Clinical trial NCT02790437
Conditions: Kidney Failure, Chronic
Sponsor: Hansa Biopharma AB
Start date: 2016-06-01; Completion date: 2018-07-03
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the effectiveness of the study drug IdeS in patients who are on the waiting list for kidney transplant and have previously undergone desensitization unsuccessfully or in whom effective desensitization will be highly unlikely. At study entry, the patients will have an available deceased or live donor with a positive crossmatch test. The study will assess IdeS efficacy and safety in removing Donor Specific Antibodies (DSAs) and thereby convert a positive crossmatch test to negative.

Detailed description:
The study will assess the IdeS efficacy in creating a negative crossmatch test (XM) in patients who exhibit donor specific antibodies (DSA) and have a positive crossmatch test to their available live or deceased donors. The first 3 patients in this study will receive a kidney from a deceased donor. The study will primarily examine the efficacy of IdeS in creating a negative XM. The first 3 patients will receive one dose of 0.25 mg/kg BW IdeS on study day 0. If it is considered safe and negative crossmatch test is not achieved after the first dose, an additional IdeS infusion can be given within 2 days of the first infusion. The dose schedule may be increased to 0.5 mg/kg BW given once or twice after the first 3 patients have been tested. The decision to escalate the dose will be done after evaluation of safety and efficacy.

Arms: arm 1: IdeS intravenous infusion
Interventions: intervention 1: IdeS intervention 2: Kidney transplantation
Intervention descriptions: intervention 1: One dose of 0.25 mg/kg BW IdeS on study day 0. If negative crossmatch is not achieved, a second dose can be given within 2 days of the first infusion. intervention 2: Performed following IdeS treatment

Protocol documents:
Prot_000.pdf: 
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STUDY PROTOCOL  
A Phase II Study to Evaluate the Efficacy of IdeS (IgG endopeptidase) to Desensitize 
Transplant Patients with a Positive Crossmatch Test 
 
 
 
 
Sponsors protocol ID: 15-HMedIdeS-06 
 
 
Sponsor: Hansa Medical AB, Lund, Sweden 
 
IND Number: 128074 
 
 
 
 


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Table of content 
 
1. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................. 5 
1 
IMPORTANT MEDICAL PROCEDURES .............................................................................................. 7 
1.1 
MEDICAL EMERGENCIES CONTACTS ............................................................................................................... 7 
1.2 
OVERDOSE .......................................................................................................................................................... 7 
2 
INTRODUCTION ....................................................................................................................................... 7 
2.1 
DISEASE AND PATIENT POPULATION ............................................................................................................. 7 
2.2 
CURRENT TREATMENT ..................................................................................................................................... 9 
2.3 
IDES ..................................................................................................................................................................... 9 
2.4 
IDES CLINICAL STUDIES ................................................................................................................................. 10 
2.5 
STUDY RATIONALE AND DISCUSSION ON OVERALL STUDY DESIGN ......................................................... 11 
2.6 
RISK/BENEFIT AND ETHICAL ASSESSMENT ................................................................................................ 12 
3 
STUDY OBJECTIVES ............................................................................................................................. 13 
3.1 
PRIMARY OBJECTIVE ....................................................................................................................................... 13 
3.2 
SECONDARY OBJECTIVES ................................................................................................................................ 13 
3.3 
PRIMARY ENDPOINT ....................................................................................................................................... 14 
3.4 
SECONDARY ENDPOINTS ................................................................................................................................... 14 
4 
STUDY DESIGN ...................................................................................................................................... 14 
4.1 
OVERALL STUDY DESIGN AND FLOWCHARTS .............................................................................................. 14 
4.2 
DECISION CRITERIA FOR DOSE ESCALATION, INCLUSION OF LIVING DONOR TRANSPLANTS AND 
STUDY TERMINATION ..................................................................................................................................................... 18 
4.3 
DATA SAFETY MONITORING BOARD ............................................................................................................. 18 
5 
PATIENT SELECTION CRITERIA ...................................................................................................... 19 
5.1 
SCREENING ....................................................................................................................................................... 19 
5.2 
INCLUSION CRITERIA ...................................................................................................................................... 19 
5.3 
EXCLUSION CRITERIA ..................................................................................................................................... 19 
5.4 
WITHDRAWAL CRITERIA ............................................................................................................................... 20 
5.4.1 
Criteria for discontinuation from the study ......................................................................................20 
5.4.2 
Procedures for discontinuation of a patient from the study .....................................................20 
6 
STUDY CONDUCT ................................................................................................................................. 20 
6.1 
STUDY TREATMENT ........................................................................................................................................ 20 
6.1.1 
IdeS .......................................................................................................................................................................20 
6.1.2 
Storage and handling ..................................................................................................................................21 
6.1.3 
Drug accountability and compliance check ......................................................................................21 
6.1.4 
Administration of investigational drug ...............................................................................................22 
6.1.5 
Desensitization protocol.............................................................................................................................22 
6.1.6 
Premedication .................................................................................................................................................22 
6.1.7 
Prophylactic antibiotic................................................................................................................................22 
6.1.8 
Induction therapy ..........................................................................................................................................22 
6.1.9 
Immunosuppressing agents ......................................................................................................................22 
6.1.10 
Other concomitant medication ..........................................................................................................22 
6.2 
STUDY PROCEDURES DESCRIBED PER VISIT ................................................................................................ 22 
6.3 
SAFETY REPORTING ........................................................................................................................................ 24 


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6.3.1 
Definition of adverse events ......................................................................................................................24 
6.3.2 
Definitions of serious adverse event ......................................................................................................25 
6.3.3 
Recording of adverse events .....................................................................................................................26 
6.3.4 
Variables ............................................................................................................................................................26 
6.3.5 
Adverse events based on signs and symptoms .................................................................................27 
6.3.6 
Adverse Events based on examinations and tests ...........................................................................27 
6.3.7 
Follow-up of unresolved adverse events .............................................................................................28 
6.3.8 
Reporting of serious adverse events .....................................................................................................28 
6.3.9 
Reporting of suspected unexpected serious adverse events (SUSARs) ..................................28 
6.3.10 
Procedures in case of pregnancy ......................................................................................................29 
6.4 
STUDY ASSESSMENTS ..................................................................................................................................... 29 
6.4.1 
Recording of data ..........................................................................................................................................29 
6.4.2 
Screening and demography procedures .............................................................................................30 
6.4.3 
Patient care after end of study ................................................................................................................30 
6.5 
LABORATORY EFFICACY ASSESSMENTS AND EVALUATION OF PRIMARY ENDPOINT ............................ 30 
6.5.1 
Analysis of crossmatch tests .....................................................................................................................30 
6.5.2 
Determination donor specific antibodies (DSAs) and complement fixation ......................30 
6.6 
CLINICAL SAFETY ASSESSMENTS .................................................................................................................. 30 
6.6.1 
Physical examination ...................................................................................................................................30 
6.6.2 
Height and weight .........................................................................................................................................31 
6.6.3 
ECG .......................................................................................................................................................................31 
6.6.4 
Vital signs ..........................................................................................................................................................31 
6.6.5 
Other safety assessments............................................................................................................................31 
6.7 
LABORATORY SAFETY ASSESSMENTS ........................................................................................................... 31 
6.7.1 
Clinical chemistry, hematology, coagulation and virology ........................................................31 
6.7.2 
Viral surveillance ...........................................................................................................................................32 
6.7.3 
Pregnancy test ................................................................................................................................................32 
6.7.4 
Determination of kidney function ..........................................................................................................32 
6.8 
PHARMACOKINETICS AND PHARMACODYNAMICS ...................................................................................... 32 
6.8.1 
Determination of drug concentration in biological samples ....................................................32 
6.8.2 
Determination of IgG levels in serum ...................................................................................................32 
6.9 
ANTI-DRUG ANTIBODY ANALYSIS ................................................................................................................. 33 
7 
BIOLOGICAL SAMPLING PROCEDURES ......................................................................................... 33 
7.1 
HANDLING, STORAGE AND DESTRUCTION OF BIOLOGICAL SAMPLES ...................................................... 33 
7.1.1 
Pharmacokinetic, pharmacodynamic and anti-drug antibody samples .............................33 
7.2 
CHAIN OF CUSTODY OF BIOLOGICAL SAMPLES ............................................................................................ 33 
7.3 
WITHDRAWAL OF INFORMED CONSENT FOR DONATED BIOLOGICAL SAMPLES .................................... 33 
8 
ETHICAL AND REGULATORY REQUIREMENTS .......................................................................... 34 
8.1 
ETHICAL CONDUCT OF THE STUDY ............................................................................................................... 34 
8.2 
PATIENT DATA PROTECTION ......................................................................................................................... 34 
8.3 
ETHICS AND REGULATORY REVIEW .............................................................................................................. 34 
8.4 
INFORMED CONSENT ...................................................................................................................................... 35 
8.5 
CHANGES TO THE PROTOCOL AND INFORMED CONSENT FORM ............................................................... 35 
8.6 
AUDITS AND INSPECTIONS ............................................................................................................................. 35 
8.7 
ARCHIVING OF INVESTIGATOR STUDY FILE AND STUDY MASTER FILE ................................................. 36 
9 
STUDY MANAGEMENT ........................................................................................................................ 36 
9.1 
PRE-STUDY ACTIVITIES .................................................................................................................................. 36 


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9.2 
MONITORING OF THE STUDY ......................................................................................................................... 37 
9.3 
SOURCE DATA .................................................................................................................................................. 37 
9.4 
STUDY AGREEMENTS ...................................................................................................................................... 37 
9.5 
INSURANCE ....................................................................................................................................................... 37 
9.6 
END OF STUDY ................................................................................................................................................. 37 
10 DATA HANDLING .................................................................................................................................. 37 
10.1 
CASE REPORT FORMS ..................................................................................................................................... 37 
10.2 
SOURCE DATA .................................................................................................................................................. 38 
10.3 
DATA MANAGEMENT ...................................................................................................................................... 38 
11 EVALUATION AND CALCULATION OF PHARMACOKINETIC AND PHARMACODYNAMICS 
VARIABLES....................................................................................................................................................... 38 
11.1 
CALCULATION OR DERIVATION OF PHARMACOKINETIC VARIABLES ....................................................... 38 
12 STATISTICAL METHODS AND SAMPLE SIZE ............................................................................... 38 
12.1 
DESCRIPTION OF ANALYSIS SETS .................................................................................................................. 38 
12.2 
METHODS OF STATISTICAL ANALYSES ......................................................................................................... 39 
12.2.1 
General principles ....................................................................................................................................39 
12.2.2 
Patient characteristics...........................................................................................................................39 
12.2.3 
Safety and tolerability ...........................................................................................................................39 
12.2.4 
Efficacy on DSA, CDC CXM and FACS CXM ....................................................................................39 
12.2.5 
Pharmacokinetics ....................................................................................................................................40 
12.2.6 
Pharmacodynamics .................................................................................................................................40 
12.2.7 
Anti-drug antibodies ...............................................................................................................................40 
12.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................................... 40 
13 PUBLICATION POLICY ........................................................................................................................ 40 
13.1 
CLINICAL STUDY REPORT .............................................................................................................................. 40 
13.2 
CONFIDENTIALITY AND OWNERSHIP OF DATA .......................................................................................... 40 
13.3 
PUBLICATION AND PUBLIC DISCLOSURE .................................................................................................... 40 
13.3.1 
Publication Policy ....................................................................................................................................40 
13.3.2 
Public Disclosure Policy ........................................................................................................................40 
14 REFERENCES .......................................................................................................................................... 41 
 
Table of figures 
 
Figure 1. Overall treatment schedule. CXM=crossmatch test, Tx=transplantation. .......... 15 
 
Table of tables 
Table 1. Study flow chart: Screening to Day 180 after IdeS infusion...................................... 16 
Table 2. Study flow chart:0/Pre-dose to 48 h after IdeS infusion. Time-points after dosing (0) 
relates to START of infusion. .................................................................................................. 17 
Table 3. The following safety variables will be contained in the DSMB safety data package 18 
Table 4. Composition of study drug ....................................................................................... 21 
Table 5. Clinical chemistry, hematology, coagulation and virology........................................ 31 
 


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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 or 
special term 
Explanation 
ABMR 
Antibody mediated rejection 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APTt 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
ATGAM 
Anti thymocyte globuline derived from horse 
AUC 
Area under serum concentration-time curve 
BMI 
Body mass index 
BP 
Blood pressure 
BW 
Body weight 
CKD 
Chronic kidney disease 
CL 
Clearance of drug from plasma/serum 
Cmax  
Maximum serum concentration 
CMV 
Cytomegalovirus 
COPD 
Chronic obstructive pulmonary disease 
CRF 
Case report form (electronic/paper) 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSR 
Clinical study report 
CTCAE 
Common toxicity criteria for adverse events 
CV 
Coefficient of variation 
CXM 
Crossmatch test 
DD 
Deceased donor 
DSMB 
Data and safety monitoring board 
DSA 
Donor specific antibodies 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
FACS 
Fluorescence-activated cell sorting 
FAS 
FDA 
Full analysis set 
Food and drug administration 
GCP 
Good clinical practice 
GODT 
Global observatory on donation and transplantation 


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Abbreviation or 
special term 
Explanation 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
IA 
Immuno adsorption 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IdeS 
IRB 
Immunoglobulin G-degrading enzyme of Streptococcus pyogenes 
Institutional review board 
IVIg 
Intravenous immunoglobulin 
LD 
Living donor 
MedDRA 
Medical dictionary for regulatory activities 
MFI 
Mean fluorescence intensity 
NOAEL 
No observed adverse effect level 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PK (INR) 
Prothrombin complex (internationally normalized ratio) 
PLEX 
Plasma exchange 
PPS 
Per protocol set 
PRA 
Panel reactive antibody 
SA 
Single antigen 
SAB 
Single antigen beads 
SAE 
SAR 
Serious adverse event 
Serious adverse reaction  
SAP 
Statistical analysis plan 
SOC 
System organ class 
SPA 
Solid phase immunoassay 
Ss 
Steady state 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Terminal half-life 
tmax 
Time to maximum plasma concentration 
Vz 
Apparent volume of distribution 
Vss 
Volume of distribution at steady state 
 




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identification of a suitable donor. As many as 15% of the listed patients are highly 
sensitized (calculated PRA ≥80) and it has been reported that less than 15% of the 
sensitized patients in US are transplanted each year despite high priority on the waitlist 
(Yabu, Pando et al. 2013). The presence of HLA donor specific antibodies (DSAs) is a direct 
contraindication to transplantation because of the risk of hyper-acute antibody-mediated 
rejection with acute allograft loss. For transplant candidates who have antibodies, which 
react against a wide range of HLA it can be difficult to find a donor against whom they 
have no antibodies. This is true both for patients waiting for a deceased donor kidney and 
for those within a paired donation program who have an available live donor against 
which they have DSAs. Consequently, sensitized patients have an extended waiting time 
for transplantation and a U.K. study demonstrated that the waiting time increased from 
788 days for patients with no or low grade of sensitization to 2232 days (> 6 years) for 
highly sensitized patients (Fuggle and Martin 2008). Along the same line, Yabu et al. 
reported that less than 15% of the highly sensitized patients in the US were transplanted 
per year, despite high priority (Yabu, Pando et al. 2013). 
Data demonstrate that desensitization followed by transplantation of patients with DSA 
is clearly associated with short- and long-term survival benefits compared to staying in 
dialysis (Montgomery, Lonze et al. 2011, Vo, Petrozzino et al. 2013, Orandi, Garonzik-
Wang et al. 2014, Orandi, Luo et al. 2016). In addition, the patient’s quality of life is 
dramatically increased and there are substantial cost-savings associated with 
desensitization compared to dialysis (Vo, Petrozzino et al. 2013).  
In a study performed at John Hopkins Hospital, Baltimore, over 11 years (Montgomery, 
Lonze et al. 2011) a total of 211 patients underwent HLA-incompatible live-donor kidney 
transplantation following desensitization, with HLA incompatibility defined as DSA 
detected by crossmatch test or multiplex assay (Luminex). In the treatment group, 
Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% 
at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5% and 
30.5%, respectively, for patients in dialysis-only group. The rate of ABMR after 
desensitization and transplantation has been reported to be 22%, most of which 
responded to treatment with plasmapheresis (Montgomery, Warren et al. 2012, Iyer, 
Jackson et al. 2013). Among patients in the desensitization group who had positive 
crossmatches on the complement-dependent cytotoxicity assay (CDC crossmatch), 
survival rates were 87.7% at 1 year, 82.0% at 3 years, 78% at 5 years and 78.0% at 8 
years, as compared with rates of 92.2%, 67.0%, 49.7% and 27.1%, respectively, in the 
dialysis-only group. Patients were matched comprehensively based on cPRA, age, blood 
group, number of renal replacement, race, sex, and the presence or absence of diabetes. 
Recently, a five-year outcome study in 535 living donor kidney transplants with a positive 
crossmatch (Orandi, Garonzik-Wang et al. 2014) was reported. In 102 patients with a 
positive complement dependent crossmatch test the 5-year survival was 70.7%, which is 
comparable to 78.0% reported by the Johns Hopkins group.  
Although many sensitized patients have been successfully transplanted using current 
desensitization protocols there are patients on the kidney transplant waitlist who have 
previously 
undergone 
desensitization 
unsuccessfully 
or 
in 
whom 
effective 
desensitization will be highly unlikely.  


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2.2 Current treatment 
In order to increase the likelihood in finding a suitable allograft and transplanting the 
highly sensitized patients, there are two main approaches (Morath, Opelz et al. 2012), 
paired donation or desensitization. These approaches may be combined.   
Paired donation programs offer opportunities for sensitized patients to receive organs 
from donors to whom they have little or no DSA, with comparable outcomes to un-
sensitized patients (Bray, Nolen et al. 2006). While 16% of the registered population in 
the Canadian Blood Services Living Donor Paired Exchange National Registry had PRA 
between 80% and 96%, they accounted for 24% of those transplanted. On the other hand, 
those with cPRA of 97% or greater make up 32% of the Registry population but accounted 
for only 10% of transplants (Cole 2015). Highly sensitized patients may remain on the 
waiting list for several years. 
Over the past decade, novel desensitization protocols have been developed to enable 
patients with high levels of anti-donor antibodies to receive a transplant with acceptable 
five-year outcomes (Montgomery, Lonze et al. 2011, Orandi, Garonzik-Wang et al. 2014). 
There is no standardized or approved protocol for desensitization; however, a few 
protocols have been developed and tested in clinical settings (Vo, Wechsler et al. 2008). 
All of these protocols use techniques to remove antibodies, either through high-dose 
intravenous immunoglobulin (IVIg) or plasma-exchange (PLEX)/immunoadsorption (IA) 
often combined with low-dose IVIg (Montgomery, Zachary et al. 2000, Vo, Wechsler et al. 
2008). In addition, some protocols use rituximab in order to inhibit the synthesis of IgG 
(Vo, Wechsler et al. 2008). The desensitization protocols are often combined with 
induction therapy using steroids and anti-thymocyte globulin (ATG), anti-CD52 (e.g. 
alemtuzumab) and/or anti-IL2R antibody (e.g. basiliximab or daclizumab) in order to 
prevent acute cellular rejections in high-risk patients. PLEX, IA and IVIg treatments have 
the disadvantage of requiring rigorous planning since they involve repeated treatments 
over a long period of time. Therefore, these treatments are difficult to apply when 
transplanting patients with deceased allografts.  
2.3 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
 In addition, 
IdeS treatment rapidly and substantially cleaved anti-HLA IgG in serum from sensitized 
CKD grade 5 patients in vitro 
. The reactivity to individual HLA-
antigens were reduced below the critical Mean Florescence Intensity (MFI) acceptable for 
transplantation and a positive crossmatch test was turned into negative. IdeS offers a 
unique and powerful approach for removing the impenetrable immunology barrier HLA 
antibodies present and would allow life-saving transplants to patients who are currently 
not eligible for kidney transplantation.  


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2.4 IdeS clinical studies 
A phase I study first in man single ascending dose study 
 showed 
that IdeS was safe and well tolerated 
 The study 
demonstrated that IdeS could be administered 
 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 
 after dosing. 
 
, IdeS completely cleaved the pool of plasma IgG 
 
 
 
 
 
 The data clearly shows that a single dose of IdeS 
is superior to both plasmapheresis and immunoadsorption with respect to efficiency and 
rate of plasma IgG reduction.
 
 
 
 
The adverse events that were reported, none of 
which were reported as serious, were as anticipated from the biological nature of the 
drug.
 
 
 
 
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 CKD patients on the 
kidney transplantation waiting list. 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 treated patients had antibodies against multiple HLA 
antigens with pre-dose MFIs between 6000 and 25000 as measured by SAB (Luminex) 
assay. There were two dose groups, 0.12 and 0.25 mg/kg body weight (BW) given once 
or twice within 48 hours. 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, measured as an MFI (LABScreen) less than 1100 within 24 hours from 
dosing. In addition, in all patients having a significant pre-dose panel-reactivity the 
percentage PRA was reduced already one hour after IdeS treatment. It was also concluded 
that in the majority of patients the CDC 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. Three of the SAEs 
were infections. Two phase II studies using IdeS in sensitized patients prior to 
transplantation are currently ongoing in Uppsala, Sweden and Los Angeles, US. 
In a phase II study in patients diagnosed with asymptomatic antibody-mediated 
Thrombotic Thrombocytopenic Purpura (TTP) with low ADAMTS13 activity, safety and 
tolerability were assessed after patients receiving a single intravenous dose of IdeS. A 
secondary objective was to investigate IdeS efficacy in significantly increasing 
ADAMTS13 activity and decreasing ADAMTS13 antibody levels. Inclusion was 
prematurely terminated after inclusion of two patients who both showed signs of serum 
sickness (further described in section 2.6).  


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2.5 Study rationale and discussion on overall study design  
This study will include patients on the kidney transplant waitlist who have previously 
undergone desensitization unsuccessfully or in whom effective desensitization will be 
highly unlikely. Patients in whom effective desensitization is highly unlikely are defined as 
patients who have been accepted into a desensitization program but have not been 
transplanted within a year despite the opportunity of desensitization and paired 
donation. Consequently, these patients have one of the highest unmet medical needs in 
transplantation today. A randomized controlled study in this patient population is not 
feasible as the potential control treatments have already been tried unsuccessfully or 
judged as highly unlikely to succeed.  
The study will assess IdeS efficacy and safety in removing DSAs and thereby convert a 
positive crossmatch test to negative. The primary endpoint is conversion of the 
crossmatch test following IdeS therapy and hence the patients may serve as their own 
controls. The patients included will have an available deceased or live donor allograft with 
a positive crossmatch test at study entry.  
For these patients there is no available treatment for a control arm and the study is 
therefore open labeled, single arm. There will be a total of 15-20 (7-13 with live donors 
and 7-13 with deceased donors) patients included in the study. The first 3 patients in this 
study will receive a kidney from a deceased donor. Patients will receive one dose of 0.25 
mg IdeS/kg BW on study day 0 with the possibility of an additional IdeS dose within two 
days. This dosing schedule was used in the completed phase II study in highly and 
moderately sensitized CKD patients described above and was found to be, effective and 
safe in removing DSAs 
 However, it is desirable to find a dose, 
which is effective in all patients after a single dose in order to minimize time to 
transplantation especially for the deceased donor setting where a short cold ischemic 
time is critical. Therefore, there will be a possibility to escalate the dose to 0.5 mg/kg BW 
after evaluation of safety in the first 3 patients. Patients will receive IVIg on day 7 and 
anti-CD20 on day 9 after IdeS treatment. In addition, induction therapy with ATGAM at 
time of transplantation or anti-CD52 (Campath) on day 4 will be given.  
There is evidence that low dose IVIg, given after DSA reduction with PLEX, suppresses 
endogenous antibody production and prevents DSA rebound. Additionally, after 
transplantation in the context of antibody reduction from plasmapheresis and low dose 
IVIg or high dose IVIg plus anti-CD20, most patients will experience a durable reduction 
in DSA but not third party HLA antibody. Thus, on about day 7 after IdeS dosing, IgG begins 
to return. From previous studies it has also been demonstrated that healthy subjects and 
some patients develop antibodies to IdeS at this time and there is no experience from 
administering a second dose of IdeS with a longer interval than 2 days. The current 
understanding of antibody depletion and reconstitution suggests that the rebound of DSA 
will be prevented or blunted by treatment with high dose IVIg given at about day 7 after 
IdeS treatment. At this point the IdeS activity is expected to be non-detectable or very low 
and not to affect the pharmacological effects of IVIg. Furthermore, the potential donor 
specific anamnestic response would likewise be reduced or prevented by memory B-cell 
depletion with the anti-CD20 antibody rituximab. With the donor antigens expressed on 
the graft the same phenomenon of donor specific B-cell unresponsiveness may be 
observed that is seen in the majority of patients desensitized with plasmapheresis and 
low dose IVIg. DSA is expected to remain low, whereas, third party antibody, including 
vaccine antibodies, will recover to normal levels (Stegall, Dean et al. 2009). 


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Based on the current knowledge, including experience from completed and ongoing 
clinical studies, it is expected that IdeS will inactivate IgG across all compartments 
allowing a rapid and potent reduction of donor specific antibody (DSA) to a level 
acceptable for transplantation.  
2.6 Risk/benefit and ethical assessment 
Patients included in this study have both a wide breadth of sensitization and high 
reactivity to common HLA antigens. Transplantation is not possible using current 
standards for desensitization due to antibodies creating a positive crossmatch test. These 
patients are so strongly sensitized that even with paired donation it is highly unlikely to 
identify a donor with a genotype that would allow desensitization with a reasonable 
likelihood of success. In addition, some of the patients will have failed on earlier attempts 
of desensitization. Eligible patients will either be on the waitlist for a deceased allograft 
or have an identified live donor. However, in both groups transplantation is not indicated 
due to antibodies creating a positive crossmatch test. Sensitized patients have an 
increased risk of ABMR associated with negative long-term graft outcome. From previous 
studies it is known that the ABMR frequency in the highly sensitized patient population is 
between 25-39% after desensitization (Abu Jawdeh, Cuffy et al. 2014). There are 
currently no approved treatments for ABMR but in the event of ABMR the patient will be 
treated according to best clinical practice. This may include plasmapheresis, IVIg, 
complement inhibitors and anti-CD20 antibodies. The risk for ABMR and graft loss should 
be weighed against the morbidities, low quality of life and increased mortality associated 
with long term dialysis. Data demonstrate that transplantation following desensitization 
is clearly associated with short- and long-term survival benefits compared to staying in 
dialysis (Montgomery, Lonze et al. 2011, Vo, Petrozzino et al. 2013, Orandi, Garonzik-
Wang et al. 2014, Orandi, Luo et al. 2016). In addition, the patient’s quality of life is 
dramatically increased after successful transplantation and there are substantial cost-
savings associated with desensitization and subsequent transplantation compared to 
long-term dialysis (Vo, Petrozzino et al. 2013).  
The patients included in the study will receive premedication with glucocorticoids 
(methylprednisolone) and antihistamines (loratadine) before each IdeS infusion in order 
to minimise the risk of infusion reactions. Patients with live donors will be screened for 
anti-IdeS IgE antibodies as part of the eligibility criteria and if positive they will not be 
included. Patients and healthy subjects who have been previously treated have formed 
antibodies to IdeS that persist for some months and then decline, the importance of which 
if unknown. In addition mild and reversible proteinuria has been detected in healthy 
subjects treated with IdeS.  
It has been demonstrated that IdeS at therapeutic levels can cleave antibody-based drugs 
and IVIG, which are administered as part of treatment of transplant patients in this study. 
These therapies are administered at appropriate intervals after IdeS therapy in which the 
plasma level of IdeS is expected to have minimal or no effect on these drugs. 
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 prophylactic antibiotics until IgG levels are back to acceptable levels. Patients will 
be screened for viruses (Hepatitis B, C and HIV, CMV, EBV and BKV) and on-going 
infections and patients having clinical signs of on-going infections at the time of 


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enrolment will not be included in the study. Patients will be hospitalised for at least 7 days 
and closely monitored for infections and after that instructed to contact the principal 
investigator immediately if they have any sign of infection. There will be a physician 
specialized in infectious diseases available for medical advice in case of a patient showing 
signs of infection. In case of infection in a patient with low IgG plasma levels, intravenous 
immunoglobulin may be indicated. 
The doses of 0.25 mg/kg and 0.5 mg/kg BW are well covered by the NOAEL 
 
 patients in the completed phase II study in 
Sweden were exposed to a total dose of 0.5 mg/kg BW. 
 
 
 
 
 
 
For this patient category the risk/possibility of becoming pregnant is extremely small due 
to their disease state. However, as an extra safety measure, the requirement for highly 
effective contraception is part of the inclusion criteria for this study. A pregnancy test will 
be done at screening and pre-dose IdeS for all women of childbearing potential.  
Patients will be closely monitored for all adverse events and the second dose will only be 
given if the investigator considers it safe after evaluating adverse events and over all 
patient status after the first IdeS dose. The principal investigator must make sure that 
sufficient facilities and procedures are available to handle emergency situations during 
the study. The study sites have extended experience in phase I/II studies within 
transplantation and graft rejection treatment as well as handling biological drugs. The 
sites have adequate procedures in place to handle unexpected adverse reactions. 
As described above in section 2.4 a phase II study in asymptomatic TTP patients, 
enrollment was stopped after two subjects showing signs of serum sickness.  Previously, 
27 patients without concomitant immunosuppression medications have been treated 
with IdeS and none of them showed signs of serum sickness. The sponsor cannot rule out 
that the underlying disease was a factor in the development of serum sickness in these 
two subjects. Based on all available safety information from non-clinical and clinical 
studies, the overall benefit/risk profile of IdeS still appears favorable. 
3 Study objectives 
3.1 Primary objective 
• To assess the IdeS efficacy in creating a negative crossmatch test 
3.2 Secondary objectives 
• To determine DSA levels at multiple times (pre-dose, 2, 6, 24 and 48 hours and days 7, 
14, 21, 28, 64, 90, 120 and 180) post IdeS treatment 
• To determine time to creating a negative CDC crossmatch test 


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• To determine time to creating a negative FACS crossmatch test 
• To evaluate safety parameters (adverse events, clinical laboratory tests, vital signs and 
ECGs) following IdeS treatment up to day 180 
• To monitor kidney function after IdeS treatment as assessed by, filtration (eGFR), 
creatinine and proteinuria 
• To establish  the pharmacokinetic (PK) profile of IdeS 
• To establish the Pharmacodynamic (PD) profile of IdeS (cleavage and recovery of 
IgG) 
• To establish the immunogenicity profile of IdeS (ADA) 
3.3 Primary endpoint 
• Efficacy defined as IdeS ability to create a negative crossmatch test within 24 hours 
after IdeS dosing 
3.4 Secondary endpoints 
• DSA levels at pre-dose and 2, 6, 24 and 48 hours and days 7, 14, 21, 28, 64, 90, 120 and 
180 post IdeS treatment 
• Time to creating a negative CDC crossmatch test 
• Time to creating a negative FACS crossmatch test 
• Safety parameters (adverse events, clinical laboratory tests, vital signs and ECGs) 
• Kidney function after IdeS treatment assessed by, filtration (eGFR), creatinine and 
proteinuria up to 180 days post treatment 
• Pharmacokinetic (PK) profile of IdeS up to day 14 
• Pharmacodynamic (PD) profile of IdeS (cleavage and recovery of IgG) up to day 180 
post IdeS 
• Immunogenicity profile of IdeS by measuring anti-drug antibodies (ADA)  
4 Study design 
4.1 Overall study design and flowcharts 
This is a phase II, open label exploratory study to assess the IdeS efficacy in creating a 
negative crossmatch test (CXM) in a total of 15-20 patients (7-13 with living donors and 
7-13 with a deceased donor) who exhibit DSAs and have a positive crossmatch test to 
their available live or deceased donors. The first 3 patients in this study will receive a 
kidney from a deceased donor. The study will primarily examine the efficacy of IdeS in 
creating a negative CXM in these patients. Included patients will be treated with IdeS on 
day 0. If it is considered safe and the desired effect is not achieved (negative crossmatch) 
a second dose can be given within 2 days of the first infusion. In addition to IdeS patients 


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will be given high dose IVIg (2 g/kg BW, maximum of 140 g) on day 7 and anti CD20 
(Rituximab) on day 9 as outlined in Figure 1. DSA levels will be monitored 2, 6, 24 and 48 
hours and 7, 14, 21, 28, 64, 90, 120 and 180 days after the last IdeS dosing. Safety, 
including kidney function will be monitored at multiple time points up to 180 days after 
treatment. Pharmacokinetics, pharmacodynamics and anti-drug antibodies will be 
followed. For details on assessments see flow chart in Table 1. Patients who are not 
eligible for transplantation after IdeS treatment will not be transplanted and thus will not 
receive any induction therapy or immunosuppression. All patients who receive IdeS will 
also be asked to remain in the study and be followed up according to the study protocol 
even if they are not transplanted. In addition, patients who lose their graft during the 
course of the study will remain in the study and be followed up according to the study 
protocol. 
 
 
Figure 1. Overall treatment schedule. CXM=crossmatch test, Tx=transplantation.  
 
 
 






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4.2 Decision criteria for dose escalation, inclusion of living donor 
transplants and study termination 
The first three patients enrolled in the study will receive a kidney from a deceased donor. 
The starting dose in this study is 0.25 mg/kg BW given once or twice, with the possibility 
of a higher dose group of less than or equal to 0.5 mg/kg BW. The decision to escalate the 
dose and to include living donor transplants will be done after evaluation of the efficacy 
and safety. Efficacy will be evaluated with regards to IdeS’ ability to create a negative 
crossmatch test in the first three patients within a timeframe suitable for transplantation. 
If a single dose of IdeS fails to produce a negative crossmatch in any of these patients a 
dose escalation will be justified based on efficacy. Before proceeding to the next dose 
group, a data and safety monitoring board (DSMB) will review available safety and 
tolerability data (see Table 3). Safety data collected up to and including the day 28 visit 
for the first three patients will be evaluated. The safety data will be compiled to a DSMB 
package and sent to all DSMB members before the DSMB meeting. The DSMB package and 
recommendation will also be sent to FDA before proceeding to a higher dose level and the 
inclusion of living donor transplants. 
 
 In addition, the DSMB will continuously monitor the study safety throughout 
the study. If an unacceptable number of serious side effects or graft losses are observed 
the DSMB can recommend premature termination of the study. 
Table 3. The following safety variables will be contained in the DSMB safety data package  
Clinical chemistry 
Coagulation 
Clinical safety data 
P-IgG 
PK (INR) 
Adverse events 
P-ALP 
P-APTT 
Vital signs 
P-ALT 
 
eGFR 
P-AST 
 
 
P-Bilirubin, total  
Hematology 
Urine 
P-Glucose 
B-Hemoglobin 
Protein electrophoresis 
P-Sodium    
B-Differential analysis of leucocytes 
Protein spot 
P-CRP 
B-Thrombocytes 
 
P-Albumin  
 
 
P-Urea 
 
 
P-Triglycerides 
 
 
P-Creatinine 
 
 
P-Creatinine 
phosphokinase 
 
 
4.3 Data safety monitoring board 
The Data and Safety Monitoring Board (DSMB) will monitor participant safety, data 
quality and evaluate the progress of the study. The constitution, activities and reports of 
the DSMB shall be governed by the FDA’s “Guidance for Clinical Study Sponsors: 
Establishment and Operation of Clinical Study Data Monitoring Committees” (detailed in 
a study specific DSMB charter). Both documents will be distributed to all DSMB members. 


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The DSMB will be an external group of experts, independent of the sponsor and consist of 
at least three physicians of which one will be the DSMB chairman.   
5 Patient selection criteria 
5.1 Screening 
To be eligible for the study patients have to meet all inclusion criteria and no exclusion 
criteria. If the patient has been screened and meets all inclusion and no exclusion criteria 
and does not receive the dose within 28 days, for reasons such as the patient did not 
receive an organ offer within the time frame etc., the patient may be rescreened. No other 
rescreening is allowed. The re-screening procedure will be the same as the previous 
screening visit with the exception for the virology tests which do not have to be repeated 
if not more than 6 months old. Medical history and concomitant medication will be updated 
if applicable. Re-screened patients will keep the original screening number. 
5.2 Inclusion criteria  
1. Male or female age 18-70 years at the time of screening 
2. Patients on the kidney transplant waitlist who have previously undergone 
desensitization unsuccessfully or in whom effective desensitization will be 
highly unlikely. The breadth and strength of sensitization will predict an 
extremely low likelihood of successful desensitization or kidney paired 
donation.   
3. Patients with a live or deceased donor with a positive crossmatch test. 
4. Patient must be able to understand and sign the informed consent.  
5.3 Exclusion criteria 
1. Previous treatment with IdeS 
2. Previous high dose IVIg treatment (2 g/kg BW) within 28 days prior to IdeS 
treatment. 
3. Lactating or pregnant females 
4. Women of child-bearing age who are not willing or able to practice FDA-
approved forms of contraception.  
5. HIV-positive patients 
6. Patients with clinical signs of HBV or HCV infection  
7. Patients with active tuberculosis 
8. A significantly abnormal general serum screening lab result according to the 
investigator’s judgement.  Hgb cannot be < 6.0 g/dL. Laboratory safety results 
from within 3 days before screening can be used  
9. 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 
10. Individuals deemed unable to comply with the protocol 
11. Patients with clinical signs of  CMV or EBV infection 
12. Patients with a history of major thrombotic events, patients with active 
peripheral vascular disease or patients with proven hypercoagulable 
conditions 
13. Patients should not have received investigational drugs within 4 half-lives (or 
similar) 


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14. Known allergy/sensitivity to IdeS infusions 
15. Patients who have a live donor and test positive for ImmunoCAP anti-IdeS IgE 
 
5.4 Withdrawal criteria 
5.4.1 Criteria for discontinuation from the study 
Patients may be discontinued from study treatment and assessments at any time. The 
patient is free to discontinue his/her participation in the study at any time and for any 
reason, without prejudice to further treatment. If a patient is withdrawn from the study 
by the investigator due to adverse events he/she will not be replaced. Patients who 
withdraw for reasons other than adverse events may be replaced.  
The study may be stopped prematurely if: 
1. DSMB recommend that the study should be terminated 
2. Findings that, at the discretion of Principal Investigator(s) and/or Sponsor, 
indicate that further dosing should be stopped 
5.4.2 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, 
he/she will be seen and assessed by an investigator(s). Adverse events will be followed. 
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 to retrieve safety and efficacy data. 
If the study is prematurely terminated, the Sponsor will promptly inform the investigators 
and the regulatory authorities of the termination and the reason(s) for the termination. 
The IRBs/IECs will also be promptly informed and provided the reason(s) for the 
termination either by Sponsor or investigators, depending on local requirements. All 
patients, those in the study at the time for termination as well as those that have 
completed the study, will be informed about the study termination and the reason(s) for 
it by their respective investigator.  
6 Study conduct 
6.1 Study treatment 
6.1.1 IdeS 
IdeS is a clear colorless liquid. It is formulated at 10 g/L in PBS and intended for 
intravenous administration after dilution. Refer to Table 4 for composition. 




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6.1.4 Administration of investigational drug 
Intravenous IdeS will be administered over at least 15 minutes. The first 3 patients will 
receive one dose of 0.25 mg/kg BW IdeS on study day 0. If it is considered safe and the 
desired effect is not achieved (negative crossmatch test) after the first dose, an additional 
IdeS infusion can be given within 2 days of the first infusion. The dose schedule may be 
increased to 0.5 mg/kg BW given once or twice after the first 3 patients have been tested. 
The decision to escalate the dose will be done after evaluation of safety and efficacy as 
described in section 4.2. 
6.1.5 Desensitization protocol 
In addition to treatment with IdeS, patients will be treated with high dose IVIg 10% 
solution 2 g/kg BW (max 140g for >70kg) 7 days after IdeS treatment and 1 g rituximab 
(anti-CD20) 9 (-11) days after IdeS treatment. If deemed necessary by the investigator the 
IVIg dose may be split into two doses administered over days 6-8. 
6.1.6 Premedication 
Patients will receive premedication with glucocorticoids (methylprednisolone, 250 mg 
intravenously) and antihistamines (loratadine 10 mg orally or an equipotent 
antihistamine) before each IdeS infusion.  
6.1.7 Prophylactic antibiotic 
All patients will receive prophylactic antibiotics or sulpha according to clinical practice at 
each site from the start of IdeS treatment until serum IgG level is back within normal 
range. 
6.1.8 Induction therapy 
Induction therapy can be used if indicated. Sites are allowed to use either ATGAM (anti 
thymocyte globuline derived from horse) or Alemtuzumab (anti-CD52 antibody). Rabbit 
ATG cannot be used since it is efficiently cleaved by IdeS. Alemtuzumab can be given 4 
days after IdeS at the earliest, based on limited experience. If alemtuzumab is used as 
induction therapy on day 4, pulse steroid treatment can be used up to day 4 to prevent T-
cell mediated rejection. 
6.1.9 Immunosuppressing agents  
Patients will be treated with immunosuppressing agents according to clinical practice at 
each study center.  
6.1.10 Other concomitant medication 
Supportive therapy considered necessary for the patient’s welfare may be given at the 
discretion of the investigator. All concomitant medication, including premedication and 
prophylactic antibiotics must be recorded on the concomitant medication page in the CRF. 
6.2 Study procedures described per visit 
Visit 1 (Screening day -28 to day 0) 
At the screening visit each subject will be informed about the study and after signing the 
informed consent form assessments for eligibility will commence. Eligibility evaluation, 
collection of concomitant medication, demographic data (age, sex, race, height, weight and 
BMI) and medical and surgical history is performed. A full physical examination, height 
and weight measurements, vital signs including resting blood pressure, pulse, respiratory 


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frequency, 12-lead resting ECG and body temperature is done. Additionally blood 
sampling for serology (HIV, hepatitis, BK, EBV and CMV), pregnancy test and clinical 
chemistry, hematology as well as blood samples for analysis of DSAs, CDC- and FACS-CXM 
and anti-IdeS IgE antibody analysis (ImmunoCAP) will be collected.  
Visit 2 (days 0-2) 
Patients found eligible at the screening visit will be included in the study. At visit 2 the 
eligibility check will be repeated within 60 min from IdeS dosing. A pregnancy test will 
be taken. If a female patient has been hospitalized between screening visit and visit 2, a 
pregnancy test at screening visit will suffice and a pregnancy test at visit 2 is not 
required.  In addition methylprednisolone and loratadine will be administered predose 
to prevent infusion reactions. Vital signs, body temperature, safety laboratory sampling, 
pharmacokinetic and pharmacodynamics sampling will be performed pre-dose, 2 h, 6 h, 
24 h and 48 h post IdeS infusion. In addition blood sampling for DSAs will be drawn at 
pre-dose, 2 h, 6 h, 24 and 48 h. Blood sampling for CDC- and FACS-CXM will be done at 
pre-dose, 2 h, 6 h, and 24 h. Any effort should be made to obtain crossmatch test for all 
time-points indicated in the study flowcharts. If this is not possible due to logistics on 
specific sites, the sponsor can allow a smaller number of time-points to be evaluated. 
However, as a minimum one crossmatch test pre-dose and one post-dose IdeS must be 
performed to allow evaluation of the primary endpoint. ADA will be sampled at pre-dose 
and 48 h post IdeS infusion. P-creatinine will be measured at 24 h and 48 h post IdeS 
infusion and eGFR will be calculated. Repeat 24 hour urine collections will be performed 
day 1-9 for urine protein electrophoresis analysis. AEs and concomitant medication will 
be recorded in the CRF throughout the visit. AEs that occur in the time period prior to 
administration of the study 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. A kidney biopsy on the donor kidney will be performed 
in deceased donor patients. 
Visit 3 (day 3-6) 
Twenty-four- (24)-hour urine collections will be performed daily, day 1-9, for urine 
protein electrophoresis analysis. AE and concomitant medication will be assessed. PK will 
be drawn at 96 hours ±4h. 
Visit 4 (day 7) 
At visit 4 high dose IVIg (2 g/kg BW) will be administered. Prior to IVIg dosing the 
following assessments are made: vital signs, blood sampling for analysis DSAs, 
safetylaboratory parameters, PK, PD, ADA and P-creatinine. The eGFR will be calculated. 
Additional samples for PD and ADA will be drawn after the IVIg infusion. If the IVIg dose 
is split into two doses given over two days the sampling will be performed before and 
after the first dosing. Repeat 24 hour urine collections will be performed day 1-9 for urine 
protein electrophoresis analysis. AE and concomitant medication will be assessed. 
Visit 5 (Day 9) 
At visit 5 the patient will be dosed with rituximab. In addition a blood sample for PK and 
PD analysis will be drawn. Repeat 24 hour urine collections will be performed day 1-9 for 
urine protein electrophoresis analysis. AE and concomitant medication will be assessed. 


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Visit 6 (day 14) 
At visit 6 the patient will be assessed for body weight, AEs and concomitant medication. 
Blood sampling for analysis of DSAs, safety laboratory tests, P-creatinine/eGFR, PK, PD, 
ADA and virus screen for BK, EBV and CMV will be drawn. Urine will be obtained for 
analysis of proteinuria. 
Visit 7 (day 21) 
Blood sampling for assessment of DSAs, safety laboratory parameters, PD, ADA and P-
creatinine/eGFR will be drawn. In addition AEs and concomitant medication will be 
assessed.Visits 8 and 9 (day 28 and 64) 
At visits 8 and 9 the patient will be assessed for AEs and concomitant medication. Blood 
sampling for analysis of DSAs, safety laboratory tests, PD, ADA, P-creatinine/eGFR and 
virus screen for BK, EBV and CMV. Urine will be obtained for assessment of proteinuria. 
At visit 8 vital signs will also be assessed. 
Visits 10 and 11 (day 90 and 120) 
At visits 10 and 11 the patient will be assessed for vital signs, AEs and concomitant 
medication. Blood sampling for analysis of DSAs, safety laboratory tests, ADA and P-
creatinine/eGFR. At visit 9 a blood sample for virus screen (BK, EBV and CMV) will also 
be drawn. Urine will be obtained for assessment of proteinuria.  
Visit 12 (day 180, end of study) 
A follow-up visit will be performed 180 +/- 14 days following IdeS infusion. This will be 
considered the end of study for the patient. At this visit the patient will be assessed for 
vital signs, ECG, AEs and concomitant medication. Blood sampling for analysis of DSAs, 
pregnancy test, safety laboratory tests, P-creatinine/eGFR, PD and ADA will be 
performed and e GFR calculated. Urine will be obtained for assessment of proteinuria 
and a physical examination will be performed. A kidney biopsy will be performed to 
assess kidney status. 
 
6.3 Safety reporting 
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. 
6.3.1 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. 


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In case of 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 the follow up period 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 the follow up period. 
6.3.2 Definitions of serious adverse event 
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 hospitalization or prolongation of existing hospitalization. 
Regular dialysis treatment in or outside hospital is not included 
• Hospitalization for transplantation is not considered an SAE  
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
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 the following will not qualify as an SAE. Elective treatment of a pre-existing 
condition that did not worsen during the clinical investigation is not considered an AE.  
Hospitalization for study drug dosing and observation as required by protocol is not 
considered an SAE. Admittance to an emergency room for observation without being 


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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. Regular dialysis treatment in or 
outside hospital is not considered an AE or SAE. 
 
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 include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyskrasias or convulsions that do not result in 
inpatient hospitalization, or the development or 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. 
6.3.3 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. and 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.  
6.3.4 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, intensity according to 
Common Toxicity Criteria grade (CTCAE v.4.03), seriousness of the AE, causality rating, 
action taken with regard to investigational product, if 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: 
o The AE does not meet the above criteria 
o There is sufficient information that the etiology of the AE is not related to 
the study drug 
• Unlikely to be related: applicable to an AE that meets the following criteria: 
o Does not follow a reasonable temporal sequence from dosing of IdeS 


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o 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 IdeS dosing appears 
unlikely but cannot be ruled out. Applicable to AEs where: 
o It follows a reasonable temporal sequence following dosing of IdeS 
o It follows a known pattern of response to dosing of IdeS (based on animal 
studies) 
• Probably related: applicable to AEs that are considered, with a high degree of 
certainty, to be related to IdeS. Applicable to AEs where: 
o It follows a reasonable temporal sequence from dosing of IdeS 
o It cannot be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of 
therapy 
o It follow a known pattern of response to IdeS (based on animal data) 
For SAEs, causal relationship will also be assessed for any study procedure. 
6.3.5 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. 
6.3.6 Adverse Events based on examinations and tests 
 
If laboratory values are judged as clinically significant and/or a treatment has been given 
for a medical event it will be captured as AEs and if SAE criteria is fulfilled they will also 
be an SAE. 
If vital signs give clinical signs/symptoms and/or require a treatment then they will be 
captured as AEs and if SAE criteria is fulfilled they will also be SAEs. 
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 and if 
SAE criteria is fulfilled it will also be an SAE. 


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Wherever possible the reporting investigator uses the clinical, rather than the laboratory 
term (e.g. anemia versus low hemoglobin value). 
6.3.7 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 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.  
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. 
6.3.8 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 admission to the clinic on day 0.  
All Serious Adverse Events (SAE) must be reported, whether or not considered related to 
the study drug, on a separate SAE Report Form. All SAEs will be recorded in the Case 
Report Form. An assigned CRO will be responsible for reporting all SAEs to regulatory 
authorities and ethics committees in accordance with ICH Good Clinical Practice and local 
regulations. As soon as the Investigator is aware of a potential SAE he/she should contact 
the safety CRO appointed by the sponsor 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, nature 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
. 
6.3.9 Reporting of suspected unexpected serious adverse events (SUSARs) 
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 investigator 
brochure or is not listed at the specificity or severity that has been observed. 
SUSAR MedWatch reports WILL NOT be filled out for any prolonged hospital admissions 
or readmissions that are related to expected complications of the patients’ primary 


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disease (CKD).  For example, prolonged admissions for dialysis or readmission for fluid 
overload as a consequence of CKD since this this is an expected complication of the 
patients’ disease state and not related to study drug. These events will be adjudicated by 
the PI. Otherwise, all SUSAR MedWatch reports will be submitted to the IRB, study 
sponsor and FDA.  
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 
15 calendar days. The SUSAR reporting procedures are detailed in the study specific 
Safety Management Plan. This plan is an agreement between the sponsor, and 
 
 will notify the appropriate regulatory agency(ies) of 
any SUSARs on an expedited basis and in accordance with applicable regulations. Sponsor 
will notify all participating site Investigators.  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 IRB and other 
appropriate institutional regulatory bodies of all unexpected serious adverse reactions 
involving risk to human subjects as per their applicable requirements. 
6.3.10 Procedures in case of pregnancy 
Pregnancy is an exclusion criteria and a pregnancy test is performed twice before the study drug 
is infused; at the screening visit and prior to infusion of the IMP. A pregnancy test is also 
performed at the last study visit.  
If a patient becomes pregnant during the follow up phase of the study, the patient will continue 
in the study according to study protocol, if possible. A Pregnancy Report Form must be sent by 
Principal Investigator to sponsor (or designee) at the latest within 24 hours of learning of the 
pregnancy. The outcome of all pregnancies (spontaneous miscarriage, elective termination, 
normal birth or congenital abnormality) will be followed up on the Pregnancy Report Form 
even after the patient has completed or discontinued the study. Sponsor (or designee) will 
follow up on pregnancy outcome 4 weeks after the projected due date.  
Pregnancy itself is not considered an AE or SAE, but any event occurring during pregnancy 
that meets serious criteria must be reported to sponsor and will be handled as a SAE. 
Spontaneous abortions, congenital abnormalities/birth defects are always considered to be a 
SAEs and will be reported and followed up in accordance with other SAEs. Any SAE occurring 
as a result of a post-study pregnancy and considered reasonably related to the study drug by the 
investigator will be reported to the sponsor (or designee).  
6.4 Study assessments 
6.4.1 
Recording of data 
The principal investigator will provide the 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 charts (Table 1 and Table 2).  It is 
important that PK sampling occurs as close as possible to scheduled time. In order to 
achieve this, other assessments scheduled at the same time may be initiated prior to the 
time point. Pre-dose assessments may be performed up to 60 minutes prior to dosing. 


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The timing priority order at a particular time point is: 
1. Blood samples for PK and PD 
2. Samples for DSA, CDC and FACS CXM  
3. Vital signs 
4. Safety laboratory samples 
5. Additional laboratory samples 
Pre-dose assessments may be performed up to 60 minutes prior to dosing. 
6.4.2 
Screening and demography procedures 
Each patient will undergo a screening between 28 and 0 days prior to admission.  
6.4.3 Patient care after end of study 
After study completion, all study patients will be followed up regularly and 
interdisciplinary (by nephrologist and transplant surgeons) according to the center’s 
follow-up routines for transplanted patients. The frequencies of outpatient visits will be 
adjusted individually to the state of patient health and transplant function.   
6.5 Laboratory efficacy assessments and evaluation of primary endpoint 
Timing of laboratory efficacy parameters (CDC and FACS crossmatch tests and DSA 
analysis) is given in the study flow charts 1 and 2 (Table 1 and Table 2). The date and time 
of collection will be recorded on the laboratory requisition form and in the CRF. Samples 
will be labelled, stored and shipped as detailed in the laboratory manual.  
6.5.1 Analysis of crossmatch tests 
Evaluation of the primary endpoint will be analyzed using the crossmatch test. CDC and 
flow cytometry (FACS) crossmatch test will be performed at the time points indicated in 
the study flowcharts (Table 1 and Table 2). 
6.5.2 Determination donor specific antibodies (DSAs) and complement fixation 
Samples for determination of DSAs will be analyzed in immunoglobulin (Ig) G single 
antigen solid-phase immunoassay (SA-SPA) for antibodies to HLA class I and class II.  The 
assay allows determination of the mean fluorescence intensity (MFI) of antibodies in 
patient serum reacting to an array of individual HLA immobilized to beads. In addition, 
anti-HLA antibodies with complement fixation ability by detection of C1q will be analyzed 
in a SAB assay. Determination of DSAs will be performed at a central laboratory. 
6.6 Clinical safety assessments 
6.6.1 Physical examination 
For timing of individual examinations refer to the study flow chart 1. A complete physical 
examination will be performed at screening and day 180 and include an assessment of the 
following: general appearance, head and neck, lymph nodes, abdomen, musculo-skeletal, 
cardiovascular, respiratory and gross neurological examination. 


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6.6.2 Height and weight 
Regarding the timing for assessments of height and weight refer to the study flow charts 
1 and 2 (Table 1 and Table 2). Measurements should be taken without shoes. Body mass 
index will be calculated from the height and weight. The timing of individual 
measurements is indicated in the study flow chart (Table 1 and Table 2). 
6.6.3 ECG 
ECG 12-lead will be taken after 10 minutes rest at screening and on day 180.  
6.6.4 Vital signs 
Vital signs, blood pressure, pulse and respiratory frequency will be measured as outlined 
in the study flow charts 1 and 2 (Table 1 and Table 2). At dosing, blood pressure and pulse 
will be recorded pre-dose, 2, 6, 24 and 48 hours post-dose. In addition, the patients will 
be monitored with oximetry during the infusion and the following 24 hours.  
6.6.5 Other safety assessments 
Body temperature will be measured as specified in the study flow charts at screening and 
study visit 2 (Table 1 and Table 2). At visit 2/dosing, body temperature will be recorded 
pre-dose, 2, 6, 24 and 48 hours post-dose.  
6.6.6 Kidney biopsy 
A kidney biopsy will be performed at visit 2 on deceased donor kidneys and at visit 12 
on living and deceased donor kidneys (Table 1). If standard of care kidney biopsies are 
performed for any reason, e.g. suspected rejections, a de-identified copy of the kidney 
biopsy report will be collected.   
6.7 Laboratory safety assessments 
Timing of laboratory efficacy parameters is given in the study flow charts 1 and 2 (Table 1 
and Table 2). The date and time of collection will be recorded on the laboratory 
requisition form and in the CRF. Samples will be labelled, stored and shipped as detailed 
in the laboratory manual.  
6.7.1 Clinical chemistry, hematology, coagulation and virology 
The following blood samples for determination of clinical chemistry, hematology, 
coagulation and total IgG in plasma will be taken: 
Table 5. Clinical chemistry, hematology, coagulation and virology 
P-IgG, total 
P-PK(INR) 
P-ALP 
P-APTt 
P-ALT 
Hematology 
P-AST 
B-Hemoglobin 
P-Bilirubin, total 
B-Differential analysis of leucocytes 
P-Glucose 
B-Thrombocytes 


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P-Sodium 
 
P-CRP 
*Virology 
P-Albumin 
B-HIV 
P-Urea 
B-Hepatitis B surface antigen 
P-Triglycerides 
P-Creatinine 
P-Creatinine 
phosphokinase 
B-Hepatitis C antibodies 
 
*Virology samples for HIV and hepatitis will be taken at screening. Test results not older 
than 6 months can be used.  
Additional laboratory variables can be performed if judged appropriate by the 
investigator.  
6.7.2 Viral surveillance 
Samples will be taken in all patients as outlined in the study flow chart for BK-, EBV and 
CMV-PCR for early diagnosis of viral activations/reactivations and early treatment, 
respectively. Extra samples should be taken if indicated. At screening, results not older 
than 6 months can be used. 
6.7.3 Pregnancy test 
Serum B-HCG will be determined at screening, pre-dose and on day 180 using validated 
standard methods 
6.7.4 Determination of kidney function 
Evaluation of kidney function will be done based on P-creatinine analysis and calculation 
of filtration rate (eGFR). Proteinuria tests (spot urine/creatinine) will be performed at the 
time points indicated in the study flowcharts. In addition 24 hour urine collections for 
electrophoresis analysis of proteins will be performed daily starting after transplantation 
and up to day 9. The amount of urine per 24 hour will be measured and two samples will 
be taken from the collection. One sample will be analyzed at the hospital laboratory and 
one sample will be stored and analyzed later if deemed necessary. 
6.8 Pharmacokinetics and pharmacodynamics 
6.8.1 Determination of drug concentration in biological samples 
Samples for determination of IdeS levels in serum (PK) will be performed at the time 
points indicated in the study flowcharts and analyzed by 
 
  
6.8.2 Determination of IgG levels in serum 
Samples for determination of IgG levels in serum (PD) will be performed at the time points 
indicated in the study flowcharts and analyzed by
, 


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England. Samples will also be qualitatively analyzed by gel electrophoresis for IgG 
integrity by 
 
6.9 Anti-drug antibody analysis 
Venous blood samples for determination of anti-drug antibodies (ADA) will be taken at 
the times presented in the study flow charts (Table 1 and Table 2) and analyzed by 
. Determination of anti-IdeS IgG 
antibody concentrations in serum will be performed using anti-IdeS ImmunoCAP. At 
screening anti-IdeS IgE antibodies will be drawn. This will be used for research purpose 
for patients with deceased donors and as part of the eligibility criteria for patients with 
live donors. 
The normal range of anti-IdeS IgG antibodies is <2-78 mg/L (HMed Doc. No. 2012-041). 
Patients who are not back within the normal ADA range at study completion will be asked 
to come back for a follow up ADA sampling at 12 months. The results from the 12 months 
ADA samples will be reported separately. 
7 Biological sampling procedures 
7.1 Handling, storage and destruction of biological samples 
Samples will be used or disposed after analyses. A detailed description on sample 
collection, handling and shipping will be provided in a separate laboratory manual. 
7.1.1 Pharmacokinetic, pharmacodynamic and anti-drug antibody samples 
Samples will be disposed after the clinical study report has been finalized, unless retained. 
 Study samples 
may be stored on behalf of the sponsor for a maximum of four years after completion of 
the study report. 
7.2 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 center 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. 
7.3 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 analyzed and documented. 
The principal investigator: 


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• 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. 
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. 
8 Ethical and regulatory requirements 
8.1 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin 
in the latest Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, 
applicable regulatory requirements. 
8.2 Patient data protection 
The informed consent form (ICF) will incorporate wording that complies with relevant 
data protection and privacy legislation.  
8.3 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. 
No patient will be enrolled in 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. 


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8.4 Informed consent 
The principal investigator(s) at the centers 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. 
• 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. 
8.5 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 changes to the study protocol, then these changes will be documented in 
a study protocol amendment.  
The substantial amendment(s) must be submitted to regulatory authorities and approved 
by the ethical review board before implementation. Local requirements must be followed 
for amended protocols and approval obtained if required. 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 center’s informed consent form, sponsor 
and the center’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. 
8.6 Audits and inspections 
The investigator(s)/institution will permit study-related monitoring, audits, IRB/IEC 
review, a regulatory inspection(s), providing direct access to source data/documents and 
give permission to examine, analyze, verify, and reproduce any records and reports that 
are important to evaluation of a clinical study. 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 patients´ identities and sponsor´s 
proprietary information. 


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Authorized representatives of sponsor or a regulatory authority may perform audits or 
inspections at the center, 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, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and 
any applicable regulatory requirements. The investigator will contact sponsor 
immediately if contacted by a regulatory agency about an inspection at the center. 
8.7 Archiving of Investigator Study File and Study Master File 
The investigator is responsible for maintaining all records, which enable the conduct of the 
study at the site to be fully understood, in compliance with ICH-GCP. The study documentation 
including all the relevant correspondence should be kept by the investigator for at least 10 years 
after the study report is final. No study documents may be destroyed without prior written 
agreement between the investigator and Hansa Medical AB. Should the investigator elect to 
assign the study documents to another party, or move them to another location, Hansa Medical 
AB must be notified.  
Hansa Medical AB will archive the Study Master File in accordance with ICG-GCP and 
applicable regulatory requirements.  
9 Study management 
9.1 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 site initiation 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. This will be documented in a site initiation visit 
report and in the clinical study agreement between sponsor and the investigator 
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). 


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9.2 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. 
• 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 center needs information and advice about the study conduct. 
9.3 Source data 
Refer to the source data document for location of source data. 
9.4 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. 
9.5 Insurance 
All patients in the study are covered by an insurance held by Hansa Medical AB.  
9.6 End of study 
The end of the study is defined as “the last visit of the last patient”. 
10 Data handling 
10.1 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.  




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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. 
12.2 Methods of statistical analyses 
12.2.1 General principles 
No formal statistical hypothesis testing will be performed in this study. Data will be 
presented by actual dose received.  
12.2.2 Patient characteristics 
The following demographic variables will be summarized: age, sex, race, height, weight 
and BMI for all dose groups as appropriate. 
Medical/surgical histories and medications taken before screening will be listed including 
comments and coded fields. 
Baseline assessments of safety variables (ECG, vital signs, and laboratory parameters) will 
be listed by dose groups as appropriate.  
12.2.3 Safety and tolerability 
All safety and tolerability data will be listed as specified in the SAP.  
Adverse events will be collected for each patient from visit 1 until follow-up. Serious 
adverse events will be recorded from the time when informed consent is obtained (Visit 
1) until the follow-up visit.  
The following summaries of AEs will be given by treatment and in total:  
The number of patients who had any AEs, SAEs, AEs that led to withdrawal, AEs related 
to study drug and AEs with severe intensity. 
If the number of AEs is sufficiently large, summaries will be presented by PT (Preferred 
term) and SOC (System organ class) according to MedDRA vocabulary. 
Severity, time of onset, duration, action taken, concomitant therapy started and patient 
outcome of the AEs will be given in data listings only. AEs which were reason for 
premature discontinuation of study drug will be listed separately.  
Furthermore, SAEs and AEs that led to withdrawal will be listed separately. 
12.2.4 Efficacy on DSA, CDC CXM and FACS CXM 
CDC crossmatch results (positive or negative and when applicable titer) before and after IdeS 
treatment will be determined for each patient and presented in listing sorted by treatment, 
patient, and time-point. In addition, time to conversion of crossmatch will be calculated. 
FACS crossmatch results (positive or negative and when applicable channel shift) before and 
after IdeS treatment will be determined for each patient and presented in listing sorted by 
treatment, patient, and time-point. In addition, time to conversion of crossmatch will be 
calculated. 


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HLA antibodies including DSA will be measured with SAB assays. Summary statistics of MFI 
values for DSA and for all HLA for each patient will be produced by time point, including min, 
10th percentile, median, 90th percentile, and max. In addition, patient listings of MFI values 
for DSA and all HLA for all patients will be produced. 
12.2.5 Pharmacokinetics 
Pharmacokinetic (PK) variables will be summarized using appropriate descriptive 
statistics (e.g. n, geometric mean, harmonic mean for t1/2, coefficient of variance (CV), min, 
median, max) by treatment group.  
12.2.6 Pharmacodynamics 
All data associated with the efficacy of IdeS in cleaving IgG will be presented using listings 
for each dose group. If feasible, the data will be explored graphically. 
12.2.7 Anti-drug antibodies  
All anti-IdeS antibody data will be presented using listings. 
12.3 Determination of sample size 
Sample size is not based on formal statistical considerations. Due to the nature of the 
primary endpoint of the study it is expected that data from 15-20 patients should suffice 
to achieve the objectives of the study. Also, the sample size is in line with experience from 
previous similar Phase II studies with other compounds to obtain adequate safety, 
tolerability and PK data to achieve the objectives of the study.  
13 Publication policy 
13.1 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). 
13.2 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. 
13.3 Publication and Public Disclosure 
13.3.1 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. 
13.3.2 Public Disclosure Policy 
The study will be uploaded to the EudraCT database. 




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study." Am J Transplant 14(7): 1573-1580. 
Orandi, B. J., X. Luo, A. B. Massie, J. M. Garonzik-Wang, B. E. Lonze, R. Ahmed, K. J. Van 
Arendonk, M. D. Stegall, S. C. Jordan, J. Oberholzer, T. B. Dunn, L. E. Ratner, S. Kapur, R. 
P. Pelletier, J. P. Roberts, M. L. Melcher, P. Singh, D. L. Sudan, M. P. Posner, J. M. El-Amm, 
R. Shapiro, M. Cooper, G. S. Lipkowitz, M. A. Rees, C. L. Marsh, B. R. Sankari, D. A. 
Gerber, P. W. Nelson, J. Wellen, A. Bozorgzadeh, A. O. Gaber, R. A. Montgomery and D. L. 
Segev (2016). "Survival Benefit with Kidney Transplants from HLA-Incompatible Live 
Donors." N Engl J Med 374(10): 940-950. 
Stegall, M. D., P. G. Dean and J. Gloor (2009). "Mechanisms of alloantibody production in 
sensitized renal allograft recipients." Am J Transplant 9(5): 998-1005. 
Wenig, K., L. Chatwell, U. von Pawel-Rammingen, L. Björck, R. Huber and P. Sondermann 
(2004). "Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict 
specificity for IgG." Proc Natl Acad Sci U S A 101(50): 17371-17376. 
Vincents, B., U. von Pawel-Rammingen, L. Björck and M. Abrahamson (2004). "Enzymatic 
characterization of the streptococcal endopeptidase, IdeS, reveals that it is a cysteine protease 
with strict specificity for IgG cleavage due to exosite binding." Biochemistry 43(49): 15540-
15549. 
Vo, A. A., J. Petrozzino, K. Yeung, A. Sinha, J. Kahwaji, A. Peng, R. Villicana, J. 
Mackowiak and S. C. Jordan (2013). "Efficacy, outcomes, and cost-effectiveness of 
desensitization using IVIG and rituximab." Transplantation 95(6): 852-858. 
Vo, A. A., E. A. Wechsler, J. Wang, A. Peng, M. Toyoda, M. Lukovsky, N. Reinsmoen and 
S. C. Jordan (2008). "Analysis of subcutaneous (SQ) alemtuzumab induction therapy in 
highly sensitized patients desensitized with IVIG and rituximab." Am J Transplant 8(1): 144-
149. 
von Pawel-Rammingen, U., B. P. Johansson and L. Björck (2002). "IdeS, a novel 
streptococcal cysteine proteinase with unique specificity for immunoglobulin G." EMBO J 
21(7): 1607-1615. 
Yabu, J. M., M. J. Pando, S. Busque and M. L. Melcher (2013). "Desensitization combined 
with paired exchange leads to successful transplantation in highly sensitized kidney transplant 
recipients: strategy and report of five cases." Transplant Proc 45(1): 82-87. 
 

SAP_001.pdf: 
Sponsor: 
Hansa Medical 
CONFIDENTIAL 
13JUL2018
Study product: imlifidase 
 
Version 1.0 Final
Study ID: 
15-HmedIdeS-06  
Statistical analysis plan 
Page 1 of 24
 
F504-0-1-9 
 
Statistical analysis plan 
 
A Phase II Study to Evaluate the Efficacy of imlifidase (IgG 
endopeptidase) to Desensitize Transplant Patients with a 
Positive Crossmatch Test 
 
 
Sponsor: 
Hansa Medical AB, Lund, Sweden 
Contract research organisation: 
  
Sponsor protocol number: 
15-HMedIdeS-06 
EudraCT number: 
2016-002064-13 
IND number: 
128074 
ClinicalTrials.gov number: 
NTC02790437 
Investigational product name: 
Imlifidase, previously HmedIdeS / IdeS 
Development phase:  
2 
Date of final SAP: 
13-Jul-2018 
 






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Table of contents 
 
Signature page ........................................................................................................... 2 
Table of contents ........................................................................................................ 4 
List of abbreviations and definition of terms ......................................................... 6 
1 
Introduction ........................................................................................................ 7 
1.1 
Study objectives and endpoints ....................................................................................... 7 
1.1.1 
Objectives ........................................................................................................... 7 
1.1.2 
Endpoints ........................................................................................................... 7 
2 
Study design ........................................................................................................ 9 
2.1 
Overview of study procedures ......................................................................................... 9 
2.2 
Determination of sample size ........................................................................................ 12 
2.3 
Blinding ......................................................................................................................... 12 
2.4 
Data pre-processing ....................................................................................................... 12 
3 
Analysis sets ...................................................................................................... 13 
3.1 
Safety analysis set ......................................................................................................... 13 
3.2 
Per protocol analysis set ................................................................................................ 13 
4 
Statistical analyses and presentation of data ................................................. 14 
4.1 
General considerations .................................................................................................. 14 
4.2 
Patient disposition ......................................................................................................... 14 
4.3 
Demographics and other baseline characteristics .......................................................... 14 
4.4 
Efficacy ......................................................................................................................... 15 
4.4.1 
Primary efficacy analysis ................................................................................. 15 
4.4.2 
Secondary efficacy analyses ............................................................................ 15 
4.4.3 
Additional analyses .......................................................................................... 16 
4.5 
Safety ............................................................................................................................. 17 
4.5.1 
Adverse events ................................................................................................. 17 
4.5.2 
Other safety endpoints ..................................................................................... 18 
4.6 
Other endpoints ............................................................................................................. 18 
5 
Deviations from protocol analysis .................................................................. 19 
6 
Quality control.................................................................................................. 20 
7 
Layout of output ............................................................................................... 21 
8 
Tables, listings and figures .............................................................................. 22 
9 
References ......................................................................................................... 23 


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10 Change log ........................................................................................................ 24 
 
 


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List of abbreviations and definition of terms  
ADA 
Anti-drug antibody 
ADaM 
Analysis data model 
AE 
Adverse event 
AUC 
Area under the concentration versus time curve 
BMI 
Body mass index 
BP 
Blood pressure 
CDC 
Complement dependent cytotoxicity 
Cmax 
Maximum observed concentration 
CRF 
Case report form 
CV 
Coefficient of variation 
DSA 
Donor specific antibodies, anti-human leukocyte antigen (HLA) donor-specific 
antibodies 
ECG 
Electrocardiogram 
FACS  
Fluorescence-activated cell sorting 
IMP 
Investigational medicinal product 
LD 
Living donor 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCA 
Non compartmental analysis 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per-protocol analysis set 
PRA 
Panel reactive antibody 
PT 
Preferred term 
SAB-HLA 
Single antigen beads - human leukocyte antigen 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class  
SDDM 
Study data tabulation model 
T½ 
Elimination half-life 
 
TEAE 
Treatment emergent adverse event 
TLF 
Tables, listings and figures 
Tmax 
Time of observed Cmax 


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1 
Introduction 
This document describes the planned statistical analyses for study 15-HmedIdeS-06 which will 
include data processing, data analyses and data presentation. This SAP is based on the protocol 
version 5.0 applicable for USA dated 20 March 2017, version 6.1 applicable for Sweden dated 14 
June 2017, and version 7.2 applicable for France dated 13 September 2017. The differences 
between the country specific protocol versions only relate to inclusion criteria and will not 
influence the presentation of data. 
The original planned collection of data was later extended by amendment 7, dated 8 December 
2017. An additional CRF was designed to include donor characterisation, recipients’ previous 
transplantation history and transplantation outcome.  
1.1 
Study objectives and endpoints 
1.1.1 
Objectives 
The primary objective of this study is: 
• To assess the imlifidase efficacy in creating a negative crossmatch test 
The secondary objectives of this study are: 
• To determine DSA levels at multiple times (pre-dose, 2, 6, 24 and 48 hours and days 7, 14, 21, 
28, 64, 90, 120 and 180) post imlifidase treatment 
• To determine time to creating a negative CDC crossmatch test 
• To determine time to creating a negative FACS crossmatch test 
• To evaluate safety parameters (adverse events, clinical laboratory tests, vital signs and ECGs) 
following imlifidase treatment up to day 180 
• To monitor kidney function after imlifidase treatment as assessed by, filtration (eGFR), 
creatinine and proteinuria 
• To establish the PK profile of imlifidase 
• To establish the PD profile of imlifidase (cleavage and recovery of IgG) 
• To establish the immunogenicity profile of imlifidase (ADA) 
1.1.2 
Endpoints 
The primary endpoint of this study is: 
• Efficacy defined as imlifidase ability to create a negative crossmatch test within 24 hours 
after imlifidase dosing 
The secondary endpoints of this study are: 
• DSA levels at pre-dose and 2, 6, 24 and 48 hours and days 7, 14, 21, 28, 64, 90, 120 and 180 
post imlifidase treatment 


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• Time to creating a negative CDC crossmatch test 
• Time to creating a negative FACS crossmatch test 
• Safety parameters (adverse events, clinical laboratory tests, vital signs and ECGs) 
• Kidney function after imlifidase treatment assessed by, filtration (eGFR), creatinine and 
proteinuria up to 180 days post treatment 
• PK profile of imlifidase up to day 14 
• PD profile of imlifidase (cleavage and recovery of IgG) up to day 180 post imlifidase 
• Immunogenicity profile of imlifidase by measuring ADA 








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2.2 
Determination of sample size 
Sample size is not based on formal statistical considerations. Due to the nature of the primary 
endpoint of the study it is expected that data from 15-20 patients should suffice to achieve the 
objectives of the study. Also, the sample size is in line with experience from previous similar 
phase II studies with other compounds to obtain adequate safety, tolerability and PK data to 
achieve the objectives of the study. 
2.3 
Blinding 
The study is open-label. 
2.4 
Data pre-processing 
Data sets 
The export data sets from the 
data management database will be transformed into SDTM 
structure and format following the implementation guide version 3.2 (current version) and also 
following “Therapeutic Area Data Standards User Guide for Kidney Transplant Version 1.0 
(Provisional)”. ADaM data sets will be prepared based on the SDTM data sets following 
implementation guide version 1.1 (current version). Tables, figures and listings will be prepared 
from the ADaM data sets. 
Derivation of pharmacokinetic parameters 
PK analysis of the serum concentration data for imlifidase will be performed at Hansa Medical. 
The actual sampling times will be used in the parameter calculations. Concentration-time raw data 
and PK parameters will be calculated for each individual as well as reported per received dose(s). 
In earlier clinical studies with imlifidase an open 2-compartment model was found to best 
describe the data. The model can be described by model parameters V (volume of central 
compartment), K21, Alpha and Beta. A similar approach will be applied to this study and non-
compartmental parameters can be calculated from these model parameters as secondary 
parameters by standard PK equations, including where possible: the area under the curve to 
infinite time (AUC), the terminal half-life (T1/2), clearance (CL), volume of distribution at steady-
state (Vss) and volume of distribution during the elimination phase (Vz). In addition, Cmax and 
Tmax may be obtained directly from the experimental data. 


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3 
Analysis sets 
The analysis sets will be determined at the data review prior to database lock. Decisions will be 
documented in the database lock minutes. 
3.1 
Safety analysis set  
The safety analysis set (SAS) will consist of all patients that received any amount of study 
medication. 
3.2 
Per protocol analysis set 
The Per protocol analysis set (PP) will consist of all patients in the safety set that has recorded at 
least one efficacy endpoint value. Data from patients with one or more major protocol violations 
are excluded. The PP analysis set will be used for presentation of efficacy, pharmacokinetic, and 
pharmacodynamic endpoints. 


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4 
Statistical analyses and presentation of data  
4.1 
General considerations 
No formal statistical hypothesis testing will be performed in this study. All presentation of data 
will be descriptive by nature. Missing data will in general not be imputed or adjusted for in other 
ways.  
The protocol states that tabulations will be by actual dose received. The protocol allowed for the 
DSMB to decide on dose escalation. All patients were administered planned dose(s) of 0.25 
mg/kg BW. For one patient the actual dose was reduced due to an allergic reaction. For 3 patients 
the protocol option of administering a 2nd dose was used. Efficacy and safety tabulations will be 
by number of administrations (1 or 2 doses) and total including all patients. The patient with 
reduced dose 
 will be included in the “1 dose” group for safety evaluation but 
excluded from the PP. 
Numerical data will be presented in summary tables by number of patients, arithmetic mean 
(geometric mean and coefficient of variation [CV] where applicable), median, standard deviation 
(SD), minimum and maximum. Categorical data will be presented by number and percent of 
patients as well as number of events (where applicable).  
Endpoints will be presented graphically as mean profile plots, individual profile plots and 
spaghetti plots. The sampling frequency is for efficacy and some safety endpoints high from pre-
dose until 48 hours followed by decreasing frequency. Therefore, the graphical presentation will, 
in most cases, be as box plots with a categorical x-axis. For other data, a plot with linear x-axis 
(0 to 180 days) may be supplemented with a subset plot where only the first 24 or 48 hours are 
included on the x-axis.  
All data will be listed. Auxiliary database parameters will not be included. Listings will be sorted 
by patient ID, parameter and time point. In general listings will not be mentioned in detail below. 
The study did not include any interim analyses. 
4.2 
Patient disposition 
A patient disposition table will include the number of patients screened, patients in the safety, PP 
analysis sets, completers and withdrawals with reason for withdrawal, and finally patients by visit 
will be summarised with frequency and percentage. 
The patients screened but not allocated to treatment will be presented with the reason(s) for 
screening failure in a listing 
All major protocol deviations will be summarised with frequency and percentage for each 
category of protocol deviation. 
4.3 
Demographics and other baseline characteristics 
The following demographic and body measurements variables will be summarised: age, sex, race, 
height, weight and BMI. 


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Medical and surgical history and concomitant illness will be summarised by MedDRA system 
organ class (SOC) and preferred term (PT) version 18.1. Prior and concomitant medication will be 
tabulated by WHO drug version 153E, level 4 (chemical/therapeutic/pharmacological subgroup) 
and level 5 (Chemical substance). Medication is categorised as “Started prior to study start” and 
“Ongoing” in the eCRF and these responses will be used to categorise as prior and concomitant 
respectively. Medication was recorded in the original eCRF. The additional data recording 
collected specifically medication for de-sensitization and rejection. There may therefore be an 
overlap with prior and concomitant medication and the de-sensitization and rejection medication 
will be tabulated separately.  
Previous kidney transplant history will be summary tabulated. 
Baseline assessments of ECG, physical examination, vital signs, body measurements and 
laboratory parameters will be presented as part of the general tables and listings for these 
parameters. 
ImmunoCAP IgE (ADA) is recorded at baseline only and will be listed. Serology and sperm 
sample will be listed. 
The drug exposure will be listed showing number of doses, planned dose and actual dose per kg 
BW. 
Donor characteristics will be listed. 
Recipient and donor HLA types will be listed. 
Recipient and donor blood groups will be listed. 
Deceased donor characteristics will be listed. 
Protocol deviations will be listed. 
4.4 
Efficacy  
4.4.1 
Primary efficacy analysis 
The primary efficacy endpoint is defined as imlifidase ability to create a negative crossmatch test 
within 24 hours after imlifidase dosing. The primary endpoint will be presented for the PP 
analysis sets. 
The planned time points (according to the flowchart) are: Screening, pre-dose, 2h, 6h, 24h, and 
48h. In general, only the pre-dose and 24h analyses are performed, while the other planned 
analyses are missing. For each of the crossmatch tests (FACS B-cell, FACS T-cell, amplified and 
non-amplified analyses of CDC B-cells and CDC T-cells, and virtual) summary tabulations by 
time point will be made.  
For each patient an overall response is defined as positive if at least one of the assays is positive at 
pre-dose and all recorded assays are negative at 24h. The overall response is summary tabulated. 
4.4.2 
Secondary efficacy analyses 
Secondary efficacy endpoints will be presented for PP. 


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SAB-HLA 
SAB-HLA levels (MFI) are determined at pre-dose and 2, 6, 24 and 48 hours and days 7, 14, 21, 
28, 64, 90, 120 and 180 days post imlifidase treatment. Positive SAB-HLA are defined as having 
pre-dose levels above 3,000 MFI. The SAB-HLA will be listed by patient flagging positive 
(yes/no) and donor specific SAB-HLAs. The positive SAB-HLA will be summarised and 
presented in box-plots.  
DSA 
DSA levels (MFI) are determined at pre-dose and 2, 6, 24 and 48 hours and days 7, 14, 21, 28, 64, 
90, 120 and 180 post imlifidase treatment. The DSA will be summarised by patient and time 
point. DSA will be presented graphically as scatter plots (MFI versus time) with one separate plot 
for each patient. The x-axis in these plots will be with the nominal time points and therefore not 
linear in the time variable. For this reason the scatter plots will be without connecting lines. 
Pharmacodynamics 
The PD profile of imlifidase (cleavage and recovery of IgG) is recorded up to day 180 post 
imlifidase dosing. PD will be summary tabulated by time point and presented graphically as mean 
profile versus time and as spaghetti profile plots. 
All PD data will be presented for the PP analysis set. 
Time to negative crossmatch 
The time to creating a negative crossmatch is specified in the protocol as an endpoint. However, 
due to many missing values and in particular missing data for time points between pre-dose and 
24 hours, the Time to creating a negative cross match will not be calculated. Crossmatch data will 
be listed.   
Pharmacokinetics 
The PK profile of imlifidase is recorded up to day 14. The PK concentrations will be summary 
tabulated by time point. The PK summary tables will not include total columns. Further, the PK 
concentrations will be presented graphically as mean profile plots by number of doses and as 
spaghetti plots. Semi-log format with log10 y-axis and a linear time x-axis will be presented. 
The PK parameters are derived as described above under pre-processing by compartment 
modelling. Further NCA parameters are calculated from the compartment parameters. Both types 
of PK parameters will be summary tabulated. In addition to standard summary measures, t1/2 will 
be described by the harmonic mean. 
Imlifidase values <LLOQ (LLOQ = 0.10 µg/mL) will be presented as 0.5*LLOQ for summary 
tables and figures. 
All PK data will be presented for the PP analysis set. 
4.4.3 
Additional analyses 
Calculated PRA (cPRA) values will be summarised using the undiluted categories <80%, 80.00% 
- 97.50%, 98% (97.51% - 98.50%), 99% (98.51% - 99.50%), > 99% (99.51% – 100%). 


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Additionally, the diluted and undiluted cPRA values will be plotted against the different cut-off 
for unacceptable HLA. 
4.5 
Safety  
Safety parameters will be evaluated for the safety analysis data set. 
4.5.1 
Adverse events 
Adverse events (AEs) will be classified according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1.  
A treatment emergent adverse event (TEAE) is any AE occurring after the administration of the 
IMP and within the time of the residual effect period or a pre-treatment AE or pre-existing 
medical condition that worsens in intensity after administration of the IMP and within the time of 
the follow up period. Based on the half-life and the PD properties of imlifidase the residual drug 
effect is considered 30 days after administration. 
An AE overview summary table will be prepared including the number of patients reporting an 
AE, the percentage of patients (%) with an AE, and the number of events (E) reported for the 
following categories:  
• TEAEs  
• Related TEAEs  
• Serious TEAEs (SAEs) 
• TEAEs leading to withdrawal  
• Deaths  
Treatment-emergent AEs will be summarised in a table by dictionary level, i.e., SOC and PT for 
MedDRA. The table will display the total number of patients reporting an AE, the percentage of 
patients (%) with an AE and the number of events (E) reported. AEs will be presented by SOC 
and PT sorted in decreasing frequency of occurrence. 
Summary tables will be prepared for: 
• All TEAEs 
• TEAEs by causality (related/unrelated) 
• TEAEs by intensity 
• Related TEAEs by intensity  
• SAEs 
• SAEs by causality (related/unrelated) 
Data listings will be provided for: 
• All TEAEs sorted by patient number and start time 
• All TEAEs sorted by MedDRA SOC and PT 


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• SAEs 
• SAEs leading to death 
• TEAEs leading to discontinuation of study drug 
• TEAEs leading to withdrawal 
• Pre-treatment AEs 
• Post-treatment AEs 
4.5.2 
Other safety endpoints 
Clinical laboratory tests will be summary tabulated and presented graphically as box plots. 
The immunogenicity profile of imlifidase is evaluated by measuring ADA, which will be be 
summary tabulated and presented graphically as box plots. 
Vital signs will be summary tabulated.  
ECG will be listed. 
The kidney function after imlifidase treatment is assessed by kidney biopsies on day 180, 
filtration rate (eGFR), plasma creatinine and proteinuria up to 180 days post treatment. These 
variables are all presented together with the safety laboratory tests. Each variable will be tabulated 
by time point 
The eGFR will be calculated as described in the MDRD equation [1]: 
eGFR (mL/min/1.73 m2) = 175 × (sCr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American), 
where sCr stands for creatinine value in serum. 
4.6 
Other endpoints 
Not applicable. 


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5 
Deviations from protocol analysis 
The protocol stated that PK analysis of the serum concentration data for imlifidase would be 
performed at the appointed CRO on behalf of sponsor, but it will be performed by the Hansa 
Medical responsible pharmacokineticist. 


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6 
Quality control 
The quality control of the data will be performed as follows: 
• 
By Hansa Medical for all lab data that Hansa Medical produce or receive and handle 
before forwarding to 
 
• 
By 
 Data Management for all data following the data validation plan 
• 
By 
 Statistics and Programming for all data received as either Trial Master export or 
directly from Hansa Medical  
Concerning the last bullet above, the QC depends on the process below, but it will follow 
 
 Single Use Programs: 
SDTM data sets will be generated by programs in the Statistical analysis system (SAS) by reading 
in lab data and export data from Trial Master and converting to SDTM formats following the 
SDTM specifications. The QC will include: 
• 
Independent Code review 
• 
CRF annotation review vs SDTM content 
• 
Direct QC of input vs output in SDTM on a sample of data 
This three-pronged approach has proven to give a high quality level corresponding to the expected 
for SDTM data  
ADaM data sets will be based on the SDTM data sets. The programming of the ADaM datasets 
will be performed in SAS and the programs will be reviewed by an independent person. 
Tables, listings and figures (TLF) will be created by SAS programs and based on the ADaM data 
sets. Summary TLFs will be QC’ed by independent code review.  
On top of the actual code review for ADaM and TLF, the review includes check of execution, 
error log, check for warnings and important notes, and check of output. On top of reviewing 
individual programs and output items, an integrated review of all output will be performed by a 
reviewer. Since there are no formal statistical analyses double programming will not be applied in 
this study. 
The programming and execution of programs for producing data sets and tables, figures and 
listings follow the
 SOPs 
 on standard programs, programming 
environment and single use programs respectively.  
SAS version 9.4 or later will be used for data handling and presentation. 


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7 
Layout of output 
TLF shells are presented in a separate document. The planned table of content will also be 
presented separately. The final output may deviate slightly as decisions on numbering and layout 
of TLF and similar may be updated after signature of this SAP. 
The output will follow 
 standard output templates. Tables and listings will first be prepared 
as individual RTF (Rich text format, which is a standard text format) files. This file type may be 
opened and saved in the currently available Microsoft Word versions. Graphical output will be 
prepared in PNG (Portable network graphics) format, which is the standard graphical format in 
current Microsoft software packages and therefore easily importable into Microsoft Word 
documents.  
Tables and figures will per default be created in portrait format while listings will be in landscape 
format. Margins and font will be chosen to respect the requirements for filing with EMA 
(European medicines agency) and FDA (the US Food and drug administration).  
The output items (tables, listings, figures) will be collected in Word documents as described in the 
TOC below. Separate Word documents will be created for tables (called 14.1), figures (called 
14.2), and listings (called 16) respectively. 


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8 
Tables, listings and figures 
Tables and figure templates are prepared as separate documents. And overall table of content for 
the output is also maintained as a separate document. Templates and the table of content are 
working documents and may be updated also after the signature of the SAP. 


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9 
References 
1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150(9): 604-12. 
 


Sponsor: 
Hansa Medical 
CONFIDENTIAL 
13JUL2018
Study product: imlifidase 
 
Version 1.0 Final
Study ID: 
15-HmedIdeS-06  
Statistical analysis plan 
Page 24 of 24
 
F504-0-1-9 
10 Change log 
Version 
Effective date 
Reason for revision 
1.0 
13-Jul-2018 
New document