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

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