A Phase II Pilot Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacodynamics and Pharmacokinetics of IdeS in Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients With Low ADAMTS13 Activity
Phase: PHASE2
Conditions: Purpura, Thrombotic Thrombocytopenic
Sponsor: Hansa Biopharma AB

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STUDY PROTOCOL  
A PHASE II PILOT STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
EFFICACY, PHARMACODYNAMICS AND PHARMACOKINETICS OF IDES 
IN 
ASYMPTOMATIC 
ANTIBODY-MEDIATED 
THROMBOTIC 
THROMBOCYTOPENIC 
PURPURA 
(TTP) 
PATIENTS 
WITH 
LOW 
ADAMTS13 ACTIVITY 
 
 
 
 
Sponsor: Hansa Medical AB, Lund, Sweden 
 
Eudract No: 2016-000249-30 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................ 3 
1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................... 7 
2. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE INVESTIGATOR ... 9 
2.1 
MEDICAL EMERGENCIES CONTACTS ........................................................................................................... 9 
3. 
INTRODUCTION.......................................................................................................................... 10 
3.1 
DISEASE AND PATIENT POPULATION ....................................................................................................... 10 
3.2 
CURRENT TREATMENTS ............................................................................................................................. 10 
3.2.1 
Plasma Exchange ................................................................................................................................. 11 
3.2.2 
Steroids ..................................................................................................................................................... 11 
3.2.3 
Rituximab ................................................................................................................................................ 11 
3.3 
IDES ................................................................................................................................................................. 11 
3.4 
IDES CLINICAL STUDIES .............................................................................................................................. 11 
3.5 
OVERDOSE ...................................................................................................................................................... 12 
3.6 
STUDY RATIONALE AND DISCUSSION ON OVERALL STUDY DESIGN ................................................. 13 
3.7 
RISK/BENEFIT AND ETHICAL ASSESSMENT .......................................................................................... 13 
4. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 16 
4.1 
OBJECTIVES .................................................................................................................................................... 16 
4.1.1 
Primary Objective ................................................................................................................................ 16 
4.1.2 
Secondary Objectives .......................................................................................................................... 16 
4.1.3 
Exploratory Objectives ....................................................................................................................... 16 
4.2 
ENDPOINTS .................................................................................................................................................... 16 
4.2.1 
Primary Endpoint ................................................................................................................................ 16 
4.2.2 
Secondary Endpoints .......................................................................................................................... 16 
4.2.3 
Exploratory Endpoints ....................................................................................................................... 16 
5. 
STUDY DESIGN ............................................................................................................................ 17 
5.1 
OVERALL STUDY DESIGN ............................................................................................................................ 17 
5.2 
PLANNED NUMBER OF TRIAL SITES AND SUBJECTS ............................................................................. 17 
5.3 
DECISION CRITERIA FOR DOSE ESCALATION ......................................................................................... 17 
5.4 
DEFINITION OF DOSE LIMITING TOXICITY (DLT) ................................................................................ 18 
5.5 
INTERNAL MONITORING COMMITTEE ..................................................................................................... 18 
6. 
PATIENT SELECTION CRITERIA ............................................................................................ 19 
6.1 
STUDY POPULATION .................................................................................................................................... 19 
6.1.1 
Inclusion Criteria ................................................................................................................................. 19 
6.1.2 
Exclusion Criteria ................................................................................................................................. 20 
6.2 
RESTRICTIONS ............................................................................................................................................... 21 
6.3 
WITHDRAWAL AND DISCONTINUATION ................................................................................................. 21 
6.3.1 
Criteria for Discontinuation from the Study ............................................................................ 21 
6.3.2 
Procedures for Discontinuation of a Patient from the Study ............................................ 21 
7. 
STUDY CONDUCT ....................................................................................................................... 22 
7.1 
STUDY TREATMENT ..................................................................................................................................... 22 
7.1.1 
IdeS ............................................................................................................................................................. 22 
7.1.2 
Storage and Handling ........................................................................................................................ 22 
7.1.3 
Packaging and Labelling .................................................................................................................. 22 

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7.1.4 
Drug Accountability and Compliance Check ............................................................................ 22 
7.1.5 
Administration of IMP........................................................................................................................ 23 
7.2 
STUDY PROCEDURES .................................................................................................................................... 23 
7.3 
STUDY FLOW CHART ................................................................................................................................... 26 
7.3.1 
Recording of Data ................................................................................................................................ 27 
7.3.2 
Patient Care After End of Study ..................................................................................................... 27 
8. 
STUDY ASSESSMENTS ............................................................................................................... 28 
8.1 
ASSESSMENTS RELATED TO ENDPOINTS ................................................................................................ 28 
8.1.1 
ADAMTS13 Activity ............................................................................................................................. 28 
8.1.2 
ADAMTS13 Antibodies ....................................................................................................................... 28 
8.1.3 
Vital Signs ................................................................................................................................................ 28 
8.1.4 
Adverse Events ...................................................................................................................................... 28 
8.1.5 
Clinical Laboratory Variables......................................................................................................... 28 
8.1.6 
Electrocardiogram .............................................................................................................................. 29 
8.1.7 
Pharmacodynamics............................................................................................................................. 30 
8.1.8 
Pharmacokinetics ................................................................................................................................ 30 
8.1.9 
Immunogenicity .................................................................................................................................... 30 
8.1.10 
.................................................................................................................................................... 30 
8.2 
OTHER ASSESSMENTS ................................................................................................................................. 30 
8.2.1 
ImmunoCAP anti-IdeS IgE ................................................................................................................ 30 
8.2.2 
Demographics and Baseline Data ................................................................................................. 31 
8.2.3 
Physical Examinations ....................................................................................................................... 31 
8.2.4 
Body Temperature ............................................................................................................................... 31 
8.2.5 
Serology .................................................................................................................................................... 31 
8.2.6 
Pregnancy Test...................................................................................................................................... 31 
8.2.7 
Prior and Concomitant Medication .............................................................................................. 31 
8.2.8 
Handling of Biological Samples ..................................................................................................... 31 
8.3 
CONCOMITANT MEDICATION..................................................................................................................... 31 
8.3.1 
Premedication ....................................................................................................................................... 31 
8.3.2 
Prophylactic Antibiotic ...................................................................................................................... 32 
8.4 
SAFETY ............................................................................................................................................................ 32 
8.4.1 
Definition of Adverse Events............................................................................................................ 32 
8.4.2 
Definition of Serious Adverse Events ........................................................................................... 33 
8.4.3 
Recording of Adverse Events ........................................................................................................... 34 
8.4.4 
Variables .................................................................................................................................................. 34 
8.4.5 
Adverse Events Based On Signs and Symptoms ...................................................................... 35 
8.4.6 
Adverse Events Based On Examinations and Tests ............................................................... 35 
8.4.7 
Follow-up of Unresolved Adverse Events ................................................................................... 35 
8.4.8 
Reporting of Serious Adverse Events ........................................................................................... 36 
8.4.9 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) ................. 36 
9. 
BIOLOGICAL SAMPLING PROCEDURES ................................................................................ 38 
9.1 
VOLUME OF BLOOD ...................................................................................................................................... 38 
9.2 
HANDLING, STORAGE AND DESTRUCTION OF BIOLOGICAL SAMPLES .............................................. 38 
9.2.1 
Pharmacokinetic, Pharmacodynamic and Anti-drug Antibody Samples .................... 38 
9.3 
CHAIN OF CUSTODY OF BIOLOGICAL SAMPLES ...................................................................................... 38 
9.4 
WITHDRAWAL OF INFORMED CONSENT FOR DONATED BIOLOGICAL SAMPLES ........................... 38 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ............................................................. 40 

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10.1 
ETHICAL CONDUCT OF THE STUDY ........................................................................................................... 40 
10.2 
PATIENT DATA PROTECTION .................................................................................................................... 40 
10.3 
ETHICS AND REGULATORY REVIEW ......................................................................................................... 40 
10.4 
INFORMED CONSENT ................................................................................................................................... 40 
10.5 
CHANGES TO THE PROTOCOL AND INFORMED CONSENT FORM ........................................................ 41 
10.6 
AUDITS AND INSPECTIONS ......................................................................................................................... 41 
11. 
STUDY MANAGEMENT ......................................................................................................... 42 
11.1 
PRE-STUDY ACTIVITIES............................................................................................................................... 42 
11.2 
TRAINING OF STUDY SITE PERSONNEL ................................................................................................... 42 
11.3 
MONITORING OF THE STUDY ..................................................................................................................... 42 
11.4 
STUDY AGREEMENTS ................................................................................................................................... 43 
11.5 
STUDY TIMETABLE AND END OF STUDY ................................................................................................. 43 
11.6 
INSURANCE .................................................................................................................................................... 43 
12. 
DATA HANDLING ................................................................................................................... 44 
12.1 
SOURCE DATA AND SOURCE DOCUMENTS .............................................................................................. 44 
12.1.1 
Source Data and Source Documents ...................................................................................... 44 
12.2 
STUDY SPECIFIC SOURCE DATA REQUIREMENTS – HANSA MEDICAL AB ....................................... 44 
12.3 
CASE REPORT FORMS .................................................................................................................................. 44 
12.4 
DATA MANAGEMENT ................................................................................................................................... 44 
13. 
EVALUATION AND CALCULATION OF PHARMACOKINETIC AND 
PHARMACODYNAMIC VARIABLES ................................................................................................. 45 
13.1 
CALCULATION OR DERIVATION OF PHARMACOKINETIC VARIABLES................................................ 45 
13.2 
CALCULATION OR DERIVATION OF THE RELATIONSHIP BETWEEN PHARMACOKINETIC AND 
PHARMACODYNAMIC VARIABLES.............................................................................................................................. 45 
14. 
STATISTICAL METHODS AND SAMPLE SIZE .................................................................. 46 
14.1 
DESCRIPTION OF ANALYSIS SETS ............................................................................................................. 46 
14.2 
METHODS OF STATISTICAL ANALYSES .................................................................................................... 46 
14.2.1 
General Principles .......................................................................................................................... 46 
14.2.2 
Patient Characteristics ................................................................................................................. 46 
14.2.3 
Safety and Tolerability ................................................................................................................. 46 
14.2.4 
Pharmacokinetics ........................................................................................................................... 47 
14.2.5 
Pharmacodynamics ....................................................................................................................... 47 
14.2.6 
Anti-drug Antibodies ..................................................................................................................... 47 
14.2.7 
Efficacy ................................................................................................................................................ 47 
14.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................................... 47 
15. 
REPORTING AND PUBLICATION ....................................................................................... 48 
15.1 
CLINICAL STUDY REPORT ........................................................................................................................... 48 
15.2 
CONFIDENTIALITY AND OWNERSHIP OF DATA ..................................................................................... 48 
15.3 
PUBLICATION AND PUBLIC DISCLOSURE................................................................................................. 48 
15.3.1 
Publication Policy ........................................................................................................................... 48 
15.3.2 
Public Disclosure Policy ............................................................................................................... 48 
16. 
ARCHIVING .............................................................................................................................. 49 
16.1 
INVESTIGATOR FILE ..................................................................................................................................... 49 
16.2 
TRIAL MASTER FILE .................................................................................................................................... 49 
17. 
REFERENCES ........................................................................................................................... 50 

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TABLE OF TABLES 
Table 1.  
Study drug   ............................................................................. 22 
Table 2.  
Study flow chart ...................................................................... 26 
Table 3.  
The following safety laboratory variables will be measured  29 
 
TABLE OF FIGURES 
Figure 1. Overall schematic study design ............................................................ 17 
 
 

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1. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study protocol.  
Abbreviation   
Explanation 
ADA 
Anti-drug antibody 
ADAMTS13 
a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 
13 
AE 
Adverse event 
APTt 
Activated partial thromboplastin time 
ATGAM 
Equine anti-thymocyte globulin 
AUCt 
Area under serum concentration time curve from t=0 to last timepoint 
BMI 
Body mass index 
BW 
Body weight 
CKD 
Chronic kidney disease 
Cmax  
Maximum serum concentration 
CRF 
Case report form (electronic/paper) 
CRO 
Contract research organisation 
CRP 
C-reactive protein 
CSR 
Clinical study report 
CTCAE 
Common toxicity criteria for adverse events 
CV 
Coefficient of variation 
DLT 
Dose Limiting Toxicity 
 
 
ECG 
Electrocardiogram 
EOS 
End of study 
FAS 
Full analysis set 
FRET 
Fluorescence resonance energy transfer 
GCP 
Good clinical practice 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International conference on harmonisation 
IdeS 
Immunoglobulin G-degrading enzyme of Streptococcus pyogenes 
IMC 
Internal Monitoring Committee 
IMP 
Investigational medicinal products 

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Abbreviation   
Explanation 
IUD 
intrauterine device  
IUS 
intrauterine system 
IVIg 
Intravenous immunoglobulin 
 
 
MAHA 
microangiopathic haemolytic anemia 
MedDRA 
Medical dictionary for regulatory activities 
MSD 
Meso Scale Diagnostic 
NOAEL 
No observed adverse effect level 
PBS 
Phosphate buffered saline 
PD 
Pharmacodynamics 
PE 
Plasma Exchange 
PK 
Pharmacokinetics 
PK (INR) 
Prothrombine complex (internationally normalised ratio) 
PPS 
Per protocol set 
PRA 
Panel reactive antibody 
rATG 
Rabbit anti-thymocyte globulin 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse events 
TEAE 
Treatment emergent adverse event 
TTP 
Thrombotic thrombocytopenic purpura 
vW 
von Willebrand factor 
 
 
 

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2. 
IMPORTANT MEDICAL PROCEDURES TO BE 
FOLLOWED BY THE INVESTIGATOR 
2.1 
Medical Emergencies Contacts 
The principal investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes a serious adverse event (SAE) and is to be reported as such. 
Name  
Role in the study  
Telephone number & Mail address  
 
Principal Investigator  
 
 
 
Medical Safety Officer 
 
 
Elisabeth Sonesson 
Sr. Clinical Research Manager 
 
elisabeth.sonesson@hansamedical.com 
 

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3. 
INTRODUCTION 
3.1 
Disease and Patient population 
Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic disorder 
of the blood-coagulation system, causing extensive microscopic clots to form in the small 
blood vessels throughout the body. These small blood clots, called thrombi, can damage 
many organs including the kidneys, heart and brain. TTP is a medical emergency that is 
almost always fatal if appropriate treatment is not initiated promptly. Treatment with plasma 
exchange (PE) and glucocorticoids reduces the mortality to between 10% and 15% 
(George 2012). 
In the majority of patients, TTP is a result of autoantibody-mediated inhibition of a 
disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 
(ADAMTS13). This type of TTP is called acquired TTP. In a minority of patients, TTP is 
due to deleterious mutations in ADAMTS13; i.e., hereditary or congenital TTP. 
Acquired TTP is characterized by thrombocytopenia and microangiopathic haemolytic 
anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and 
neurologic deficits (Sayani and Abrams 2015). The majority of the patients suffering from 
acquired TTP develop autoantibodies that bind and neutralize the proteolytic activity of 
ADAMTS13 and/or accelerate its clearance in vivo (Scheiflinger, Knöbl et al. 2003). 
Recently published data suggest that depletion of ADAMTS13 antigen, rather than enzyme 
inhibition, is the dominant pathogenic mechanism in acquired TTP (Thomas, de Groot et al. 
2015). A severe deficiency of plasma ADAMTS13 activity (less than 5%) and the presence 
of autoantibodies are considered to be highly specific for the diagnosis of acquired TTP 
(Hovinga and Lämmle 2012). Anti-ADAMTS13 antibodies are present in the majority of 
patients (94–97%) suffering from acquired TTP and are considered to be strongly involved 
in the pathogenesis of the disease (Verbij, Fijnheer et al. 2014). 
Early intervention improves prognosis dramatically. As a result, measurement of serum 
ADAMTS13 activity is not performed for diagnosis, as turn-around time tends to be long 
and awaiting results may delay life-saving treatment. However, measurement of 
ADAMTS13 and antibodies to ADAMTS13 are conducted for diagnostic confirmation.  
3.2 
Current Treatments 
Due to the rarity of the disease very few randomized studies with definitive conclusions 
have been performed in TTP and its management is largely based on clinical experience 
(Verbij, Fijnheer et al. 2014). The mainstay of treatment is PE, while monitoring 
 
and
. The ADAMTS13 assays may not be immediately 
available. Therefore, the treatment must be based on clinical symptoms and other laboratory 
tests and the decision to start PE should not wait for results of the ADAMTS13 assay 
(Sayani and Abrams 2015). In addition to plasma exchange, other methods are necessary to 
treat patients because of high frequency of relapse, especially in patients with high titre 
inhibitory antibodies. Most patients are treated with steroids and rituximab is part of 
standard therapy (Said, Haddad et al. 2014). Treatment must be started as soon as possible 
after diagnosis or even suspicion of TTP.
, 
level and ADAMTS13 results 
are indicators of disease severity and forms the basis for treatment decision. 
Immunosuppressive therapies like corticosteroids, anti-CD20 or cyclosporine are also being 
used in the treatment of acquired TTP. 

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3.2.1 
Plasma Exchange 
The mortality rate of TTP prior to the use of PE was approximately 90 percent but is now 
down to 15 percent or less (Sayani and Abrams 2015). PE is the standard treatment in 
acquired TTP and is considered to remove circulating antibodies to ADAMTS13 and the 
subsequent 
plasma 
replacement, 
replenish 
the 
deficient 
ADAMTS13 
(Verbij, Fijnheer et al. 2014). Despite the rarity of TTP, these patients are the single largest 
consumers of plasma, with an average volume per episode of 40 L (Scully 2014). PE is 
performed once or twice daily until the 
 has recovered. Complications 
associated with plasma exchange (incidence 10%) are mostly related to the use of central 
venous catheter and the plasma replenishment (Said, Haddad et al. 2014). 
According to the 2012 American Society of Apheresis Consensus Conference on TTP, 
response is defined as a 
 of at least 150 000/mL for 2 consecutive days, a 
normal or near normal 
, and stable or improving neurologic symptoms. The number of 
treatments needed varies, and may be higher in patients with high antibody titre 
(Sayani and Abrams 2015). 
3.2.2 
Steroids 
Glucocorticoids are used in the acute management of acquired TTP and should be started 
directly together with PE (Sayani and Abrams 2015). Steroids are used to target the 
autoimmune component of the disease and are believed to suppress the production of anti-
ADAMTS13. The effect of steroids may also be due to down-regulation of various cytokines 
involved in TTP pathogenesis (Verbij, Fijnheer et al. 2014). 
3.2.3 
Rituximab 
Anti-CD20 (rituximab) was initially used in patients with a suboptimal response to standard 
treatment, such as those with refractory or relapsed disease (Verbij, Fijnheer et al. 2014) but 
is now standard of care as up-front treatment. Anti-CD20 therapy has been demonstrated to 
be effective in prolonging the duration of remission as well as decreasing the frequency of 
remission (Scully, McDonald et al. 2011). 
3.3 
IdeS 
Immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) is an IgG specific 
endopeptidase. Cleavage of IgG generates one F(ab’)2- and one homodimeric Fc-fragment 
and efficiently neutralizes Fc-mediated activities of IgG (HMed doc. No. 2012-003) 
(von Pawel-Rammingen, Johansson et al. 2002, Wenig, Chatwell et al. 2004, 
Vincents, von Pawel-Rammingen et al. 2004). IdeS-mediated IgG degradation constitutes a 
novel therapeutic principle for the treatment of IgG-driven human diseases.  
Hansa Medical AB has performed in vitro studies and clearly demonstrated that IdeS 
effectively cleaves purified IgG as well as IgG in serum from human and rabbit. IdeS is very 
specific in that no other substrate has been found (HMed Doc. No. 2012-003). 
3.4 
IdeS Clinical Studies 
A phase I study first in man single ascending dose study in 29 healthy subjects showed that 
IdeS was safe and well tolerated in doses up to 0.24 mg/kg body weight (BW). The study 
demonstrated that IdeS could be administered at 0.24 mg/kg BW with a favourable safety 
profile. It also showed that IdeS could effectively reduce the levels of plasma IgG and that 
newly synthesised IgG was not detectable until two weeks after dosing. At the two highest 

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doses, 0.12 and 0.24 mg/kg BW, IdeS completely cleaved the pool of plasma IgG within 
14 minutes after initiation of infusion and the level of intact IgG was reduced to less than 
5% of its original level. In addition, newly synthesized IgG was not detectable until two 
weeks after dosing (HMed Doc. No. 2014-003). The data clearly indicates that a single dose 
of IdeS is superior to both plasmapheresis and immunoadsorption with respect to efficiency 
and rate of plasma IgG reduction. Since IdeS degrades IgG there was concern that study 
subjects would have an increased risk of infection and that subclinical infections (e.g., 
pneumococci) would pose a problem. Therefore, subjects received antibiotic prophylaxis 
until plasma IgG levels had returned to levels >4.5 g/L and there were no signs of an 
increased rate of infections within the study group. The adverse events that were reported, 
none of which were reported as serious, were as anticipated from to the biological nature of 
the drug. Hence, headache and fatigue were more common in the IdeS treated subjects 
compared to placebo. One possible infusion reaction was reported among the placebo treated 
subjects and one among the IdeS treated, the latter resolved within 60 minutes after treatment 
with antihistamine and glucocorticoids and the infusion was completed. All adverse events 
were mild or moderate.  
One phase II study was completed at Uppsala University Hospital, Sweden in March 2015. 
The study was a single arm study with ascending doses of IdeS in 8 chronic kidney disease 
(CKD) patients on the kidney transplantation waiting list and sensitized to human leucocyte 
antigens (HLAs). The patients enrolled were diagnosed with CKD, in dialysis and on the 
waiting list for a kidney transplant. However, transplantation was not part of the study 
protocol. The study showed that one or two doses of IdeS at 0.25 mg/kg BW in the majority 
of the patients resulted in HLA antibody levels, acceptable for transplantation within 24 
hours from dosing. In addition, in all patients having a significant pre-dose panel-reactivity 
the percentage panel reactive antibody (PRA) was reduced one hour after IdeS treatment. It 
was also concluded that in the majority of patients the complement dependent cytotoxic 
crossmatches were converted to negative already one hour after a single dose of IdeS 
(0.12 or 0.25 mg/kg BW) and the crossmatches remained negative for one week. There were 
a total of five SAEs reported in the study of which four were classified as probable or 
possible related to study drug, i.e., suspected serious adverse reactions (SARs). Three of the 
SARs were infections and one myalgia. Two phase II studies using IdeS in sensitized 
patients prior to kidney transplantation are currently ongoing in Uppsala, Sweden and Los 
Angeles, US. 
3.5 
Overdose 
An overdose is a dose in excess of the dose specified in the protocol.  There are no data on 
overdosing of IdeS. There is no known antidote but depletion of IgG can be restored with 
intravenous immunoglobulin (IVIg). In the event of an overdose the patient should be 
monitored closely and treated symptomatically. This should be recorded as follows:  
• An overdose with associated adverse events (AEs) is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the case report form (CRF) 
• An overdose without associated symptoms is only reported in the patient file 

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3.6 
Study Rationale and Discussion on Overall Study Design  
Asymptomatic patients with low ADAMTS13 activity are at significant risk of relapse. 
Patients may never have recovered a normal ADAMTS13 activity after the acute episode, 
or more commonly, ADAMTS13 activity may fall in remission, predisposing to clinical 
relapse. Elective rituximab is used in this situation to clear anti-ADAMTS13 antibodies and 
normalise ADAMTS13 activity, thus reducing the risk of a clinical relapse. It is possible 
that addition of IdeS will be an advantage in asymptomatic patients by quickly removing 
ADAMTS13 antibodies from circulation, thus allowing ADAMTS13 to return to normal 
levels.  
The primary objective of the proposed pilot study is to monitor safety and tolerability in 
patients diagnosed with asymptomatic antibody-mediated TTP with low ADAMTS13 
activity after receiving single intravenous doses of IdeS. The secondary objective is to 
investigate IdeS efficacy in significantly increasing ADAMTS13 activity and decreasing 
ADAMTS13 antibody levels in patients with asymptomatic antibody-mediated TTP. In the 
current study this will be investigated in asymptomatic patients with reduced levels of 
ADAMTS13 activity and measurable levels of circulating ADAMTS13 antibodies. 
Eligible patients must have ADAMTS13 activity levels less than 10% of normal levels. Each 
patient will receive one dose of 0.25 mg/kg BW IdeS. Following an evaluation of safety and 
efficacy in 3 patients dosed at 0.25 mg/kg, there will be a possibility to increase the dose to 
0.5 mg/kg for the next 3 patients. The dose will be given as a single intravenous infusion 
(for details see section 7, Study conduct). Single doses up to 0.24 mg/kg BW (maximum 
dose tested) has previously been given to healthy volunteers and doses up to two times 0.25 
mg/kg BW has been given to CKD patients. In asymptomatic patients with acquired TTP it 
is expected that the pharmacokinetic of IdeS pharmacokinetics is similar to healthy subjects. 
Based on the current knowledge, including experience from completed and ongoing clinical 
studies, it is expected that IdeS will degrade IgG into F(ab’)2 and Fc fragments across all 
compartments allowing a rapid and potent reduction of the specific anti-ADAMTS13 
antibodies. The F(ab’)2-fragment created by IdeS treatment will not be able to clear 
ADAMTS13 via Fc-mediated activities. However, the remaining F(ab’)2 seen in serum after 
24-48 hours may still have the capacity to block ADAMTS13 activity for example by 
interfering with binding to von Willebrand (vW) factor. However, as shown by Thomas et. 
al. (Thomas, de Groot et al. 2015) depletion of ADAMTS13 antigen, rather than enzyme 
inhibition, is the dominant pathogenic mechanism in acquired TTP.  
The hypothesis is that the reduction in anti-ADAMTS13 IgG will translate into a rise in 
ADAMTS13 activity and hence reduce the risk of clinical relapse.  
3.7 
Risk/Benefit and Ethical Assessment 
A starting dose of 0.25 mg/kg BW has been selected for this study. The phase I study did 
not identify any dose limiting factors even at the highest tested dose (0.24 mg/kg BW) and 
CKD patients in a completed phase II study in Sweden were exposed to a total dose of 
0.5 mg/kg BW with acceptable safety profile. In addition, the doses of 0.25 mg/kg and 
0.5 mg/kg BW are well covered by the no observed adverse effect level (NOAEL) of 
2.0 mg/kg BW obtained in toxicology studies. The pharmacokinetics (PK) of IdeS in 
asymptomatic TTP patients is expected to be similar to what is observed in healthy subjects, 
thus, a starting dose of 0.25 mg/kg BW is considered to be safe. 

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Since IdeS effectively removes the IgG pool, there may be an increased risk of infection. In 
order to minimise the risk for bacterial infections all patients treated with IdeS will receive 
a two-week regimen of prophylactic antibiotics following IdeS dosing. Patients will be 
screened for viruses (Hepatitis B, C and human immunodeficiency virus [HIV]) and on-
going infections and patients having clinical signs of on-going infections will be excluded 
from the study. Patients will be instructed to contact the principal investigator immediately 
if they have any sign of infection. In case of infection in a patient with low IgG plasma 
levels, intravenous immunoglobulin may be indicated.  
It has been demonstrated in laboratory studies that IdeS cleaves biologics based on human 
IgG including; IVIg, basiliximab, rituximab, adalimumab, denosumab, belatacept and 
etanercept. IdeS also cleaves rabbit anti-thymocyte globulin (rATG) but not equine anti-
thymocyte globulin (ATGAM). The optimal interval between HMedIdeS administration and 
these biologics have not been defined (HMed Doc. No. 2012-003). Rituximab is cleaved by 
IdeS and therefore rituximab treatment within 7 days prior to IdeS dosing will not be allowed 
in TTP patients. The concomitant use of these other biologics and IdeS will continue to be 
closely monitored in order to mitigate any changes in the efficacy of these biologics. 
To date, there have been 3 reports of myalgia in completed studies, 1 was serious and 
unexpected and occurred in a patient with a previous history of myalgia to atorvastatin who 
was on chronic glucocorticoid treatment. The remaining 2 were non-serious. The 
non-serious cases resolved and the serious case was improving upon steroid tapering. Of 
note, an extensive workup including muscle biopsy, electromyograms and other muscle 
related biomarkers showed no abnormalities. Myalgias have been reported with treatment 

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with 
other 
biologics 
such 
as 
IVIg 
and 
rituximab 
(Orbach et al., 2005, 
Rituximab Summary of Product Characteristics). 
Creatine kinase (CK) levels will be assessed in this study. 
The patients will be closely monitored for all adverse events. The principal investigator must 
make sure that sufficient facilities and procedures are available to handle emergency 
situations during the study. The University College London Hospitals has extensive 
experience in early phase studies and there are adequate procedures in place to handle 
unexpected adverse reactions. 

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4. 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
4.1.1 
Primary Objective 
To assess safety and tolerability of single intravenous doses of IdeS in patients diagnosed 
with asymptomatic antibody-mediated TTP with low ADAMTS13 activity 
4.1.2 
Secondary Objectives 
To determine the following in patients diagnosed with asymptomatic antibody-mediated 
TTP with low ADAMTS13 activity 
1. ADAMTS13 antigen, activity and antibody (IgG and F(ab’)2) levels following a 
single intravenous dose of IdeS during 64 days following IdeS dosing 
2. Serum concentration of IdeS following a single intravenous dose of IdeS 
3. Pharmacodynamic (PD) profile as measured by IgG levels and F(ab’)2 fragments 
concentrations during 64 days following IdeS dosing 
4. Immunogenicity profile of IdeS 
4.1.3 
Exploratory Objectives 
 
4.2 
Endpoints  
4.2.1 
Primary Endpoint 
Safety as measured by type, frequency and intensity of adverse events and change from 
baseline in parameters of clinical laboratory tests, vital signs and electrocardiograms (ECGs) 
4.2.2 
Secondary Endpoints 
• Change from baseline in ADAMTS13 activity and antibody levels (IgG and F(ab’)2).  
• Time for ADAMTS13 activity to return to normal levels  
• 
Number of cases with normalisation of ADAMTS13 at 64 days  
• Serum concentration of IdeS 
• Change from baseline in pharmacodynamics as measured by level of IgG and F(ab’)2 
fragments 
• Immunogenicity of IdeS by measuring anti-drug antibodies 
4.2.3 
Exploratory Endpoints 
• 
 

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5. 
STUDY DESIGN 
5.1 
Overall Study Design  
 
 
Figure 1. Overall schematic study design 
This is a phase II, single arm study. The primary objective of the study is to assess safety 
and tolerability of IdeS in asymptomatic patients diagnosed with acquired TTP in clinical 
remission with ADAMTS13 activity less than 10% of normal levels. Secondary objectives 
include monitoring of ADAMTS13 activity and levels of ADAMTS13 antibodies. In 
addition, IdeS serum concentration, PD (total IgG and F(ab’)2 fragment concentrations) and 
immunogenicity profile of IdeS will be assessed. 
Patients will be treated at the College University London Hospital, and will be subject to a 
single 30 minutes infusion with IdeS on day 0. Blood sampling for safety and efficacy will 
be performed and the patient will be closely monitored over a 24 h period after infusion after 
which they will be discharged. The follow-up visits will be in the out-clinic setting. Patients 
will receive premedication with paracetamol, Solu-Medrol and Loratidine before IdeS 
infusions. All patients will also receive a two-week regimen of prophylactic antibiotics 
starting pre-dose.  
Following an evaluation of safety (clinical chemistry, haematology and coagulation and 
AEs) and efficacy in 3 patients receiving 0.25 mg/kg there will be a potential to increase the 
IdeS dose to 0.5 mg/kg for the remaining 3 patients. 
5.2 
Planned Number of Trial Sites and Subjects 
The study will be conducted at one site, University College London Hospital, UK and will 
include 6 asymptomatic patients diagnosed with acquired TTP.  
5.3 Decision Criteria for Dose Escalation 
The decision for dose escalation to 0.5 mg/kg BW or an intermediary dose will be taken 
after the first 3 patients have been administered a dose of 0.25 mg/kg BW. The decision to 
escalate the dose will be a consensus between the Principal Investigator and the Sponsor. 
The safety, tolerability and efficacy of the dose will be evaluated prior to dose escalation. 
An internal monitoring committee (IMC) at Hansa Medical will review available safety and 
tolerability data after 3 patients have received a dose of 0.25 mg/kg before proceeding to the 
next dose. Safety data collected up to and including day 14 will be evaluated. The safety 
data will be compiled in an IMC package and also sent to the Principal Investigator for 
review. Safety data available for evaluation by the IMC and Principal Investigator before a 
dose escalation decision is shown in Table 3. In addition, ADAMTS13 activity, 
Eligibility
Day -28 -4
Visit 1
IdeS infusion 30 min
Visit 2
Screening
Treatment period
End of study
Day 0-1
Follow up
Visit 8
Follow up
Follow up
Follow up
Visit 3
Visit 4
Visit 5
ADAMTS13 act
ADAMTS13 ab
ADAMTS13 act
ADAMTS13 ab
ADAMTS13 act
ADAMTS13 ab
ADAMTS13 act
ADAMTS13 ab
ADAMTS13 act
ADAMTS13 ab
ADAMTS13 act
ADAMTS13 ab
Day 3
Day 7
Day 10
Follow up
Visit 6
ADAMTS13 act
ADAMTS13 ab
Day 14
Follow up
Visit 7
ADAMTS13 act
ADAMTS13 ab
Day 30
Day 64

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ADAMTS13 antibodies and 
 will be included in the evaluation of a dose escalation. 
There will be at least 14 days between dosing of the first patient in a higher dose group and 
dosing of the last patient in the previous dose group. 
If a Dose Limiting Toxicity (DLT) is demonstrated in one patient who has received a dose 
of 0.25 mg/kg BW and the underlying AE(s) is at least possibly related to the investigational 
drug, dose escalation will not occur and 3 additional patients will be administered 
0.25 mg/kg. A well-tolerated 0.25 mg/kg dose may also be administered to the next three 
patients entered in the study if the pharmacodynamics effect of the dose is judged as 
satisfactory. A dose of 0.5 mg/kg BW or an intermediate dose may be given in the next three 
patients, if considered safe by the Principal Investigator and the Sponsor.  
5.4 
Definition of Dose Limiting Toxicity (DLT) 
A significant reduction of total IgG levels in serum is a desired effect of IdeS treatment and 
is not considered a DLT. Any novel AE (including infusion reactions) with a Common 
Toxicity Criteria for Adverse Events (CTCAE) v.4.0 grade 3 or more and with a possible 
relationship to the investigational drug is considered a DLT (see Appendix 1 for 
CTCAE v. 4.0). 
5.5 Internal Monitoring Committee 
An IMC will be formed and will be convened to assess safety data on each patient enrolled 
in the study. If at any time in the study, 2 or more patients have experienced a Grade 3 of 
related adverse event (NCI CTCAE v 4.0), the IMC will be convened. The IMC will also 
review a safety data package (Table 3) prior to dose escalation. An IMC charter will be 
written to pre-specify roles, responsibilities, procedures, and deliverables, as well as the 
purpose, scope, and timing of meetings. 

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6. 
PATIENT SELECTION CRITERIA 
6.1 
Study Population 
6.1.1 
Inclusion Criteria  
For inclusion in the study patient must fulfil the following criteria.  
1. Ability to understand and must sign the informed consent form 
2. Age 18 years or above 
3. Patients diagnosed with acquired TTP with ADAMTS13 levels of ≤ 10 % in clinical 
remission and with measurable or previously confirmed ADAMTS13 antibodies  
4. Females of childbearing potential and males must use highly effective contraception 
during the study and at least for 12 weeks after IdeS dosing 
Highly effective contraception methods include: 
1. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
2. Female sterilisation (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment 
3. Male sterilisation (at least 6 months prior to screening). For female subjects in 
the study, the vasectomised male partner should be the sole partner for that 
subject 
4. Combination of any two of the following methods (a+b or a+c or b+c): 
a) Use of oral, injected or implanted hormonal methods of contraception or 
other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception 
b) Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
c) Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal 
suppository 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. Women are considered 
post-menopausal and not of child bearing potential if they have had 12 months of 
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks 
prior to screening. In the case of oophorectomy alone, only when the reproductive 

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status of the woman has been confirmed by follow up hormone level assessment is 
she considered not of child bearing potential.  
 
6.1.2 
Exclusion Criteria  
Patients must not enter the study if any of the following exclusion criteria are fulfilled  
1. Prior malignancy within 5 years excluding adequately treated basal cell or squamous 
cell skin cancer, cervical carcinoma in situ 
2. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C 
antibody and HIV 
3. Clinical signs of ongoing infectious disease. This includes P-C-reactive protein 
(CRP) >10.  
4. Tested positive for IgE antibodies against IdeS as measured by ImmunoCap. 
5. No secondary cause of TTP 
6. Rituximab treatment or other antibody-based therapy within 7 days prior to IdeS 
dosing 
7. Treatment with investigational medicinal product within the last 12 weeks preceding 
screening or longer if judged by the investigator to possibly influence the outcome 
of the current study 
8. Severe other conditions requiring treatment and close monitoring, e.g. cardiac 
failure > NYHA (New York Heart Association) grade 3, unstable coronary disease 
or oxygen dependent COPD 
9. History of any other clinically significant disease or disorder which, in the opinion 
of the investigator, may either put the patient at increased risk because of 
participation in the study, or influence the results or the patient’s ability to participate 
in the study 
10.  Hypogammaglobulinemia defined as any values of P-total IgG less than 3 g/L  
11. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as 
judged by the investigator or history of hypersensitivity to drugs with a similar 
chemical structure or class to IdeS (e.g., streptokinase and/or staphylokinase) 
12. Substance abuse or other concurrent medical condition that, in the investigator’s 
opinion, could confound study interpretation or affect the patient’s ability to tolerate 
or complete the study 
13. Investigator considers patient unlikely to comply with study procedures, restrictions 
and requirements 
14. Breast feeding women or women with a positive pregnancy test 
15. Previously received IdeS treatment 

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6.2 
Restrictions 
Patients should abstain from drinking alcoholic beverages for 72 hours before the screening 
visit and all subsequent visits to the clinic. In addition, patients should abstain from alcoholic 
beverages during the residential stay. 
The patients should abstain from strenuous physical activity that is not within the patient’s 
normal weekly routine for 48 h prior to any visit until the end of study. 
Patients must not participate in another clinical study during the course of the present study. 
6.3 
Withdrawal and Discontinuation 
6.3.1 
Criteria for Discontinuation from the Study 
Patients may be discontinued from study treatment and assessments at any time. Specific 
reasons for discontinuation can be: 
• Voluntary discontinuation by the patient who is at any time free to discontinue 
his/her participation in the study, without prejudice to further treatment 
• Risk to patients as judged by the investigator and/or sponsor 
• Severe non-compliance to protocol as judged by the investigator and/or sponsor 
• Incorrectly enrolled patients 
• Patient lost to follow-up  
• Adverse events 
• Withdrawal of informed consent to the use of biological samples may be a reason 
for withdrawal of a patient  
Patients who are withdrawn from the study by the investigator due to adverse events will 
not be replaced. Patients who withdraw for reasons other than adverse events may be 
replaced. A replacement patient must be an eligible patient according to the protocol and 
inclusion will follow the procedures described in this protocol. 
6.3.2 
Procedures for Discontinuation of a Patient from the Study 
A patient who discontinues after study drug administration will always be asked about the 
reason(s) for discontinuation and the presence of any adverse events. If possible, they will 
be seen and assessed by an investigator(s). Adverse events will be followed until they 
resolve, stabilize or the clinical outcome of the patient is ascertained. If possible, patients 
who discontinue from the study before completion should undergo the assessments and 
procedures scheduled for the end of study follow up visit. Patients who, for a medical reason, 
cannot comply with the protocol procedures will be followed by best procedure, e.g., 
telephone call, to retrieve safety and efficacy data. 

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7. 
STUDY CONDUCT 
7.1 
Study Treatment 
7.1.1 
IdeS 
IdeS is a clear colourless liquid. It is formulated at 10 g/L in phosphate buffered saline (PBS) 
and intended for intravenous infusion after dilution. Refer to Table 1 for composition. 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
  
 
 
  
 
 
  
 
 
7.1.2 
Storage and Handling 
All patients will receive treatment with IdeS. IdeS will be supplied to the hospital pharmacy 
by 
 in 7 mL vials packed into cartons containing 10 vials each. Vials should be kept 
dark at - 20°C. IdeS infusion solution will be prepared by pharmacy staff at the study unit. 
Administration will be performed using an infusion syringe or infusion bag with a filter 
containing infusion set and an infusion pump. Details on preparation, labelling and 
administration of IdeS are described in the pharmacy manual.  
7.1.3 
Packaging and Labelling 
Packaging and labelling of the investigational medical product (IMP) will be performed in 
accordance with GMP and national regulatory requirements. The IMP will be labelled 
according to Annex 13, EudraLex Volume 4 and national regulatory requirements. 
7.1.4 
Drug Accountability and Compliance Check 
The administration of all medication (including investigational products) must be recorded 
in the appropriate sections of the CRF. Treatment compliance will be assured by supervised 
administration of the investigational product by the investigator or delegate. The dose, date 
and time of administration of the investigational product will be checked by the monitor at 
monitoring visits. 
It is the principal investigators/institution’s responsibility to establish a system for handling 
study treatments, including investigational medicinal products, to ensure that: 
1. Deliveries are correctly received by a responsible person (e.g., pharmacist or 
designated study personnel) 

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2. Deliveries are recorded 
3. Study treatments are handled and stored safely and properly 
4. The study drug provided for this study will be used only as directed in the study 
protocol 
5. The study personnel will account for all drugs dispensed and returned. Any 
discrepancies must be documented, investigated and appropriately resolved 
6. At the end of the study, the pharmacy personnel will account for all unused drugs 
and for appropriate destruction/return of all unused drugs to the sponsor for 
destruction. Certificates of delivery, destruction and return must be signed by a study 
team member. 
7.1.5 
Administration of IMP 
An intravenous dose of IdeS will be administered over 30 minutes. Each patient will receive 
a single dose of 0.25 or 0.5 mg/kg BW. Detailed instructions on preparation and 
administration are provided in the pharmacy manual. The infusion may be slowed down or 
stopped and restarted if required. 
7.2 
Study Procedures 
For each patient the duration of the treatment period including screening and follow up visits 
will be approximately 3 months. Timing (45 min, 2 h, 6 h and 24 h respectively as indicated 
in the flow chart in Table 2) of sampling on day 0 relates to start of infusion. 
Visit 1 (Screening Day -28 – 4) 
All patients considered for the study must give their written consent before screening or any 
other study procedure is performed. Screening of a patient can take place up to 28 days 
before the first dosing on study day 0. To be eligible for the study patients have to meet all 
inclusion criteria and no exclusion criteria. A patient failing screening may not be 
rescreened. However, if a patient has been screened and found eligible he or she can be 
rescreened if dosing could not be performed within 28 days due to logistical reasons. 
At the screening visit each subject will be informed about the study and after signing the 
informed consent form assessments for eligibility will commence. The eligibility evaluation 
includes adherence to inclusion and exclusion criteria, collection of concomitant medication, 
demographic data and medical history. A full physical examination, height and weight 
measurements, vital signs including resting blood pressure, pulse, respiratory frequency, 
12-lead resting ECG and body temperature will be measured. AEs that occur in the time 
period between informed consent and administration of the trial drug should be recorded as 
part of the patient’s medical history, but will not be considered a treatment emergent adverse 
event (TEAE) unless directly related to study procedures (e.g., hematoma secondary to 
laboratory testing) or it meets the definition of an SAE. 
Additionally, blood sampling for serology (HIV, hepatitis), pregnancy test, clinical 
chemistry (including 
and immunoglobulins), haematology (including
) 

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and urine sampling for urinalysis as well as blood samples for analysis of ADAMTS13 
activity, ADAMTS13 antibodies, and anti-IdeS IgE will be collected. 
Visit 2 (Residential stay Day 0 to Day 1) 
Patients found eligible at the screening visit will be included in the study. At visit 2 an 
eligibility check will be performed pre-dose within 60 min prior to IdeS infusion 
(inclusion/exclusion criteria, medical history, concomitant medication, vital signs, body 
temperature, urinalysis, blood sampling for pregnancy test, safety laboratory parameters 
(including
, 
 and immunoglobulins (IgG, IgM and IgA), ADAMTS13 
activity, ADAMTS13 antibodies,
, IdeS concentration, total IgG and F(ab’)2 fragment 
concentrations (PD) and ADA. Hydrocortison, paracetamol and antihistamine 
(chlorphenamine maleate) will be administered pre-dose to prevent/minimise risk of 
infusion reactions. Weight will be measured and prophylactic antibiotics will be 
administered. 
Patients will receive a single intravenous dose of IdeS over 30 minutes. 
At 2, 6 and 24 h post IdeS infusion blood sampling for determination of total IgG and 
F(ab’)2 fragment concentrations (PD), ADAMTS13 activity and antibodies, safety 
laboratory parameters, body temperature and
 as well as urine sampling will be 
performed. Assessment of vital signs and ECG will be performed at 6 hours post dosing.  
At 45 min, 2, 6 and 24 h post IdeS infusion sampling for determination of IdeS concentration 
will be performed. 
AEs and concomitant medication will be recorded on the applicable CRFs throughout the 
visit. 
Visit 3, 4, 5 and 6 (Days 3, 7, 10 and 14 respectively) 
At visits 3, 4, 5 and 6 safety laboratory parameters, IdeS concentration, total IgG and 
F(ab’)2 fragment concentrations (PD), AEs and concomitant medication will be assessed as 
well as vital signs, ADAMTS13 activity, ADAMTS13 antibodies and 
. Urine will be 
collected for urinalysis. Additionally, at visits 3, 4 and 6 ADA will be measured. Body 
temperature, weight and 12-lead resting ECG will only be measured at visit 6. 
Visit 7 (Day 30) 
At visits 7 safety laboratory parameters, total IgG and F(ab’)2 fragment concentrations (PD), 
AEs and concomitant medication will be assessed as well as vital signs, weight, body 
temperature, 12-lead resting ECG, ADAMTS13 activity, ADAMTS13 antibodies and 
. A physical examination will be performed. Urine will be collected for urinalysis.  
Visit 8 (End of Study, Day 64) 
A follow-up visit will be performed 64 days following IdeS infusion. This will be considered 
the end of study for the patient. At this visit a physical examination will be performed and 
the patient will be assessed for vital signs, weight, body temperature, 12-lead resting ECG, 
AEs and concomitant medication. Blood sampling for analysis of safety laboratory 

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parameters, pregnancy test, ADAMTS13 activity, ADAMTS13 antibodies,
, total IgG 
and F(ab’)2 fragment concentrations (PD) and anti-drug antibody (ADA) will be performed. 
Urine will be collected for urinalysis. 

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7.3 
Study Flow Chart 
Table 2.  
Study flow chart 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
Screening 
Treatment period 
EOS 
Assessment/Day 
-28 to -4 
0-1 
3 
7 
10 
14 
30 
64 
Informed Consent 
x 
 
 
 
 
 
 
 
Demographics  
x 
 
 
 
 
 
 
 
Medical history 
x 
xb 
 
 
 
 
 
 
Inclusion/exclusion 
x 
xb 
 
 
 
 
 
 
Physical examination 
x 
 
 
 
 
 
x 
x 
Weight 
x 
xb 
 
 
 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
 
Vital signs (blood 
pressure & pulse 
respiratory frequency) 
x 
xa 
x 
x 
x 
x 
x 
x 
Body temperature 
x 
xc 
 
 
 
x 
x 
x 
Clinical chemistry (incl. 
immunoglobulins and 
), haematology
. 
 urinalysis 
x 
xc 
x 
x 
x 
x 
x 
x 
Serum pregnancy test 
x 
xb 
 
 
 
 
 
x 
ADAMTS13 activity 
x 
xc 
x 
x 
x 
x 
x 
x 
ADAMTS13 antibodies 
x 
xc 
x 
x 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
12-lead ECG 
x 
xa 
 
 
 
x 
x 
x 
IdeS infusion 
 
x 
 
 
 
 
 
 
Hydrocortison, 
paracetamol, 
antihistamine 
 
xb 
 
 
 
 
 
 
Prophylactic antibiotic  
 
x 
 
 
 
 
 
 
IdeS concentration (PK) 
 
xd 
x 
x 
x 
x 
 
 
 
 
xc 
x 
x 
x 
x 
x 
x 
PD sampling (IgG SDS-
PAGE, IgG and F(ab’)2 
concentration) 
 
xc 
x 
x 
x 
x 
x 
x 
ImmunoCAP IgG (ADA) 
 
xb 
x 
x 
 
x 
 
x 
ImmunoCAP IgE  
x 
 
 
 
 
 
 
 
HIV, Hepatitis B and C 
x 
 
 
 
 
 
 
 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
apredose and 6 h post dose 
bpredose 
cpredose, 2 h, 6 h and 24 h post dose 
dpredose, 45 min (+/- 5 min), 2 h (+/- 15 min), 6 h (+/- 30 min) and 24 h (+/- 2 h) post dose 

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7.3.1 
Recording of Data 
The investigator will ensure that all data collected in the study are provided to the Sponsor. 
He/she ensures the accuracy, completeness, legibility and timeliness of the data recorded in 
the appropriate sections of the CRF and according to any instructions provided. The 
principal investigator will provide sponsor with all data produced during the study from the 
scheduled study assessments. He/she ensures the accuracy, completeness, legibility, and 
timeliness of the data reported to sponsor in the CRF and in all required reports. The study 
assessments are described in the sections below and the timing of these assessments are 
detailed in the study flow chart. Predose assessments should be performed within 60 minutes 
prior to dosing. 
The timing priority order at a particular time point is: 
1. Samples for ADAMTS13 activity and ADAMTS13 antibodies 
2. 
,
, Immunoglobulin (safety laboratory parameters) 
3. Samples for IgG and F(ab’)2 concentration and samples for IdeS concentration 
4. Vital signs 
5. ECG 
7.3.2 
Patient Care After End of Study 
All study patients will be followed up regularly according to the follow-up routines for TTP 
patients. The frequencies of outpatient visits will be adjusted individually to the state of 
patient health. 

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8. 
STUDY ASSESSMENTS 
All sampling, shipping and analysing of laboratory samples will be detailed in the laboratory 
manual. All safety samples as well as 
, Immunoglobulins and 
 will be analysed 
using standard tests by HSL at University College London Hospitals, UK, unless otherwise 
stated in the respective sections below. 
8.1 
Assessments Related to Endpoints 
8.1.1 
ADAMTS13 Activity 
Evaluation of the primary endpoint will be analysed using fluorescence resonance energy 
transfer (FRET) assay for ADAMTS13 activity. The results will be confirmed using a 
commercial chromogenic Technozym® ADAMTS-13 Activity ELISA. The tests will be 
performed at HSL at University College London Hospitals, UK. Samples will be drawn at 
the time points indicated in the study flowchart.  
8.1.2 
ADAMTS13 Antibodies 
Evaluation of the primary endpoint will be analysed using an IgG ELISA. The results will 
be confirmed using a commercial chromogenic Technozym® ADAMTS-13 autoantibody 
ELISA.  The tests will be performed at HSL at University College London Hospitals, UK. 
Samples will be drawn at the time points indicated in the study flowchart.  
8.1.3 
Vital Signs 
Blood pressure (systolic and diastolic arterial pressure, including calculation of mean arterial 
pressure), pulse and respiratory frequency will be measured at time points indicated in the 
study flowchart. 
Systolic and diastolic blood pressure will be measured after the patient has been in supine 
position for at least 5 minutes. All recordings will be performed using validated standard 
equipment. Clinically significant abnormal findings will be reported as AEs. 
8.1.4 
Adverse Events 
AEs will be recorded during the trial period, from obtaining the informed consent to the 
follow-up visit. For further information on definitions and reporting of AEs and SAEs, see 
Section 8.4. 
8.1.5 
Clinical Laboratory Variables 
8.1.5.1 
Clinical Chemistry and Haematology 
Blood samples for safety laboratory evaluations of clinical chemistry and haematology 
parameters (see Table 3) will be collected at the time-points indicated in the study flow 
chart. Actual sampling time will be recorded. Clinically significant abnormal findings will 
be reported as AEs. The clinical chemistry and haematology will be analysed locally. 
8.1.5.2 
Urinalysis 
Urine samples (see Table 3) are taken at the time points indicated in the study flowchart. 
Samples will be analysed locally. In case of abnormal results, a microscopic test will be 
performed. 

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Table 3.  
The following safety laboratory variables will be measured  
Clinical chemistry 
Coagulation 
P-Alanine aminotransferase 
P-Activated partial thromboplastin time (APTt) 
P-Albumin 
P-PK (internationally normalized ratio [INR]) 
P-Alkaline phosphatase 
 
P-Aspartate aminotransferase 
Haematology 
P-Bilirubin, total  
B-Haemoglobin 
P-Bilirubin, indirect 
B- Haematocrit 
P-Calcium 
B- Reticulocytes 
P-Cholesterol 
B- Neutrophils, lymphocytes eosinophils, and 
basophils 
P-Creatine phosphokinase 
B- White blood cell count with differential 
count 
P-C-reactive protein 
 
P-Creatinine 
B- Red blood cell count 
P- Gamma-glutamyltransferase 
B- Monocytes, large unclassified cells 
P-Glucose  
Mean cellular volume 
P-Potassium 
Mean corpuscular haemoglobin content 
P-Sodium 
Mean corpuscular haemoglobin concentration 
P-Magnesium 
 
P-Phosphorus 
Urinalysis 
P-haptoglobin 
U-Glucose 
P-triglycerides 
U-Haemoglobin 
P- troponin T 
U-Protein 
P-Urea (blood urea nitrogen) 
U-bilirubin 
P-IgG 
U-pH 
P-Total protein 
U-Nitrite 
P-Lactate dehydrogenase 
U-Ketone 
P-immunoglobulins (IgG, IgM and 
IgGA) 
U-Urobilinogen 
  
8.1.6 
Electrocardiogram 
The 12-lead ECG will be recorded with a validated ECG device. The parameters for heart 
rate (HR), PR interval, RR, QRS, QT and QTc(F) will be assessed (i.e., QT correction 
according to the Fridericia formula QTcF=QT/RR0.33). ECG recordings will capture at least 

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four QRS complexes, i.e., evaluable RR intervals. The Investigator or designee will evaluate 
whether the ECG is normal or abnormal and whether it is clinically significant, if abnormal. 
Any occurrence or de- or re-polarization disorders, arrhythmic disorders or other 
abnormalities will be assessed and any changes compared to the baseline (i.e., predose, 
treatment day 0) record will be commented. Clinically significant abnormal findings will be 
reported as AEs.  
Additional ECGs may be collected by the Investigator for safety reasons. 
8.1.7 
Pharmacodynamics  
Samples for the determination of IgG and F(ab’)2 fragment levels (total and ADAMTS13 
specific) in serum (PD) will be taken at the times presented in the study flow chart. The date 
and actual time of collection of each sample will be recorded on the laboratory requisition 
form and in the CRF. Samples will be analysed with electroluminescence based 
immunoassays using the MSD (Meso Scale Diagnostic) technology. The analyses will be 
performed at
 Full details of the analytical method used 
and the analysis results will be detailed in a separate bioanalytical report. 
8.1.8 
Pharmacokinetics 
Samples for determination of concentrations of IdeS in serum will be taken at the times 
presented in the study flow chart. The actual date and time of collection of each sample will 
be recorded on the laboratory requisition form and in the CRF. Samples will be analysed by 
an electroluminescence based immunoassay using the MSD technology. The analyses will 
be performed at
. Full details of the analytical method 
used and the analysis results will be detailed in a separate bioanalytical report.  
8.1.9 
Immunogenicity 
Samples for the determination of anti-drug antibody (ADA) levels in serum will be taken at 
the times presented in the study flow chart. The date and time of collection of each sample 
will be recorded on the laboratory requisition form and in the CRF. Samples will be analysed 
for anti-IdeS IgG using a customized IdeS ImmunoCAP test, developed by
 
 The analysis will be performed by
 
 Full details of the analytical 
method used and the analysis results will be detailed in a separate bioanalytical report. 
8.1.10 
 
 
8.2 
Other Assessments  
8.2.1 
ImmunoCAP anti-IdeS IgE 
A sample for detection of anti-IdeS antibodies of IgE type will be taken at screening. The 
sample will be sent for analysis at 
 
Full details of the analytical method used and the analysis 
results will be detailed in a separate bioanalytical report. 

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8.2.2 
Demographics and Baseline Data 
Information about gender, race, date of birth, body weight and height will be collected at the 
screening visit for each subject. Weight will also be recorded predose on the day of dosing 
as well as on day 14, 30 and 64. Measurements should be taken without shoes. Body mass 
index will be calculated from the height and weight. Medical history will be recorded at 
screening and at day 0. 
8.2.3 
Physical Examinations 
A complete physical examination will be performed at screening, day 30 and on day 64 and 
include an assessment of the following: general appearance, head and neck (including ears, 
eyes, nose, mouth and throat), lymph nodes, abdomen, musculo-skeletal, cardiovascular, 
respiratory, gross neurological examination, skin and urinary system. 
8.2.4 
Body Temperature 
Body temperature will be measured at screening and study visit 2. At visit 2/dosing, body 
temperature will be recorded pre-dose, 2, 6 and 24 hours post-dose as well as on days 14, 
30 and 64. 
8.2.5 
Serology 
Determination of HIV-1 and HIV-2 antibodies, hepatitis B surface-antigen and hepatitis C 
virus antibodies will be performed at screening for eligibility purposes.  
8.2.6 
Pregnancy Test 
Serum β-hCG will be determined at screening, per-dose and at the end of study (EOS) visit, 
using validated standard methods. 
8.2.7 
Prior and Concomitant Medication 
Information about prior and concomitant medication will be collected for each patient 
throughout the study. 
8.2.8 
Handling of Biological Samples 
A detailed description of all sample collections and shipment procedures will be included in 
a separate laboratory manual. The sponsor or third part(ies) will store the blood samples for 
up to 2 years after reporting the trial. 
8.3 
Concomitant Medication 
Therapeutic IgG based drugs such as Rituximab will be cleaved by IdeS during 7 days 
following dosing therefore Rituximab treatment within 7 days prior to IdeS dosing is not 
allowed (See Section 6.1.2). Other concomitant medication may be administered at the 
discretion of the Investigator. All concomitant medication, including premedication and 
prophylactic antibiotics will be recorded in the CRF, together with the main reason for its 
prescription. 
8.3.1 
Premedication 
Patients will receive premedication with Solu-Medrol 250 mg i.v. and 10 mg loratadine p.o. 
before the IdeS infusion. 

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8.3.2 
Prophylactic Antibiotic 
All patients will receive a two-week regimen of Penicillin V (or alternatively Ciprofloxacin 
in case of allergy to penicillin) from the start of IdeS treatment.  
8.4 
Safety 
It is of the utmost importance that all staff involved in the study is familiar with the content 
of this section. The principal investigator is responsible for ensuring this. 
8.4.1 
Definition of Adverse Events  
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. 
Relationship to the study drug will be deemed as not related, unlikely, possible or probable. 
An undesirable medical condition can be symptoms (e.g., nausea and chest pain), signs (e.g., 
tachycardia and enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings and electrocardiograms).  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered as the AE rather than the procedure itself.  
In case of a fatality, the cause of death is considered as the AE, and the death is considered as 
its outcome. 
Pre-treatment Adverse Event 
A pre-treatment adverse event is any untoward medical occurrence arising or observed 
between signing of informed consent and the first administration of the IMP. 
Treatment Emergent Adverse Event 
A treatment emergent adverse event is any AE occurring after the administration of the IMP 
and within the time of residual drug effect, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after administration of the IMP and within the 
time of residual drug effect.  
The time of residual drug effect is the estimated period of time after the administration of 
IMP, where the effect of the product is still considered to be present based on PK, PD or 
other substance characteristics. The residual dug effect is generally accepted to be 5 times 
the terminal half-life. Based on the data from healthy subjects, the terminal half-life of IdeS 
is expected to be approximately 5 days (mean of 118 hours in healthy subjects), i.e., in this 
study the residual drug effect is likely to be well within the 30 day visit.  
Post-treatment Emergent Adverse Events 
A post-treatment emergent adverse event is any event occurring after the time of residual 
drug effect of the IMP, i.e., from the visit on day 30. 

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8.4.2 
Definition of Serious Adverse Events 
A serious adverse event (SAE) is an AE or suspected adverse reaction (SAR) that is 
considered "serious" if, in the view of either the investigator or sponsor, it results in any of 
the following outcomes: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation.  
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent one of the outcomes listed above 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical 
judgment, they may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events include 
allergic bronchospasm 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. 
Life-threatening event: An adverse event or suspected adverse reaction is considered "life-
threatening" if, in the view of either the investigator or sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death.   
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
Hospitalization for inpatient hospitalization or prolongation of existing hospitalization. 
• In this study for elective treatment of a pre-existing condition that did not worsen 
during the clinical investigation is not considered an AE.  Hospitalisation for study 
drug dosing and observation as required by protocol is not considered an SAE. 
Admittance to an emergency room for observation without being admitted to the 
hospital may be considered to be an AE but is not considered as an SAE.  However, 
complications that occur during hospitalization are AEs, and if a complication 
prolongs hospitalization, the event is considered serious. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.  Examples of such medical events 

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include allergic bronchospasm 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. 
SAEs should be followed until the event resolves, stabilizes, or returns to baseline.  If the 
patient is discontinued from the study prior to resolution/stabilization of the SAE, then the 
patient will be followed as part of the SAE/pharmacovigilance system. 
8.4.3 
Recording of Adverse Events 
In clinical studies, an AE/SAE can occur at any time after signing of the informed consent 
until the end of the study, including run-in or washout periods, even if no study treatment 
has been administered, e.g., an AE can be related to a procedure in the protocol.  
AEs will therefore be collected on the AE CRF from the time of signing of the informed 
consent and throughout the study period including the follow-up period. However, AEs that 
occur in the time period between informed consent and administration of the trial drug 
should be recorded as part of the patient’s medical history, but will not be considered a 
treatment emergent adverse event (TEAE) unless directly related to study procedures (e.g., 
hematoma secondary to laboratory testing) or it meets the definition of an SAE. 
8.4.4 
Variables 
The following variables will be recorded in the CRF for each AE; description of the AE, the 
date and time (if applicable) when the AE started and stopped, severity based on Common 
Toxicity Criteria grade (according to CTCAE v.4.0, see appendix 1) whether the AE is 
serious or not, causality rating, action taken with regard to investigational product, e.g., the 
AE caused patient to discontinue the study, and outcome.   
For each reported AE the investigator will assess a causal assessment of the relationship of 
the event to study procedures and/or IdeS using the following criteria. 
• Unrelated:  applicable to an AE that occurs when the subject was not exposed to 
study treatment or another cause is obvious. 
• Unlikely to be related:  applicable to an AE that meets the following criteria 
• Does not follow a reasonable temporal sequence from study drug dosing 
• May readily have been produced by the patient’s clinical state, 
environmental, or toxic factors, or other therapy administered to the patient 
• Possibly related:  applicable to AEs where connection with dosing of study drug 
appears unlikely but cannot be ruled out.  Applicable to AEs where: 
• It follows a reasonable temporal sequence dosing with study drug 
• It follows a known pattern of response to study drug dosing (based on 
animal studies) 

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• Probably related:  applicable to AEs that are considered, with a high degree of 
certainty, to be related to the study drug.  Applicable to AEs where 
• It follows a reasonable temporal sequence study drug dosing 
• It cannot be reasonably explained by the know characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of 
therapy 
• It follows a known patter of response to study drug dosing (based on animal 
data). 
• For SAEs causal relationship will also be assessed for any study procedure.  
8.4.5 
Adverse Events Based On Signs and Symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: “Have you had any health problems since you were last asked?” 
or revealed by observation will be collected and recorded in the CRF. When collecting AEs, 
the recording of diagnoses is preferred (when possible) rather than recording a list of signs 
and symptoms, for example: congestive heart failure rather than low ejection fraction, rales 
and dyspnea. However, if a diagnosis is known and there are other signs or symptoms that 
are not generally part of the diagnosis, the diagnosis and each sign or symptom not part of 
the diagnosis will be recorded separately, for example: congestive heart failure and 
conjunctivitis. 
8.4.6 
Adverse Events Based On Examinations and Tests 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs 
and other safety variables will only be reported as AEs if they fulfil any of the SAE criteria 
or are the reason for discontinuation of treatment with the investigational product. If 
deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign/symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Any new or aggravated clinically relevant 
abnormal medical finding at a physical examination as compared with the baseline 
assessment will be reported as an AE. 
Clinically relevant deterioration in non-protocol-mandated measurements will be reported 
as AE(s). Wherever possible the reporting investigator uses the clinical, rather than the 
laboratory term (e.g., anaemia versus low haemoglobin value). 
8.4.7 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed 
up by the investigator until stabilization, for as long as medically indicated or the overall 
clinical outcome of the patient is known, unless the patient is documented as “lost to follow-
up”. All SAEs and AEs leading to discontinuation should be followed until the event 
resolves, stabilizes, or returns to baseline.  

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Reasonable attempts to obtain this information must be made and documented. Sponsor 
retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) 
at the end of the study, if judged necessary. 
8.4.8 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the CRF. 
SAEs will be recorded from the time of informed consent.  
All SAEs must be reported, whether or not considered related to the study drug, on a separate 
SAE Report Form. All SAEs will also be recorded in the CRF. An assigned contract research 
organisation (
) will be responsible for reporting all SAEs to 
regulatory authorities and ethics committees in accordance with International conference on 
harmonisation (ICH) Good Clinical Practice and local regulations. As soon as the 
Investigator is aware of a potential SAE he/she should contact 
 by fax 
or e-mail and in any case no later than 24 hours after the knowledge of such a case. At the 
time of initial reporting the investigator must provide as a minimum requirement, patient 
number, birth date, description of the SAE and a preliminary assessment of causality.  
 
 
 
 
 
 
 
 
  
 
For fatal or life-threatening adverse events where important or relevant information is 
missing, active follow-up is undertaken immediately. Investigators or other site personnel 
inform the sponsor and monitor of any follow-up information on a previously reported SAE 
immediately but no later than within 24 hours of when he or she becomes aware of it. The 
monitor or sponsor will advise the investigator/study site personnel how to proceed. 
The SAE reporting procedures are detailed in the study specific Safety Management Plan. 
This plan is an agreement between the sponsor, and 
. 
8.4.9 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)  
Suspected unexpected serious adverse reactions (SUSARs) must be reported to Regulatory 
Authorities. A suspected serious adverse reaction is any serious adverse event for which 
there is a reasonable possibility that the investigational product caused the adverse event. A 
serious adverse reaction is considered "unexpected" if it is not listed in the Reference Safety 
Information section of the investigator brochure or is not listed at the specificity or severity 
that has been observed. 
SUSARs with an outcome of death or are life threatening must be reported to the relevant 
Regulatory Authorities within 7 calendar days, all other SUSARs must be submitted within 

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15 calendar days. The SUSAR reporting procedures are detailed in the study Safety 
Management Plan. This plan is an agreement between the sponsor, and 
 
. The sponsor will notify the appropriate regulatory agency(ies) and all 
participating site Investigators of any SUSARs on an expedited basis and in accordance with 
applicable regulations.  In addition, the sponsor is responsible for informing all investigators 
in all ongoing studies involving IdeS about all SUSARs.  
It is the responsibility of the site Investigator to promptly notify the Ethics Committee and 
other appropriate institutional regulatory bodies of all SUSARs received involving risk to 
human subjects as per their applicable requirements. 

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9. 
BIOLOGICAL SAMPLING PROCEDURES  
9.1 
Volume of Blood 
The maximum volume to be drawn from each patient in the study will not exceed 300 mL. 
9.2 
Handling, Storage and Destruction of Biological Samples 
Safety samples will be used or disposed after analyses. 
9.2.1 
Pharmacokinetic, Pharmacodynamic and Anti-drug Antibody Samples 
Samples will be shipped to
 for analysis either in house or at external 
laboratory. Study samples may be stored for a maximum of two years after completion of 
the study report. 
9.3 
Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their life cycle. 
The principal investigator keeps full traceability of collected biological samples from the 
patients while in storage at the centre until shipment and keeps documentation of receipt of 
arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use 
until used or disposed. 
Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers. 
9.4 
Withdrawal of Informed Consent for Donated Biological Samples 
If a patient withdraws consent to the use of biological samples donated the samples will be 
disposed/destroyed, if not already analysed and documented. 
The principal investigator: 
• will ensure that patient withdrawal of informed consent is notified immediately to 
sponsor 
• will ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed/destructed and the action documented.  
• will ensure the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destructed and the 
action documented returned to the study site. 
Sponsor ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destructed and the action 
documented returned to the study site. 

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In the event that analysis/research has already been performed, sponsor will retain the results 
and associated data for regulatory reasons but these will not be used in any subsequent 
analyses. 

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10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements. 
10.2 
Patient Data Protection 
The informed consent form (ICF) will incorporate wording that complies with relevant data 
protection and privacy legislation.  
10.3 
Ethics and Regulatory Review 
An ethical review board must approve the final study protocol, including the final version 
of the ICF and any other written information to be provided to the patients. The investigator 
will ensure the distribution of these documents to the applicable ethical review board, and 
to the study site staff. The opinion of the ethical review board must be given in writing.  
Sponsor must approve any modifications to the ICF that are needed to meet local 
requirements. 
Before enrolment of any patient into the study, the final study protocol, and the final version 
of the informed consent form are approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
The distribution of any of these documents to the national regulatory authorities will be 
handled by sponsor. 
Sponsor will provide ethical review boards and principal investigators with safety 
updates/reports according to local requirements. 
Progress reports and notifications of serious and unexpected adverse drug reactions will be 
provided to the ethical review board according to local regulations and guidelines. 
10.4 
Informed Consent 
The principal investigator(s) at the centre will: 
• Ensure that the patient is given full and adequate oral and written/read information 
about the nature, purpose, possible risk and benefit of the study.  
• Ensure that the patients are notified that they are free to discontinue the study at any 
time.  
• Ensure that the patient is given the opportunity to ask questions and allowed time to 
consider the information provided. 
• Obtain and document the patient’s signed and dated informed consent before 
conducting any procedure specifically for the study. 

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• Ensure the original, signed informed consent form is stored in the Investigator’s 
Study File. 
• Ensure a copy of the signed informed consent form is given to the patient. 
10.5 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the principal 
investigator and sponsor. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment.  
The amendment must be approved by regulatory authorities and the ethical review board 
before implementation. Local requirements must be followed for amended protocols. 
Sponsor will distribute any subsequent amendments and new versions of the protocol to the 
principal investigator. 
If a protocol amendment requires a change to a centre’s informed consent form, sponsor and 
the centre’s ethical review board must approve the revised informed consent form before the 
revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by the ethical review board. 
10.6 
Audits and Inspections 
The investigator(s)/institution will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s), providing direct access to source data/documents. 
Permission to examine, analyze, verify, and reproduce any records and reports that are 
important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory 
authorities, sponsor´s monitors and auditors) with direct access should take all reasonable 
precautions within the constraints of the applicable regulatory requirements(s) to maintain 
the confidentiality of subjects´ identities and sponsor´s proprietary information. 
Authorised representatives of sponsor or a regulatory authority may perform audits or 
inspections at the centre, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements. The investigator will contact sponsor immediately if contacted by 
a regulatory agency about an inspection at the centre. 

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11. 
STUDY MANAGEMENT 
11.1 
Pre-study Activities 
Before the first patient is entered into the study, it is necessary for a representative of sponsor 
to visit the investigational study site for a pre-study visit to: 
• Determine the adequacy of the facilities to give the sponsor information about 
whether the study centre has knowledge, enough time, a sufficient patient pool, and 
sufficient training to manage the study in a good way in terms of patient inclusion, 
patient handling, data and overall study management. 
• Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence and the responsibilities of sponsor 
or its representatives.  
11.2 
Training of Study Site Personnel 
Before the first patient is entered into the study, a sponsor representative will review and 
discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and also train them in any study specific procedures and system(s) 
utilised. 
The principal investigator will ensure that appropriate training relevant to the study is given 
to all staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
11.3 
Monitoring of the Study 
During the study, a sponsor representative will have regular contacts with the study site, 
including visits to: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, data are being 
accurately and timely recorded in the CRFs, and investigational product 
accountability checks are being performed. 
• Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating patients. This will 
be done using print outs of records for each patient. 
• Perform drug accountability. 

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• Ensure withdrawal of informed consent to the use of the patient’s biological samples 
is reported and biological samples are identified and disposed/destructed 
accordingly, and the action is documented, and reported to the patient. 
The sponsor and the CRO will be available between visits if the investigator(s) or other staff 
at the centre needs information and advice about the study conduct. 
11.4 
Study Agreements 
The principal investigator must comply with all the terms, conditions, and obligations of the 
clinical study agreement for this study. In the event of any inconsistency between this 
clinical study protocol and the clinical study agreement, the clinical study protocol will 
prevail. 
Agreements between sponsor and the principal investigator must be in place before any 
study-related procedures can take place, or patients be enrolled. 
11.5 
Study Timetable and End of Study 
The end of the entire study is defined as “the last visit of the last patient undergoing the 
trial”. 
The study is expected to start in Quarter 2 2016 and to be completed by Quarter 2 2017.  
Sponsor may terminate the entire study prematurely if concerns for safety arise within the 
study. 
11.6 
Insurance 
All patients in the study are covered by an insurance held by Hansa Medical AB.  

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12. 
DATA HANDLING 
12.1 
Source Data and Source Documents 
12.1.1 
Source Data and Source Documents 
Source data – ICH Definition 
Source data are defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for 
the reconstruction and evaluation of the study. Source data are contained in source 
documents (original records or certified copies). 
Source documents – ICH Definition 
Source documents are defined as original documents, data, and records (e.g., hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical study). 
12.2 
Study specific Source Data Requirements – Hansa Medical AB 
Any study specific source data will be described and defined in a Source Data document 
produced for this study. 
12.3 
Case Report Forms 
A CRF/eCRF will be provided by a CRO. If an eCRF is chosen the system should be 
validated in accordance with regulatory and system requirements.  
12.4 
Data Management 
All data management procedures will be outsourced to a CRO. Activities will be specified 
in a Data Management Plan prepared by the CRO and reviewed and approved by the 
Sponsor. The plan will be issued before data collection begins and will describe all 
functions, processes and specifications for data collection, cleaning and validation. 
For medical coding of AEs, medical history and concomitant medication the most recent 
versions of the Medical Dictionary for Regulatory Activities (MedDRA) and WHO Drug 
will be used. The coding will be outsourced to a third party. When all data has been 
processed, queries resolved, medical coding completed and any issues from review of 
protocol violations and data listings resolved, the data base will be locked and any further 
update will be denied. 

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13. 
EVALUATION AND CALCULATION OF 
PHARMACOKINETIC AND PHARMACODYNAMIC 
VARIABLES 
13.1 
Calculation or Derivation of Pharmacokinetic Variables 
IdeS concentration will be determined in collected PK samples and the result will be 
correlated with the achieved pharmacodynamic results. Only a limited pharmacokinetic 
evaluation will be performed. Where possible, the following PK parameters will be 
determined for IdeS: maximum plasma concentration (Cmax) and area under the 
concentration-time curve (AUCt). 
13.2 
Calculation or Derivation of the Relationship Between 
Pharmacokinetic and Pharmacodynamic Variables  
Relationship between IdeS serum or plasma concentration and IgG and F(ab’)2 fragment 
concentrations (PD) as well as levels of ADAMTS13 activity and ADAMTS13 antibodies 
(IgG and F(ab’)2), respectively, will be presented graphically. If appropriate, concentration-
effect relationships will be explored. 

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14. 
STATISTICAL METHODS AND SAMPLE SIZE 
Prior to clean file a Statistical Analysis Plan (SAP) with details on statistical analysis and 
data presentation will be written. This will be outsourced to a CRO. 
14.1 
Description of Analysis Sets 
The safety analysis set will consist of all subjects that received any amount of study 
medication. 
The Full Analysis Set (FAS) will consist of all subjects in the safety set. 
The Per Protocol Set (PPS) will be defined by the PK analyst. 
The final criteria for the PPS, regarding which protocol deviations that warrant exclusions, 
will be determined when all data on protocol violations/deviations are available. 
14.2 
Methods of Statistical Analyses 
14.2.1 
General Principles 
No formal statistical hypothesis testing will be performed in this study. Data will be 
presented by actual dose received.  
14.2.2 
Patient Characteristics 
The following demographic variables will be tabulated: gender, race, date of birth, body 
weight, height and body mass index (BMI) for all patients as appropriate. 
Medical history and medications taken before screening will be tabulated including 
comments and coded fields. 
Baseline assessments of safety variables (ECG, vital signs, body temperature, physical 
examination, IgE and laboratory parameters) will be tabulated by dose groups as 
appropriate. Base line is defined as pre-dose assessments on treatment day 0. 
14.2.3 
Safety and Tolerability 
All safety and tolerability data including safety labs, vital signs, weight, body temperature, 
ECG and physical exams will be tabulated as specified in the SAP.  
Adverse events and serious adverse events will be collected for each patient from time when 
informed consent is obtained (visit 1) until end of study. AEs will be presented as pre-
treatment emergent, treatment emergent and post-treatment emergent in separate listings. 
The following summaries of AEs will be given by treatment and in total:  
Severity, action taken, concomitant therapy started and subject outcome of the AEs will be 
given in data listings only. AEs with a fatal outcome and AEs which were reason for 
premature discontinuation of study drug will be listed separately, respectively. 
The number of patients who had any AEs, SAEs, AEs that led to withdrawal, AEs related to 
study drug and AEs with severe intensity will be summarized. If the number of AEs are 

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sufficiently large summary will be broken down on PT (Preferred term) and SOC (System 
organ class) according to MedDRA vocabulary. Furthermore, SAEs and AEs that led to 
withdrawal will be tabulated separately. 
14.2.4 
Pharmacokinetics 
Pharmacokinetic (PK) variables will be summarized using appropriate descriptive statistics 
(e.g., n, geometric mean, coefficient of variation (CV), min, median, max) by treatment 
group.   
14.2.5 
Pharmacodynamics 
All data associated with the efficacy of IdeS in cleaving IgG (IgG and F(ab’)2 fragments 
concentrations) will be presented using listings for each dose group. 
14.2.6 
Anti-drug Antibodies 
All anti‐IdeS antibody data will be presented using listings for each dose group. 
 
14.2.7 
Efficacy 
All data associated with the efficacy of IdeS; levels of ADAMTS13 activity, ADAMTS13 
antibodies, 
 
, immunoglobulins (IgG, IgM and IgA) and 
 will be 
determined for each patient and presented in listings sorted by treatment, patient, and time-
point. In addition, time for ADAMTS13 activity to return to normal levels and number of 
cases with normalisation of ADAMTS13 at 64 days will be presented per patient. 
14.3 
Determination of Sample Size 
Sample size is not based on formal statistical considerations. Due to the exploratory nature 
of the study it is expected that data from six patients should suffice to achieve the objectives 
of the study.  

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15. 
REPORTING AND PUBLICATION 
15.1 
Clinical Study Report 
The results from this study will be reported in a clinical study report (CSR) within one year 
after completion of the last patient. This will be prepared by Hansa Medical AB and 
submitted for comments and signature to the signatory investigator(s). 
15.2 
Confidentiality and Ownership of Data 
Any confidential information relating to the IMP or the study, including any data and results 
from the study will be the exclusive property of Hansa Medical AB. The investigator and 
any other persons involved in the trial will protect the confidentiality of the proprietary 
information belonging to Hansa Medical AB. 
15.3 
Publication and Public Disclosure 
15.3.1 
Publication Policy 
At the end of the study, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator(s) offered authorship and Hansa Medical AB.  
Any external Contract Research Organisation or laboratory involved in the conduct of this 
study has no publication rights regarding the study. 
15.3.2 
Public Disclosure Policy 
The study will be uploaded to the EudraCT database. 

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16. 
ARCHIVING 
16.1 
Investigator File 
The investigator is responsible for maintaining all the records, which enable the conduct of 
the trial at the site to be fully understood, in compliance with ICH-GCP. The trial 
documentation including all the relevant correspondence should be kept by the investigator 
for at least 15 years after the completion or discontinuation of the trial, if no further 
instructions are given by Hansa Medical AB. 
The investigator is responsible for the completion and maintenance of the confidential 
subject identification code, which provides the sole link between named subject source 
records and anonymous CRF data for Hansa Medical AB. The investigator must arrange for 
the retention of this Subject Identification Log and signed Informed Consent Documents for 
at least 15 years after the completion or discontinuation of the trial. 
No trial site document may be destroyed without prior written agreement between the 
investigator and Hansa Medical AB. Should the investigator elect to assign the trial 
documents to another party, or move them to another location, Hansa Medical AB must be 
notified. If the investigator retires and the documents no longer can be archived by the site, 
Hansa Medical AB can arrange having the Investigator File archived at an external archive. 
16.2 
Trial Master File 
Hansa Medical AB will archive the Trial Master File in accordance with ICH-GCP and 
applicable regulatory requirements. 

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17. 
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HMed doc. No. 2012-003. IdeS in vitro efficacy in 
 
. 
HMed Doc. No. 2014-003. Clinical study report 11-HMedIdeS-01.