INFORMATION .......................................................................... 5 
PRODUCT QUALITY COMPLAINTS ..................................................................................... 6 
TABLE OF CONTENTS ............................................................................................................. 7 
1. PROTOCOL SUMMARY ..................................................................................................... 12 
1.1 Synopsis.............................................................................................................................. 12 
1.2 Schema ............................................................................................................................... 21 
1.3 Schedule of Activities ........................................................................................................ 22 
2. INTRODUCTION................................................................................................................... 26 
2.1 Indication and Current Treatment Options ................................................................... 26 
2.1.1 Current Standard of Care (SoC) .............................................................................. 26 
2.1.1.1 Plasma Exchange (PEX)..................................................................................... 27 
2.1.1.2 Corticosteroids .................................................................................................... 27 
2.1.1.3 Rituximab ............................................................................................................ 28 
2.1.1.4 Caplacizumab ...................................................................................................... 28 
2.1.2 Unmet Medical Needs of Current Therapy ............................................................. 29 
2.2 Product Background and Clinical Information. ............................................................ 30 
2.3 Study Rationale ................................................................................................................. 31 
2.4 Benefit/Risk Assessment ................................................................................................... 31 
2.5 Compliance Statement ...................................................................................................... 32 
3. OBJECTIVES AND ENDPOINTS ....................................................................................... 33 
3.1 Study Objectives ............................................................................................................... 33 
3.1.1 Co-Primary Objectives .............................................................................................. 33 
3.1.2 Secondary Objectives ................................................................................................ 33 
3.1.3 Exploratory Objectives ............................................................................................. 34 
3.2 Study Endpoints ................................................................................................................ 35 
4. STUDY DESIGN ..................................................................................................................... 39 
4.1 Overall Design ................................................................................................................... 39 
4.2 Scientific Rationale for Study Design .............................................................................. 40 
4.2.1 Rationale for control group ...................................................................................... 40 
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4.2.2 Rationale for Primary and Key Secondary Endpoints .......................................... 41 
4.2.3 Justification for the use of placebo ........................................................................... 41 
4.3 Justification for Dose ........................................................................................................ 41 
4.4 Duration of Subject Participation and Study Completion Definition .......................... 41 
4.5 Sites and Regions .............................................................................................................. 42 
5. STUDY POPULATION ......................................................................................................... 43 
5.1 Inclusion Criteria .............................................................................................................. 43 
5.2 Exclusion Criteria ............................................................................................................. 43 
5.2.1 Contraception ............................................................................................................. 44 
6. STUDY INTERVENTION ..................................................................................................... 46 
6.1 Investigational Product .................................................................................................... 46 
6.1.1 Identity of Investigational Product .......................................................................... 46 
6.1.2 Blinding the Treatment Assignment ........................................................................ 46 
6.2 Administration of Investigational Product ..................................................................... 46 
6.2.1 Hypersensitivity to SHP655 ...................................................................................... 46 
6.2.2 Interactive Response Technology for Investigational Product Management ...... 47 
6.2.3 Allocation of Subjects to Treatment ........................................................................ 47 
6.2.4 Dosing .......................................................................................................................... 47 
6.2.5 Unblinding the Treatment Assignment during the Placebo-Controlled Portion of 
the Study ..................................................................................................................... 48 
6.2.6 Dose Modification ...................................................................................................... 48 
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product .................... 49 
6.3.1 Labeling ...................................................................................................................... 49 
6.3.2 Packaging .................................................................................................................... 49 
6.3.3 Storage ........................................................................................................................ 49 
6.3.4 Special Handling ........................................................................................................ 50 
6.4 Drug Accountability ......................................................................................................... 50 
6.5 Subject Compliance .......................................................................................................... 52 
6.6 Plasma Exchange (PEX) ................................................................................................... 52 
6.7 Immunosuppression.......................................................................................................... 53 
6.8 Prior and Concomitant Therapy ..................................................................................... 53 
6.8.1 Prior Treatment ......................................................................................................... 53 
6.8.2 Concomitant Treatment ............................................................................................ 53 
6.8.3 Permitted Treatment ................................................................................................. 53 
6.8.4 Prohibited Treatment ................................................................................................ 54 
7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ............................................................................. 55 
7.1 Discontinuation of Study Treatment ............................................................................... 55 
7.2 Reasons for Discontinuation ............................................................................................ 55 
7.3 Withdrawal from the Study ............................................................................................. 56 
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7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit .................................. 56 
8. STUDY ASSESSMENTS AND PROCEDURES ................................................................. 57 
8.1 Study Schedule .................................................................................................................. 57 
8.1.1 Screening Period ........................................................................................................ 57 
8.1.1.1 Screening/Baseline Visit ..................................................................................... 57 
8.1.2 Treatment Period ....................................................................................................... 57 
8.1.2.1 Final Visit ............................................................................................................ 58 
8.1.3 Follow-up Period ........................................................................................................ 58 
8.1.4 Additional Care of Subjects after the Study ........................................................... 58 
8.2 Study Assessments ............................................................................................................ 58 
8.2.1 Demographic and Other Baseline Characteristics ................................................. 58 
8.2.1.1 Height and Weight .............................................................................................. 58 
8.2.1.2 Medical, Medication History, and Non-drug Therapies ................................. 59 
8.2.2 Efficacy ....................................................................................................................... 59 
8.2.3 Safety ........................................................................................................................... 59 
8.2.3.1 Physical Examination ......................................................................................... 60 
8.2.3.2 Adverse Events .................................................................................................... 60 
8.2.3.3 Vital Signs ............................................................................................................ 61 
8.2.3.4 Clinical Laboratory Tests .................................................................................. 62 
8.2.3.5 Pregnancy Test .................................................................................................... 63 
8.2.4 Other ........................................................................................................................... 63 
8.2.4.1 Clinical Pharmacokinetics ................................................................................. 63 
8.2.4.2 Pharmacodynamics............................................................................................. 63 
8.2.4.3 Genetics ................................................................................................................ 63 
8.2.4.4
.............................................................. 64 
8.2.4.5
....................................................................... 64 
8.2.4.6
 
...................................................................................................... 64 
8.2.4.7
..................................................................................................... 66 
8.2.5 Volume of Blood to Be Drawn from Each Subject ................................................. 66 
8.2.6 Retention of Study Samples ...................................................................................... 66 
9. STATISTICAL CONSIDERATIONS .................................................................................. 67 
9.1 Statistical Analysis Process .............................................................................................. 67 
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ......... 67 
9.3 Sample Size and Power Considerations .......................................................................... 68 
9.4 Statistical Analysis Set(s) .................................................................................................. 68 
9.5 Efficacy Analyses .............................................................................................................. 69 
9.5.1 Primary Efficacy Endpoint ....................................................................................... 69 
9.5.2 Secondary Efficacy Endpoints .................................................................................. 69 
9.5.3 Multiplicity Adjustment ............................................................................................ 70 
9.5.4 Control of Type I Error ............................................................................................ 70 
9.5.5 Exploratory Endpoints .............................................................................................. 70 
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9.6 Safety Analyses .................................................................................................................. 71 
9.6.1 Secondary Safety Endpoints ..................................................................................... 71 
9.6.2 Safety Endpoint Analyses .......................................................................................... 71 
9.7
.......................................... 72 
9.7.1
......................................... 72 
9.7.2
........................... 72 
9.7.3 
 ............................................................... 72 
9.7.4 
.................................... 73 
9.8 Phar
..................................... 73 
9.8.1 Secondary PK/PD Endpoints .................................................................................... 73 
9.8.2 PK/PD Analyses ......................................................................................................... 74 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .. 75 
Appendix 1  REGULATORY, ETHICAL, AND STUDY OVERSIGHT Considerations
 ............................................................................................................................................ 75 
Appendix 1.1  Regulatory and Ethical Considerations ................................................... 75 
Appendix 1.2  Sponsor’s Responsibilities ......................................................................... 75 
Appendix 1.3  Investigator’s Responsibilities .................................................................. 76 
Appendix 1.4  Data Management Considerations ........................................................... 79 
Appendix 1.5  Ethical Considerations ............................................................................... 80 
Appendix 2  Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting ................................................................................................ 84 
Appendix 2.1  Adverse Event Definitions ......................................................................... 84 
Appendix 2.2  Collection of Adverse Events .................................................................... 87 
Appendix 2.3  Assessment of Adverse Events .................................................................. 87 
Appendix 2.4  Serious Adverse Event Collection Time Frame ...................................... 90 
Appendix 2.5  Serious Adverse Event Onset and Resolution Dates ............................... 90 
Appendix 2.6  Fatal Outcome ............................................................................................ 90 
Appendix 2.7  Pregnancy ................................................................................................... 91 
Appendix 2.8  Abuse, Misuse, Overdose and Medication Error .................................... 91 
Appendix 2.9  Urgent Safety Measures ............................................................................. 92 
Appendix 2.10  Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting ............................................................................................................ 93 
Appendix 3  Genetics .............................................................................................................. 94 
Appendix 4  Diagnostic Criteria/Disease Classification ...................................................... 95 
Appendix 5  Abbreviations..................................................................................................... 96 
Appendix 6  Protocol History .............................................................................................. 100 
11. REFERENCES .................................................................................................................... 101 
 
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Tables 
Table 1. Schedule of Study Procedures and Assessments ............................................................ 22 
Table 2. Non-PK Laboratory Assessments in Screening and Treatment ...................................... 24 
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 ..................................................................... 25 
Table 4. Objectives and Endpoints ............................................................................................... 35 
 
Figures 
Figure 1. Study Schematic Diagram ............................................................................................. 21 
 
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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 27 sites in North America and Europe 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 activity 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 from baseline in 
response to daily PEX, with or without SHP655 supplementation, during the acute episode and up to 
30 days after the resolution of the acute aTTP episode 
2. 
Evaluate ADAMTS-13 activity levels in subjects up to 30 days after acute aTTP 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 
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2. 
Evaluate the occurrences of aTTP related complications, (including death, stroke, MI, and organ failure), 
aTTP relapses*, exacerbations** and end-organ function improvement 
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 
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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. 
Investigational product, dose, and mode of administration: 
• 
SHP655 40 IU/kg ±4 IU/kg once daily, i.v. or 40 IU/kg ±4 IU/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 ±4 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 ±4 IU/kg SHP655 twice daily 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 
 
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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. If the ADAMTS-13 levels 
(based on local labs) are <50% between discharge and first weekly follow-up visit then the investigator may treat 
the patient with the IP prior to the scheduled visit. Any additional assessments may be conducted as per the 
investigator’s judgement. 
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  
±4 IU/kg for Arms 2 and 3) once weekly if ADAMTS-13 activity at the local lab is <50%. 
Discretionary Rescue Therapy 
Study investigators may elect to administer rescue therapy to a subject if platelet count have not increased at least 
2-fold from screening and LDH remains above ULN after 4 days of treatment. Rescue therapy will be defined as 
any product with a known interruption to the PK/PD relationship between ADAMTS-13 activity, VWF activity, 
and platelet count. Additional administration of FFP, S/D treated plasma, and immunosuppressive therapies will 
not be considered rescue therapy unless otherwise agreed after consultation with the Sponsor. However, they may 
be prohibited medication after initiation of plasma exchange (refer to section 6.8.4). The rescue therapy treatment 
should follow local standard of care practices. If rescue therapy is initiated, the administration of IP (SHP655 or 
placebo) will be suspended for the duration of the study. The patient will continue to follow the same visit and 
assessment schedule to be monitored for safety. PK samples should continue to be collected to monitor safety and 
the subject should be followed for three months post remission. 
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. 
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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 at the central lab; if screening samples are not 
taken until after the first PEX, ADAMTS-13 activity from the local lab is permitted to determine 
eligibility. 
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 1 months prior to study enrollment.  
6. 
Subject is human immunodeficiency virus positive (HIV+) with unstable disease or CD4+ count 
≤200 cells/mm3 within 3 months screening. 
7. 
Subjects with conditions of severe immunodeficiency. 
8. 
Subject has had a previous aTTP event in the past 30 days. 
9. 
Subject has another underlying progressive fatal disease and/or life expectancy of less than 3 months.  
10. Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures. 
11. 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. 
12. If female, subject is pregnant or lactating. 
13. Subject is a family member or employee of the Sponsor or investigator. 
14. Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing information. 
15. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule 
ADAMTS-13, hamster protein, or other constituents of SHP655. 
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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 
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 subjects with ADAMTS-13 activity trough levels >10% 
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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 titers of binding and inhibitory antibodies to ADAMTS-13 relative to baseline 
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 
13. Occurrence of subjects receiving rescue therapy 
14. Occurrence of subjects meeting rescue criteria 
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Exploratory 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 PK/PD 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. 
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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. 
• 
An interim analysis will be performed after 18 subjects have achieved remission and when approximately 
50% of the planned sample size has been enrolled and treated in the three arms. The IA will include all 
data, collected by this time point, for all subjects enrolled in the study. IA results will be used to evaluate a 
preliminary treatment effect, assess initial PK/PD parameters, and inform the phase 3 clinical development 
planning. Access to results from the IA will be restricted to a small group of Takeda personnel designated 
as unblinded who thereafter will be removed from participation in oversight of daily conduct of this study. 
The interim analysis data and results may be used in regulatory interactions but will not be made public or 
used in scientific manuscripts. 
Details on the specific analyses to be performed during the IA will be provided in the Statistical Analysis Plan. 
 
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1.2 Schema 
Figure 1. Study Schematic Diagram  
 
 
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1.3 Schedule of Activities 
Table 1. Schedule of Study Procedures and Assessments 
Procedures/ 
Assessments 
Screening/ 
Enrollmenta 
Interval Study Visits 
Study Completion/ 
Termination 
Visitc 
(12 weeks ± 7 days 
following 
remission) 
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 
 
 
 
 
Serum pregnancy test 
(females) 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Demographic and 
Baseline Characteristics 
X 
 
 
 
 
Medications 
X 
X q 
X q 
X 
X 
Non-drug Therapies 
X 
X q 
X q 
X 
X 
Physical Examo 
(including weight) 
X 
 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Laboratoriesg 
X 
Xh 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
Evaluation of schistocytes 
X 
 
 
 
 
Randomizationk 
X 
 
 
 
 
IP 
 
Xe,q 
Xf,q 
 
 
Plasma exchange 
X 
X q 
 
 
 
Cognitive assessment 
tests 
X 
X 
X 
 
 
Modified ITP Bleeding 
Score 
X 
X 
 
 
 
ADAMTS-13 Antigen & 
Activity 
X 
Xh 
Xp 
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 
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Table 1. Schedule of Study Procedures and Assessments 
Procedures/ 
Assessments 
Screening/ 
Enrollmenta 
Interval Study Visits 
Study Completion/ 
Termination 
Visitc 
(12 weeks ± 7 days 
following 
remission) 
Treatment 
Period 
(Daily)b 
Weekly Follow 
Up Study Visitsl 
(Q1Week ±3 days 
x4 weeks) 
Biweekly Follow 
Up Study Visitsl 
(Q2Week ±3 days 
x2 visits) 
Anti-rADAMTS-13 
Inhibitory antibodies 
X 
 
 
 
X 
VWF antigen and 
multimers 
 
 
Xi 
 
 
Urine-albumin-creatinine 
ratio 
X 
X 
Xr 
 
 
Methylprednisolone 
(tapering permitted) 
 
X q 
Xb, q 
 
 
Rituximab 
 
Xb, q 
Xb, q 
 
 
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 double 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; follow-up visits may be conducted in the home setting 
by a healthcare professional if consistent with local procedures. 
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. 
p. ADAMTS-13 activity during the weekly follow up period will be measured locally (in addition to centrally) for 
determining the need for IP supplementation in the first 4 weekly follow up visits. 
q. Administration of rescue therapy will be at the discretion of the investigator and will not include IP. 
r. Urine-albumin-creatinine ratio to be measured during the weekly follow-up period if IP is administered. 
 
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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 b 
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 
Chemistry (except LDH) 
L 
L 
 
LDH 
L 
L 
L 
Schistocytes 
L 
 
 
Urine-albumin-creatinine ratio 
L 
L 
L 
L = local lab; C = Central (sponsor) lab; B= Bioanalytical specialty lab (sponsor) 
b Subjects receiving rescue therapy should not have samples taken within 1 h Pre-PEX, IP should not be 
administered, and samples should be taken only within 30 minutes post-PEX. 
 
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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 d 
Within 15 
min post 
end of IP 
infusion 
#2 d 
0.5-3 h 
post end 
of IP 
infusion 
#2 d 
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 6.2.3). 
b Do not collect if daily IP infusion #2 (dose 12h post-PEX) is discontinued (see section 6.2.6).  
c Collect these time-points in relation to the end of PEX if IP infusion #1 (dose immediately post-PEX) is 
discontinued (see section 6.2.6) or if the subject is receiving rescue therapy.  
d For subjects receiving rescue therapy, collect within 15 min post end of PEX and 0.5-3 h post end of PEX (no IP 
administered when on rescue therapy). 
 
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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 were recently approved by EMA and FDA. 
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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). 
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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 Caplacizumab 
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 3, controlled study, 145 patients underwent 
randomization (72 were assigned to receive caplacizumab, and 73 to receive placebo). In the 
caplacizumab group, 50% of patients had platelet normalization within 2.69 median days 
(95% confidence interval [CI], 1.89 to 2.83) compared to 2.88 median days in the placebo group 
(95% confidence interval 2.68 to 3.56, P = 0.01) and 75% of patients had platelet normalization 
in 2.95 days compared to 4.50 days in the placebo group (95% confidence interval). Three 
patients in the caplacizumab group had an exacerbation, as compared with 28 patients in the 
placebo group. Six patients in the caplacizumab group had a relapse in the first month after 
stopping the study drug, all of whom had ADAMTS-13 activity that remained below 10%, 
suggesting unresolved autoimmune activity. The median duration of exposure to caplacizumab 
was longer than the duration of exposure to placebo (35 days [range, 1 to 65] vs. 23 days 
[range, 2 to 66]). Bleeding-related adverse events (AEs), most of which were mild to moderate in 
severity, were more common with caplacizumab than with placebo (65% of patients vs. 48%). 
Bleeding events were severe in 3 patients in the caplacizumab group, and one patient had severe 
bleeding in the placebo group. Serious adverse events of bleeding were reported in 8 patients 
(11%) in the caplacizumab group and in 1 patient (1%) in the placebo group.  
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Normalization of the three organ-damage markers (lactate dehydrogenase, cardiac troponin I, 
and serum creatinine) occurred in 0 patients in the caplacizumab group versus 3 patients in the 
placebo group (P=0.06) (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, 8% on the caplacizumab and none on 
the placebo arms of the Phase 3 study had a recurrence during first month after discontinuing the 
therapy (Peyvandi et al., 2016).There have been no long-term safety studies to assess organ 
damage. 
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.  
 
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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. 
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. 
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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.  
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/PD 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.  
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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. 
 
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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 from 
baseline in response to daily PEX, with or without SHP655 supplementation, during the 
acute episode and up to 30 days after the resolution of the acute aTTP episode 
• 
Evaluate ADAMTS-13 activity levels in subjects up to 30 days after acute aTTP 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 
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3.1.3 Exploratory Objectives 
 
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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 titers of binding and inhibitory 
antibodies to ADAMTS-13 relative to baseline 
• 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)  
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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) 
• 
Occurrence of subjects receiving rescue therapy 
• 
Occurrence of subjects meeting rescue criteria 
• 
Occurrence of antibodies to SHP655 
• 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 
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Table 4. Objectives and Endpoints 
Objective 
Endpoint(s) 
Exploratory Objectives 
 
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Table 4. Objectives and Endpoints 
Objective 
Endpoint(s) 
 
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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 
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 ±4 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 ±4 IU/kg SHP655 twice daily 
immediately after PEX and 12±1 hours after completion of PEX. 
The first PEX and IP may be administered in three scenarios: 
• 
First PEX completed >4 hours prior to study enrollment: the first dose of IP should be 
administered immediately after the second PEX (first PEX completed on study) 
• 
First PEX completed ≤4 hours prior to study enrollment: the first dose of IP should be 
administered as soon as possible, but no more than 4 hours after the initial PEX 
 
First PEX delayed and randomization into study is complete: 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. 
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. 
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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. 
After resolution of the TTP episode, IP (placebo in Arm 1; SHP655 40 IU/kg ±4 IU/kg Arms 2 
and 3) will be administered once weekly (maximum of 4 weekly doses of 40 IU/kg ±4 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. 
Discretionary Rescue Therapy 
Study investigators may elect to administer rescue therapy to a subject if platelet count have not 
increased at least 2-fold from screening and LDH remains above ULN after 4 days of treatment. 
Rescue therapy will be defined as any product with a known interruption to the PK/PD 
relationship between ADAMTS-13 activity, VWF activity, and platelet count. Additional 
administration of FFP, S/D treated plasma, and immunosuppressive therapies will not be 
considered rescue therapy unless otherwise agreed after consultation with the Sponsor. However, 
they may be prohibited medication after initiation of plasma exchange (refer to section 6.8.4). 
The rescue therapy treatment should follow local standard of care practices. If rescue therapy is 
initiated, the administration of IP (SHP655 or placebo) will be suspended for the duration of the 
study. The patient will continue to follow the same visit and assessment schedule to be 
monitored for safety. PK samples should continue to be collected to monitor safety and the 
subject should be followed for three months post remission. 
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.  
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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 ±4 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. 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 ±4 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 1.5 years. 
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The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s). This includes the 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 27 sites across North America and Europe. 
 
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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 at the central lab; if screening 
samples are not taken until after the first PEX, ADAMTS-13 activity from the local lab is 
permitted to determine eligibility 
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) 
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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 1 month prior to 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. Subjects with conditions of severe immunodeficiency. 
8. Subject has had a previous aTTP event in the past 30 days 
9. Subject has another underlying progressive fatal disease and/or life expectancy of less than 
3 months. 
10. Subject is identified by the investigator as being unable or unwilling to cooperate with 
study procedures.  
11. 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. 
12. If female, subject is pregnant or lactating. 
13. Subject is a family member or employee of the Sponsor or investigator.  
14. Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing 
information 
15. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent 
molecule ADAMTS-13, hamster protein, or other constituents of SHP655. 
 
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 16 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 
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• 
Of childbearing potential with a negative serum β-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. 
Acceptable methods of contraception include the following: 
• 
Intrauterine devices plus condoms 
• 
Double-barrier methods (e.g., 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. 
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6. STUDY INTERVENTION 
6.1 Investigational Product 
6.1.1 Identity of Investigational Product 
SHP655 and placebo (0.9% saline) 
Dosage form:  
Lyophilized formulation  
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 Hypersensitivity to SHP655 
SHP655 should not be administered in patients with known hypersensitivity to any of the 
components of rADAMTS-13. As with any i.v. protein product, allergic-type hypersensitivity 
reactions are possible. Subjects must be closely monitored for any symptoms throughout the 
infusion period. Subjects should be informed of the early signs of hypersensitivity reactions 
including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and 
anaphylaxis. If these symptoms occur, the administration should be discontinued immediately. 
In case of shock, standard medical treatment for shock should be implemented. 
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6.2.2 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. 
6.2.3 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. 
6.2.4 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. 
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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. 
6.2.5 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. 
The interim analysis (IA) data and results will be provided in unblinding fashion to a pre-
specified sub-team of the current clinical team.  Newly appointed members of the clinical team, 
who are blinded to the treatment assignments and unaware of the interim data and results will 
support the remaining portion of the study.  The rest of the study team will remain blinded to the 
restricted data and the results of the interim statistical and PK analyses until the time after 
database lock and study unblinding.  All individuals involved in the conduct of the trial post IA 
are to remain unaware of unblinding information related to the interim analysis. The study will 
continue after the IA as double blinded for the duration of the trial. 
6.2.6 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. If the ADAMTS 13 levels (based on local labs) are <50% between 
discharge and first weekly follow-up visit then the investigator may treat the patient with the IP 
prior to the scheduled visit. Any additional assessments may be conducted as per the 
investigator’s judgement. 
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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 ±4 IU/kg) if a weekly ADAMTS-13 activity at the local lab is 
<50% (drawn >72 hours after last IP infusion). 
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 (e.g., 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.  
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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.  
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 (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the 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), e.g., 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. 
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The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the 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 (i.e., 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. 
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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 (e.g., 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. 
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). 
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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: recommended dose of 375mg/m2 iv once weekly x 4 weeks. The first dose will 
be administered within two days of enrollment. All doses are recommended to 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 30 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.  
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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 1 month prior to the study and during the study. During the 
study, Caplacizumab may be used as discretionary rescue therapy if part of the local standard of 
care and a subject’s platelet count has not increased 2x from screening and LDH remains above 
ULN after 4 days of treatment. In this instance, the administration of all study IP should be 
suspended for the duration of 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 except for subjects receiving rescue 
therapy. Platelet transfusion and factor concentrates are prohibited except for instances of life-
threatening hemorrhage. 
Investigators should always use their clinical judgement to determine the best course of 
treatment for a patient. If prohibited treatments are administered, the Medical Monitor should be 
immediately notified to make a decision on continued participation in the study. 
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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 
• 
Screen failure 
• 
Other (must be specified in CRF) 
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7.3 Withdrawal from the Study 
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (e.g., in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible. 
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. 
 
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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 randomized. 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). 
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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 except for subjects receiving rescue therapy. 
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 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). 
All follow-up visits except the completion/termination visit may be conducted by a healthcare 
provider in the home setting if consistent with local procedures and all study requirements are 
met. 
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. 
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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. 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 1 month ± 7 days following the last interval study visit. 
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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 (e.g., 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) 
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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 
6. Decrease in platelet count 
7. Increase of serum creatinine 
8. An increase in schistocytes in peripheral blood smear 
9. Fever (≥100.4°F/38°C) 
10. Abdominal pain 
 
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 and second post-PEX IP infusion each day thereafter. 
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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. 
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 is performed locally and 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 is performed locally and consists of ALT, AST, total bilirubin, 
alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.  
The measurement of urine-albumin-creatinine ratio should be completed daily in the local lab 
during the acute treatment period and the weekly follow-up period if IP is administered to 
monitor for early signs of vasculitis. 
A complete list of the clinical laboratory tests to be performed is provided in Table 1 and 
Table 2. 
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8.2.3.5 Pregnancy Test 
A beta human chorionic gonadotropin (β hCG) pregnancy test will be performed locally 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. 
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). 
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 
PK sampling should continue as scheduled for subjects receiving rescue therapy. 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.  
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8.2.4.4 
 
 
 
 
 
 
 
 
 
 
8.2.4.5 
 
 
 
 
 
 
 
8.2.4.6 
 
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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. 
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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, 
PK/PD 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 
An interim analysis will be performed after 18 subjects have achieved remission and when 
approximately 50% of the planned sample size has been enrolled and treated in the three arms. 
The IA will include all data, collected by this time point, for all subjects enrolled in the study. IA 
results will be used to evaluate a preliminary treatment effect, assess initial PK/PD parameters, 
and inform the phase 3 clinical development planning. Access to results from the IA will be 
restricted to a small group of Takeda personnel designated as unblinded who thereafter will be 
removed from participation in oversight of daily conduct of this study. The interim analysis data 
and results may be used in regulatory interactions but will not be made public or used in 
scientific manuscripts. Details on the specific analyses to be performed during the Interim 
Analysis will be provided in the Statistical Analysis Plan. 
An external DMC will be established to review the overall safety of the study subjects on an 
ongoing basis. 
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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). The DMC will be consulted if the 
study is discontinued.  
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. 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. 
9.4 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 (PPS) 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.  Samples 
from subjects receiving rescue medicine will be excluded from the primary and secondary 
endpoint analysis after the rescue medicine is initiated.   
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• 
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. 
Samples from subjects receiving rescue medicine will be excluded from the primary and 
secondary endpoint analysis after the rescue medicine is initiated. 
 
9.5 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 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. 
9.5.1 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 9.8. 
9.5.2 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.  
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8. Occurrence of subjects receiving rescue therapy 
9. Occurrence of subjects meeting rescue criteria 
 
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.  
Data handling and imputation approaches for subjects receiving rescue therapy will be described 
in the SAP. 
An interim analysis will be performed after 18 subjects have achieved remission and when 
approximately 50% of the planned sample size has been enrolled and treated in the three arms. 
The IA will include all data, collected by this time point, for all subjects enrolled in the study. IA 
results will be used to evaluate a preliminary treatment effect, assess initial PK/PD parameters, 
and inform the phase 3 clinical development planning. Access to results from the IA will be 
restricted to a small group of Takeda personnel designated as unblinded who thereafter will be 
removed from participation in oversight of daily conduct of this study. 
The interim statistical analysis will be performed by an unblinded CRO team which is separate 
from the CRO team that is involved in the conduct of the study. An interim population PK/PD 
analysis will be performed by an independent unblinded team at another CRO with no 
involvement in the conduct of the study. 
9.5.3 Multiplicity Adjustment 
Not applicable. 
9.5.4 Control of Type I Error 
Not applicable. 
9.5.5 Exploratory Endpoints 
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9.6 Safety Analyses 
9.6.1 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 titers of binding and inhibitory antibodies to ADAMTS-13 relative to 
baseline 
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 
 
9.6.2 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. 
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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. 
9.7 
 
9.7.1 
 
9.7.2 
 
  
 
 
9.7.3 
 
 
  
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9.7.4 
 
9.8 Pharmacokinetic Analyses 
9.8.1 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 
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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% 
 
9.8.2 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. 
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10. 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 (e.g., 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. 
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Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information. 
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements. 
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
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. 
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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.  
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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 except Richmond Agitation Sedation 
Scale (RASS) 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 (e.g., 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 (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
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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. 
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. 
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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 (i.e., 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 (i.e., 
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 
national provisions) prior to study start that another party (i.e., 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. 
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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 and applicable 
regulatory authority 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. 
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 
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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. 
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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 
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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 
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Is an important medical event. Note: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include: 
Bronchospasm associated with anaphylaxis requiring intensive treatment in an emergency room 
or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or the 
development of drug dependency or drug abuse. 
Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A 
virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V) 
Unexpected Adverse Event 
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation.  
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated form the pharmacological properties of a product. 
Suspected Unexpected Serious Adverse Reaction  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (i.e., including active comparators) that is both serious and 
unexpected.  
The event(s) must meet all of the following: 
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected 
• 
Assessed as related to study treatment 
 
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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 to 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 or vital sign measure can represent an 
AE if the change is clinically relevant or if, during administration of investigational product, a 
shift of a parameter is observed from a value in the normative range to a value that is outside the 
normal range and considered clinically significant, or a further waning of an already clinically 
significant value. When evaluating such changes, the extent of deviation from the reference 
range, the duration until return to the reference range, either while continuing administration or 
after the end of administration with the investigational product, and the range of variation of the 
respective parameter within its reference range, should also be considered. 
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel) or vital sign values which were not present at the pretreatment 
evaluation observed closest to the start of study treatment, further investigations should be 
performed until the values return to within the reference range or until a plausible explanation 
(e.g., concomitant disease or expected disease evolution) is found for the abnormal values. 
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value or vital sign is clinically significant and 
represents an AE. 
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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. 
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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 (i.e., 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 
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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 
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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 (e.g., 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 (e.g., 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. 
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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 β-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. 
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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 (e.g., 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 
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The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations. 
Appendix 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). 
 
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Appendix 3  Genetics  
Shire intends to apply genetic research across the SHP655 development program to differentiate 
participants with congenital (genetic) versus acquired TTP to determine eligibility to participate 
in this study.  
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.  
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.  
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.  
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 4 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.  
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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  
 
 
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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 
β-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 
EMA 
European Medicines Agency 
 
 
EU 
European Union 
EUDRACT 
European Union clinical trials database 
F 
degree Fahrenheit 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration  
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Abbreviation 
Definition 
FFP 
Fresh frozen plasma 
FVIII 
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 
 
 
MCHC 
mean corpuscular hemoglobin concentration 
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Abbreviation 
Definition 
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) 
PPS 
per-protocol set 
  
 
 
 
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  
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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 
 
 
 
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Appendix 6  Protocol History  
Document 
Date 
Global/Country/Site Specific 
Protocol Amendment 3.0 
08 JUN 2020 
Non – UK, CH, FR 
Protocol Amendment 2.3  
07 NOV 2019 
France 
Protocol Amendment 2.2  
07 NOV 2019 
UK 
Protocol Amendment 2.1 
23 SEP 2019 
Non-UK 
Protocol Amendment 1.3 
18 JUN 2019 
France 
Protocol Amendment 1.2 
01 APR 2019 
Non-UK 
Protocol Amendment 1.1  
18 MAR 2019 
UK 
Original Protocol 
03 OCT 2018 
Global 
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11. REFERENCES 
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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. 
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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. 
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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. 
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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. & The British Committee for Standards in Haematology 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. 
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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

Prot_002.pdf: 
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: 
Protocol Amendment 2.1 (non-UK) : 23-SEP-2019
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:
018577
EUDRACT NUMBER:
2018-003775-35
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:
Protocol Amendment 2.1 (non-UK): 23 SEP 2019
Replaces: 
Protocol Amendment 1.2 (non-UK): 01 APR 2019
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


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Page 2
SHP655-201 Protocol Amendment 2.1
rADAMTS-13
23 SEP 2019
PROTOCOL SIGNATURE PAGE
Sponsor’s (Shire) Approval
Signature:
Date:
, MD
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CONFIDENTIAL
Page 3
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rADAMTS-13
23 SEP 2019
Investigator’s Acknowledgement
I have read this protocol for Study SHP 655-201.
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
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:
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CONFIDENTIAL
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SHP655-201 Protocol Amendment 2.1
rADAMTS-13
23 SEP 2019
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
Protocol Amendment 2.1 Non-UK
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
2.1
Amendment Date
23 SEP 2019
Country Specific
Non-UK
Protocol Amendment Summary and Rationale:
Added rescue therapy for subjects not adequately responding to treatment after 4 days.  
Description of Each Change and Rationale
Section(s) Affected by Change
Updated Emergency Contact 
Information
The protocol was updated to reflect current 
contact information for medical monitors
Emergency Contact Information
Updated number of sites
The protocol was updated to reflect 27 sites 
planned to participate in the study
Synopsis,
Section 4.5
Added exploratory objective
Synopsis, 
Section 3.1.3, 
Section 3.2,
Section 9.5.5
Added study endpoints
Added the following study endpoints

Incidence of subjects receiving rescue 
therapy

Incidence of subjects meeting rescue 
criteria
Synopsis, 
Section 3.2, 
Section 9.5.2
Added discretionary rescue 
therapy
Added rescue therapy treatment option if 
platelet count has not increased at least 
2-fold from screening and LDH remains 
above ULN after 4 days of treatment
Synopsis, 
Section 1.3, 
Section 4.1, 
Section 6.8.4, 
Section 8.1.2, 
Section 8.2.4, 
Section 9.4, 
Section 9.5
Added details on Caplacizumab 
study results and regulatory 
approval
Caplacizumab has been approved for 
treatment in aTTP
Section 2.1, 
References
Removed information about 
genetics testing
Limited the genetics testing section to the 
determination of eligibility to participate in 
the study
Appendix 3
Minor typos repaired, 
formatting repaired.
Clarity.
Throughout
See Appendix 6 for protocol history, including all amendments.
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Page 5
SHP655-201 Protocol Amendment 2.1
rADAMTS-13
23 SEP 2019
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
Direct Line: 
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
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rADAMTS-13
23 SEP 2019
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 (e.g., inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (e.g., wrong product such that the label and contents are different products); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or design 
function, e.g., reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (e.g., potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product causing it to 
malfunction or to present a hazard or fail to meet label claims
For instructions on reporting AEs related to product complaints, see Appendix 1.
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
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rADAMTS-13
23 SEP 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................. 2
Sponsor’s (Shire) Approval...................................................................................................... 2
Investigator’s Acknowledgement ............................................................................................ 3
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.......................... 4
EMERGENCY CONTACT INFORMATION .......................................................................... 5
PRODUCT QUALITY COMPLAINTS..................................................................................... 6
TABLE OF CONTENTS ............................................................................................................. 7
1. PROTOCOL SUMMARY ..................................................................................................... 12
1.1 Synopsis.............................................................................................................................. 12
1.2 Schema ............................................................................................................................... 20
1.3 Schedule of Activities........................................................................................................ 21
2. INTRODUCTION................................................................................................................... 25
2.1 Indication and Current Treatment Options................................................................... 25
2.1.1 Current Standard of Care (SoC).............................................................................. 25
2.1.1.1 Plasma Exchange (PEX)..................................................................................... 26
2.1.1.2 Corticosteroids.................................................................................................... 26
2.1.1.3 Rituximab............................................................................................................ 27
2.1.1.4 Caplacizumab...................................................................................................... 27
2.1.2 Unmet Medical Needs of Current Therapy............................................................. 28
2.2 Product Background and Clinical Information............................................................. 29
2.3 Study Rationale................................................................................................................. 30
2.4 Benefit/Risk Assessment................................................................................................... 30
2.5 Compliance Statement...................................................................................................... 31
3. OBJECTIVES AND ENDPOINTS ....................................................................................... 32
3.1 Study Objectives ............................................................................................................... 32
3.1.1 Co-Primary Objectives.............................................................................................. 32
3.1.2 Secondary Objectives ................................................................................................ 32
3.1.3 Exploratory Objectives ............................................................................................. 33
3.2 Study Endpoints................................................................................................................ 34
4. STUDY DESIGN..................................................................................................................... 38
4.1 Overall Design................................................................................................................... 38
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4.2 Scientific Rationale for Study Design.............................................................................. 39
4.2.1 Rationale for control group ...................................................................................... 39
4.2.2 Rationale for Primary and Key Secondary Endpoints .......................................... 39
4.2.3 Justification for the use of placebo........................................................................... 39
4.3 Justification for Dose........................................................................................................ 40
4.4 Duration of Subject Participation and Study Completion Definition.......................... 40
4.5 Sites and Regions .............................................................................................................. 40
5. STUDY POPULATION ......................................................................................................... 41
5.1 Inclusion Criteria.............................................................................................................. 41
5.2 Exclusion Criteria............................................................................................................. 41
5.2.1 Contraception............................................................................................................. 42
6. STUDY INTERVENTION..................................................................................................... 44
6.1 Investigational Product .................................................................................................... 44
6.1.1 Identity of Investigational Product .......................................................................... 44
6.1.2 Blinding the Treatment Assignment ........................................................................ 44
6.2 Administration of Investigational Product..................................................................... 44
6.2.1 Hypersensitivity to SHP655 ...................................................................................... 44
6.2.2 Interactive Response Technology for Investigational Product Management ...... 45
6.2.3 Allocation of Subjects to Treatment ........................................................................ 45
6.2.4 Dosing.......................................................................................................................... 45
6.2.5 Unblinding the Treatment Assignment during the Placebo-Controlled Portion of 
the Study..................................................................................................................... 46
6.2.6 Dose Modification ...................................................................................................... 46
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product.................... 47
6.3.1 Labeling ...................................................................................................................... 47
6.3.2 Packaging.................................................................................................................... 47
6.3.3 Storage ........................................................................................................................ 47
6.3.4 Special Handling........................................................................................................ 48
6.4 Drug Accountability ......................................................................................................... 48
6.5 Subject Compliance.......................................................................................................... 50
6.6 Plasma Exchange (PEX)................................................................................................... 50
6.7 Immunosuppression.......................................................................................................... 51
6.8 Prior and Concomitant Therapy..................................................................................... 51
6.8.1 Prior Treatment......................................................................................................... 51
6.8.2 Concomitant Treatment............................................................................................ 51
6.8.3 Permitted Treatment................................................................................................. 52
6.8.4 Prohibited Treatment................................................................................................ 52
7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL............................................................................. 53
7.1 Discontinuation of Study Treatment............................................................................... 53
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7.2 Reasons for Discontinuation ............................................................................................ 53
7.3 Withdrawal from the Study............................................................................................. 54
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit.................................. 54
8. STUDY ASSESSMENTS AND PROCEDURES................................................................. 55
8.1 Study Schedule.................................................................................................................. 55
8.1.1 Screening Period ........................................................................................................ 55
8.1.1.1 Screening/Baseline Visit..................................................................................... 55
8.1.2 Treatment Period....................................................................................................... 55
8.1.2.1 Final Visit ............................................................................................................ 56
8.1.3 Follow-up Period........................................................................................................ 56
8.1.4 Additional Care of Subjects after the Study ........................................................... 56
8.2 Study Assessments ............................................................................................................ 56
8.2.1 Demographic and Other Baseline Characteristics ................................................. 56
8.2.1.1 Height and Weight.............................................................................................. 56
8.2.1.2 Medical, Medication History, and Non-drug Therapies................................. 57
8.2.2 Efficacy ....................................................................................................................... 57
8.2.3 Safety........................................................................................................................... 57
8.2.3.1 Physical Examination......................................................................................... 58
8.2.3.2 Adverse Events.................................................................................................... 58
8.2.3.3 Vital Signs............................................................................................................ 59
8.2.3.4 Clinical Laboratory Tests .................................................................................. 60
8.2.3.5 Pregnancy Test.................................................................................................... 60
8.2.4 Other ........................................................................................................................... 61
8.2.4.1 Clinical Pharmacokinetics ................................................................................. 61
8.2.4.2 Pharmacodynamics............................................................................................. 61
8.2.4.3 Genetics................................................................................................................ 61
8.2.4.4
................................................................ 61
8.2.4.5
....................................................................... 61
8.2.4.6 
...................................................................................................... 62
8.2.4.7
....................................................................................................... 64
8.2.5 Volume of Blood to Be Drawn from Each Subject ................................................. 64
8.2.6 Retention of Study Samples ...................................................................................... 64
9. STATISTICAL CONSIDERATIONS .................................................................................. 65
9.1 Statistical Analysis Process .............................................................................................. 65
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......... 65
9.3 Sample Size and Power Considerations.......................................................................... 66
9.4 Statistical Analysis Set(s).................................................................................................. 66
9.5 Efficacy Analyses .............................................................................................................. 67
9.5.1 Primary Efficacy Endpoint....................................................................................... 67
9.5.2 Secondary Efficacy Endpoints.................................................................................. 67
9.5.3 Multiplicity Adjustment............................................................................................ 68
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9.5.4 Control of Type I Error ............................................................................................ 68
9.5.5 Exploratory Endpoints.............................................................................................. 68
9.6 Safety Analyses.................................................................................................................. 69
9.6.1 Secondary Safety Endpoints..................................................................................... 69
9.6.2 Safety Endpoint Analyses.......................................................................................... 69
9.7
.................................................. 69
9.7.1
......................................... 69
9.7.2
........................... 70
9.7.3 
.............................................................. 70
9.7.4 
.................................... 70
9.8 Pharmacokinetic Analyses ............................................................................................... 71
9.8.1 Secondary PK/PD Endpoints.................................................................................... 71
9.8.2 PK/PD Analyses ......................................................................................................... 71
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .. 72
Appendix 1  REGULATORY, ETHICAL, AND STUDY OVERSIGHT Considerations
............................................................................................................................................ 72
Appendix 1.1  Regulatory and Ethical Considerations ................................................... 72
Appendix 1.2  Sponsor’s Responsibilities ......................................................................... 72
Appendix 1.3  Investigator’s Responsibilities .................................................................. 73
Appendix 1.4  Data Management Considerations ........................................................... 76
Appendix 1.5  Ethical Considerations............................................................................... 77
Appendix 2  Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting................................................................................................ 81
Appendix 2.1  Adverse Event Definitions......................................................................... 81
Appendix 2.2  Collection of Adverse Events .................................................................... 84
Appendix 2.3  Assessment of Adverse Events .................................................................. 84
Appendix 2.4  Serious Adverse Event Collection Time Frame ...................................... 87
Appendix 2.5  Serious Adverse Event Onset and Resolution Dates............................... 87
Appendix 2.6  Fatal Outcome ............................................................................................ 87
Appendix 2.7  Pregnancy ................................................................................................... 88
Appendix 2.8  Abuse, Misuse, Overdose and Medication Error.................................... 88
Appendix 2.9  Urgent Safety Measures............................................................................. 89
Appendix 2.10  Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting ............................................................................................................ 90
Appendix 3  Genetics .............................................................................................................. 91
Appendix 4  Diagnostic Criteria/Disease Classification...................................................... 92
Appendix 5  Abbreviations..................................................................................................... 93
Appendix 6  Protocol History ................................................................................................ 97
11. REFERENCES...................................................................................................................... 98
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Tables
Table 1. Schedule of Study Procedures and Assessments............................................................ 21
Table 2. Non-PK Laboratory Assessments in Screening and Treatment...................................... 23
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 ..................................................................... 24
Table 4. Objectives and Endpoints ............................................................................................... 34
Table A1 Adverse Event Relationship Categorization ................................................................. 85
Figures
Figure 1. Study Schematic Diagram ............................................................................................. 20
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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 27 sites in North America and Europe 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
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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.
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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.
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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%.
Discretionary Rescue Therapy
Study investigators may elect to administer rescue therapy to a subject if platelet count have not increased at least 
2-fold from screening and LDH remains above ULN after 4 days of treatment. Rescue therapy will be defined as 
any product with a known interruption to the PK/PD relationship between ADAMTS-13 activity, VWF activity, 
and platelet count. Additional administration of FFP, S/D treated plasma, and immunosuppressive therapies will 
not be considered rescue therapy unless otherwise agreed after consultation with the Sponsor. However, they may 
be prohibited medication after initiation of plasma exchange (refer to section 6.8.4). The rescue therapy treatment 
should follow local standard of care practices. If rescue therapy is initiated, the administration of IP (SHP655 or 
placebo) will be suspended for the duration of the study. The patient will continue to follow the same visit and 
assessment schedule to be monitored for safety. PK samples should continue to be collected to monitor safety and 
the subject should be followed for three months post remission.
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 at the central lab.
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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 prior to 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.
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.
14.
Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule
ADAMTS-13, hamster protein, or other constituents of SHP655.
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.
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
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
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
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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
13.
Incidence of subjects receiving rescue therapy
14.
Incidence of subjects meeting rescue criteria
Exploratory Endpoints
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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 PK/PD 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 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.
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1.2 Schema
Figure 1. Study Schematic Diagram 
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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
Serum pregnancy test 
(females)
X
Medical History
X
Demographic and 
Baseline Characteristics
X
Medications
X
X q
X q
X
X
Non-drug Therapies
X
X q
X q
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,q
Xf,q
Plasma exchange
X
X q
Cognitive assessment 
tests
X
X
X
Modified ITP Bleeding 
Score
X
X
ADAMTS-13 Antigen & 
Activity
X
Xh
Xp
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
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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)
Anti-rADAMTS-13 
Inhibitory antibodies
X
X
VWF antigen and 
multimers
Xi
Methylprednisolone 
(tapering permitted)
X q
Xb, q
Rituximab
Xb, q
Xb, q
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 double 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.
p. ADAMTS-13 activity during the weekly follow up period will be measured locally (in addition to centrally) for 
determining the need for IP supplementation in the first 4 weekly follow up visits.
q. Administration of rescue therapy will be at the discretion of the investigator and will not include IP.
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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 b
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
Chemistry (except LDH)
L
L
LDH
L
L
L
L = local lab; C = Central (sponsor) lab; B= Bioanalytical specialty lab (sponsor)
b Subjects receiving rescue therapy should not have samples taken within 1 h Pre-PEX, IP should not be 
administered, and samples should be taken only within 30 minutes post-PEX.
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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 d
Within 15 
min post 
end of IP 
infusion 
#2 d
0.5-3 h 
post end 
of IP 
infusion 
#2 d
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 6.2.3).
b Do not collect if daily IP infusion #2 (dose 12h post-PEX) is discontinued (see section 6.2.6). 
c Collect these time-points in relation to the end of PEX if IP infusion #1 (dose immediately post-PEX) is 
discontinued (see section 6.2.6) or if the subject is receiving rescue therapy.
d For subjects receiving rescue therapy, collect within 15 min post end of PEX and 0.5-3 h post end of PEX (no IP 
administered when on rescue therapy).
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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 were recently approved by EMA and FDA.
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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).
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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 Caplacizumab
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 3, controlled study, 145 patients underwent 
randomization (72 were assigned to receive caplacizumab, and 73 to receive placebo). In the 
caplacizumab group, 50% of patients had platelet normalization within 2.69 median days 
(95% confidence interval [CI], 1.89 to 2.83) compared to 2.88 median days in the placebo group
(95% confidence interval 2.68 to 3.56, P = 0.01) and 75% of patients had platelet normalization 
in 2.95 days compared to 4.50 days in the placebo group (95% confidence interval). Three
patients in the caplacizumab group had an exacerbation, as compared with 28 patients in the 
placebo group. Six patients in the caplacizumab group had a relapse in the first month after 
stopping the study drug, all of whom had ADAMTS-13 activity that remained below 10%, 
suggesting unresolved autoimmune activity. The median duration of exposure to caplacizumab 
was longer than the duration of exposure to placebo (35 days [range, 1 to 65] vs. 23 days 
[range, 2 to 66]). Bleeding-related adverse events (AEs), most of which were mild to moderate in 
severity, were more common with caplacizumab than with placebo (65% of patients vs. 48%). 
Bleeding events were severe in 3 patients in the caplacizumab group, and one patient had severe 
bleeding in the placebo group. Serious adverse events of bleeding were reported in 8 patients 
(11%) in the caplacizumab group and in 1 patient (1%) in the placebo group. 
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Normalization of the three organ-damage markers (lactate dehydrogenase, cardiac troponin I, 
and serum creatinine) occurred in 0 patients in the caplacizumab group versus 3 patients in the 
placebo group (P=0.06) (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, 8% on the caplacizumab and none on 
the placebo arms of the Phase 3 study had a recurrence during first month after discontinuing the 
therapy (Peyvandi et al., 2016).There have been no long-term safety studies to assess organ 
damage.
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. 
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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.
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.
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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.
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. 
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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.
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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
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3.1.3 Exploratory Objectives
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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) 
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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)
•
Incidence of subjects receiving rescue therapy
•
Incidence of subjects meeting rescue criteria
•
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
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Exploratory Objectives
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
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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.
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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.
Discretionary Rescue Therapy
Study investigators may elect to administer rescue therapy to a subject if platelet count have not 
increased at least 2-fold from screening and LDH remains above ULN after 4 days of treatment. 
Rescue therapy will be defined as any product with a known interruption to the PK/PD 
relationship between ADAMTS-13 activity, VWF activity, and platelet count. Additional 
administration of FFP, S/D treated plasma, and immunosuppressive therapies will not be 
considered rescue therapy unless otherwise agreed after consultation with the Sponsor. However, 
they may be prohibited medication after initiation of plasma exchange (refer to section 6.8.4). 
The rescue therapy treatment should follow local standard of care practices. If rescue therapy is 
initiated, the administration of IP (SHP655 or placebo) will be suspended for the duration of the 
study. The patient will continue to follow the same visit and assessment schedule to be 
monitored for safety. PK samples should continue to be collected to monitor safety and the 
subject should be followed for three months post remission.
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.
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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. 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 1.5 years.
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 27 sites across North America and Europe.
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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 at the central lab
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)
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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 prior to 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
14. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent 
molecule ADAMTS-13, hamster protein, or other constituents of SHP655.
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 16 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
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
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.
Acceptable methods of contraception include the following:

Intrauterine devices plus condoms

Double-barrier methods (e.g., 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.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
SHP655 and placebo (0.9% saline)
Dosage form:
Lyophilized formulation 
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 Hypersensitivity to SHP655
SHP655 should not be administered in patients with known hypersensitivity to any of the 
components of rADAMTS-13. As with any i.v. protein product, allergic-type hypersensitivity 
reactions are possible. Subjects must be closely monitored for any symptoms throughout the 
infusion period. Subjects should be informed of the early signs of hypersensitivity reactions 
including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and 
anaphylaxis. If these symptoms occur, the administration should be discontinued immediately. 
In case of shock, standard medical treatment for shock should be implemented.
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6.2.2 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.
6.2.3 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.
6.2.4 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. 
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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.
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.
6.2.5 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.
6.2.6 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).
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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 (e.g., 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. 
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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 (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the 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), e.g., 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.
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The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the 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 (i.e., 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.
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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 (e.g., 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.
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).
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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: recommended dose of 375mg/m2 iv once weekly x 4 weeks. The first dose will 
be administered within two days of enrollment. All doses are recommended to 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.
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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.
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. During the 
study, Caplacizumab may be used as discretionary rescue therapy if part of the local standard of 
care and a subject’s platelet count has not increased 2x from screening and LDH remains above 
ULN after 4 days of treatment. In this instance, the administration of all study IP should be
suspended for the duration of 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 except for subjects receiving rescue 
therapy. Platelet transfusion and factor concentrates are prohibited except for instances of life-
threatening hemorrhage.
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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

Screen failure

Other (must be specified in CRF)
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7.3 Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (e.g., in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
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.
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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 randomized. 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).
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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 except for subjects receiving rescue therapy.
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.
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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. 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 1 month ± 7 days following the last interval study visit.
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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 (e.g., 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)
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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 and second 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. 
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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 is performed locally and 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 is performed locally and 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 locally 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).
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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
PK sampling should continue as scheduled for subjects receiving rescue therapy. 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
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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.
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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). The DMC will be consulted if the 
study is discontinued.
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. 
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Analyses of the data for DMC review will be conducted according to the DMC charter and DMC 
SAP. 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.
9.4 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.  Samples 
from subjects receiving rescue medicine will be excluded from the primary and secondary 
endpoint analysis after the rescue medicine is initiated.  

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.
Samples from subjects receiving rescue medicine will be excluded from the primary and 
secondary endpoint analysis after the rescue medicine is initiated.
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9.5 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 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.
9.5.1 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 9.8.
9.5.2 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.
8.
Incidence of subjects receiving rescue therapy
9.
Incidence of subjects meeting rescue criteria
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.
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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.
Data handling and imputation approaches for subjects receiving rescue therapy will be described 
in the SAP.
9.5.3 Multiplicity Adjustment
Not applicable.
9.5.4 Control of Type I Error
Not applicable.
9.5.5 Exploratory Endpoints
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9.6 Safety Analyses
9.6.1 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
9.6.2 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.
9.7
9.7.1
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9.7.2
 
 
9.7.3
 
 
9.7.4
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9.8 Pharmacokinetic Analyses
9.8.1 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%
9.8.2 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.
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10. 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 (e.g., 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.
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Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements.
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
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.
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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. 
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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 except Richmond Agitation Sedation 
Scale (RASS) 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 (e.g., 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 (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
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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.
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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 (i.e., 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 (i.e., 
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 
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national provisions) prior to study start that another party (i.e., 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 and applicable 
regulatory authority 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.
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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.
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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 
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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
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Is an important medical event. Note: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include:
Bronchospasm associated with anaphylaxis requiring intensive treatment in an emergency room 
or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or the 
development of drug dependency or drug abuse.
Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A 
virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V)
Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated form the pharmacological properties of a product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (i.e., including active comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
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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 to 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 (e.g., 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.
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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.
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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 (i.e., 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
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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
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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 (e.g., 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 (e.g., 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.
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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.
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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 (e.g., 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
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The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
Appendix 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).
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Appendix 3  Genetics
Shire intends to apply genetic research across the SHP655 development program to differentiate 
participants with congenital (genetic) versus acquired TTP to determine eligibility to participate 
in this study. 
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. 
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. 
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. 
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 4 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. 
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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 
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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
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Abbreviation
Definition
FDA
Food and Drug Administration 
FFP
Fresh frozen plasma
FVIII
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
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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 
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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
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Appendix 6  Protocol History 
Document
Date
Global/Country/Site Specific
Protocol Amendment 2.1
23 SEP 2019
Non-UK
Protocol Amendment 1.3
18 JUN 2019
France
Protocol Amendment 1.2
01 APR 2019
Non-UK
Protocol Amendment 1.1 UK
18 MAR 2019
UK
Original Protocol
03 OCT 2018
Global
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For non-commercial use only

Prot_004.pdf: 
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: 
Protocol Amendment 4.0 : 17-SEP-2020
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:
018577
EUDRACT NUMBER:
2018-003775-35
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:
Protocol Amendment 4.0: 17 Sep 2020
Replaces: 
Protocol Amendment 3.0: 08 JUN 2020
                      Protocol Amendment 3.2 (Italy): 16 JUL 2020
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


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Shire
CONFIDENTIAL
Page 3
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
Protocol Amendment 4.0 
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
4.0
Amendment Date
17 Sep 2020
Country Specific
Protocol Amendment Summary and Rationale:
Implemented open label supplementation with rADAMTS13 in remission and increased frequency of follow-up
Description of Each Change and Rationale
Section(s) Affected by Change
Implemented open label supplementation 
with rADAMTS13 in remission and 
increased frequency of follow-up
Decrease natural occurrence of 
exacerbations
Section 1.1, 1.2, 1.3, 4.1
See Appendix 6 for protocol history, including all amendments.
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Shire
CONFIDENTIAL
Page 4
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
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 
Direct Line:
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 Amendment 4.0
rADAMTS-13
17 Sep 2020
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
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Shire
CONFIDENTIAL
Page 6
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE........................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.....................3
EMERGENCY CONTACT INFORMATION .....................................................................4
PRODUCT QUALITY COMPLAINTS................................................................................5
TABLE OF CONTENTS ........................................................................................................6
LIST OF IN-TEXT TABLES ...............................................................................................10
LIST OF IN-TEXT FIGURES .............................................................................................10
LIST OF APPENDICES .......................................................................................................10
1. PROTOCOL SUMMARY ................................................................................................11
1.1 Synopsis........................................................................................................................11
1.2 Schema .........................................................................................................................20
1.3 Schedule of Activities..................................................................................................21
2. INTRODUCTION..............................................................................................................25
2.1 Indication and Current Treatment Options.............................................................26
2.1.1 Current Standard of Care (SoC).........................................................................26
2.1.1.1 Plasma Exchange (PEX)................................................................................26
2.1.1.2 Corticosteroids ...............................................................................................27
2.1.1.3 Rituximab .......................................................................................................27
2.1.1.4 Caplacizumab.................................................................................................28
2.1.2 Unmet Medical Needs of Current Therapy........................................................29
2.2 Product Background and Clinical Information.......................................................30
2.3 Study Rationale ...........................................................................................................30
2.4 Benefit/Risk Assessment.............................................................................................31
2.5 Compliance Statement................................................................................................31
3. OBJECTIVES AND ENDPOINTS ..................................................................................32
3.1 Study Objectives..........................................................................................................32
3.1.1 Co-Primary Objectives ........................................................................................32
3.1.2 Secondary Objectives ...........................................................................................32
3.1.3 Exploratory Objectives ........................................................................................33
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CONFIDENTIAL
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SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
3.2 Study Endpoints ..........................................................................................................35
4. STUDY DESIGN................................................................................................................38
4.1 Overall Design .............................................................................................................38
4.2 Scientific Rationale for Study Design........................................................................40
4.2.1 Rationale for control group .................................................................................40
4.2.2 Rationale for Primary and Key Secondary Endpoints .....................................40
4.2.3 Justification for the use of placebo......................................................................40
4.3 Justification for Dose ..................................................................................................40
4.4 Duration of Subject Participation and Study Completion Definition....................41
4.5 Sites and Regions.........................................................................................................41
5. STUDY POPULATION ....................................................................................................42
5.1 Inclusion Criteria ........................................................................................................42
5.2 Exclusion Criteria .......................................................................................................42
5.2.1 Contraception .......................................................................................................43
6. STUDY INTERVENTION................................................................................................44
6.1 Investigational Product...............................................................................................44
6.1.1 Identity of Investigational Product .....................................................................44
6.1.2 Blinding the Treatment Assignment...................................................................45
6.2 Administration of Investigational Product...............................................................45
6.2.1 Hypersensitivity to SHP655.................................................................................45
6.2.2 Interactive Response Technology for Investigational Product Management.45
6.2.3 Allocation of Subjects to Treatment ...................................................................46
6.2.4 Dosing ....................................................................................................................46
6.2.5 Unblinding the Treatment Assignment during the Placebo-Controlled 
Portion of the Study.............................................................................................47
6.2.6 Dose Modification.................................................................................................47
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product..............48
6.3.1 Labeling.................................................................................................................48
6.3.2 Packaging ..............................................................................................................48
6.3.3 Storage...................................................................................................................48
6.3.4 Special Handling...................................................................................................49
6.4 Drug Accountability....................................................................................................50
6.5 Subject Compliance ....................................................................................................51
6.6 Plasma Exchange (PEX).............................................................................................51
6.7 Immunosuppression....................................................................................................52
6.8 Prior and Concomitant Therapy ...............................................................................52
6.8.1 Prior Treatment....................................................................................................52
6.8.2 Concomitant Treatment.......................................................................................53
6.8.3 Permitted Treatment............................................................................................53
6.8.4 Prohibited Treatment...........................................................................................53
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CONFIDENTIAL
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SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .......................................................................54
7.1 Discontinuation of Study Treatment.........................................................................54
7.2 Reasons for Discontinuation ......................................................................................54
7.3 Withdrawal from the Study .......................................................................................55
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit............................55
8. STUDY ASSESSMENTS AND PROCEDURES............................................................55
8.1 Study Schedule ............................................................................................................55
8.1.1 Screening Period...................................................................................................55
8.1.1.1 Screening/Baseline Visit ................................................................................56
8.1.2 Treatment Period..................................................................................................56
8.1.2.1 Final Visit........................................................................................................56
8.1.3 Follow-up Period ..................................................................................................56
8.1.4 Additional Care of Subjects after the Study......................................................57
8.2 Study Assessments.......................................................................................................57
8.2.1 Demographic and Other Baseline Characteristics ............................................57
8.2.1.1 Height and Weight.........................................................................................57
8.2.1.2 Medical, Medication History, and Non-drug Therapies ............................57
8.2.2 Efficacy..................................................................................................................57
8.2.3 Safety .....................................................................................................................58
8.2.3.1 Physical Examination ....................................................................................58
8.2.3.2 Adverse Events...............................................................................................59
8.2.3.3 Vital Signs.......................................................................................................60
8.2.3.4 Clinical Laboratory Tests..............................................................................61
8.2.3.5 Pregnancy Test...............................................................................................61
8.2.4 Other......................................................................................................................62
8.2.4.1 Clinical Pharmacokinetics.............................................................................62
8.2.4.2 Pharmacodynamics........................................................................................62
8.2.4.3 Genetics...........................................................................................................62
8.2.4.4
...........................................................62
8.2.4.5
..................................................................63
8.2.4.6
.................................................................................................63
8.2.4.7
.................................................................................................65
8.2.5 Volume of Blood to Be Drawn from Each Subject............................................65
8.2.6 Retention of Study Samples.................................................................................65
9. STATISTICAL CONSIDERATIONS .............................................................................65
9.1 Statistical Analysis Process.........................................................................................65
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee...66
9.3 Sample Size and Power Considerations....................................................................67
9.4 Statistical Analysis Set(s)............................................................................................67
9.5 Efficacy Analyses.........................................................................................................67
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CONFIDENTIAL
Page 9
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
9.5.1 Primary Efficacy Endpoint..................................................................................68
9.5.2 Secondary Efficacy Endpoints.............................................................................68
9.5.3 Multiplicity Adjustment.......................................................................................69
9.5.4 Control of Type I Error .......................................................................................69
9.5.5 Exploratory Endpoints.........................................................................................69
9.6 Safety Analyses............................................................................................................70
9.6.1 Secondary Safety Endpoints................................................................................70
9.6.2 Safety Endpoint Analyses ....................................................................................70
9.7 
.............................................71
9.7.1 
....................................71
9.7.2
.....................71
9.7.3 
.........................................................71
9.7.4 
...............................71
9.8 Pharmacokinetic Analyses .........................................................................................72
9.8.1 Secondary PK/PD Endpoints...............................................................................72
9.8.2 PK/PD Analyses....................................................................................................73
10. REFERENCES.................................................................................................................74
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CONFIDENTIAL
Page 10
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
LIST OF IN-TEXT TABLES
Table 1. Schedule of Study Procedures and Assessments ..................................................21
Table 2. Non-PK Laboratory Assessments in Screening and Treatment.........................24
Table 3. Treatment Period PK Laboratory Assessments...................................................25
Table 4. Objectives and Endpoints.......................................................................................35
LIST OF IN-TEXT FIGURES
Figure 1. Study Schematic Diagram.....................................................................................20
LIST OF APPENDICES
Appendix 1
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
Considerations................................................................................................78
Appendix 2
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting.............................................................................88
Appendix 3
Genetics...........................................................................................................98
Appendix 4
Diagnostic Criteria/Disease Classification.................................................100
Appendix 5
Abbreviations ...............................................................................................101
Appendix 6
Protocol History ...........................................................................................105
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Shire
CONFIDENTIAL
Page 11
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
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 27 sites in North America and Europe 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 activity 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 from baseline in
response to daily PEX, with or without SHP655 supplementation, during the acute episode and up to
30 days after the resolution of the acute aTTP episode
2.
Evaluate ADAMTS-13 activity levels in subjects up to 30 days after acute aTTP 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
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CONFIDENTIAL
Page 12
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
2.
Evaluate the occurrences of aTTP related complications, (including death, stroke, MI, and organ failure), 
aTTP relapses*, exacerbations** and end-organ function improvement
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 (eg, PEX, SHP655 infusions) related adverse events
Exploratory Objectives:
*Defined as >30 days after achieving remission
**Defined as ≤30 days after achieving remission
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CONFIDENTIAL
Page 13
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
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.
Investigational product, dose, and mode of administration:

SHP655 40 IU/kg ±4 IU/kg once daily, i.v. or 40 IU/kg ±4 IU/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 ±4 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 ±4 IU/kg SHP655 twice daily 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
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CONFIDENTIAL
Page 14
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
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. If the ADAMTS-13 levels 
(based on local labs) are <50% between discharge and first weekly follow-up visit then the investigator may treat 
the patient with the IP prior to the scheduled visit. Any additional assessments may be conducted as per the 
investigator’s judgment.
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.
The occurrence of relapse and time to relapse will be summarized separately by subjects enrolled before or after 
Protocol Amendment 4.0, which introduced open label supplementation with rADAMTS13 in remission.
Discretionary Rescue Therapy
Study investigators may elect to administer rescue therapy to a subject if platelet count have not increased at least 
2-fold from screening and LDH remains above ULN after 4 days of treatment. Rescue therapy will be defined as 
any product with a known interruption to the PK/PD relationship between ADAMTS-13 activity, VWF activity, 
and platelet count. Additional administration of FFP, S/D treated plasma, and immunosuppressive therapies will 
not be considered rescue therapy unless otherwise agreed after consultation with the Sponsor. However, they may 
be prohibited medication after initiation of plasma exchange (refer to Section 6.8.4). The rescue therapy treatment 
should follow local standard of care practices. If rescue therapy is initiated, the administration of IP (SHP655 or 
placebo) will be suspended for the duration of the study. The patient will continue to follow the same visit and 
assessment schedule to be monitored for safety. PK samples should continue to be collected to monitor safety and 
the subject should be followed for three months post remission.
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.
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CONFIDENTIAL
Page 15
SHP655-201 Protocol Amendment 4.0
rADAMTS-13
17 Sep 2020
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 at the central lab; if screening samples are not 
taken until after the first PEX, ADAMTS-13 activity from the local lab is permitted to determine 
eligibility.
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 (eg, gemcitabine, mitomycin C, clopidogrel) and pregnancy-
related thrombocytopenia syndromes (eg, 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 1 months prior to study enrollment. 
6.
Subject is human immunodeficiency virus positive (HIV+) with unstable disease or CD4+ count 
≤200 cells/mm3 within 3 months screening.
7.
Subjects with conditions of severe immunodeficiency.
8.
Subject has had a previous aTTP event in the past 30 days.
9.
Subject has another underlying progressive fatal disease and/or life expectancy of less than 3 months. 
10.
Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures.
11.
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.
12.
If female, subject is pregnant or lactating.
13.
Subject is a family member or employee of the Sponsor or investigator.
14.
Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing information.
15.
Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule
ADAMTS-13, hamster protein, or other constituents of SHP655.
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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 (eg, 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 (eg, 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 subjects with ADAMTS-13 activity trough levels >10%
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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 titers of binding and inhibitory antibodies to ADAMTS-13 relative to baseline
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
13.
Occurrence of subjects receiving rescue therapy
14.
Occurrence of subjects meeting rescue criteria
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Exploratory 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 PK/PD 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.
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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.

The occurrence of relapse and time to relapse will be summarized separately by subjects enrolled before or 
after Protocol Amendment 4.0, which introduced open label supplementation with rADAMTS13 in 
remission.An interim analysis will be performed after 18 subjects have achieved remission and when 
approximately 50% of the planned sample size has been enrolled and treated in the three arms. The IA will 
include all data, collected by this time point, for all subjects enrolled in the study. IA results will be used 
to evaluate a preliminary treatment effect, assess initial PK/PD parameters, and inform the phase 3 clinical 
development planning. Access to results from the IA will be restricted to a small group of Takeda 
personnel designated as unblinded who thereafter will be removed from participation in oversight of daily 
conduct of this study. The interim analysis data and results may be used in regulatory interactions but will 
not be made public or used in scientific manuscripts.
Details on the specific analyses to be performed during the IA will be provided in the Statistical Analysis Plan.
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1.2 Schema
Figure 1. Study Schematic Diagram 
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1.3 Schedule of Activities
Table 1. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening/ 
Enrollmenta
Interval Study Visits
Study 
Completion/
Termination
Visitc
(12 weeks ± 7 
days following 
remission)
Treatment 
Period
(Daily)b
Semi-Weekly 
Follow Up 
Study Visitsl
(Q3Day ±1 
day x2 weeks)
Weekly Follow 
Up Study 
Visitsl
(Q1Week ±3 
days x2 weeks)
Biweekly 
Follow Up 
Study Visitsl
(Q2Week ±3 
days x2 visits)
Informed Consentd
X
Eligibility Criteria
X
Serum pregnancy 
test (females)
X
Medical History
X
Demographic and 
Baseline 
Characteristics
X
Medications
X
X q
X q
X q
X
X
Non-drug Therapies
X
X q
X q
X q
X
X
Physical Examo
(including weight)
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Laboratoriesg
X
Xh
X
X
X
X
Vital Signs
X
X
X
X
X
X
Evaluation of 
schistocytes
X
Randomizationk
X
IP
Xe,q
Xf,q
Xf,q
Plasma exchange
X
X q
Cognitive 
assessment tests
X
X
Xt
X
Modified ITP 
Bleeding Score
X
X
ADAMTS-13 
Antigen & Activity
X
Xh
Xp
Xp
X
X
Anti-rADAMTS-13 
Binding antibodies, 
total Ig (IgG, IgA, 
IgM)m
X
Xh
X
X
X
X
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Table 1. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening/ 
Enrollmenta
Interval Study Visits
Study 
Completion/
Termination
Visitc
(12 weeks ± 7 
days following 
remission)
Treatment 
Period
(Daily)b
Semi-Weekly 
Follow Up 
Study Visitsl
(Q3Day ±1 
day x2 weeks)
Weekly Follow 
Up Study 
Visitsl
(Q1Week ±3 
days x2 weeks)
Biweekly 
Follow Up 
Study Visitsl
(Q2Week ±3 
days x2 visits)
Anti-rADAMTS-13 
Binding antibodies, 
IgE n
Anti-ADAMTS-13 
Inhibitory antibodies
(for native protein)
X
Xh
X
X
X
X
Anti-rADAMTS-13 
Inhibitory antibodies
X
X
VWF antigen and 
multimers
Xi
Xi
Urine-albumin-
creatinine ratio
X
X
Xr
Xr
Methylprednisolone 
(tapering permitted)
X q
Xb, q
Xb, q
Rituximab
Xb, q
Xb, q
Xb, q
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Table 1. Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening/ 
Enrollmenta
Interval Study Visits
Study 
Completion/
Termination
Visitc
(12 weeks ± 7 
days following 
remission)
Treatment 
Period
(Daily)b
Semi-Weekly 
Follow Up 
Study Visitsl
(Q3Day ±1 
day x2 weeks)
Weekly Follow 
Up Study 
Visitsl
(Q1Week ±3 
days x2 weeks)
Biweekly 
Follow Up 
Study Visitsl
(Q2Week ±3 
days x2 visits)
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 double blinded and administered only after local ADAMTS-13 activity levels are <50% 
(measured >72 hours after last IP dose).
f.
Open label dosing with SHP-655; 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.
Only measured at 2nd semi-weekly visit and 2nd weekly visit follow up visits.
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; follow-up visits may be conducted in the home setting by a 
healthcare professional if consistent with local procedures.
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.
p.
ADAMTS-13 activity during the follow up period will be measured locally (in addition to centrally) for determining 
the need for IP supplementation in the first 4 weekly follow up visits.
q.
Administration of rescue therapy will be at the discretion of the investigator and will not include IP.
r.
Urine-albumin-creatinine ratio to be measured during the weekly follow-up period if IP is administered.
t.
Only measured at 2nd and 4th semi-weekly visits.
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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 b
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
Chemistry (except LDH)
L
L
LDH
L
L
L
Schistocytes
L
Urine-albumin-creatinine ratio
L
L
L
L = local lab; C = Central (sponsor) lab; B= Bioanalytical specialty lab (sponsor)
b Subjects receiving rescue therapy should not have samples taken within 1 h Pre-PEX, IP should not be administered, and 
samples should be taken only within 30 minutes post-PEX.
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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 d
Within 15 
min post 
end of IP 
infusion 
#2 d
0.5-3 h 
post end 
of IP 
infusion 
#2 d
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 6.2.3).
b Do not collect if daily IP infusion #2 (dose 12h post-PEX) is discontinued (see Section 6.2.6). 
c Collect these time-points in relation to the end of PEX if IP infusion #1 (dose immediately post-PEX) is discontinued (see 
Section 6.2.6) or if the subject is receiving rescue therapy. 
d For subjects receiving rescue therapy, collect within 15 min post end of PEX and 0.5-3 h post end of PEX (no IP administered 
when on rescue therapy).
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 
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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 were recently approved by EMA and FDA.
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 (eg, 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 
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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).
2.1.1.3 Rituximab
Rituximab (humanized anti-CD20 monoclonal antibody) was first used in patients with 
suboptimal responses to PEX (ie, 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 
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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 Caplacizumab
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 3, controlled study, 145 patients 
underwent randomization (72 were assigned to receive caplacizumab, and 73 to receive 
placebo). In the caplacizumab group, 50% of patients had platelet normalization within 
2.69 median days (95% confidence interval [CI], 1.89 to 2.83) compared to 2.88 median 
days in the placebo group (95% confidence interval 2.68 to 3.56, P = 0.01) and 75% of 
patients had platelet normalization in 2.95 days compared to 4.50 days in the placebo 
group (95% confidence interval). Three patients in the caplacizumab group had an 
exacerbation, as compared with 28 patients in the placebo group. Six patients in the 
caplacizumab group had a relapse in the first month after stopping the study drug, all of 
whom had ADAMTS-13 activity that remained below 10%, suggesting unresolved 
autoimmune activity. The median duration of exposure to caplacizumab was longer than 
the duration of exposure to placebo (35 days [range, 1 to 65] vs. 23 days [range, 2 to 66]). 
Bleeding-related adverse events (AEs), most of which were mild to moderate in severity, 
were more common with caplacizumab than with placebo (65% of patients vs. 48%). 
Bleeding events were severe in 3 patients in the caplacizumab group, and one patient had 
severe bleeding in the placebo group. Serious adverse events of bleeding were reported in 
8 patients (11%) in the caplacizumab group and in 1 patient (1%) in the placebo group. 
Normalization of the three organ-damage markers (lactate dehydrogenase, cardiac 
troponin I, and serum creatinine) occurred in 0 patients in the caplacizumab group versus 
3 patients in the placebo group (P=0.06) (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, 8% on the 
caplacizumab and none on the placebo arms of the Phase 3 study had a recurrence during 
first month after discontinuing the therapy (Peyvandi et al., 2016).There have been no 
long-term safety studies to assess organ damage.
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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 
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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.
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., 
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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. 
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/PD 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 
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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.
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 from
baseline in response to daily PEX, with or without SHP655 supplementation, during the
acute episode and up to 30 days after the resolution of the acute aTTP episode

Evaluate ADAMTS-13 activity levels in subjects up to 30 days after acute aTTP 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.
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
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 (eg, PEX, SHP655 infusions) related adverse events
*Defined as >30 days after achieving remission 
**Defined as ≤30 days after achieving remission
3.1.3 Exploratory Objectives
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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 titers of binding and inhibitory 
antibodies to ADAMTS-13 relative to baseline
•
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 (eg, platelet count, LDH levels), as a 
function of ADAMTS-13 activity
•
The relationship between ADAMTS-13 activity and 
end-organ disease status (eg, renal, neurologic, and 
cardiac) 
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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)
•
Occurrence of subjects receiving rescue therapy
•
Occurrence of subjects meeting rescue criteria
•
Occurrence of antibodies to SHP655
•
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 (eg, SHP655 
infusions) related adverse events
•
Incidence PEX, 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
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Exploratory Objectives
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
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 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 ±4 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)
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Subjects will receive daily plasma exchange and 40 IU/kg ±4 IU/kg SHP655 twice daily 
immediately after PEX and 12±1 hours after completion of PEX.
The first PEX and IP may be administered in three scenarios:

First PEX completed >4 hours prior to study enrollment: the first dose of IP should be 
administered immediately after the second PEX (first PEX completed on study)

First PEX completed ≤4 hours prior to study enrollment: the first dose of IP should be 
administered as soon as possible, but no more than 4 hours after the initial PEX
First PEX delayed and randomization into study is complete: 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.
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 (eg,
1.5 or 2 plasma volumes) or the frequency of PEX (eg, BID or every other day) require 
sponsor approval. Changes in PEX treatment due to logistical or emergent issues (eg,
venous access problems, AEs leading to PEX discontinuation) do not require sponsor 
approval but must be documented.
After confirmed remission of the TTP episode, subjects will be given additional open-label 
IP (SHP655 40 IU/kg ±4 IU/kg) if ADAMTS-13 activity at the local lab is <50%. ADAMTS13 
activity should be monitored Q3Day ±1 days for 2 weeks and Q1Week ±3 days for 2 
additional weeks.
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Discretionary Rescue Therapy
Study investigators may elect to administer rescue therapy to a subject if platelet count 
have not increased at least 2-fold from screening and LDH remains above ULN after 4 days 
of treatment. Rescue therapy will be defined as any product with a known interruption to 
the PK/PD relationship between ADAMTS-13 activity, VWF activity, and platelet count. 
Additional administration of FFP, S/D treated plasma, and immunosuppressive therapies 
will not be considered rescue therapy unless otherwise agreed after consultation with the 
Sponsor. However, they may be prohibited medication after initiation of plasma exchange 
(refer to Section 6.8.4). The rescue therapy treatment should follow local standard of care 
practices. If rescue therapy is initiated, the administration of IP (SHP655 or placebo) will be 
suspended for the duration of the study. The patient will continue to follow the same visit 
and assessment schedule to be monitored for safety. PK samples should continue to be 
collected to monitor safety and the subject should be followed for three months post 
remission.
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 ±4 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 
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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. 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 ±4 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 1.5 years.
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 27 sites across North America and Europe.
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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 at the central lab; if screening
samples are not taken until after the first PEX, ADAMTS-13 activity from the local lab is
permitted to determine eligibility
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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 (eg, gemcitabine, 
mitomycin C, clopidogrel) and pregnancy-related thrombocytopenia syndromes (eg,
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 1 month prior to 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.
Subjects with conditions of severe immunodeficiency.
8.
Subject has had a previous aTTP event in the past 30 days
9.
Subject has another underlying progressive fatal disease and/or life expectancy of less than 
3 months.
10. Subject is identified by the investigator as being unable or unwilling to cooperate with 
study procedures. 
11. 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.
12. If female, subject is pregnant or lactating.
13. Subject is a family member or employee of the Sponsor or investigator. 
14. Any contraindication to PEX, methylprednisolone and/or rituximab as per prescribing 
information
15. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent 
molecule ADAMTS-13, hamster protein, or other constituents of SHP655.
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 16 days following the last dose of 
investigational product. If used, hormonal contraceptives should be administered 
according to the package insert.
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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 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.
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.
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.
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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 Hypersensitivity to SHP655
SHP655 should not be administered in patients with known hypersensitivity to any of the 
components of rADAMTS-13. As with any i.v. protein product, allergic-type hypersensitivity 
reactions are possible. Subjects must be closely monitored for any symptoms throughout 
the infusion period. Subjects should be informed of the early signs of hypersensitivity 
reactions including hives, generalized urticaria, tightness of the chest, wheezing, 
hypotension, and anaphylaxis. If these symptoms occur, the administration should be 
discontinued immediately. In case of shock, standard medical treatment for shock should 
be implemented.
6.2.2 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.
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6.2.3 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.
6.2.4 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.
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.
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6.2.5 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.
The interim analysis (IA) data and results will be provided in unblinding fashion to a pre-
specified sub-team of the current clinical team. Newly appointed members of the clinical 
team, who are blinded to the treatment assignments and unaware of the interim data and 
results will support the remaining portion of the study. The rest of the study team will 
remain blinded to the restricted data and the results of the interim statistical and PK 
analyses until the time after database lock and study unblinding. All individuals involved in 
the conduct of the trial post IA are to remain unaware of unblinding information related to 
the interim analysis. The study will continue after the IA as double blinded for the duration 
of the trial.
6.2.6 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. If the ADAMTS 13 levels (based on local labs) are <50% between 
discharge and first weekly follow-up visit then the investigator may treat the patient with 
the IP prior to the scheduled visit. Any additional assessments may be conducted as per the 
investigator’s judgment.
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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 ±4 IU/kg) if a weekly ADAMTS-13 activity at the 
local lab is <50% (drawn >72 hours after last IP infusion).
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 
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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. 
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 (i.e., certified min/max thermometer) would require manual 
resetting upon each recording. The sponsor must be notified immediately upon discovery 
of any excursion from the established range. Temperature excursions will require site 
investigation as to cause and remediation. The sponsor will determine the ultimate impact 
of excursions on the 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.
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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.
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 (i.e., 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 
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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.
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, eg, 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)
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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 (eg, central venous catheter interventions, escalation in 
care).
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: recommended dose of 375mg/m2 iv once weekly x 4 weeks. The first dose will 
be administered within two days of enrollment. All doses are recommended to 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 30 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 
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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. 
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 1 month prior to the study and during the study. During 
the study, Caplacizumab may be used as discretionary rescue therapy if part of the local 
standard of care and a subject’s platelet count has not increased 2x from screening and 
LDH remains above ULN after 4 days of treatment. In this instance, the administration of all 
study IP should be suspended for the duration of the study. 
Treatments for aTTP in addition to glucocorticoids and rituximab (eg, bortezomib, 
N-acetylcysteine, cyclophosphamide, splenectomy, cyclosporine, vincristine) require prior 
approval by the sponsor. 
Plasma infusion after PEX has been initiated is prohibited except for subjects receiving 
rescue therapy. Platelet transfusion and factor concentrates are prohibited except for 
instances of life-threatening hemorrhage.
Investigators should always use their clinical judgment to determine the best course of 
treatment for a patient. If prohibited treatments are administered, the Medical Monitor 
should be immediately notified to make a decision on continued participation in the study.
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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

Screen failure

Other (must be specified in CRF)
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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.
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 randomized. Subjects may not re-enroll if previously 
randomized in this study. 
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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).
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 except for subjects 
receiving rescue therapy.
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 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 
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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).
All follow-up visits except the completion/termination visit may be conducted by a 
healthcare provider in the home setting if consistent with local procedures and all study 
requirements are met.
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.
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. 
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Assessments are to be performed during the daytime at a similar time of day, where 
feasible. 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 (eg, 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 1 month ± 7 days following the last interval study visit.
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.
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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 
(eg, 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 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 (eg, confusion, visual changes, dysphonia, paresthesias, dysarthria, 
focal or general motor symptoms)
4.
Abnormal ADAMTS-13 activity
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5.
Positive anti-ADAMTS-13 inhibitor
6.
Decrease in platelet count
7.
Increase of serum creatinine
8.
An increase in schistocytes in peripheral blood smear
9.
Fever (≥100.4°F/38°C)
10. Abdominal pain
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 and second 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. Additional tests and other evaluations required to establish the significance or 
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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 is performed locally and 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 is performed locally and consists of ALT, AST, total bilirubin, 
alkaline phosphatase, blood urea nitrogen, creatinine, and glucose.
The measurement of urine-albumin-creatinine ratio should be completed daily in the local 
lab during the acute treatment period and the weekly follow-up period if IP is administered 
to monitor for early signs of vasculitis.
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 locally 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.
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 
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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).
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
PK sampling should continue as scheduled for subjects receiving rescue therapy. 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
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8.2.4.5
 
 
 
8.2.4.6
 
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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.
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, 
PK/PD 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.
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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
An interim analysis will be performed after 18 subjects have achieved remission and when 
approximately 50% of the planned sample size has been enrolled and treated in the three 
arms. The IA will include all data, collected by this time point, for all subjects enrolled in the 
study. IA results will be used to evaluate a preliminary treatment effect, assess initial 
PK/PD parameters, and inform the phase 3 clinical development planning. Access to results 
from the IA will be restricted to a small group of Takeda personnel designated as unblinded 
who thereafter will be removed from participation in oversight of daily conduct of this 
study. The interim analysis data and results may be used in regulatory interactions but will 
not be made public or used in scientific manuscripts. Details on the specific analyses to be 
performed during the Interim Analysis will be provided in the Statistical Analysis Plan.
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). The DMC 
will be consulted if the study is discontinued. 
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 
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DMC SAP. 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.
9.4 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 (PPS) 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. Samples from 
subjects receiving rescue medicine will be excluded from the primary and secondary 
endpoint analysis after the rescue medicine is initiated.

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. 
Samples from subjects receiving rescue medicine will be excluded from the primary and 
secondary endpoint analysis after the rescue medicine is initiated.
9.5 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 the treatment they actually received. 
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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.
9.5.1 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 9.8.
9.5.2 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. 
8.
Occurrence of subjects receiving rescue therapy
9.
Occurrence of subjects meeting rescue criteria
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. 
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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. 
The occurrence of relapse and time to relapse will be summarized separately by subjects enrolled 
before or after Protocol Amendment 4.0, which introduced open label supplementation with 
rADAMTS13 in remission.
Data handling and imputation approaches for subjects receiving rescue therapy will be 
described in the SAP.
An interim analysis will be performed after 18 subjects have achieved remission and when 
approximately 50% of the planned sample size has been enrolled and treated in the three 
arms. The IA will include all data, collected by this time point, for all subjects enrolled in the 
study. IA results will be used to evaluate a preliminary treatment effect, assess initial 
PK/PD parameters, and inform the phase 3 clinical development planning. Access to results 
from the IA will be restricted to a small group of Takeda personnel designated as unblinded 
who thereafter will be removed from participation in oversight of daily conduct of this 
study.
The interim statistical analysis will be performed by an unblinded CRO team which is 
separate from the CRO team that is involved in the conduct of the study. An interim 
population PK/PD analysis will be performed by an independent unblinded team at 
another CRO with no involvement in the conduct of the study.
9.5.3 Multiplicity Adjustment
Not applicable.
9.5.4 Control of Type I Error
Not applicable.
9.5.5 Exploratory Endpoints
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9.6 Safety Analyses
9.6.1 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 titers of binding and inhibitory antibodies to ADAMTS-13 relative to 
baseline
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
9.6.2 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.
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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.
9.7
9.7.1
9.7.2
 
 
 
9.7.3
 
 
9.7.4
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9.8 Pharmacokinetic Analyses
9.8.1 Secondary PK/PD Endpoints
1.
The PK/PD temporal relationship of efficacy parameters (eg, 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 (eg, renal, 
neurologic, and cardiac) 
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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%
9.8.2 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 (eg,
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.
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10. REFERENCES
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Correlates with Clinical Outcome in Acute Thrombotic Thrombocytopenic Purpura. 
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F., Re, R., Spedini, P., Vianelli, N. & Zaccari 2010. High versus standard dose 
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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 
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Bryant, B. J. & Klein, H. G. 2007. Pathogen inactivation: the definitive safeguard for the 
blood supply. Archives of Pathology & Laboratory Medicine, 131, 719-33.
Cataland, S. R. & Wu, H. M. 2015. Acquired thrombotic thrombocytopenic purpura: New 
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Coppo, P. & Veyradier, A. 2012. Current management and therapeutical perspectives in 
thrombotic thrombocytopenic purpura. Presse Med, 41, e163-e176.
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Terrell, D. R., Vesely, S. K. & George, J. N. 2015. Depression and cognitive impairment 
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rituximab infusions after remission efficiently prevent relapses in acquired 
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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,
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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.
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Lewis, Q. F., Lanneau, M. S., Mathias, S. D., Terrell, D. R., Vesely, S. K. & George, J. N. 2009. 
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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 
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Plaimauer, B., Kremer Hovinga, J. A., Juno, C., Wolfsegger, M. J., Skalicky, S., Schmidt, M., 
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solvent detergent treated plasma. Transfus Apher Sci, 35, 235-238.
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Scully, M., Hunt, B. J., Benjamin, S., Liesner, R., Rose, P., Peyvandi, F., Cheung, B., Machin, S. J. 
& The British Committee for Standards in Haematology 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 
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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. 
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Zheng, X. L. 2015. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic 
purpura. Annu. Rev. Med, 66, 211-225.
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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.
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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.
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.
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It is the investigator’s responsibility to ensure that adequate time and appropriately 
trained resources are available at the site prior to commitment to participate in this study. 
The investigator should also be able to estimate or demonstrate a potential for recruiting 
the required number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 
demonstrate such qualification. Curriculum vitae for investigators and sub-investigators 
are provided to the study sponsor (or designee) before starting the study.
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
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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. 
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 except Richmond Agitation 
Sedation Scale (RASS) 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.
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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.
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 
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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.
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 (i.e., 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
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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 (i.e., 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 national provisions) prior to study start that another party (i.e., 
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.
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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 and applicable 
regulatory authority 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.
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 
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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.
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 
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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.
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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
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
Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include:
o
Bronchospasm associated with anaphylaxis requiring intensive treatment in an 
emergency room or at home 
o
Blood dyscrasias or convulsions that do not result in inpatient hospitalization
o
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 (i.e., including active comparators) that is both serious 
and unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected
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
Assessed as related to study treatment
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 to 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 or vital sign measure can represent 
an AE if the change is clinically relevant or if, during administration of investigational 
product, a shift of a parameter is observed from a value in the normative range to a value 
that is outside the normal range and considered clinically significant, or a further waning of 
an already clinically significant value. When evaluating such changes, the extent of 
deviation from the reference range, the duration until return to the reference range, either 
while continuing administration or after the end of administration with the investigational 
product, and the range of variation of the respective parameter within its reference range, 
should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as 
hematology panel or clinical chemistry panel) or vital sign values which were not present 
at the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or 
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until a plausible explanation (eg, concomitant disease or expected disease evolution) is 
found for the abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value or vital sign is clinically significant 
and represents an AE.
Appendix 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.
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
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention.
The event interferes with usual activities of daily living, causing discomfort but poses no
significant or permanent risk of harm to the research subject.

Severe: A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention.
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational 
product for each AE. The investigator should decide whether, in his or her medical 
judgment, there is a reasonable possibility that the event may have been caused by the 
investigational product. If there is no valid reason for suggesting a relationship, then the AE 
should be classified as “not related”. Otherwise, if there is any valid reason, even if 
undetermined or untested, for suspecting a possible cause-and-effect relationship between 
the investigational product and the occurrence of the AE, then the AE should be considered 
“related”. The causality assessment must be documented in the source.
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
 
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
Unknown
If applicable, action taken (i.e., 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
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
o
Results in a life-threatening illness or injury
o
Results in a permanent impairment/ damage of a body function or body structure
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o
Requires in-patient hospitalization or prolongation of existing hospitalization
o
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
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 
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as “dose not changed” or “not applicable” (if the subject never received investigational 
product). The investigational product action of withdrawn should not be selected solely as 
a result of the subject’s death.
Appendix 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 
-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.
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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
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
Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
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).
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APPENDIX 3
GENETICS 
Shire intends to apply genetic research across the SHP655 development program to 
differentiate participants with congenital (genetic) versus acquired TTP to determine 
eligibility to participate in this study. 
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. 
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. 
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. 
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 4 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 
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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 
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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 
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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
EMA
European Medicines Agency
EU
European Union
EUDRACT
European Union clinical trials database
F
degree Fahrenheit
FAS
Full Analysis Set
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Abbreviation
Definition
FDA
Food and Drug Administration 
FFP
Fresh frozen plasma
FVIII
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
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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)
PPS
per-protocol set
 
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
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Abbreviation
Definition
SAE
serious adverse event 
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
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APPENDIX 6
PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Protocol Amendment 4.3
17 Sep 2020
France
Protocol Amendment 4.1
17 Sep 2020
UK
Protocol Amendment 4.0
17 Sep 2020
Non – UK, CH, FR
Protocol Amendment 3.3
16 Jul 2020
France
Protocol Amendment 3.2
16 Jul 2020
Italy
Protocol Amendment 3.1
16 Jul 2020
UK
Protocol Amendment 3.0
08 Jun 2020
Non – UK, CH, FR
Protocol Amendment 2.3 
07 Nov 2019
France
Protocol Amendment 2.2 
07 Nov 2019
UK
Protocol Amendment 2.1
23 Sep 2019
Non-UK
Protocol Amendment 1.3
18 Jun 2019
France
Protocol Amendment 1.2
01 Apr 2019
Non-UK
Protocol Amendment 1.1 
18 Mar 2019
UK
Original Protocol
03 Oct 2018
Global
For non-commercial use only

Prot_001.pdf: 
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: 
Protocol Amendment 1.2 (non-UK) : 01-APR-2019
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:
Protocol Amendment 1.2 (non-UK): 01 APR 2019
Replaces: 
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.
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PROTOCOL SIGNATURE PAGE
Sponsor’s (Shire) Approval
Signature:
Date:
, MD
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Investigator’s Acknowledgement
I have read this protocol for Study SHP 655-201.
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
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:
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SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
Protocol Amendment 1.2 Non-UK
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1.2
Amendment Date
01 APR 2019
Country Specific
Non-UK
Protocol Amendment Summary and Rationale:
Added exclusion for hypersensitivity to SHP655 and added minor protocol clarifications.  
Description of Each Change and Rationale
Section(s) Affected by Change
Addition of Section 6.2.1
Hypersensitivity
The protocol was updated to include 
information regarding the potential risk of
infusion/hypersensitivity reactions, as 
reflected in the IB, and guidance on how 
to manage such reactions should they 
occur.
Synopsis, Section 6.2.1
Additional exclusion criterium was 
added
The protocol was updated to address the 
contraindication for SHP655 identified in
the Investigator’s Brochure (IB): “Known 
life-threatening hypersensitivity reaction, 
including anaphylaxis, to the parent 
molecule ADAMTS-13, hamster protein, 
or other constituents of SHP655.”
Synopsis, Section 5.2
Minor typos repaired, formatting 
repaired.
Clarity.
Throughout
See Appendix 6 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Shire 
Clinical Study Adverse Event Form for 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
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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
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................. 2
Sponsor’s (Shire) Approval...................................................................................................... 2
Investigator’s Acknowledgement ............................................................................................ 3
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.......................... 4
EMERGENCY CONTACT INFORMATION .......................................................................... 5
PRODUCT QUALITY COMPLAINTS..................................................................................... 6
TABLE OF CONTENTS ............................................................................................................. 7
1. PROTOCOL SUMMARY ..................................................................................................... 12
1.1 Synopsis.............................................................................................................................. 12
1.2 Schema ............................................................................................................................... 20
1.3 Schedule of Activities........................................................................................................ 21
2. INTRODUCTION................................................................................................................... 24
2.1 Indication and Current Treatment Options................................................................... 24
2.1.1 Current Standard of Care (SoC).............................................................................. 24
2.1.1.1 Plasma Exchange (PEX)..................................................................................... 25
2.1.1.2 Corticosteroids.................................................................................................... 25
2.1.1.3 Rituximab............................................................................................................ 26
2.1.1.4 Investigational Drugs.......................................................................................... 26
2.1.2 Unmet Medical Needs of Current Therapy............................................................. 27
2.2 Product Background and Clinical Information............................................................. 28
2.3 Study Rationale................................................................................................................. 28
2.4 Benefit/Risk Assessment................................................................................................... 29
2.5 Compliance Statement...................................................................................................... 29
3. OBJECTIVES AND ENDPOINTS ....................................................................................... 30
3.1 Study Objectives ............................................................................................................... 30
3.1.1 Co-Primary Objectives.............................................................................................. 30
3.1.2 Secondary Objectives ................................................................................................ 30
3.1.3 Exploratory Objectives ............................................................................................. 31
3.2 Study Endpoints................................................................................................................ 32
4. STUDY DESIGN..................................................................................................................... 36
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4.1 Overall Design................................................................................................................... 36
4.2 Scientific Rationale for Study Design.............................................................................. 37
4.2.1 Rationale for control group ...................................................................................... 37
4.2.2 Rationale for Primary and Key Secondary Endpoints .......................................... 37
4.2.3 Justification for the use of placebo........................................................................... 37
4.3 Justification for Dose........................................................................................................ 37
4.4 Duration of Subject Participation and Study Completion Definition.......................... 38
4.5 Sites and Regions .............................................................................................................. 38
5. STUDY POPULATION ......................................................................................................... 39
5.1 Inclusion Criteria.............................................................................................................. 39
5.2 Exclusion Criteria............................................................................................................. 39
5.2.1 Contraception............................................................................................................. 40
6. STUDY INTERVENTION..................................................................................................... 42
6.1 Investigational Product .................................................................................................... 42
6.1.1 Identity of Investigational Product .......................................................................... 42
6.1.2 Blinding the Treatment Assignment ........................................................................ 42
6.2 Administration of Investigational Product..................................................................... 42
6.2.1 Hypersensitivity to SHP655 ...................................................................................... 42
6.2.2 Interactive Response Technology for Investigational Product Management ...... 43
6.2.3 Allocation of Subjects to Treatment ........................................................................ 43
6.2.4 Dosing.......................................................................................................................... 43
6.2.5 Unblinding the Treatment Assignment during the Placebo-Controlled Portion of 
the Study..................................................................................................................... 44
6.2.6 Dose Modification ...................................................................................................... 44
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product.................... 45
6.3.1 Labeling ...................................................................................................................... 45
6.3.2 Packaging.................................................................................................................... 45
6.3.3 Storage ........................................................................................................................ 45
6.3.4 Special Handling........................................................................................................ 46
6.4 Drug Accountability ......................................................................................................... 46
6.5 Subject Compliance.......................................................................................................... 48
6.6 Plasma Exchange (PEX)................................................................................................... 48
6.7 Immunosuppression.......................................................................................................... 49
6.8 Prior and Concomitant Therapy..................................................................................... 49
6.8.1 Prior Treatment......................................................................................................... 49
6.8.2 Concomitant Treatment............................................................................................ 49
6.8.3 Permitted Treatment................................................................................................. 50
6.8.4 Prohibited Treatment................................................................................................ 50
7. DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL............................................................................. 51
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7.1 Discontinuation of Study Treatment............................................................................... 51
7.2 Reasons for Discontinuation ............................................................................................ 51
7.3 Withdrawal from the Study............................................................................................. 52
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit.................................. 52
8. STUDY ASSESSMENTS AND PROCEDURES................................................................. 53
8.1 Study Schedule.................................................................................................................. 53
8.1.1 Screening Period ........................................................................................................ 53
8.1.1.1 Screening/Baseline Visit..................................................................................... 53
8.1.2 Treatment Period....................................................................................................... 53
8.1.2.1 Final Visit ............................................................................................................ 54
8.1.3 Follow-up Period........................................................................................................ 54
8.1.4 Additional Care of Subjects after the Study ........................................................... 54
8.2 Study Assessments ............................................................................................................ 54
8.2.1 Demographic and Other Baseline Characteristics ................................................. 54
8.2.1.1 Height and Weight.............................................................................................. 54
8.2.1.2 Medical, Medication History, and Non-drug Therapies................................. 55
8.2.2 Efficacy ....................................................................................................................... 55
8.2.3 Safety........................................................................................................................... 55
8.2.3.1 Physical Examination......................................................................................... 56
8.2.3.2 Adverse Events.................................................................................................... 56
8.2.3.3 Vital Signs............................................................................................................ 57
8.2.3.4 Clinical Laboratory Tests .................................................................................. 58
8.2.3.5 Pregnancy Test.................................................................................................... 58
8.2.4 Other ........................................................................................................................... 59
8.2.4.1 Clinical Pharmacokinetics ................................................................................. 59
8.2.4.2 Pharmacodynamics............................................................................................. 59
8.2.4.3 Genetics................................................................................................................ 59
8.2.4.4
................................................................ 59
8.2.4.5
....................................................................... 59
8.2.4.6 
..................................................................................................... 60
8.2.4.7
.................................................................................................... 62
8.2.5 Volume of Blood to Be Drawn from Each Subject ................................................. 62
8.2.6 Retention of Study Samples ...................................................................................... 62
9. STATISTICAL CONSIDERATIONS .................................................................................. 63
9.1 Statistical Analysis Process .............................................................................................. 63
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......... 63
9.3 Sample Size and Power Considerations.......................................................................... 64
9.4 Efficacy Analyses .............................................................................................................. 64
9.4.1 Primary Efficacy Endpoint....................................................................................... 65
9.4.2 Secondary Efficacy Endpoints.................................................................................. 65
9.4.3 Multiplicity Adjustment............................................................................................ 66
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9.4.4 Control of Type I Error ............................................................................................ 66
9.4.5 Exploratory Endpoints.............................................................................................. 66
9.5 Safety Analyses.................................................................................................................. 66
9.5.1 Secondary Safety Endpoints..................................................................................... 66
9.5.2 Safety Endpoint Analyses.......................................................................................... 67
9.6 
.................................................. 67
9.6.1
......................................... 67
9.6.2
........................... 68
9.6.3
.............................................................. 68
9.6.4
..................................... 68
9.7 Pharmacokinetic Analyses ............................................................................................... 69
9.7.1 Secondary PK/PD Endpoints.................................................................................... 69
9.7.2 PK/PD Analyses ......................................................................................................... 69
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .. 70
Appendix 1  REGULATORY, ETHICAL, AND STUDY OVERSIGHT Considerations
............................................................................................................................................ 70
Appendix 1.1  Regulatory and Ethical Considerations ................................................... 70
Appendix 1.2  Sponsor’s Responsibilities ......................................................................... 70
Appendix 1.3  Investigator’s Responsibilities .................................................................. 71
Appendix 1.4  Data Management Considerations ........................................................... 74
Appendix 1.5  Ethical Considerations............................................................................... 75
Appendix 2  Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting................................................................................................ 79
Appendix 2.1  Adverse Event Definitions......................................................................... 79
Appendix 2.2  Collection of Adverse Events .................................................................... 82
Appendix 2.3  Assessment of Adverse Events .................................................................. 82
Appendix 2.4  Serious Adverse Event Collection Time Frame ...................................... 85
Appendix 2.5  Serious Adverse Event Onset and Resolution Dates............................... 85
Appendix 2.6  Fatal Outcome ............................................................................................ 85
Appendix 2.7  Pregnancy ................................................................................................... 86
Appendix 2.8  Abuse, Misuse, Overdose and Medication Error.................................... 86
Appendix 2.9  Urgent Safety Measures............................................................................. 87
Appendix 2.10  Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting ............................................................................................................ 88
Appendix 3  Genetics .............................................................................................................. 89
Appendix 4  Diagnostic Criteria/Disease Classification...................................................... 91
Appendix 5  Abbreviations..................................................................................................... 92
Appendix 6  Protocol History ................................................................................................ 96
11. REFERENCES...................................................................................................................... 97
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Tables
Table 1. Schedule of Study Procedures and Assessments............................................................ 21
Table 2. Non-PK Laboratory Assessments in Screening and Treatment...................................... 23
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 ..................................................................... 23
Table 4. Objectives and Endpoints ............................................................................................... 32
Table A1 Adverse Event Relationship Categorization ................................................................. 83
Figures
Figure 1. Study Schematic Diagram ............................................................................................. 20
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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 North America and Europe 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
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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.
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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.
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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 at the central lab.
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.
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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.
14.
Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule
ADAMTS-13, hamster protein, or other constituents of SHP655.
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
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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%
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
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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.
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
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 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.
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1.2 Schema
Figure 1. Study Schematic Diagram 
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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
Serum 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
Modified ITP Bleeding 
Score
X
X
ADAMTS-13 Antigen & 
Activity
X
Xh
Xp
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
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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)
Anti-rADAMTS-13 
Inhibitory antibodies
X
X
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 double 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.
p. ADAMTS-13 activity during the weekly follow up period will be measured locally (in addition to centrally) for 
determining the need for IP supplementation in the first 4 weekly follow up visits.
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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
Chemistry (except LDH)
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 6.2.3).
b Do not collect if daily IP infusion #2 (dose 12h post-PEX) is discontinued (see section 6.2.6).
c Collect these time-points in relation to the end of PEX if IP infusion #1 (dose immediately post-PEX) is 
discontinued (see section 6.2.6).
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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.
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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).
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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).
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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.
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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.
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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.
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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
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3.1.3 Exploratory Objectives
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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) 
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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
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Exploratory Objectives
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
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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.
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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. 
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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 1.5 years. 
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.
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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 at the central lab
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)
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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
14. Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent 
molecule ADAMTS-13, hamster protein, or other constituents of SHP655.
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 16 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
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
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.
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.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
SHP655 and placebo (0.9% saline)
Dosage form:
Lyophilized formulation 
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 Hypersensitivity to SHP655
SHP655 should not be administered in patients with known hypersensitivity to any of the 
components of rADAMTS13. As with any i.v. protein product, allergic-type hypersensitivity 
reactions are possible. Subjects must be closely monitored for any symptoms throughout the 
infusion period. Subjects should be informed of the early signs of hypersensitivity reactions 
including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and 
anaphylaxis. If these symptoms occur, the administration should be discontinued immediately. 
In case of shock, standard medical treatment for shock should be implemented.
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6.2.2 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.
6.2.3 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.
6.2.4 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. 
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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.
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.
6.2.5 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.
6.2.6 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).
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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.
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Investigational product must be stored in accordance with labeled storage conditions. 
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.
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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.
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 
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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.
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).
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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: recommended dose of 375mg/m2 iv once weekly x 4 weeks. The first dose will 
be administered within two days of enrollment. All doses are recommended to 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.
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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.
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.
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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

Screen failure

Other (must be specified in CRF)
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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.
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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 randomized. 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).
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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.
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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.
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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)
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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. 
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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 is performed locally and 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 is performed locally and 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).
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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
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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. 
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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). The DMC will be consulted if the 
study is discontinued.
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. 
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Analyses of the data for DMC review will be conducted according to the DMC charter and DMC 
SAP. 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.
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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.
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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
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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
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9.6.2
 
 
9.6.3
 
 
9.6.4
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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.
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10. 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.
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Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements.
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
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.
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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. 
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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 except Richmond Agitation Sedation 
Scale (RASS) 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.
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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.
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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 
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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 and applicable 
regulatory authority 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.
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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.
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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 
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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
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Is an important medical event. Note: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include:
Bronchospasm associated with anaphylaxis requiring intensive treatment in an emergency room 
or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or the 
development of drug dependency or drug abuse.
Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A 
virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V)
Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated form the pharmacological properties of a product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
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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 to 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.
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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.
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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
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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
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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.
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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.
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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
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The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
Appendix 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).
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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. 
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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.
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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 
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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
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Abbreviation
Definition
FDA
Food and Drug Administration 
FFP
Fresh frozen plasma
FVIII
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
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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 
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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
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Appendix 6  Protocol History 
Document
Date
Global/Country/Site Specific
Protocol Amendment 1.2
01 APR 2019
Non-UK
Protocol Amendment 1.1 UK
18 MAR 2019
UK
Original Protocol
03 OCT 2018
Global
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11. 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 
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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-
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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-
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Bryant, B. J. & Klein, H. G. 2007. Pathogen inactivation: the definitive safeguard for the blood 
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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 
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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,
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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,
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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-
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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.
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allergic reactions with fresh frozen plasma or cryo-supernatant plasma in the treatment of 
thrombotic thrombocytopenic purpura. J. Clin. Apher, 16, 134-138.
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solvent detergent treated plasma. Transfus Apher Sci, 35, 235-238.
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Spasoff, R. A. 1991. Comparison of plasma exchange with plasma infusion in the 
treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N 
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pathogenesis, diagnosis and potential novel therapeutics. Journal of Thrombosis and 
Haemostasis, 15, 1889-1900.
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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.
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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.
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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.
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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.
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For non-commercial use only

Prot_000.pdf: 
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.
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PROTOCOL SIGNATURE PAGE
Sponsor’s (Shire) Approval
Signature:
Date:
, MD
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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:
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Shire 
Clinical Study Adverse Event Form for 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
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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
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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
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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
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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
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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
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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
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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
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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.
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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.  
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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. 
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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
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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
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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.
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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.
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1.2 Schema
Figure 1. Study Schematic Diagram 
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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
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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.
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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).
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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.
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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).
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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).
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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.
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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.
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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.
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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
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3.1.3 Exploratory Objectives
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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) 
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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
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Exploratory Objectives
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
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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. 
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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. 
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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.
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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)
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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.
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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.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
SHP655 and placebo (0.9% saline)
Dosage form:
Lyophilized formulation 
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.
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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.
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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).
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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. 
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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.
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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.
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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).
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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.
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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.
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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)
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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.
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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).
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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.
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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.
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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)
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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. 
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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).
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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
 
 
 
 
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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. 
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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. 
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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.
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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.
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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
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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
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9.6.2
 
.
9.6.3
 
 
9.6.4
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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.
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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.
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Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements.
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
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.
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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. 
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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.
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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.
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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 
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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.
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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.
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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 
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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
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Is an important medical event. Note: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include:
Bronchospasm associated with anaphylaxis requiring intensive treatment in an emergency room 
or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization; or the 
development of drug dependency or drug abuse.
Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), hepatitis A 
virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), or 
parvovirus B19 (B19V)
Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed, but 
not on the basis of what might be anticipated form the pharmacological properties of a product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
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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.
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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.
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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
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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
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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.
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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.
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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
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The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
Appendix 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).
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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. 
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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.
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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 
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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
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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
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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 
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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
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APPENDIX 6  PROTOCOL HISTORY 
Document
Date
Global/Country/Site Specific
Original Protocol
03 OCT 2018
Global
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10. REFERENCES
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Alwan F, Vendramin C, Langley K & Et Al. 2016. Presenting ADAMTS13 Antigen Level 
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Balduini, C., Gugliotta, L., Luppi, M., Laurenti, L., Klersy, C., Pieresca, C., Quintini, G., Iuliano, 
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methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic 
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Bandarenko, N. & Brecher, M. E. 1998. United States thrombotic thrombocytopenic purpura 
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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 
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Terrell, D. R., Vesely, S. K. & George, J. N. 2013. Multiple major morbidities and 
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George, J. N. 2007. Evaluation and management of patients with thrombotic thrombocytopenic 
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Terrell, D. R., Vesely, S. K. & George, J. N. 2015. Depression and cognitive impairment 
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Benhamou, Y., Vanhille, P., Servais, A., Bordessoule, D. & Coindre 2014. Preemptive 
rituximab infusions after remission efficiently prevent relapses in acquired thrombotic 
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Köhler, M. 2000. Hepatitis C Virus Transmission through Quarantine Fresh-frozen 
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Kessler, C. S., Khan, B. A. & Lai-Miller, K. 2012. Thrombotic Thrombocytopenic Purpura: A 
Hematological Emergency. Journal of Emergency Medicine, 43, 538-544.
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Giuffrida, G., Laurenti, L. & Mannucci, P. M. 2008. ADAMTS13 and anti-ADAMTS13 
antibodies as markers for recurrence of acquired thrombotic thrombocytopenic purpura 
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Grillberger, L., Hasslacher, M., Knöbl, P., Ehrlich, H. & Scheiflinger, F. 2011. 
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ADAMTS13. J Thromb Haemost, 13, 2053-62.
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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.
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thrombotic thrombocytopenic purpura - current perspectives and new treatment 
strategies. Expert Rev Hematol, 9, 209-221.
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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.
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during acute episodes and use of prophylaxis to prevent relapse. Journal of Thrombosis 
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Zheng, X. L. 2015. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic 
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For non-commercial use only

SAP_005.pdf: 
STATISTICAL ANALYSIS PLAN 
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
SAP Version and Date: 
Version Final : 06-JAN-2022
SHP655-201
For non-commercial use only


Takeda                                                       CONFIDENTIAL 
Page 1 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
  
STATISTICAL ANALYSIS PLAN 
SHP655-201 (rADAMTS-13) 
PHASE 2 
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 IDENTIFIER: SHP655-201 
 
Study Sponsor(s): 
Takeda Development Center Americas, Inc. (TDC Americas) 
95 Hayden Avenue, Lexington, MA 02421, US 
AND 
Baxalta Innovations GmbH*, 
Industriestrasse 67, A-1221 Vienna, AUSTRIA 
 
*Baxalta, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited 
 
Author: 
 IQVIA  
Protocol: 
SHP655-201 Protocol Amendment 4.0 17Sep2020 
SAP Version #: 1.0 
 
SAP Date: 
2022 January 06 
Status: 
 Final 
 
 
For non-commercial use only


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CONFIDENTIAL 
Page 3 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
REVISION HISTORY 
Version  Issue Date 
Summary of Changes 
Author 
0.1 
07 Feb 2020 
New Document 
0.2 
19 Apr 2020 
Development version 
0.3 
14Oct2020 
Final version 
Note: This is the first filed version as 
considered approved for first use to 
handle analysis. 
0.4 
 05 Oct 2021 
x Updated as per the latest 
protocol amendment 4.0. 
1.0 
06 Jan 2022 
Added rescue medication 
Updated ADA and NDA 
classification in Section 7.2.1 
Update censoring rules for “time to” 
variables 
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Page 4 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
TABLE OF CONTENTS 
REVISION HISTORY ......................................................................................................3 
TABLE OF CONTENTS ..................................................................................................4 
ABBREVIATIONS ............................................................................................................8 
1. 
INTRODUCTION................................................................................................10 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS .......................................10 
2.1 
Objectives ..........................................................................................................10 
2.1.1 Co-Primary Objectives...............................................................................10 
2.1.2 Secondary Objectives.................................................................................10 
2.1.2.1 PK/PD Objectives ............................................................................10 
2.1.2.2 Safety/Efficacy Objectives ...............................................................11 
2.1.3 Exploratory Objectives ..............................................................................11 
2.2 
Estimands ..........................................................................................................12 
2.3 
Endpoints ..........................................................................................................14 
2.3.1 Primary Endpoints .....................................................................................14 
2.3.2 Secondary Endpoints .................................................................................14 
2.3.2.1 Pharmacokinetic (PK) and Pharmacokinetic/Pharmacodynamic 
(PK/PD) Endpoints ...........................................................................14 
2.3.2.2 Safety and efficacy ...........................................................................14 
2.3.2.3 Exploratory outcomes ......................................................................15 
2.3.2.4 
 .....................................15 
3. 
STUDY DESIGN ..................................................................................................16 
3.1 
General Description ..........................................................................................16 
3.2 
Randomization ..................................................................................................19 
3.3 
Blinding .............................................................................................................19 
3.4 
Sample Size and Power Considerations ............................................................19 
4. 
STATISTICAL ANALYSIS SETS .....................................................................19 
4.1 
Screened Set (SCR) ...........................................................................................19 
4.2 
Randomized Set (RAND) .................................................................................19 
4.3 
Safety Analysis Set ...........................................................................................20 
4.3.1 Safety Analysis Set (SAS) .........................................................................20 
4.3.2 aTTP Safety Analysis Set (aTTP-SAS) .....................................................20 
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Page 5 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
4.4 
Full Analysis Set (FAS) ....................................................................................20 
4.5 
Per-protocol Analysis Set (PP) .........................................................................20 
4.5.1 COVID-19 Impact Assessment..................................................................21 
4.6 
Pharmacokinetic Set (PK) .................................................................................21 
4.7 
Pharmacodynamic Analysis Set (PD) ...............................................................21 
5. 
STUDY SUBJECTS .............................................................................................22 
5.1 
Disposition of Subjects .....................................................................................22 
5.2 
Demographic and Other Baseline Characteristics.............................................22 
5.3 
Medical History .................................................................................................23 
5.4 
Prior Medications, Therapies, Procedures and Non-Drug Therapies ...............23 
5.5 
Concomitant Medications, Therapies, Procedures and Non-Drug Therapies ...24 
5.6 
Immunosuppressive Therapies ..........................................................................25 
5.7 
Exposure to Investigational Product .................................................................25 
5.8 
Exposure to PEX ...............................................................................................26 
5.9 
Measurements of Treatment Compliance .........................................................26 
5.10 
Protocol Deviations ...........................................................................................26 
5.11 
COVID-19 Vaccination Follow Up ..................................................................27 
6. 
EFFICACY ANALYSES ....................................................................................27 
6.1 
Analyses of Primary Efficacy Endpoint ............................................................27 
6.2 
Analyses of Secondary Efficacy Endpoints ......................................................27 
6.2.1 Assessment of Remission ..........................................................................28 
6.2.1.1 Platelet and LDH Recovery ..............................................................28 
6.2.1.2 Clinically Relevant Bleeding ...........................................................28 
6.2.1.3 PEX administration ..........................................................................28 
6.2.2 Exacerbation and Relapse ..........................................................................29 
6.2.3 aTTP related complications .......................................................................29 
6.2.4 
 ............................................................29 
6.2.5 Rescue Medication .....................................................................................30 
6.2.6 Sensitivity Analyses of Secondary Efficacy Endpoint(s) ..........................30 
6.3 
Multiplicity Adjustment ....................................................................................30 
6.4 
Control of Type I Error .....................................................................................30 
6.5 
Analyses of Exploratory Endpoints ..................................................................30 
6.5.1 
.................30 
6.5.2 
...............................30 
6.5.2.1
..........................................................................30 
6.5.2.2
..........................................................................31 
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Page 6 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
6.5.2.3 
.............................................31 
6.5.2.4 
..........................................................................31 
6.5.2.5 
.....................................................................................32 
7. 
SAFETY ANALYSIS...........................................................................................32 
7.1 
Adverse Events..................................................................................................32 
7.2 
Clinical Laboratory Data ...................................................................................33 
7.2.1 Immunogenicity .........................................................................................35 
7.3 
Vital Signs .........................................................................................................36 
8. 
PHARMACOKINETIC ANALYSIS .................................................................36 
8.1 
Statistical Analysis of Pharmacokinetic Data ...................................................37 
9. 
PHARMACODYNAMIC ANALYSIS...............................................................37 
9.1 
Pharmacodynamic Data ....................................................................................37 
9.1.1 Primary Pharmacodynamic Endpoint and Analysis ..................................37 
9.1.1.1 Analyses of Pharmacokinetic/Pharmacodynamic Relationships .....37 
10. 
OTHER ANALYSES ...........................................................................................38 
10.1 
....................................38 
10.1.1 
.....................................38 
10.1.1.1 
.....................................................................38 
10.1.1.2 
...................39 
10.1.1.3 
 ....................................................39 
10.1.1.4 
 
............................................................................................39 
10.1.1.5 
 ...................40 
10.1.1.6 
 
 ..................................................................................40 
10.1.1.7 
 
 ..........41 
10.1.1.8 
 ..........................................42 
10.1.1.9 
 .........................................42 
10.2 
 ......................................................................42 
10.3 
 .....50 
10.4 
 ............................................50 
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Page 7 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
11. 
INTERIM ANALYSIS/ DATA MONITORING COMMITTEE ...................51 
11.1 
Data Monitoring Committee (DMC) ................................................................51 
11.2 
Interim Analyses ...............................................................................................51 
12. 
DATA HANDLING CONVENTIONS ..............................................................52 
12.1 
General Data Reporting Conventions ...............................................................52 
12.2 
Definition of Baseline .......................................................................................52 
12.3 
Definition of Visit Windows .............................................................................53 
12.4 
Repeated or Unscheduled Assessments of Safety Parameters ..........................53 
12.5 
Handling of Missing, Unused, and Spurious Data ............................................53 
12.5.1 Missing Severity Assessment for Adverse Events.....................................53 
12.5.2 Missing Causality assessment for Adverse Events ....................................53 
12.5.3 Character Values of Clinical Laboratory Variables ...................................54 
12.5.4 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ..............................................................................54 
12.5.4.1 Incomplete Start Date ..................................................................54 
12.5.4.2 Incomplete Stop Date ..................................................................55 
12.5.5 Missing Relationship to Investigational Product or Study Procedure for 
Adverse Events ..........................................................................................56 
13. 
ANALYSIS SOFTWARE ...................................................................................56 
14. 
REFERENCES .....................................................................................................57 
15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ............................59 
16. 
APPENDICES ......................................................................................................59 
 
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Page 8 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
ABBREVIATIONS 
AE 
Adverse Event 
ALQ 
Above Limit of Quantitation 
SHP655 
rADAMTS-13 
BMI 
Body Mass Index 
BLQ 
Below Limit of Quantitation 
CI 
Confidence Interval 
CTMS 
Clinical Trials Management System 
aTTP 
Acquired Thrombotic Thrombocytopenic Purpura 
DMC 
Data Monitoring Committee 
ENR 
All Subjects Enrolled Set 
 
 
GH 
General Health 
H 
upper limit of the normal range 
 
 
 
 
 
 
IA 
Interim Analysis 
IP 
Investigational Product 
IRT 
Interactive Response Technology 
IU 
International Units 
L 
Lower limit of the normal range 
LDH 
Lactate dehydrogenase 
 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MOCA 
Montreal Cognitive Assessment 
 
 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamic 
 
 
PEX 
Plasma Exchange 
 
 
PK 
Pharmacokinetic 
 
 
 
RASS 
Richmond Agitation Sedation Scale  
 
 
SAE 
Serious Adverse Event 
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Page 9 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation (Specify This Spelling, To Use "SD" Consistently 
Instead Of "STD") 
SOC 
Standard of Care 
TEAE 
Treatment Emergent Adverse Event 
TTP 
Thrombotic Thrombocytopenic Purpura 
ULN 
Upper Limit of Normal 
 
 
WHO-DD 
World Health Organization-Drug Dictionary 
 
 
VWF 
Von Willebrand factor  
 
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Takeda                                                       CONFIDENTIAL 
Page 10 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
1. 
INTRODUCTION  
This statistical analysis plan (SAP) describes the rules and conventions to be used in the 
planned presentation and analysis of efficacy, pharmacokinetic (PK)/ pharmacodynamic 
(PD), laboratory and other safety data for the final study protocols version 4.0, dated 2020 
SEP17 (Global). It describes the data to be summarized and analyzed, including specifics 
of the statistical analyses to be performed. While this SAP defines the outlines the PK 
analysis, the specifics of PK analysis are detailed in the Clinical Pharmacology Analysis 
Plan (CPAP). 
All analysis and summaries as well as health economics and outcome research data, will 
be prepared and reported according to this SAP document except the population PK/PD 
modeling. The population PK/PD modeling will be conducted outside the SAP, a modeling 
report will be generated and provided with clinical study report. 
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.  
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Co-Primary Objectives 
x Assess the PK of ADAMTS-13 in aTTP subjects treated for an acute episode by 
daily PEX, immunosuppressant therapy, with or without SHP655 supplementation 
x Study the PK/PD relationship between ADAMTS-13 activity levels on 
pathophysiological biomarkers as well as clinical efficacy parameters 
2.1.2 Secondary Objectives 
2.1.2.1 
PK/PD Objectives 
x 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 
x Evaluate ADAMTS-13 activity levels in subjects up to 30 days after TTP episode 
remission  
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Takeda                                                       CONFIDENTIAL 
Page 11 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
x 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 
2.1.2.2 
Safety/Efficacy Objectives  
x 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 
x Evaluate the occurrences of aTTP related complications, (including death, stroke, 
MI, and organ failure) aTTP relapses*, exacerbations** and end-organ function 
improvement 
x Evaluate the time to aTTP related complications (including death, stroke, MI, and 
organ failure), aTTP relapses*, exacerbations** and end-organ function 
improvement  
x 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 
2.1.3 Exploratory Objectives 
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Takeda                                                       CONFIDENTIAL 
Page 12 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
2.2 
Estimands 
There is no primary estimand relating to PK/PD or safety for this study due to the type of 
data being collected to support the primary objective.  
The primary efficacy estimand, based on the secondary efficacy endpoint, that is likely to 
support regulatory decisions, is described in Table 1.
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Takeda                                                       CONFIDENTIAL 
Page 13 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
Table 1 List of Select Estimands  
 
* When developing estimands for the study, it was decided that using the intention to treat principal with focus on time to 
resolution of an acute event, regardless of use of rescue medication as an intercurrent event was not appropriate for analysis of this 
study due to the purpose of a subject needing this type of intercurrent event. It was decided that due to the need of administering 
rescue medication to resolve the event it would provide an unbiased estimate of the efficacy endpoint and therefore not used. 
 
Estimand 
 
Definition 
Attributes 
A: Population 
B: Variable (or 
endpoint) 
C: Strategy for addressing intercurrent 
event 
D: 
Population-
level 
summary 
Primary 
Efficacy  
The primary 
efficacy estimand 
is based on the 
secondary 
efficacy 
endpoint, time to 
remission.   
Adults (18-75 
years old) with 
aTTP as defined 
through inclusion 
and exclusion 
criteria as stated 
in the protocol, 
who are 
experiencing an 
acute TTP event. 
Time to 
remission, 
defined as 
platelet count 
≥150,000/μL, 
confirmed by a 
second platelet 
count 
≥150,000/μL and 
LDH <2 ULN 48 
hours following 
initial 
normalization. 
Subjects who drop out will be censored at 
their last visit date at which normalization 
assessments could not be determined. 
 
Subjects who complete the study will be 
censored at their study completion date at 
which normalization assessments could not 
be determined. 
 
Subjects receiving rescue medicine will be 
included as failure (no event) and will be 
right censored for the purpose of the KM 
survival curve estimate *. 
KM 
survival 
curve and 
log rank test 
to compare 
the SoC to 
each IP arm. 
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Page 14 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
2.3 
Endpoints 
2.3.1 Primary Endpoints 
1. PK: ADAMTS-13 activity levels  
2. PD: Platelet count and LDH levels 
2.3.2 Secondary Endpoints 
2.3.2.1  Pharmacokinetic (PK) and Pharmacokinetic/Pharmacodynamic (PK/PD) 
Endpoints 
1. The PK/PD temporal relationship of safety and 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% 
2.3.2.2 Safety and efficacy 
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 ULN48 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 ≤30days 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:  
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Takeda                                                       CONFIDENTIAL 
Page 15 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
 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 relative to 
baseline. 
10. Occurrence of antibodies to SHP655 
11. Occurrence of AEs and SAEs, and specifically product-related AEs and SAEs 
12. Clinically relevant changes in vital signs, clinical chemistry, and hematology 
13. Occurrence of subjects receiving rescue therapy 
14. Occurrence of subjects meeting rescue criteria 
2.3.2.3 Exploratory outcomes  
2.3.2.4 
  
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Page 16 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
3. 
STUDY DESIGN 
3.1 
General Description 
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:  
x Arm 1 – SoC plus placebo (n=10) Subjects will receive daily PEX and placebo 
immediately after PEX and 12±1 hour after completion of PEX.  
x Arm 2 – SoC with SHP655 once daily (n=10) Subjects will receive daily PEX and 40 
IU/kg ±4 IU/kg SHP655 once daily immediately after PEX and placebo 12±1 hour after 
completion of PEX. 
x Arm 3 – SoC with SHP655 twice daily (n=10) Subjects will receive daily plasma 
exchange and 40 IU/kg ±4 IU/kg SHP655 twice daily immediately after PEX and 12±1 
hour after completion of PEX. 
The first PEX and IP may be administered in three scenarios: 
x First PEX completed >4 hours prior to study enrollment: the first dose of IP should be 
administered immediately after the second PEX (first PEX completed on study) 
x First PEX completed İ4 hours prior to study enrollment: the first dose of IP should 
be administered as soon as possible, but no more than 4 hours after the initial PEX 
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Page 17 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
x First PEX delayed and randomization into study is complete: subject may receive a 
dose of IP prior to initiation of PEX, provided post-infusion PK samples according to 
Table 2 in Protocol are anticipated to be drawn. PEX initiation should never be 
delayed in order to complete study enrollment or study procedures. 
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.  
 Prior to protocol amendment 4, after resolution of the TTP episode, IP (placebo in Arm 1; 
SHP655 40 IU/kg ±4 IU/kg Arms 2 and 3) will be administered once weekly (maximum of 4 
weekly doses of 40 IU/kg) if ADAMTS-13activity at the local lab is <50%. Activity must be 
measured at least once weekly and >72h after the last IP dose.  
Post protocol amendment 4, after confirmed remission of the TTP episode, subjects will be 
given additional open-label IP (SHP655 40 IU/kg ±4 IU/kg) if ADAMTS-13 activity at the 
local lab is <50%. ADAMTS13 activity should be monitored Q3 Day ±1 days for 2 weeks and 
Q1Week ±3 days for 2 additional weeks. The overall study design is illustrated in Figure1. 
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Page 18 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
Figure 1 Study Design  
 
 
 
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Takeda                                                       CONFIDENTIAL 
Page 19 of 59 
Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
3.2 
Randomization 
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule. 
After screening, individual subject treatment is automatically assigned by the interactive 
response technology (IRT) to 1 of 3 arms. In the event enrollment in an arm is full, subjects will 
be randomly assigned to the remaining arm(s). 
Subjects will independently be randomized to PK sampling schedule A or B, which differ in 
the sampling days starting with PEX#4 and thereafter.   
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. 
3.3 
Blinding  
This is a double blinded study.  
Double blind administration of placebo or SHP655 is given twice daily in all arms until 
remission is achieved. Prior to protocol amendment 4, the supplementation with placebo or 
SHP655 after remission was blinded. After the amendment, the supplementation after 
remission is open label.  
3.4 
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. 
4. 
STATISTICAL ANALYSIS SETS 
Analysis set identification will be established and approved ahead of database lock or any 
intermediate interim analyses that are planned for submission.  
4.1 
Screened Set (SCR)  
The screened set will consist of all subjects who have signed an informed consent document. 
4.2 
Randomized Set (RAND) 
The randomized set will consist of all subjects in the screened set for whom a randomization 
number has been assigned.  
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Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
For analysis, information on randomization, such as date of randomization will be pulled from 
the eCRF and treatment assignment will be pulled directly from the IRT randomization file. 
Handling of unblinded data is discussed in the Biostatistics unblinding plan. 
4.3 
Safety Analysis Set  
4.3.1 Safety Analysis Set (SAS)  
The safety analysis set will consist of all subjects randomized, who receive any dose of 
investigational product.  
All safety analyses will be performed according to the treatment regimen actually received 
regardless of the randomized treatment regimen. 
4.3.2 aTTP Safety Analysis Set (aTTP-SAS) 
The aTTP safety analysis set will consist of all subjects in the safety analysis set with a 
confirmed aTTP diagnosis. Subjects provisionally randomized, and subsequently diagnosed 
with a condition different from aTTP, will not be included in this analysis set.  
No supplemental analyses are planned for this analysis set.  
4.4 
Full Analysis Set (FAS) 
The full analysis set will include all enrolled subjects with confirmed aTTP diagnosis who are 
treated with a study product and have an ADAMTS-13 activity reading from at least one post 
infusion sample. Analysis will be performed according to allocated treatment regimen 
regardless of the treatment regimen actually received. 
4.5 
Per-protocol Analysis Set (PP) 
The per-protocol set will consist of all subjects in the full analysis set who do not have protocol 
deviations that may affect the efficacy endpoints. Protocol deviations documented during the 
conduct of the study in the Clinical Trials Management System (CTMS) will be taken into 
consideration during the review. 
During the study, protocol deviations review meetings will be held on a regular basis. Potential 
protocol deviations will be identified to be included into the CTMS upon team agreement. 
Prior to study unblinding, a meeting will be held to assess the impact on efficacy outcomes of 
the 
protocol 
deviations 
identified 
throughout 
the 
conduct 
of 
the 
study. 
A 
major/important/critical deviation from CTMS will not necessarily influence the study results 
and will therefore not necessarily lead to exclusion from the Per Protocol analysis set. At this 
meeting the decision will be made on whether a subject will be excluded from the Per Protocol 
analysis set or not. The meeting will be attended by participants from Data Management, 
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Statistical Analysis Plan v 1.0 
Protocol Number: SHP655-201 
06 Jan 2022 
 
 
Biostatistics Clinical Development (including medical monitors/advisors). Team members 
from both IQVIA and the sponsor will attend. 
As part of blind data review prior to database lock, study medics may identify further events 
that exclude subjects from analysis.  Such events will either be documented in the CTMS tracker 
if appropriate to conduct of the study or flagged through programming. As discussed above, 
assessment will be made to their impact on leading to exclusion from the analysis set or not.  
Analysis will be performed according to the treatment regimen received. 
4.5.1 COVID-19 Impact Assessment 
In reaction to the COVID-19 pandemic, deviations listed in the CTMS tracker with prefix 
“COVID-19” will be considered separately as part of the subject selection for exclusion from 
the per-protocol analysis set. The impact to this study is likely minimal since the study was not 
put on enrollment hold.  The acute event the enrolled subjects are experiencing requires 
hospitalization which assures that protocol procedures will be followed for the duration.  No 
additional measures are anticipated to compensate for missing data. Supportive analyses are 
detailed in section 5.10. Additionally, during the blind data review meeting, if the rate of 
protocol deviations recorded as an impact of COVID-19 is higher than anticipated, analyses 
described in section 6, may be repeated and an additional COVID-19 per-protocol analysis set 
may be developed as part of a sensitivity analysis.  
4.6 
Pharmacokinetic Set (PK) 
The Pharmacokinetic set will consist of all enrolled subjects with confirmed aTTP diagnosis 
who have received at least 1 dose of investigational product and who have at least 1 evaluable 
post-dose PK value (ADAMTS-13 antigen and ADAMTS-13 activity). The PK data may be 
excluded from the summaries on the affected days if not valid due to protocol 
violations/deviations or events with potential to significantly affect the concentration data 
(examples include, but may not be limited to: incomplete or missed corresponding dose, sample 
processing errors that lead to inaccurate bioanalytical results, rescue treatment). 
Samples from subjects receiving rescue medicine will be excluded from the primary and 
secondary endpoint analysis after the rescue medicine is initiated. For pharmacokinetic 
modeling, all available PK data may be considered.  For further details, refer to the separate 
Modeling and Simulation Plan. 
4.7 
Pharmacodynamic Analysis Set (PD) 
The pharmacodynamic (PD) set will consist of all enrolled subjects with confirmed aTTP 
diagnosis who have received at least 1dose of investigational product and who have at least 1 
evaluable post-dose PD value; this includes LDH and platelets results. Samples from subjects 
receiving rescue medicine will be excluded from the primary and secondary endpoint analysis 
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after the rescue medicine is initiated. For PK/PD modeling, all available PD data may be 
considered. 
Subjects in this population will be included for all PD summaries. All PD analyses will be 
performed according to the treatment received regardless of the randomized treatment regimen. 
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
Disposition of subjects will be presented for the Screened analysis set in the planned listings 
and the table summaries.  
The number of subjects included in each analysis set (i.e., Randomized, Safety, aTTP safety, 
Full, PK, PD and Per Protocol Set) will be summarized by treatment arm and overall. The 
Screened Set will be summarized only overall. 
Additionally, the number and percentage of subjects who completed or prematurely 
discontinued during the study will be presented for treatment arm. Reasons for premature 
discontinuation from the study as recorded on the termination page of the eCRF will be 
summarized (number and percentage) by treatment as a subset of the subjects who prematurely 
discontinued the study. Percentages for withdrawal are based on the number of subjects who 
prematurely withdraw from the study. 
The number of subjects screened, randomized and completed will be tabulated by site and 
country.  In addition, the duration of enrollment, in days, will be summarized for each site, 
country, and overall.  Duration of enrollment will be calculated as (last date of contact for any 
subject at that site - the first date of informed consent for any subject at that site + 1). 
Additionally, the presentation of planned listings will include the following: 
x Screen Failures (i.e., subjects who were screened but not randomized) including 
reasons for screen fail and details of any AEs. 
x Subject disposition. 
x Prior subject participation. 
x Inclusion/Exclusion criterion exceptions. 
x Assignment to analysis sets. 
x All subjects who prematurely discontinued during the study. 
5.2 
Demographic and Other Baseline Characteristics 
Demographic data and other Baseline characteristics will be presented by treatment arm and 
overall for the Safety Analysis Set and the Full Analysis Set. 
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No statistical testing will be performed for demographic or other Baseline characteristics.  
Quantitative and qualitative assessments will be summarized as specified in Section 12.1 
General Data Reporting Conventions.  
The following demographic characteristics will be summarized in the following order in the 
tables: age (years), sex, ethnicity, race, weight (kg), height (cm), and BMI (kg/m2). In addition, 
baseline creatinine clearance will be summarized for the purpose of capturing kidney 
manifestations.  
The following derivations based on eCRF reported results will be performed: 
 Subjects may fall under multiple race categories, if this occurs i.e. more than one race is 
selected on the eCRF, they will be counted in each. 
Height will be converted from inches (in) to centimeter (cm) as follows: 
ܪ݁݅݃ℎݐ (ܿ݉) = ܪ݁݅݃ℎݐ (݅݊) × 2.54 
Weight will be converted from pounds (lb.) to kilograms (kg) as follows: 
ܹ݁݅݃ℎݐ (݇݃) = ܹ݁݅݃ℎݐ (݈ܾ) × 0.453592 
Body mass index (BMI) will be derived as: 
ܤܯܫ ൬݇݃
݉ଶ൰=
ܹ݁݅݃ℎݐ(݇݃)
൤ܪ݁݅݃ℎݐ(ܿ݉)
100
൨
ଶ 
Creatinine Clearance derivations are described in section 6.5.2.1. 
5.3 
Medical History 
Medical history will be collected at the screening/ enrollment visit and will be coded using 
MedDRA Version 24.0, as documented by Data Management in the Data Coding guideline at 
the time of performing the analysis. They will be listed for the Safety Analysis Set. 
 The medical history will be summarized by system organ class (SOC) and preferred term (PT) 
for each treatment arm and overall for the Safety Analysis Set.  
5.4 
Prior Medications, Therapies, Procedures and Non-Drug Therapies 
Prior medications will be coded using the World Health Organization-Drug Dictionary (WHO-
DD) as documented by Data Management in the Data Coding guideline at the time of 
performing the analysis. Prior therapies and procedures will be coded using MedDRA Version 
24.0. 
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Prior medications, therapies or procedures are defined as any medication, therapy or procedure 
with both a start date and a stop date prior to the date of the first dose of investigational product. 
Missing and partial dates will be handled as described in section 12.5.4.  
The prior therapies, procedures and medication usage will be summarized by the number and 
proportion of subjects in each treatment arm and in overall subjects within each preferred term 
for the Safety Analysis Set. Multiple medication usage by a subject in the same category will 
be counted only once.  
All prior therapies, procedures and medication will be listed for the Safety Set. Listings will 
report the data as captured in the database and not make use of imputations as set out in section 
12.5.4. 
5.5 
Concomitant Medications, Therapies, Procedures and Non-Drug Therapies 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD) as documented by Data Management in the Data Coding guideline at the time of 
performing the analysis.  
Concomitant medication/Non-Drug Therapy/procedure is defined as any medication/ Non-
Drug Therapy/procedure with a start date prior to the date of the first dose of investigational 
product and continuing after the first dose of investigational product or with a start date between 
the dates of the first and last doses of investigational product (including follow up treatment), 
inclusive.   
Any medication/ Non-Drug Therapy/procedure with a start date after the date of the last dose 
of investigational product (including follow up treatment) is not be considered a concomitant 
medication/ Non-Drug Therapy/procedure. 
The concomitant therapies, procedure and medication usage will be summarized by the number 
and proportion of subjects in each treatment arm receiving each medication and in overall 
subjects within each preferred term for the Safety Analysis Set. Multiple medication usage by 
a subject in the same category will be counted only once.  
All concomitant therapies, procedures and medication will be listed for the Safety Analysis Set. 
Listings will report the data as captured in the database and not make use of imputations as set 
out in section 12.5.4. 
Immunosuppressive daily treatments will not be captured within the concomitant medications 
eCRF page. Presence of Methylprednisolone, Prednisone, Prednisolone, Rituximab or other 
approved treatment for this purpose will not be programmatically checked but as part of data 
review will be monitored.  
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5.6 
Immunosuppressive Therapies 
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.  
Corticosteroids will be coded using the World Health Organization-Drug Dictionary (WHO-
DD). 
All Immunosuppressive therapies will be summarized by the number and proportion of subjects 
in each treatment arm and in overall subjects within each category and preferred term (for 
Corticosteroids) for the Safety Analysis Set, separating by daily treatment period (collected on 
Immunosuppression Daily Treatment Period eCRF page), follow up (collected on 
Immunosuppression Follow Up Visits eCRF page) and overall. Multiple treatment usage by a 
subject in the same category will be counted only once. 
All Immunosuppressive therapies will be listed for the Safety Analysis Set. 
5.7 
Exposure to Investigational Product 
Exposure to investigational product will be summarized for the Safety Analysis Set by 
treatment arm and a listing will be presented by subject number giving administration details. 
Dose modifications made as a result of a TTP episode will be captured within this listing.  
Potency of ADAMTS13 activity in the SHP655 dosing solution will be used to derive the actual 
dose as follows:   
Actual dose (IU/kg) 
 = [FRETS (IU/mL) x actual dose volume (mL)]/ Baseline body weight (kg) 
Exposure to investigational product will be summarized by quantity, total number of doses 
and duration on treatment, defined as the sum of durations (stop date/time minus start 
date/time, in minutes) of all the infusions administered, accounting for interruptions, for 
Safety Analysis Set by treatment arm and by acute period (with reason for administration as 
“Acute treatment” as collected on eCRF page), post-remission period (with reason for 
administration as “Post-remission supplementation” as collected on eCRF page), and overall 
study. Actual dose will be listed and summarized.  
The number and percentage of subjects having an incidence of dose modifications (their second 
daily IP dose terminated) prompted by a TTP event, including a 95% confidence interval for 
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each of the proportions, will be summarized by treatment arm. The 95% confidence interval 
will be obtained from an exact Clopper-Pearson test in SAS®.  
5.8 
Exposure to PEX 
 
. PEX will be assigned to the period using the following 
logic: 
x 
For subjects who experience exacerbation, PEX with start date before exacerbation 
date will be considered as acute period; PEX with start date on or after exacerbation 
date will be considered as follow up period. 
x For subject without exacerbation, all PEX will be considered as acute period. 
A listing will be created by subject number and visit giving the date and time of PEX 
administration details, anticoagulant details, as well as volumes and types of replacement 
fluid(s) exchanged and blood losses. 
5.9 
Measurements of Treatment Compliance  
 Treatment compliance is not applicable for this protocol. 
A listing will be produced to display a subject planned treatment and actual treatment what 
they have received. 
5.10 
Protocol Deviations 
Protocol deviations will be recorded by the site separately from the clinical database. It will be 
obtained from the CTMS. The CRO/ sponsor will classify major and minor protocol deviations 
per the agreed protocol deviation management plan. The Takeda study team will review the 
protocol deviations and their classification throughout the study and before treatment 
unblinding and database lock. 
Decisions of the review will include accuracy of major and minor protocol deviations 
categorization. 
Confirmed major and minor protocol deviations will be documented in the Protocol Deviation 
tracker for the study. Major/minor protocol deviations will be summarized by category and site 
for each treatment arm (SHP655 and Placebo) and overall. Major/minor protocol deviations 
will be listed. Reporting of protocol deviations will be based on the randomized Set. 
COVID-19 related deviations will be summarized and listed in the same handling as described 
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5.11 
COVID-19 Vaccination Follow Up 
A listing will be created by subject number for COVID-19 vaccination follow up, as well as 
date of contact and method of contact. 
6. 
EFFICACY ANALYSES 
All efficacy analyses will be presented by treatment arm for the Full Analysis Set and then 
repeated on the Per-Protocol Analysis Set. Listings will be presented only on the Full Analysis 
Set. 
Baseline for all efficacy analyses is defined as the last observed value for the efficacy 
assessment prior to taking the first dose of investigational product (IP) (SHP655 or placebo) 
(based on dates or date/times), regardless of PEX administration timing. When time is not 
available, assessment occurring on the same day as the first dose are assumed to be pre-dose.  
It should be noted that due to the study design and entry of patients into the emergency room, 
Screening/ Enrollment visit may occur on the same day as the start of the treatment period, 
meaning scheduled assessments will not need to be duplicated. Any assessments taken on the 
day of treatment period start can be assumed to be prior to administration of IP.  
No formal statistical testing is planned for this study. and no significant tests are planned. All 
confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise. 
6.1 
Analyses of Primary Efficacy Endpoint 
Details of the primary endpoints, platelet counts and LDH levels, are discussed in the PK 
(section 8) and PD (section 9) analysis sections for both assessment of PK profiles of 
ADAMTS-13 and PK/PD relationships between ADAMTS-13 activity levels and 
pathophysiological biomarkers as well as clinical efficacy parameters.   
6.2 
Analyses of Secondary Efficacy Endpoints 
All time to event efficacy endpoints will be analyzed by the non-parametric Kaplan Meier (KM) 
estimator of the survival curve and by use of hazard ratios for SHP655 against Placebo arms. 
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. Graphical presentations of Kaplan-
Meier plot will be presented. Details on censoring is discussed in subsequent sections.  
Occurrence endpoints will be assessed as proportions and two-sided 95% CI for the proportions 
will be derived by exact Clopper-Pearson test in SAS®. 
Occurrence rates will include a Poisson CI using a normal approximation (estimate lambda 
from event proportion, using follow-up days as a time unit) 
λ= #events/person-days 
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95% CI :  
[λ −1.96 ∗ඨ(
λ
persondays),
λ + 1.96 ∗ඨ ൬
λ
persondays൰] 
6.2.1 Assessment of Remission 
Time to normalization of platelet count is 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. An event of this type is identified by the investigator and 
captured in the eCRF as date of remission. A subject’s time to normalization of platelet counts 
will be censored at the day they take rescue therapy for those who do not adequately respond 
to treatment and take rescue medication or for those who respond to treatment after they receive 
rescue medication. Subjects who do not adequately respond to treatment and do not complete 
the study will be censored at the last available visit date. And subjects who do not adequately 
respond to treatment and complete the study will be censored at the date of study completion. 
Occurrence of remission is defined as a normal platelet count and LDH <2 ULN for at least 48 
hours following initial normalization of platelet count (acute episode period). An event of this 
type is identified as the date of visit to which remission is recorded. 
6.2.1.1 
Platelet and LDH Recovery 
Additional to assessment of remission, which is analyzed based on the site entered response to 
remission on platelet counts and LDH. Time to platelet recovery and time to LDH recovery will 
be individually analyzed based on post IP administration laboratory reported results. Platelet 
recovery is defined as the first recovery of platelet count ≥ 150,000/μL. LDH recovery is 
defined as the first recovery of LDH <2 ULN. A subject’s time to platelet recovery and time to 
LDH recovery will be censored at the day they take rescue therapy for those who do not 
experience the event and take rescue medication or for those who experience the event after 
they receive rescue medication. Subjects who do not experience the event and do not complete 
the study will be censored at the last available visit date. And subjects who do not experience 
the event and complete the study will be censored at the date of study completion. 
6.2.1.2 
Clinically Relevant Bleeding  
Modified Immune Thrombocytopenic Purpura (ITP) scores, per body system, are collected until 
remission of the acute event is achieved. Occurrence of ITP bleeding scores will be summarized 
over time by body system and treatment group. Individual scoring will be listed.  
6.2.1.3 
PEX administration 
Time to the stopping of PEX administration will be analyzed to gain an understanding of how 
consistently PEX use is being stopped compared to that of remission. An event of this type is 
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identified by the last known administration date of PEX. Subjects who do not experience the 
event and do not complete the study will be censored at the last available visit date. And 
subjects who do not experience the event and complete the study will be censored at the date 
of study completion. 
Incidence of PEX related events, including thrombosis at the site of line insertion, adverse 
reactions to plasma, including citrate reactions, allergic reactions, and TRALI will be 
summarized during the acute period, during the follow up period and for the study overall. 
Refer to Section 5.8 for the derivation of period for PEX administration 
6.2.2 Exacerbation and Relapse 
Time to first exacerbation (aTTP episode ≤30 days following remission) and time to first relapse 
(aTTP episode >30 days following remission) endpoints will be counted from the date of 
remission. If a subject experiences multiple exacerbations/relapses during their time on the 
study, for the purposes of this analysis they will only be considered at their earliest 
exacerbation/ relapse, i.e. if a subject relapse’s having already experienced an exacerbation, 
they will only be counted in their earliest (first) exacerbation. Subjects who do not experience 
the event and do not complete the study will be censored at the last available visit date. And 
subjects who do not experience the event and complete the study will be censored at the date of 
study completion. 
The occurrence of relapse/exacerbations and the time to relapse/exacerbation will be 
summarized separately by subjects enrolled before or after Protocol Amendment 4.0. 
6.2.3 aTTP related complications  
The occurrence of an aTTP related complications including death, stroke, myocardial infarction 
(MI) and organ dysfunction will be assessed from the time a subject is first administered 
treatment.  
Death in the context of an aTTP related complication will be determined as any AE where 
‘Serious Reason(s)’ is captured as ‘Death’. 
All AEs will be coded, as discussed in section 7.1 and prior to database lock/ any interim 
reporting, a review of the adverse event form will occur at which point identification of AEs 
will be assessed by the study medics to classify terminology associated with stroke and MI. 
6.2.4 End-Organ Function Improvement 
Organ dysfunction definitions are described in section 6.5.2. Individually, chronic renal 
insufficiency, neurologic impairment and neurocognitive deficits will be assessed as the 
number of subjects not reaching normalization within the 90-day observation period. 
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6.2.5 
Rescue Medication 
The number and percentage of subjects who met rescue medication criteria will be tabulated 
by treatment arm and reason for initiating rescue medication.  
The number and percentage of subjects who received rescue medication will be tabulated by 
treatment arm and preferred term.  
Rescue medications will be listed. 
6.2.6 
Sensitivity Analyses of Secondary Efficacy Endpoint(s) 
As part of a sensitivity analysis on the secondary efficacy endpoints, reporting of time to 
remission will be repeated, accounting for the use of rescue medication, where applicable. For 
subjects where rescue therapy is initiated and the administration of IP (SHP655 or placebo) is 
suspended, subjects will not be censored and instead followed to remission for the purpose of 
analysis. Subjects who do not adequately respond to treatment and do not complete the study 
will be censored at the last available visit date. And subjects who do not adequately respond to 
treatment and complete the study will be censored at the date of study completion. 
6.3 
Multiplicity Adjustment 
Not applicable. 
6.4 
Control of Type I Error 
Not applicable 
6.5 
Analyses of Exploratory Endpoints 
6.5.1 
  
 
6.5.2 
 
6.5.2.1 
  
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6.5.2.2 
  
6.5.2.3 
  
6.5.2.4 
  
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6.5.2.5 
 
7. 
SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Analysis Set. Listings will be presented 
only on the Safety Analysis Set. Safety variables include AEs, clinical laboratory variables, and 
vital signs. For each safety variable, the last value collected before the first dose of 
investigational product will be used as baseline for all analyses of that safety variable. Listings 
will be presented only on the Safety Analysis Set. 
All safety analyses will be conducted according to the treatment the subject received. 
7.1 
Adverse Events  
Adverse events will be coded using MedDRA Version 24.0.  
An AE (classified by preferred term) that occurs during the Double-blind Evaluation Phase will 
be considered a TEAE if it has a start date on or after the first dose of double-blind 
investigational product or if it has a start date before the date of the first dose of double-blind 
investigational product but increases in severity on or after the date of the first dose of double-
blind investigational product.  If more than 1 AE with the same preferred term is reported before 
the date of the first dose of double-blind investigational product, then the AE with the greatest 
severity will be used as the benchmark for comparison to the AEs occurring during the Double-
blind Evaluation Phase under the preferred term.  All AEs reported in the database will be used 
for analysis.  
An overall summary of the number of subjects with TEAEs as well as the number of events 
will be presented, including the number and percentage of subjects with any TEAEs within each 
of the following categories will be presented: 
x All TEAEs. 
x Severe TEAEs. 
x TEAEs related to IP. 
x TEAEs not related to IP. 
x TEAEs related to study procedure. 
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x Serious TEAEs. 
x TEAEs leading to discontinuation of study. 
x TEAEs leading to discontinuation/interruption of IP. 
x TEAEs leading to death. 
x Serious TEAEs related to IP. 
The overall summary will include the number and percentage of subjects having an TEAE by 
category.  
The number and percentage of subjects reporting TEAEs, as well as the number of events, in 
each treatment arm and overall will be tabulated by system organ class (SOC) and preferred 
term; by SOC, preferred term, and maximum severity. TEAEs considered related to 
investigational product will also be summarized by SOC and preferred term. If more than 1 AE 
occurs with the same preferred term for the same subject, then the subject will be counted only 
once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to investigational product. Presentation by SOC 
and PT will present SOC sorted alphabetically and PT within SOC by descending incidence. 
TEAEs and related TEAEs will be summarized by preferred term by descending frequency. 
Serious TEAEs, TEAEs leading to discontinuation of investigational product and serious 
TEAEs leading to death, will be summarized by SOC, preferred term and treatment arm.  
All AEs for each subject, including “was this AE a COVID-19 vaccination related 
complication?” information, will be listed for the Safety Analysis Set. 
The following derivations based on eCRF reported results will be performed: 
- 
Handling of unknown causality and unknown severity grades are described in Section 
12.5. 
- 
An AE is considered leading to discontinuation of study medication if indicated as 
“Drug withdrawn” in the eCRF. 
- 
An AE is considered leading to discontinuation of study if the AE is indicated as the 
primary reason why the subject did not complete the study from the Study 
Completion/Termination eCRF panel. 
- 
An AE is considered as leading to death if the question “Did the serious event result in 
death?” is indicated as “Yes” or if the outcome in the eCRF is indicated as “Fatal”. 
7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values (in SI units or conventional units depending 
on the study) and changes from baseline at each assessment time point as well as shift tables 
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from baseline to each visit for quantitative variables will be presented by treatment arm and 
overall for clinical laboratory variables. All laboratory results will be summarized by treatment 
arm. Serum pregnancy tests will only be listed. 
Results from the central laboratory, bioanalytical specialty laboratories and local laboratories 
will be included in the reporting for this study. Results will be presented using CDISC 
compliant terms and standard international (SI) units. Conversion factors to standardize results 
to SI units will be developed and maintained for sign off prior to database lock. 
The hematology panel is performed locally and 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 is performed locally and consists of ALT, AST, total bilirubin, 
alkaline phosphatase, blood urea nitrogen, creatinine, and glucose. LDH samples are collected 
separately to chemistry testing, tested locally. 
Other laboratory assessments include, ADAMTS-13 Gene mutation (central), blood type testing 
is (local), HIV1/2, HBV, HCV (central). ADAMTS-13 Activity is performed locally prior to 
IP, confirmed by the bioanalytical lab alongside the ADAMTS-13 Antigen testing. Anti-
rADAMTS-13 binding and inhibitory antibodies, including Anti-rADAMTS-13 binding total 
Ig, Anti-ADAMTS-13 inhibitory Ab, Anti-rADAMTS-13 inhibitory Ab are analyzed at the 
bioanalytical lab. VWF antigen and multimers (central) and pregnancy test: serum (local). 
 
 
The following derivations will be performed based on results obtained from the central 
laboratory and eCRF: 
- 
A result will be considered out of range if the observed result is less than the lower 
limit of the normal range (indicated as “L”) or larger than the upper limit of the 
normal range (indicated as “H”). The normal range will be provided by the central 
laboratory. 
- 
A result will be considered clinically significant if indicated as such by the 
Investigator on the eCRF. 
Central and local laboratory results for all parameters (planned or unplanned) will be listed for 
the Safety Analysis Set, including separate listings for abnormal and clinically significant 
results. 
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7.2.1 
Immunogenicity 
Summaries of both anti-drug antibodies (ADA) including rADAMTS-13 binding total Ig 
(Evaluation and Titers) and neutralizing antibodies (NAb), endogenous (Anti-ADAMTS13 
inhibitory antibody) and exogenous (Anti-rADAMTS13 inhibitory antibody) will be presented 
as a count based on detection of each antibody type by subject at both baseline and post baseline. 
These will be also assessed by acute period and a follow up period. Acute period and follow up 
period for ADA and Nab summary as classified as below: 
x Acute period: assessment occurred from the first to last doses of investigational 
product for acute treatment, inclusive. 
x Follow up period: assessments occurred from the date of last dose of investigational 
product for acute treatment, exclusive, to date of last dose of investigational product 
(including follow up treatment), inclusive. 
Where multiple assessments are collected at any given timepoint, if there is at least one positive 
identification this will be used for analyses.  
Each subjects ADA and NAb endogenous profiles will be categorized and summary counts will 
be presented by the following terms: persistent positive and transient positive. 
A subject’s profile on ADA or Nab endogenous results is thought to be transient positive if the 
subject is seen to have positive detection of the given antibody post administration of IP that 
later becomes negative by the time of study completion, regardless of the baseline assessment 
result and any in-between assessment results.  
A subject’s profile on ADA or Nab endogenous is thought to be persistent positive if the subject 
is seen to have a positive detection of the given antibody post administration of IP that is 
maintained through to the time of study completion, regardless of the baseline assessment result 
and any in-between assessment results. If the only positive detection is their end of study visit 
assessment this is also deemed persistent positive. 
For Nab exogenous, the following categories are defined based on Baseline (Screening) and 
post-dose (End of Study [EOS]) values: 
Persistent negative: negative at both Baseline/Screening and post-dose/EOS  
Persistent positive: positive at both Baseline/Screening and post-dose/EOS  
Baseline positive only: positive at Baseline/Screening and negative post-dose/EOS 
Missing: missing at Baseline/Screening, or post-dose/EOS, or both. 
Additionally, in order to assess the effect of ADA and NAb on primary efficacy endpoints, 
summary counts on ADA and NAb status at the time of remission, exacerbation and relapse 
will be presented. As well as summary counts of ADA and NAb titer values over time. 
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Since some patients might have unscheduled plasma exchange before their screening assay, all 
of the aforementioned summaries will be repeated on a subset of subjects that did not administer 
PEX prior to their screening assessment in order to see if there is an immediate change in 
antibody detection as a result of taking PEX. 
Multiple figures will be produced, these include:  
x Subject profile plot of ADAMTS-13 activity over time, by ADA status at baseline. 
x Subject profile plot of ADAMTS-13 antigen results over time, by ADA status at 
baseline. 
x Subject profile plot of ADAMTS-13 activity over time, by NAb status at baseline. 
x Subject profile plot of ADAMTS-13 antigen results over time, by NAb status at 
baseline 
x Subject profile plot of ADA titer results over time. 
x Subject profile plot of NAb titer results over time. 
Separate to the listing produced as part of the laboratory reporting as described in section 7.2 
ADA evaluations and titers and NAb concentrations will be listed with identification of is the 
ADA and NAb profiles are treatment induced and or treatment boosted. 
7.3 
Vital Signs 
Descriptive Summary statistics for vital sign (e.g., systolic and diastolic blood pressure, pulse 
rate and body weight) and their changes from baseline at each post-baseline visit and at the end 
of study will be presented by treatment arm and overall. 
The following derivations based on eCRF reported results will be performed: 
Body Temperature will be converted from Fahrenheit scale (ºF) to Celsius scale (ºC) as 
follows: 
B݋݀ݕ ܶ݁݉݌݁ݎܽݐݑݎ݁ (ᵒC) = 5
9 (ܤ݋݀ݕ ܶ݁݉݌݁ݎܽݐݑݎ݁ [ᵒF] −32) 
Weight and height will be converted as specified in Section 5.2. 
All vital signs data will be listed for the Safety Analysis Set. 
8. 
PHARMACOKINETIC ANALYSIS  
The pharmacokinetic analysis will be conducted by the pharmacokinetics CRO (IQVIA 
Pharmacokineticist) for Clinical Pharmacology and Pharmacokinetics Department of Takeda. 
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The methodology for the PK analysis is described in the Clinical Pharmacology Analysis Plan 
(CPAP). 
8.1 
Statistical Analysis of Pharmacokinetic Data 
Only descriptive statistical analysis will be done as detailed in the CPAP.  
Drug Concentration 
A listing of PK blood sample collection times, derived sampling time deviations, and levels of 
ADAMTS-13 activity and ADAMTS-13:Ag in original units reported by the bio-analytical 
laboratory and converted units, and change-from-baseline concentrations will be provided.   
Individual PK observed levels of ADAMTS-13 activity and ADAMTS-13:Ag in converted 
units and change-from-baseline values will be summarized and presented graphically.  
Pharmacokinetic Parameters 
Individual PK parameters of ADAMTS-13 activity and ADAMTS-13:Ag will be listed and 
summarized, and presented graphically.   
The categories for PK parameters summarized by status for ADA (binding total Ig) and for 
NAb (endogenous [Anti-ADAMTS13 inhibitory antibody] and exogenous [Anti-
rADAMTS13 inhibitory antibody]) are defined as follows.   
For ADA and Nab endogenous, the status will be considered as positive if at least one result 
measured on the corresponding study day is positive; otherwise, the status will be considered 
as negative for that study day.  
9. 
PHARMACODYNAMIC ANALYSIS 
9.1 
Pharmacodynamic Data 
9.1.1 
Primary Pharmacodynamic Endpoint and Analysis  
9.1.1.1 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships 
PK/PD relationships between ADAMTS-13 activity levels and pathophysiological biomarkers 
as well as clinical efficacy parameters will be explored through graphical displays. By use 
of scatter plots, individual subject ADAMTS-13 activity levels will be plotted against Platelet 
count and LDH levels over time differentiated by treatment group. 
Additionally, further analysis of PD data including modelling and relationships will be 
performed as set out in the Modelling and Simulation Plan. Secondary Pharmacodynamic 
Endpoints and Analysis 
The relationship between ADAMTS-13 activity and end-organ disease status (e.g., renal, 
neurologic, and cardiac) will be assessed graphically. By use of scatter plots and trend lines, 
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individual subject and central tendencies (mean, median) of ADAMTS-13 activity levels will 
be plotted against Creatinine Clearance levels, RASS scores and MoCA scores over time 
differentiated by treatment group. All three endpoints derivations are to be calculated as 
described in section 6.5.2. 
10. 
OTHER ANALYSES 
10.1 
 
10.1.1 
)  
10.1.1.1 
  
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10.1.1.2 
 
  
10.1.1.3 
 
10.1.1.4 
 
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10.1.1.5 
 
10.1.1.6 
 
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10.1.1.7 
 
 
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10.1.1.8 
 
10.1.1.9 
 
10.2 
 
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10.3 
 
 
  
10.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11. 
INTERIM ANALYSIS/ DATA MONITORING COMMITTEE  
11.1 
Data Monitoring Committee (DMC) 
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 Takeda for review and for a final 
decision. Takeda 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). The DMC will be consulted if the 
study is discontinued. 
Analyses of the data for DMC review will be conducted according to the DMC charter. Because 
no formal hypothesis testing for safety assessments is planned, multiplicity concerns regarding 
repeated analyses are not applicable. 
11.2 
Interim Analyses 
An interim analysis (IA) will be performed after 18 subjects have achieved remission and 
when approximately 50% of the planned sample size has been enrolled and treated in the three 
arms.  
The IA will include all data, collected by this time point, for all subjects enrolled in the study. 
IA results will be used to evaluate a preliminary treatment effect, assess initial PK/PD 
parameters, and inform the phase 3 clinical development planning.  
Analyses will cover the co-primary objectives, both secondary PK/PD and safety/ efficacy 
objectives and a subset of exploratory objectives.
 
 
   
Access to results from the IA will be restricted to a small group of Takeda personnel 
designated as unblinded who thereafter will be removed from participation in oversight of 
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daily conduct of this study. The interim analysis data and results may be used in regulatory 
interactions but will not be made public or used in scientific manuscripts.  
12. 
DATA HANDLING CONVENTIONS  
12.1 
General Data Reporting Conventions  
Unless otherwise specified the default summary statistics for quantitative variables will be as 
follows: 
x The number of subjects in each category (n). 
x Mean. 
x Standard deviation (SD). 
x Median. 
x Minimum. 
x Maximum. 
If the original data has N decimal places (as derived from the raw data) (i.e., decimal precision 
[N]) then the summary statistics are to contain the following decimal places (with a maximum 
of 3 decimals): 
x Minimum and maximum: N. 
x Mean and median: N+1. 
x Standard deviation: N+2. 
Continuous variables will be summarized using the following descriptive statistics:  n, mean, 
median, standard deviation, minimum, maximum. Categorical and count variables will be 
summarized by the number of subjects (n) and the percent of subjects in each category. 
All values will be rounded using the SAS® function ROUND. All computed percentages will 
be presented using 1 decimal place.  
It is to be noted that all verbatim text from the eCRF to be presented in any outputs are to be 
presented “as is” with no “manual hard coding” corrections for such data. 
12.2 
Definition of Baseline  
Unless otherwise stated, Baseline is defined as the last non-missing (scheduled or unscheduled) 
measurement obtained prior to the date and time of the first dose of investigational product. 
When time is not available, assessment occurring on the same date as the first dose are assumed 
to be pre dose.  
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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.  
12.3 
Definition of Visit Windows  
All data will be presented by nominal visit date as recorded on the eCRF. Visits will not be 
reassigned from the recorded nominal visit to any other visit based on dates. For summaries, 
only scheduled visits will be considered. All visits including unscheduled visits will be listed. 
Study day will be calculated as follows (if the first dosing day is Study Day 1. If it is Day 0, the 
formula needs to be adjusted): 
x If the assessment date is on or after the date of first dose of IP:  
Study day = assessment date – first dosing date + 1 
x If the assessment date is before the date of first dose of IP: 
 
 
Study day = assessment date – first dosing date 
12.4 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product will be used as 
baseline. If end of study assessments is repeated or unscheduled, the last post-baseline 
assessment will be used as the end of study assessment for generating descriptive statistics. 
However, all assessments will be presented in the data listings. 
12.5 
Handling of Missing, Unused, and Spurious Data  
Except for the below specified, missing data will not be imputed. 
12.5.1 Missing Severity Assessment for Adverse Events  
−   If severity is missing for an AE starting prior to the date of the first dose of 
investigational product, then a severity of “Mild” will be assigned.   
− If the severity is missing for an AE starting on or after the date of the first dose of 
investigational product, then a severity of “Severe” will be assigned.  The imputed 
values for severity assessment will be used for incidence summaries, while both the 
actual and the imputed values will be used in data listings. 
12.5.2 Missing Causality assessment for Adverse Events  
Handling of unknown causality assessment: 
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− If a subject experience an AE with a missing causality assessment, the relationship of 
the AE will be counted as “related 
12.5.3 Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable.  For the quantitative 
laboratory measurements reported as “<X”, i.e., BLQ, or “>X”, i.e., ALQ are to be presented 
in listings as “<X” or “>X” and summarized in summaries as “X” for “<X” and “X” for “>X”. 
12.5.4 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
For prior or concomitant medications (and/or therapies/procedures), including rescue 
medications, incomplete (i.e., partially missing) start date and/or stop date will be imputed.  
When the start date and the stop date are both incomplete for a subject, impute the start date 
first. 
12.5.4.1 Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
12.5.4.1.1 
Missing Day and Month 
− If the year of the incomplete start date is the same as the year of the date of the first dose of 
investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields 
− If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields 
− If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
12.5.4.1.2 
Missing Month Only 
− The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
12.5.4.1.3 
Missing Day Only 
− If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of investigational product, then the day of the date of the first dose of 
investigational product will be assigned to the missing day 
− If either the year is before the year of the date of the first dose of investigational product or 
if both years are the same but the month is before the month of the date of the first dose of 
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investigational product, then the last day of the month will be assigned to the missing day 
− If either the year is after the year of the date of the first dose of investigational product or if 
both years are the same but the month is after the month of the date of the first dose of 
investigational product, then the first day of the month will be assigned to the missing day. 
12.5.4.2 Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the date of the 
last dose of investigational product is missing, then replace it with the last visit date.  If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date. If the stop date of any event is missing and the 
corresponding status indication of “ongoing” is missing, all attempts to capture the information 
should be made but should this not be possible, the same approach should be taken as described 
above for last dose of investigational product.  
12.5.4.2.1 
Missing Day and Month 
− If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
− If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 
− If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
12.5.4.2.2 
Missing Month Only 
− The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
12.5.4.2.3 
Missing Day Only 
− If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of investigational product, then the day of the date of the last dose of 
investigational product will be assigned to the missing day 
− If either the year is before the year of the date of the last dose of investigational product or 
if both years are the same but the month is before the month of the date of the last dose of 
investigational product, then the last day of the month will be assigned to the missing day 
− If either the year is after the year of the last dose of investigational product or if both years 
are the same but the month is after the month of the date of the last dose of investigational 
product, then the first day of the month will be assigned to the missing day. 
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12.5.5 Missing Relationship to Investigational Product or Study Procedure for Adverse 
Events  
If the relationship to investigational product or study procedure is missing for an AE starting 
on or after the date of the first dose of investigational product, a causality of “Related” will be 
assigned.  The imputed values for relationship to double-blind investigational product will be 
used for incidence summaries, while both the actual and the imputed values will be presented 
in data listings. 
13. 
ANALYSIS SOFTWARE  
All data processing, summarization, and analyses are to utilize SAS® software package, 
Version 9.4 or later.  If the use of other software is warranted the final clinical study report 
(CSR) is to detail what software was used. 
All derivations, statistical analyses, summaries, and listings for PK data will be generated using 
SAS Version 9.4 or higher (SAS Institute, Inc., Cary, North Carolina).  Non-compartmental PK 
parameter calculations will be performed using Phoenix® WinNonlin® 8.0 or higher (Certara, 
L.P., Princeton, New Jersey).  The PK figures may be prepared using the same versions of SAS. 
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14. 
REFERENCES 
All questionnaires are filed in eTMF in English on Study level, folder 02.02.02 Subject 
Questionnaire. The local language ones are filed on Country level. 
 
 
 
Orphanet. Acquired thrombotic thrombocytopenic purpura. 2015. (Accessed 27 March,2017, 
at https://www.orpha.net/consor/cgi-
bin/Disease_Search.php?lng=EN&data_id=12423&Disease_Disease_Search_diseaseGroup=t
hrombotic-thrombocytopenic-
purpura&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=A
cquired-thrombotic-thrombocytopenic-
purpura&title=Acquired%20thrombotic%20thrombocytopenic%20purpura&search=Disease_
Search_Simple  
 
 
. 
 
  
 
 
 
Sullivan MJ, Edgley K, Dehoux E. A survey of multiple sclerosis: I. Perceived cognitive 
problems and compensory strategy use. Can J Rehabil 1990;4:99-105. 
 
 
 
Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective 
outcome measures. J Manipulative Physiol Ther 2004;27:26-35. 
 
. 
Cohen J. A power primer. Psychol Bull. 1992 Jul;112(1):155-9. PubMed PMID:19565683 
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Liang, Matthew. (2000). Longitudinal construct validity: Establishment of clinical meaning in 
patient evaluative instruments. Medical care. 38. II84-90. 
 
 
 
 
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15. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
Updated sponsor from Shire to Takeda 
16. 
APPENDICES 
None 
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