Conditions: Kidney Transplant Rejection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this study was to investigate how efficiently the study medication imlifidase reduces the amount of donor specific antibodies (DSA) in comparison with plasma exchange (PE) therapy, in patients who have had an active or chronic active antibody mediated rejection (AMR) after being kidney transplanted. The purpose was also to investigate and compare safety for these two treatments.

Detailed description:
Antibodies to human leukocyte antigens (HLAs) have a strong correlation with allograft injury and loss. Treatment with imlifidase, PE and immunoabsorption (IA) all aim to reduce antibody levels.

This study compared the reduction in DSA levels after treatment with imlifidase and PE in patients diagnosed with active or chronic active AMR (according to Banff 2017 or Banff 2019 criteria) having at least a 25% rise in serum creatinine compared with last measurement prior to the AMR. (Patients with delayed graft function and AMR within 10 days after kidney transplantation could be included regardless of serum creatinine level.) Eligible patients were randomized to either 1 dose of imlifidase (0.25 mg/kg) or 5-10 sessions of PEs (IA could replace PE at the discretion of the investigator).

All patients received pulse methylprednisolone Day 1 to Day 3, followed by a tapering schedule with prednisolone/prednisone. Patients randomised to imlifidase received their first dose of methylprednisolone before imlifidase was administered. The patients did also receive high dose intravenous immunoglobulin (IVIg) 3 days after imlifidase treatment or directly after the last PE. In addition a single dose of rituximab was given 5 days after completed IVIg infusion.

Arms:
arm 1: Subjects randomized to imlifidase treatment received one intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes. arm 2: Subjects randomized to plasma exchange (PE) treatment received 5-10 sessions of PE, as judged by the investigator. Immunoadsorption (IA) could replace PE, at the discretion of the investigator.

Interventions: intervention 1: Imlifidase intervention 2: Plasma Exchange
Intervention descriptions: intervention 1: Imlifidase is an immunoglobulin G (IgG) degrading enzyme of Streptococcus pyrogenes that cleaves all 4 human subclasses of IgG with strict specificity. intervention 2: The subject's plasma is removed and discarded and the subject receives replacement donor plasma, albumin, or a combination of albumin and saline. IA may be used instead of PE to the discretion of the investigator. IA is achieved by passing a subject's plasma over columns that bind immunoglobulins and then the plasma is passed back to the subject.

Protocol document:
SAP_002.pdf: 
Sponsor: 
Hansa Biopharma 
CONFIDENTIAL 
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Study product: Imlifidase 
Version 2.0 Final
Study ID: 
16-HMedIdeS-12
Statistical analysis plan 
Page 1 of 33
F504-0-1-9 
Statistical analysis plan 
A Randomized, Open-Label, Multi-Centre, Active Control Study Investigating 
the Efficacy and Safety of Imlifidase in Eliminating Donor Specific Anti-HLA 
Antibodies in the Treatment of Active Antibody-Mediated Rejection in Kidney 
Transplant Patients 
Sponsor: 
Hansa Biopharma 
Contract research organisation: 
Larix A/S 
Sponsor protocol number: 
16-HMedIdeS-12
EudraCT number: 
2018-000022-66
IND number:
128074
Universal trial number (UTN): 
NA
Investigational product name: 
Imlifidase
Development phase:  
II
Date of final SAP: 
27- Sep-2022


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Signature page 
Author 
 
 
 
Date  
(dd-Mmm-yyyy) 
 
Signature 
 
 
Name: 
 
 
 
Title:  Biostatistician 
 
Larix approval 
 
 
 
N/A 
 
N/A 
Date  
(dd-Mmm-yyyy) 
 
Signature 
 
 
Name:  N/A 
Title:  N/A 
 
Sponsor approval 
 
 
 
Date  
(dd-Mmm-yyyy) 
 
Signature 
 
 
Name: 
 
 
 
Title:  Senior Medical Director 
 
 
 
 
 
 
Date  
(dd-Mmm-yyyy) 
 
Signature 
 
 
Name: 
 
 
 
Title:  Biostatistician 
 
 
 


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Table of contents 
Signature page ........................................................................................................... 2 
Table of contents ........................................................................................................ 3 
List of abbreviations and definition of terms ......................................................... 5 
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 ....................................................................................... 10 
2.1.1 
Flow Chart imlifidase arm ............................................................................... 10 
2.1.2 
Flow Chart PE arm ........................................................................................... 12 
2.2 
Determination of sample size ........................................................................................ 15 
2.3 
Blinding ......................................................................................................................... 15 
2.4 
Randomisation ............................................................................................................... 15 
2.5 
Data pre-processing ....................................................................................................... 15 
3 
Analysis sets ...................................................................................................... 16 
3.1 
Full Analysis Set ........................................................................................................... 16 
3.2 
Per Protocol Analysis Set .............................................................................................. 16 
3.3 
Safety Analysis Set ........................................................................................................ 16 
3.4 
Pharmacokinetic Analysis Set ....................................................................................... 16 
4 
Statistical analyses and presentation of data ................................................. 17 
4.1 
General considerations .................................................................................................. 17 
4.1.1 
Data presentation .............................................................................................. 17 
4.1.2 
Baseline definition ........................................................................................... 17 
4.1.3 
Multiplicity ....................................................................................................... 17 
4.1.4 
Data imputation ................................................................................................ 17 
4.2 
Patient disposition ......................................................................................................... 18 
4.3 
Protocol deviations ........................................................................................................ 18 
4.4 
Demographics and other baseline characteristics .......................................................... 19 
4.5 
Compliance and exposure ............................................................................................. 19 
4.6 
Efficacy ......................................................................................................................... 19 
4.6.1 
Primary efficacy analysis ................................................................................. 19 
4.6.2 
Secondary efficacy analyses ............................................................................ 20 


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4.6.3 
Additional analyses .......................................................................................... 22 
4.7 
Safety ............................................................................................................................. 22 
4.7.1 
Adverse events ................................................................................................. 23 
4.7.2 
Other safety endpoints ..................................................................................... 24 
4.8 
Other endpoints ............................................................................................................. 24 
5 
Deviations from protocol analysis .................................................................. 25 
6 
Quality control.................................................................................................. 26 
7 
Layout of output ............................................................................................... 27 
8 
Tables, Listings and figures ............................................................................ 28 
9 
References ......................................................................................................... 32 
10 Change log ........................................................................................................ 33 
 
 


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List of abbreviations and definition of terms  
ADA 
Antidrug Antibody 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AMR 
Antibody Mediated Rejection 
ANOVA 
Analysis Of Variance 
AUC 
Area Under the Concentration Versus Time Curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI 
Confidence Interval 
CL 
Total systemic clearance of drug  
Cmax 
Maximum Serum Concentration 
CRF 
Case Report Form 
CV 
Coefficient of Variation 
DSA 
Donor Specific Antibody 
ECG 
Electrocardiogram 
eGFR 
estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
HLA 
Human Leukocyte Antigen 
HR 
Heart Rate 
IA 
Immunoadsorption 
IgG 
Immunoglobin G 
IMP 
Investigational Medicinal Product 
LLQ 
Lower Limit of Quantification 
MDRD 
Modification of Diet in Renal Disease Study 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
Mean Fluorescence Intensity 
 
 
NCA 
Non-Compartment Analysis 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamics  
PE 
Plasma Exchange 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetic analysis set 
PPS 
Per-protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
Screened 
Patient who enters the screening phase of the study 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class  
STDM 
Study data Tabulation Model 
TEAE  
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
Tmax 
Time of observed Cmax 


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T½  
Elimination half-life 
TM 
Trial Master 
Vz 
Apparent Volume of Distribution during the terminal phase 
WHO 
World Health Organization 


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1 
Introduction 
This document describes the planned statistical analyses for 16-HMedIdeS-12 which will include data 
processing, data analyses and data presentation. This Statistical Analysis Plan (SAP) is based on the 
study protocol version 4.3, 5.3, 6.3, 7.3 and 8.3 (1). These are country-specific protocols for 
5 different countries (France, Austria, US, Australia and Germany), allowing the countries to have 
minor differences regarding some exclusion criteria. These differences are deemed to not influence the 
analysis specified in this SAP.  
1.1 
Study objectives and endpoints 
These are the objectives as stated in the protocols above.  
1.1.1 
Objectives 
The primary objective of this study is to: 
• 
Investigate the efficacy of imlifidase compared with plasma exchange (PE) in removal of Donor 
Specific Antibody (DSA) in patients who are experiencing an active or chronic active Antibody 
Mediated Rejection (AMR) episode after kidney transplantation  
The secondary objectives of this study are to: 
• 
Evaluate DSA levels up to 180 days after treatment  
• 
Evaluate Human Leukocyte Antigen (HLA)-antibodies levels up to 180 days after treatment  
• 
Evaluate the overall kidney function up to 180 days after treatment  
• 
Investigate the occurrence of AMR up to 180 days after treatment  
• 
Investigate the safety and tolerability of imlifidase compared to PE in patients experiencing active 
or chronic active AMR episodes  
• 
Evaluate the number of PE-sessions needed 
• 
Evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of imlifidase 
(ADA) 
1.1.2 
Endpoints 
The primary endpoint of this study is: 
• 
Maximum reduction in DSA level at any time point during the 5 days following the start of 
treatment  
The secondary endpoints of this study are: 
• 
DSA levels up to 180 days after treatment  
• 
HLA-antibodies levels up to 180 days after treatment  
• 
Kidney function change from baseline (at screening) as evaluated by estimated Glomerular 
Filtration Rate (eGFR), P-creatinine and albumin/creatinine ratio in urine up to 180 days after 
treatment  


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• 
Proportion of patients with graft loss within 180 days of treatment  
• 
Signs of transplant glomerulopathy 180 days post treatment  
• 
Change from baseline (at screening) in histopathology per Banff Criteria at 29 and 180 days  
• 
Change from baseline (at screening) in mRNA levels in kidney biopsies evaluated by 
 
 at 29 and 180 days from baseline. If kidney biopsy is 
performed before screening, mRNA levels will be evaluated on day 29 and day 180 (no baseline 
will be available)  
• 
Safety parameters (adverse events [AEs], safety laboratory tests, vital signs and electrocardiogram 
[ECG]) 
• 
Type, frequency and intensity of adverse events  
• 
Number of sessions with PE  
• 
Total Serum Immunoglobin G (IgG) levels over time  
• 
Presence of intact IgG on SDS-page until start of IVIg treatment  
• 
DSA functionality determined by C1q or C3d analysis pre- and post-treatment  
• 
PK profile of imlifidase (Cmax, Tmax, t½, AUC, CL, Vz)  
• 
Presence of anti-imlifidase IgG (ADA) 
• 
Number of patients with resolution of AMR at day 180 
• 
Patient survival at day 180 


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2 
Study design 
The study is a phase II, randomized, open-label, multi-centre study with an active control investigating 
the efficacy and safety of imlifidase compared with PE, in removing anti-HLA antibodies to treat 
active and chronic active AMR post-transplant. A total of 30 male and/or female patients will be 
included in the study. The 30 patients are planned to be distributed in 5 countries (France, Austria, US, 
Australia and Germany) and 14 sites.  
DSA measurements and biopsies will be done at screening. If deemed eligible for the study during the 
screening visit, patients will be randomized in ratio 2:1 in the following way: 
• 
20 patients will be randomized to treatment with a single dose of 0.25 mg/kg imlifidase. The 
20 patients will receive treatment with 0.25 mg/kg imlifidase at visit 2 (Day 1). On day 4 the 
20 patients will be given high dose IVIg (may be given over 2 days). A single dose of rituximab 
will be given 5 days after completion of the high dose of IVIg. DSA will be measured at multiple 
timepoints during visit 2, and at all following visits. On day 29 and 180 kidney biopsies will be 
performed.  
• 
10 patients will be randomized to be treated with 5-10 sessions of PEs. The 10 patients will start 
the treatment with PEs at visit 2. After the last PE session, the 10 patients will be given high dose 
IVIg (may be given over 2 days). A single dose of rituximab will be given 5 days after completion 
of the high dose of IVIg. DSA will be measured at multiple timepoints during visit 2, and at all 
following visits. On day 29 and 180 kidney biopsies will be performed.  
Figure 1 and 2 below shows a summarized outline in the study for the imlifidase arm and PE arm. 
 
 














Sponsor: 
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Statistical analysis plan 
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3 
Analysis sets 
Every patient will be classified according to the below definitions of the Full analysis set (FAS), Per-
Protocol analysis set (PPS), Safety analysis set (SAF) and Pharmacokinetic analysis set (PKS). 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 
Full Analysis Set 
FAS will consist of all patients treated with any amount of study medication. Patients will contribute 
to the analysis ‘as randomized’. 
3.2 
Per Protocol Analysis Set 
PPS will include all patients in the FAS who have no major protocol deviations. Examples of major 
deviations are: 
• 
Violations of inclusion/exclusion criteria 
• 
The use of prohibited or discourage medication  
• 
Gross violation of visit schedules 
Patients will contribute to the analysis ‘as treated’. 
3.3 
Safety Analysis Set  
The SAF consists of all treated patients that received any amount of study medication (imlifidase or 
PE). Patients will contribute to the analysis ‘as treated’. 
3.4 
Pharmacokinetic Analysis Set 
PKS will include patients receiving any amount of imlifidase. It will also be further defined by the PK 
analyst taking admission criteria, protocol deviations and other non-compliance into consideration. 


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4 
Statistical analyses and presentation of data  
4.1 
General considerations 
In general FAS and PPS are used to efficacy data, SAF are used on safety data and PKS is used on 
Pharmacokinetics (PK) data.  
4.1.1 
Data presentation  
No formal statistical hypothesis testing will be performed in this study.  
The data will be presented descriptive and for some of the endpoints 95% confidence intervals for the 
treatment difference will be presented. 
Numerical data will be presented in summary tables by number of patients, arithmetic mean, median, 
standard deviation (SD), minimum and maximum.  
When numerical data are recorded at different time points, absolute values at each time point and 
changes from baseline may be presented in the summary tables.  
Categorical data will be presented by frequency and percent of patients. Number of events will also be 
reported where applicable.  
Summary tables will in general be presented by treatment group and total across treatment groups 
unless this is not appropriate for specific tables. 
Data will be listed by treatment group, patient and time point (if applicable). 
4.1.2 
Baseline definition 
Baseline value is defined as the last non-missing assessment before the patients start on the treatment. 
Change from baseline will be calculated as the difference between values for a given timepoint after 
baseline and baseline values (timepoint after baseline value minus baseline value). If the post-baseline 
value or baseline value are missing, then the change from baseline will also be missing.  
4.1.3 
Multiplicity 
The study is descriptive so no multiple testing will be done. This study will not include any interim 
analyses. 
4.1.4 
Data imputation 
In general, missing data will remain as missing and the missing values will not be adjusted. There are 
some exceptions described below. 
Adverse events 
Missing values will be treated as missing except for causality, toxicity, intensity, seriousness and 
outcome of an AE, in which case a “worst case” approach will be taken. If causality is missing, it will 
be set to “related”. If intensity is missing, it will be set to “severe”. If seriousness is missing, it will be 
considered as a Serious Adverse Event (SAE). If outcome is missing and no date is given for the 
outcome it will set to “not yet recovered”. 


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Dates for adverse event and concomitant medication 
Missing or partial start dates for AEs and concomitant medication data will be handled in the 
following way: 
• 
If the start date is totally missing, the date will still be missing.  
• 
If the start date is partial where only months and year are given, then the two cases are considered:  
1 If the available partial date (month and year) is before the month and year of treatment start 
date, then the AE/medication will be considered as pre-treatment and the date will be imputed 
as the start (1st) of the month. 
2 If the available partial date does not indicate that the AE/medication has started before the 
treatment start, then the AE/medication will be considered as treatment emergent/concomitant. 
The date will be imputed as the start (1st) of the month (if the month is not same as that of the 
treatment start date) or treatment start date (if the month is same as the treatment start date). 
• 
If the start date is partial where only the year is given, then the two cases are considered: 
3 If the available partial date (year) is clearly before the year of treatment start date, then the 
start date is imputed as start of the year (1st January YYYY). 
4 If the available partial date (year) is equal to or after the year of treatment start date, then the 
start date will be imputed as start of the year (1st January YYYY) (if the year is not same as 
that of the treatment start date) or treatment start date (if the year is same as the treatment start 
date). 
• 
For the partial end dates, similar procedure will be used as for the start dates. The only difference 
is the imputation for missing days and months. Missing days is imputed to the end of the month 
instead of the start of the month. If only year is available, the end date is set to 31st December 
YYYY. It will be checked that the imputed end dates fall after the corresponding start dates. 
All completely missing end dates will be missing. 
4.2 
Patient disposition 
The summary table for patient disposition will be presented in the following way: 
The number of patients screened, the number of patients in the FAS, PPS, PKS and SAF analysis sets, 
completers and withdrawals with reason for withdrawal will be summarised with frequency and 
percentage by treatment. 
The patient disposition will also be listed by patient.  
The patients screened but not allocated to treatment will be presented with the reason(s) for screening 
failure in a listing. 
4.3 
Protocol deviations  
Deviations from the protocol, as continuously tracked by investigator and sponsor, will be classified as 
‘minor’ or ‘major’. The final classification of the deviations will be done before the database lock. 


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All protocol deviations will be summarised with frequency and percentage for each category of 
protocol deviation. The FAS dataset will be applied. The protocol deviations will also be listed by 
patient.  
4.4 
Demographics and other baseline characteristics 
The following demographic variables will be summarised by treatment: Age, sex, race, height, weight 
and Body Mass Index (BMI). The table will be made for FAS. The demographics variables will also 
be listed by patient.  
Medical and surgical history and concomitant illness will be summarised by using latest effective 
version of Medical Dictionary for Regulatory Activities (MedDRA), System Organ Class (SOC) and 
Preferred Term (PT). The FAS dataset will be used. Medical and surgical history and concomitant 
illness will also be presented in a list by patient. 
Only concomitant medication during the treatment will be tabulated by World Health Organization 
(WHO) drug version 153E, level 4 (chemical/therapeutic/pharmacological subgroup) and level 5 
(Chemical substance). The FAS dataset will be used. Concomitant medication during the treatment 
and before the start of the treatment will be presented in a list. 
Previous kidney transplant history will be presented in a summary table by treatment and listed by 
patient. The FAS set will be used. 
The donor type (living or deceasing) will be listed by patient.  
4.5 
Compliance and exposure  
A summary table will be presented for exposure. In the table we will have the total dose and 
percentage of planned dose. The time point for IVIg and Rituximab will also be included in the table. 
Compliance and the drug exposure will be presented in a list by patient.  The list will show start date 
of treatment, end date of treatment, number of doses or sessions (as applicable), planned dose and 
actual dose. 
4.6 
Efficacy  
4.6.1 
Primary efficacy analysis 
The primary endpoint is the maximum reduction in DSA at any time point during 5 days following 
start of treatment. No formal statistical hypothesis will be tested for the primary endpoint. The FAS 
and PPS set will both be used for the primary endpoint. The primary endpoint will be calculated as 
part of the ADaM programming. 
The DSAs are given as levels of mean fluorescence intensity (MFI) and genetic region of interest. 
These parameters are used to calculate the reduction in DSA for individual patients in the following 
steps:  
1) Determine the DSAs having MFI levels larger than or equal to 1000 at baseline for the 
considered patient. Calculate DSA0 as the sum of these MFI levels. 
2) Calculate DSAt for each patient as the sum of the MFI levels for the time point t, using the 
DSAs from step 1.  
3) The reduction (%) is calculated as 100×(DSA0 – DSAt)/DSA0 for each patient and time point. 
In the formula DSAt is the total MFI level at time t. 
4) The time point with maximum reduction within 5 days is found and chosen for each patient. 


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5) The maximum reduction per patient is a single value as the primary endpoint for the patient.  
 
The difference in reduction between the two treatments will be presented with 95% CI in a table.  
The confidence interval for the difference in the reduction is found by using an Analysis of variance 
(ANOVA) model with treatment as fixed effect.   
The reduction of DSAs calculated per patient will also be presented in a summary table by treatment 
and visit and presented in a mean plot by treatment and time point. The maximum reduction per 
patient will be listed by patient. 
If the normality assumption is violated, sensitivity analyses using transformations of the primary 
endpoint will be performed. 
 
4.6.2 
Secondary efficacy analyses 
DSA levels up to 180 days after treatment 
DSAs will be measured using SAB-HLA assay and a functional assay e.g. C1q or C3d assay. A 
summary table for the C1q assay will be generated for the sum of MFI levels for DSAs from step 1 for 
primary endpoint (see Section 4.6.1) by treatment and time point. MFI levels will be listed per patient 
and time point. Spaghetti plots will show the DSA level versus time for each patient. A mean plot by 
treatment and time point will be presented.  
A list with all DSA by patient and time point will be presented.  
HLA-antibodies levels up to 180 days after treatment  
Patient listings of MFI values for all HLAs will be presented. 
Kidney function change from baseline  
The kidney function will be evaluated by the parameters eGFR, P-creatinine and albumin/creatinine 
ratio in urine. The laboratory parameters will be summarised as part of the safety data tabulation.  
 
The eGFR will be calculated as a part of ADaM programming, using the Modification of Diet in Renal 
Disease Study (MDRD) equation (2): 
eGFR (mL/min/1.73 m2) = 175 × (Cr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American), 
where Cr stands for creatinine value and Age are measured in years from birth to screening visit. This 
formula assumes that Cr is given in the mg/dL unit. 
Proportion of patients with graft loss at day 180  
The number of patients with graft loss at day 180 will be handled as a binary variable. Graft loss is 
defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or transplantectomy. 
The endpoint is a success if the patients have absence of graft loss at day 180. The proportion of 
patients, which satisfy the success criterium, will be summarized by treatment and listed by patient. 
The FAS set will be applied.  
Signs of transplant glomerulopathy 180 days post treatment  
Possible transplant glomerulopathy 180 days post treatment will be handled as a binary variable.  
The endpoint is a success if the patients have no possible transplant glomerulopathy 180 days post 
treatment. The proportion of patients, which satisfy the success criterium, will be tabulated by 
treatment. A list will also be created by patient. The FAS set will be applied.  
Change from baseline in histopathology per Banff Criteria at 29 and 180 days 
Kidney biopsies will be assessed according to the Banff (2017 or later version) criteria pre-dose and at 
day 29 and 180. The biopsy data are measured as scores. The scores will be presented by time point in 


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a summary table. The change from baseline will be summarised by treatment, Banff lesion score and 
time point. 
The overall interpretations for the biopsies will be presented in a summary table by time point. Shift 
tables will also be presented for overall interpretation from the biopsies. The possible categories for 
the overall interpretation are: Active AMR, Chronic Active AMR, CMR, Borderline CMR and No 
rejection. Possible combinations for the overall interpretation are: Active AMR + CMR, Active AMR 
+ Borderline CMR, Chronic Active AMR + CMR and Chronic Active AMR + Borderline CMR.  
A list will also be presented by patient where the scores and diagnosis are presented. 
Change from baseline in mRNA levels in kidney biopsies evaluated by 
 at 29 and 
180 days from baseline 
data will be presented in a summary table and in a list for day 29 and day 180. The 
 
data is also given as score. The change from baseline will also be presented in a summary table. If 
baseline data is not available for 
, only the values on day 29 and 180 will be presented. 
Number of sessions with PE for 180 days  
The number of PE and immunoadsorption (IA) sessions within 180 days will be summarized by 
treatment and listed by patient. In addition, the number of PE and IA sessions after start of IVIg 
administration and up to 180 days after start of study treatment will be summarized by treatment. The 
FAS set will be applied.  
Total serum IgG over time 
The FAS set will be applied when analysing total serum IgG. 
The IgG levels in serum will be analyzed centrally by a validated ECL based immunoassay using the 
Meso Scale Diagnostic technology. The total serum IgG levels will be summarized by time point. 
Total serum IgG levels will also be presented by mean and spaghetti plots. Finally, data will be listed 
by patient.  
In addition, the reduction of total serum IgG levels will be analyzed as a binary endpoint. The binary 
endpoint is defined as a success, if the minimum IgG value at any time point during the 5 days 
following the start of treatment is less than 5% of baseline for the patient. The proportion of patients, 
which satisfy the success criterium, will be presented in a summary table by treatment. The difference 
in proportion between the two treatments will be presented with a 95% CI in a summary table. The 
95% CI for the difference between the two treatments will be based on exact Confidence Limits. In 
addition, the proportion of patients which satisfy the success criterium will be presented by treatment 
and time point. 
The composition of IgG-fragments will be analyzed centrally using SDS-PAGE. Each sample will be 
assigned a score depending on the observed composition of fragments as follows: 
0=no intact IgG, scIgG or F(ab’)2 
1=only F(ab’)2 
2=mix of scIgG and F(ab’)2 
3=only scIgG 
4=mix of intact IgG and scIgG 
5=only intact IgG 
SDS-PAGE scores will be summarized by time point. 
Presence of intact IgG on SDS-PAGE until start of IVIg treatment 
The endpoint is a success for a patient if no detectable intact IgG is found by the SDS-PAGE assay for 
at least one time point between the start of study medication (imlifidase) treatment and start of 
administration of IVIg. No detectable intact IgG is defined as SDS-PAGE scores 0, 1, 2 or 3. The 


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proportion of patients, who reached the success criterium, will be summarized in a table using the PKS 
set. 
Number of patients with resolution of AMR at day 180  
The number of patients with resolution of AMR at day 180 will be handled as a binary variable. 
Resolution is defined as “Active AMR” or “Chronic active AMR” not being selected from the biopsy 
protocol.  
The endpoint is a success if the patients have resolution of AMR at day 180. The proportion of 
patients, which satisfy the success criterium, will be tabulated by treatment. A list will be created by 
patient. The FAS set will be applied.  
Patient survival at day 180  
The patient survival on day 180 will be handled as a binary variable.  
The endpoint is a success if the patients have survived on day 180. The proportion of patients, which 
satisfy the success criterium, will be summarized and listed by patient. The FAS set will be applied.  
Pharmacokinetic  
The Pharmacokinetic (PK) characteristics of imlifidase will be analyzed using the PKS. Imlifidase 
concentration in serum will be analyzed centrally using a validated electrochemiluminescence (ECL) 
based immunoassay (Meso Scale Diagnostic) technology. Full details of the analytical method used, 
and the analysis results will be detailed in a separate bioanalysis report. 
The PK parameters will be calculated by non-compartmental analysis (NCA) and/or compartmental 
analysis using the software WinNonlin (Pharsight Corporation, USA). Actual sampling time points 
relative to dosing will be used for the calculation and on the individual plots of plasma concentration 
versus time. Plasma concentration values missing (e.g., no blood sample collected, or no value 
obtained at analysis) will be excluded from the calculations. Values below lower limit of 
quantification (LLQ) will be represented by ‘0’ (zero) in the descriptive statistics and as LLQ/2 in the 
plots. No formal analysis of outliers is planned.  
PK parameters will be estimated based on measurements of the plasma concentration-time data of 
imlifidase, and the following parameters will be estimated, if possible, but not limited to: AUC, Cmax, 
tmax, t½, CL, and Vz. 
Imlifidase concentrations will be listed by patient, visit and time point. Imlifidase concentrations will 
also be presented in a summary table by time point. PK parameters including but not limited to AUC, 
Cmax, tmax, t½, CL, and Vz, will be listed by patient and visit, by treatment arm, and summarized with 
number of measurements, arithmetic mean, standard deviation, percentage coefficient of variation 
(%CV) (arithmetic), median, minimum, maximum, geometric mean, and %CV (geometric mean). For 
t½, the harmonic mean, median, minimum, and maximum will be presented, and for tmax only the 
median, minimum, and maximum will be displayed.  
Further, the PK concentrations will be presented graphically as mean profile plots and as spaghetti 
(individual lines) plots. Semi-log format with log10 on the y-axis and a linear time on the x-axis will 
be presented in the plots. Linear-linear plots may also be presented. 
4.6.3 
Additional analyses 
No additional analyses are applied. 
4.7 
Safety  
Safety parameters will be evaluated for the safety analysis data set. 


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4.7.1 
Adverse events 
Adverse events (AEs) will be classified according to the latest effective version of MedDRA.  
A treatment emergent adverse event (TEAE) is any adverse event occurring after the administration of 
the IMP and within the time of residual drug effect, or a pre-treatment adverse event or pre-existing 
medical condition that worsens in intensity after administration of the IMP and within the time of 
residual drug effect. 
The time of residual drug effect is the estimated period after the administration of the IMP, where the 
effect of the product is still considered to be present based on pharmacokinetic, pharmacodynamic or 
other substance characteristics. The residual drug effect is generally accepted to be 5 times the 
terminal half-life. The terminal half-life of imlifidase is expected to be within the range of approx. 
100 hours, i.e. in this study the residual drug effect is likely to be well within the 29 Day assessments. 
All AEs occurring up to Day 29 are regarded as treatment emergent.  
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 (TEAEs considered to be possibly or probably related to IMP as judged by the 
investigator) 
• 
Related Serious TEAEs 
• 
Deaths  
• 
Treatment-emergent Serious Adverse Events (SAEs) 
• 
TEAEs leading to withdrawal  
• 
Severe and life-threatening AEs 
Treatment-emergent AEs will be summarised in a table by dictionary level, i.e., System Organ Class 
(SOC) and Preferred Term (PT) for MedDRA. The table will display the total number of patients 
reporting a TEAE, the percentage of patients (%) with a TEAE and the number of events (E) reported. 
TEAEs will be presented by SOC sorted alphabetically and PT sorted in decreasing frequency of 
occurrence. For the summary tables the SAF set will be applied.  
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) 
• 
Treatment-emergent SAEs 
• 
Treatment-emergent SAEs by causality (related/unrelated) 


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F504-0-1-9 
• 
Treatment-emergent SAEs leading to death 
• 
TEAEs leading to withdrawal 
Data listings will be provided for: 
• 
All TEAEs sorted by patient number  
• 
All TEAEs sorted by MedDRA SOC and PT 
• SAEs 
• 
Treatment-emergent SAEs 
• 
Treatment-emergent SAEs leading to death 
• 
TEAEs leading to withdrawal 
• 
Pre-treatment emergent AEs 
• 
Post-treatment emergent AEs 
4.7.2 
Other safety endpoints 
The clinical safety laboratory tests, vital signs, and ECG parameters will be summarised for both 
absolute values and changes from baseline by treatment and time point. The SAF set will be applied. 
The parameters will also be listed by patient. Values outside the reference ranges will be flagged in 
listings.  
A list for physical examination will be created. 
The results for the Polymerase Chain Reaction (PCR) tests for SARS-CoV-2 and pregnancy tests will 
be listed by patient.  
Anti-imlifidase antibody data (ADA) is numerical and will be summarized by time point in a summary 
table, where PKS is used. Anti-imlifidase antibody data will also be presented graphically as boxplots 
and listed by patient. 
4.8 
Other endpoints 
No other endpoints are included in the study. 


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F504-0-1-9 
5 
Deviations from protocol analysis 
The primary endpoint from the protocol was: “Maximum reduction in mean DSA level at any time 
point during the 5 days following the start of treatment.” This has been changed to: “Maximum 
reduction in DSA level at any time point during the 5 days following the start of treatment” to avoid a 
misinterpretation that it is a mean across patients.  
The Western blot is not applied for detectable intact IgG. Instead, the scoring is done on the SDS-
PAGE where the scores 0, 1, 2, 3 mean no detectable intact IgG. The Western blot does not generate 
any quantifiable data as SDS-PAGE does. Therefore, it is not applied in the analyses. 
The difference in proportion between treatments and 95% CI are not done for detectable intact IgG. 
The treatment group (not including imlifidase) will only generate score 5. Therefore, no additional 
information will be gained by comparing the two groups.  
The time for the endpoint “Presence of intact IgG on SDS-PAGE until start of IVIg treatment”, also 
referred to as “Detectable intact IgG on a Western blot” in protocol, is changed. Instead of over 180 
days, the endpoint is considered between the start of treatment and start of administration of IVIg. 
This is changed because the high dose IVIg will lead to detectable intact IgG, i.e. no meaningful 
conclusions on remaining intact IgG can be drawn after the administration on IVIg.  
PKS is updated to only include patients treated with imlifidase. Blood samples will still be taken as 
planned for central analysis for non-imlifidase patients, but no portion will be used for PK and ADA 
analysis, as this is not applicable for non-imlifidase patients.  
IA has been added to the endpoint “Number of sessions with PE within 180 days” as it is used for the 
same purpose as PE. 
 
 


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6 
Quality control 
SDTM data sets will be generated by programs in SAS software 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 
•           Apply the Pinnacle 21 validator for STDM and ADAM 
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 Larix SOPs 701, 702 and 703 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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F504-0-1-9 
7 
Layout of output 
The output will follow Larix 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. Separate Word 
documents will be created for tables, figures and listings respectively. 
An overview of the relevant tables, listings and figures can be seen in section 8 in this SAP.  








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F504-0-1-9 
16.4.1.10 
Listing 
Physical examination - by patient and time point (SAF) 
16.4.1.11 
Listing 
PCR test - by patient (SAF) 
16.4.1.12 
Listing 
Pregnancy test - by patient (SAF) 
16.4.1.13 
Listing 
Anti-Imlifidase IgG (ADA) - by patient and time point 
(PKS) 
16.4.1.14 
Listing 
Anti-Imlifidase IgE (ADA) - by patient and time point 
(PKS) 
 
 
 
 
 
 
 


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F504-0-1-9 
9 
References  
1) Clinical study protocol 16-HMedIdes-12: A Randomized, Open-Label, Multi-Centre, Active 
Control Study Investigating the Efficacy and Safety of Imlifidase in Eliminating Donor 
Specific Anti-HLA Antibodies in the Treatment of Active Antibody-Mediated Rejection in 
Kidney Transplant Patients version 4.3, 5.3, 6.3, 7.3 and 8.3 
2) 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: 
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F504-0-1-9 
10 Change log 
Version 
Effective date 
Reason for revision 
1.0 
29-Jun-2022 
New document 
2.0 
29-Aug-2022 
Changes in section 4.1.4 for imputation dates for concomitant medication and 
adverse events. Changes in title for figure 15.1.34 and 15.1.36 and section 8 is 
updated.  
 
 
 
 

Prot_001.pdf: 
Hansa Biopharma AB 
Date: 17NOV2021 
Project: IdeS AMR 
Version: 6.3_US Incl Amendment No 03 
Clinical Study Protocol No.: 16-HMedIdeS-12 
Hansa Biopharma Doc No.: 2017-182 
1 (64) 
CONFIDENTIAL 
Clinical Study Protocol 
A Randomized, Open-Label, Multi-Centre, Active Control Study 
Investigating the Efficacy and Safety of Imlifidase in Eliminating Donor 
Specific Anti-HLA Antibodies in the Treatment of Active Antibody-
Mediated Rejection in Kidney Transplant Patients 
Clinical Study Protocol No.: 
16-HMedIdeS-12
Investigational Medicinal Product: 
Imlifidase 
Phase: 
Version: 
II 
6.3_US 
EudraCT Number: 
2018-000022-66 
IND Number: 
128074 
Name and Address of Sponsor: 
Hansa Biopharma AB 
P.O. Box 785 
SE-220 07 Lund 
Sweden 
This confidential document is the property of Hansa Bioharma AB. No unpublished information contained herein may be disclosed 
without prior written approval from Hansa Biopharma AB. Access to this document must be restricted to relevant parties.


Hansa Biopharma AB 
Date: 17NOV2021 
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Version: 6.3_US Incl Amendment No 03 
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Hansa Biopharma Doc No.: 2017-182 
 
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SYNOPSIS 
Name of Sponsor/Company 
Hansa Biopharma AB (hereafter referred to as Hansa Biopharma) 
Title of the study 
A Randomized, Open-Label, Multi-Centre, Active Control Study Investigating the Efficacy 
and Safety of Imlifidase in Eliminating Donor Specific Anti-HLA Antibodies in the 
Treatment of Active Antibody-Mediated Rejection in Kidney Transplant Patients 
Co-ordinating Signing Principal Investigator  
Stanley C. Jordan, M.D. 
Study Site(s) 
Approximately 14 sites, in US, Europe and Australia will be included  
Planned study period 
First subject first visit: Q1 2019 
Recruitment period: 35 months 
Last subject last visit: Q3 2022 
Completion of the clinical study report: Q1 2023 
Clinical Phase  
II 
 


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Background and Scientific Justification for Conducting the Study 
Antibody mediated rejection (AMR) is one of the most challenging adverse events after kidney 
transplantation and despite advances in the understanding of the pathophysiological processes 
causing this reaction it remains the main cause for graft dysfunction. AMR can occur in 
patients with preexisting anti-Human Leukocyte Antigen (HLA) Donor-Specific Antibodies 
(DSA) or in patients without DSA at transplantation but who develop de novo DSA. 
Transplant Glomerulopathy (TG) is a known consequence of persistent DSA positivity which 
rapidly dissipates allograft function resulting in graft failure and return to dialysis with 
attendant emotional consequences for the patients and financial costs for the health care 
system.  
Currently used therapies include high dose IVIg +/- rituximab, Plasma Exchange (PE) with 
low dose IVIg +/- rituximab, eculizumab and a minimal experience with bortezomib. However, 
no therapy is currently approved, and patients are often treated with combination therapies that 
make analysis of efficacy of any one agent difficult. Thus, there is a large unmet clinical need 
for new therapies to prevent and treat AMR.   
This study is designed to investigate the safety and efficacy of imlifidase removing anti-HLA 
antibodies in the treatment of active or chronic active AMR after transplantation. The primary 
objective of this study is to determine if imlifidase is effective in removing DSAs and thus 
lessen antibody mediated kidney damage in subjects experiencing post-transplant antibody 
mediated rejection.  
Objectives 
The primary objective of this study is to: 
• Investigate the efficacy of imlifidase compared with PE in removal of DSA in 
patients who are experiencing an active or chronic active AMR episode after kidney 
transplantation 
Secondary objectives of this study are to: 
• Evaluate DSA levels up to 180 days after treatment 
• Evaluate HLA-antibodies levels up to 180 days after treatment 
• Evaluate the overall kidney function up to 180 days after treatment 
• Investigate the occurrence of AMR up to 180 days after treatment 
• Investigate the safety and tolerability of imlifidase compared to PE in patients 
experiencing active or chronic active AMR episodes 
• Evaluate the number of PE-sessions needed 
• Evaluate the pharmacokinetics, pharmacodynamics and immunogenicity of imlifidase 
 


Hansa Biopharma AB 
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Endpoints 
The primary endpoint of this study is: 
• Maximum reduction in mean DSA level at any time point during the 5 days following 
the  start of treatment  
Secondary endpoints of this study are: 
• DSA levels up to 180 days after treatment 
• HLA-antibodies levels up to 180 days after treatment 
• Kidney function change from baseline, (at screening), as evaluated by eGFR, 
P-creatinine and albumin/creatinine ratio in urine up to 180 days after treatment  
• Proportion of subjects with graft loss within 180 days of treatment 
• Signs of transplant glomerulopathy 180 days post treatment 
• Change from baseline (at screening) in histopathology per Banff Criteria at 29 and 
180 days 
• Change from baseline (at screening) in mRNA levels in kidney biopsies evaluated 
 
at 29 and 180 days from baseline. If kidney biopsy is performed before 
screening, mRNA levels will be evaluated on day 29 and day 180 (no baseline will be 
available) 
• Safety parameters (AEs, safety laboratory tests, vital signs and ECG) 
• Type, frequency and intensity of adverse events  
• Number of sessions with PE 
• Total Serum IgG levels over time 
• Presence of intact IgG on SDS-page/Western blot until start of IVIg treatment 
• DSA functionality determined by C1q or C3d analysis pre- and post-treatment 
• PK profile of imlifidase (Cmax, Tmax, t½, AUC, CL, V) 
• Presence of ADA (anti-imlifidase IgG)  
Methodology 
This is a randomized, open label, multi-centre, active control study. The study will primarily 
examine the reduction in mean levels of DSA after treatment with imlifidase compared with 
PE in patients diagnosed with active or chronic active AMR according to Banff 2017 criteria, 
including presence of DSA(s). Included subjects will be randomized to receive either one dose 
of imlifidase 0.25 mg/kg or 5-10 sessions of PEs. All subjects will receive pulse 
methylprednisolone for three days, starting before the first treatment, followed by a tapering 
schedule with prednisolone/prednisone. Subjects will receive high dose IVIg 3 days after 
imlifidase treatment and directly after the last PE. A single dose of rituximab will be given 5 
days after completed IVIg infusion.   


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Study Procedures/Assessments 
Before inclusion into the study, a biopsy will be collected from all subjects, and assessments 
of DSA and ADA (IgE), vital signs, ECG as well as laboratory parameters including 
haematology, clinical chemistry, haemostasis, urinalysis, and PCR test for SARS-CoV-2  will 
take place. Subjects will be randomised to imlifidase infusion, 0.25 mg/kg over 15 min, or 5-
10 PE treatment, and subsequently followed for 180 days after start of treatment. Blood 
samples for DSA, PK, PD and ADA will be collected at multiple time points during the study. 
Protocol biopsies will be performed on day 29 and on day 180 and kidney function will be 
followed by plasma or serum creatinine measurements, eGFR calculations and urine sample 
for measurement of albumin/creatinine ratio during the full study period. 
Safety parameters will be assessed up to day 180. Reporting of adverse events will be done 
throughout the study.  
Number of subjects 
A total of 30 subjects will be included in the study distributed as 20 subjects in the imlifidase 
arm and 10 subjects in the PE arm. The sample size is not based on a formal calculation but 
with 20+10 subjects the expected width of the 95% CI of the difference in DSA reduction at 
any timepoint during the 5 days following the  start of treatment (primary endpoint) is 8% 
point. This expected width is considered acceptable for evaluating a possible difference or 
similarity between the two treatments. 
Diagnosis and main criteria for inclusion/exclusion  
Main inclusion criteria are: 
• Male and/or female donor kidney recipients, age ≥18 years at the time of screening 
• Presence of DSA(s) 
• Meet the Banff 2017 criteria for active or chronic active AMR  
• At least 25% rise in serum creatinine compared to last individual value taken prior to 
the AMR. Patients with delayed graft function and AMR within 10 days after 
transplant (confirmed by kidney biopsy) can be included regardless of serum 
creatinine level 
Main exclusion criteria are: 
• Previous treatment with imlifidase 
• Previous high dose IVIg treatment (2 g/kg) within 28 days prior to inclusion 
• Subjects with significantly abnormal general serum screening lab results, judged 
inappropriate for inclusion in the study by the investigator   
• Clinically relevant active infection(s) as judged by the investigator 
• Any condition that in the opinion of the investigator could increase the subject’s risk 
by participating in the study such as severe immune deficiency and severe cardiac 
insufficiency (New York Heart Association (NYHA) Class IV) or severe uncontrolled 
heart disease  


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• Known allergy/sensitivity to imlifidase, IVIg and/or rituximab and the respective 
excipients 
• Patient unable to tolerate treatment with plasmapheresis or immunoadsorption, as 
judged by the investigator 
• Positive PCR test for SARS-CoV-2 virus infection 
• Current diagnosis or history of thrombotic thrombocytopenic purpura (TTP), or known 
familial history of TTP 
Medicinal Product(s) 
Imlifidase is provided as a freeze-dried powder for concentrate for solution for infusion, 11 mg 
per vial. After reconstitution with sterile water for injection, the concentrate contains 
10 mg/mL imlifidase. The concentrate will be added to 50 mL sodium chloride 9 mg/mL 
(0.9 %) solution for infusion and administered as an infusion. 
PE will be prepared and administered according to standard at each site. 
Duration of treatment  
Subjects randomized to imlifidase treatment will receive one intravenous dose of imlifidase, 
0.25 mg/kg, administered over 15 minutes. 
Subjects randomized to PE treatment will receive 5-10 sessions of PE, as judged by the 
investigator.  
Statistical methods 
This is an open-label study and the statistical evaluation and presentation of data will be 
descriptive by nature. For the primary endpoint and certain secondary endpoints, the treatment 
difference will be presented with 95% CI. The continuous efficacy endpoints will be summary 
tabulated by n, mean, median, standard deviation, minimum and maximum and presented 
graphically when relevant. Categorical efficacy responses will be presented by counts and 
percentages. The safety endpoints will be summarised as for the efficacy endpoints. 
 
 
 


Hansa Biopharma AB 
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Protocol Revision History including Summary of Changes 
Protocol 
Version 
Date 
Including 
Amendment 
Type and No. 
Overall Rationale for Changes 
6.3_US 
17Nov2021 
Non-
substantial 
amendment 
no. 03 
• 
Change in CRO responsible for 
SAE/SUSAR reporting 
• 
Extension of study duration by 6 months 
• 
Updated number of study sites to 
approximately 14 
6.2_US 
06Oct2020 
Substantial 
amendment 
no. 02 
• 
To ensure that patients with asymptomatic 
Covid-19 are not included in the trial 
• 
Serum sickness no longer classified as a 
risk 
• 
Thrombocytopenic purpura (TTP) is now 
defined as a contraindication 
Extension of study duration by 9 months 
6.1_US 
03Mar2020 
Amendment 
No. 01 
• 
Allow for a kidney biopsy performed 
within standard of care to be used for 
inclusion. 
• 
Clarify inclusion criteria #5 by adding 
chronic active AMR. 
• 
Clarify that the 3 latest creatinine values 
prior to the current AMR will be collected. 
• 
Extension of study duration by 8 months. 
• 
Benefit/risk section was updated with new 
number for infusion reactions according to 
the latest version of IB. 
6.0 
22 Mar 2019 
N/A 
Initial approved protocol 
 
See Appendix 1 “Clinical Study Protocol Amendment” for details of Amendment No 03 
 


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TABLE OF CONTENT 
Protocol Revision History including Summary of Changes ..................................................... 7 
1. 
Introduction ...................................................................................................................... 14 
1.1. 
Background .......................................................................................................... 14 
1.2. 
Study Design and Dose Rationale ........................................................................ 17 
1.3. 
Benefit/Risk Aspects ............................................................................................ 17 
2. 
Study Objectives and Endpoints ...................................................................................... 19 
2.1. 
Objectives ............................................................................................................. 19 
2.1.1. 
Primary Objective .................................................................................. 19 
2.1.2. 
Secondary Objectives ............................................................................ 19 
2.2. 
Endpoints ............................................................................................................. 19 
2.2.1. 
Primary Endpoint ................................................................................... 19 
2.2.2. 
Secondary Endpoints ............................................................................. 19 
3. 
Investigational Plan .......................................................................................................... 21 
3.1. 
Overall Study Design ........................................................................................... 21 
3.1.1. 
Follow-up Procedures ............................................................................ 22 
3.1.2. 
Safety Review Committee ..................................................................... 22 
3.2. 
Study timeline ...................................................................................................... 22 
3.3. 
Planned number of study sites and subjects ......................................................... 22 
3.4. 
End-of-Study ........................................................................................................ 23 
4. 
Study Population .............................................................................................................. 24 
4.1. 
Selection Criteria .................................................................................................. 24 
4.2. 
Inclusion Criteria .................................................................................................. 24 
4.3. 
Exclusion Criteria ................................................................................................ 25 
4.4. 
Method of Assigning Subjects to Treatment Groups ........................................... 25 
4.5. 
Discontinuation of Subjects ................................................................................. 25 
5. 
Study Treatments ............................................................................................................. 26 
5.1. 
Investigational Medicinal Product ....................................................................... 26 
5.1.1. 
Conditions for Storage and Use ............................................................. 26 
5.1.2. 
Packaging and labelling ......................................................................... 26 
5.2. 
Control treatment ................................................................................................. 27 
5.3. 
Non-Investigational Medicinal Product(s) ........................................................... 27 
5.3.1. 
Conditions for Storage and Use ............................................................. 28 
5.4. 
Blinding ................................................................................................................ 28 
5.5. 
Compliance, Accountability and Destruction of IMP(s) and NIMP(s) ............... 28 
5.5.1. 
Compliance ............................................................................................ 28 
5.5.2. 
Accountability and Destruction of IMP(s) and NIMP(s) ...................... 28 
5.6. 
Product Quality Complaints ................................................................................. 29 
5.7. 
Concomitant Medication(s) and Therapy ............................................................ 29 
6. 
Study Procedures .............................................................................................................. 30 
6.1. 
Study Visits .......................................................................................................... 30 
6.1.1. 
Visit 1 (screening).................................................................................. 30 
6.1.2. 
Visit 2 (treatment), Day 1-5 ................................................................... 31 
6.1.3. 
Visit 3, Day 6 ......................................................................................... 32 


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6.1.4. 
Visit 4, Day 8 ......................................................................................... 32 
6.1.5. 
Visit 5, Day 11 (+/- 2 days) ................................................................... 32 
6.1.6. 
Visit 6, Day 15 (+/- 2 days) ................................................................... 32 
6.1.7. 
Visit 7, Day 22 (+/- 3 days) ................................................................... 32 
6.1.8. 
Visit 8, day 29 (+/- 3 days) .................................................................... 33 
6.1.9. 
Visit 9, Day 64 (+/- 7 days) and Visit 10, Day 90 (+/- 7 days) ............. 33 
6.1.10. Visit 11 (follow up, end of study), day 180 (+/- 14 days) ..................... 33 
6.2. 
Flow Chart imlifidase arm ................................................................................... 34 
6.3. 
Flow Chart PE arm ............................................................................................... 37 
7. 
Study Assessments ........................................................................................................... 40 
7.1. 
Assessments related to endpoints ......................................................................... 40 
7.1.1. 
Determination of donor specific antibodies ........................................... 40 
7.1.2. 
Pharmacodynamics ................................................................................ 40 
7.1.3. 
Kidney function as evaluated by eGFR, P-creatinine and 
albumin/creatinine ratio in urine ............................................................ 40 
7.1.4. 
Kidney biopsy ........................................................................................ 41 
7.1.5. 
Pharmacokinetics ................................................................................... 41 
7.1.6. 
Immunogenicity ..................................................................................... 41 
7.2. 
Safety Assessments related to Endpoints ............................................................. 41 
7.2.1. 
Safety Laboratory .................................................................................. 41 
7.2.2. 
Physical Examination ............................................................................ 42 
7.2.3. 
Vital Signs ............................................................................................. 42 
7.2.4. 
ECG ....................................................................................................... 42 
7.2.5. 
Adverse Events ...................................................................................... 42 
7.3. 
Other Assessments ............................................................................................... 43 
7.3.1. 
Demographics and Baseline Data .......................................................... 43 
7.3.2. 
Pregnancy Test....................................................................................... 43 
7.3.3. 
Concomitant medication and other treatments ...................................... 43 
7.3.4. 
Analysis of SARS-CoV-2 virus ............................................................. 43 
8. 
Biological Sampling Procedures ...................................................................................... 44 
8.1. 
Handling, Storage and Destruction of Biological Samples .................................. 44 
8.2. 
Chain of Custody of Biological Samples ............................................................. 44 
8.3. 
Withdrawal of Informed Consent for Biological Samples ................................... 44 
9. 
Adverse Events and Serious Adverse Events .................................................................. 45 
9.1. 
Definitions ............................................................................................................ 45 
9.1.1. 
Adverse event ........................................................................................ 45 
9.1.2. 
Serious adverse event ............................................................................ 45 
9.2. 
Collection and Recording of Adverse Events ...................................................... 46 
9.2.1. 
Variables ................................................................................................ 46 
9.2.1.1. 
Causality Assessment .............................................................. 46 
9.2.2. 
Adverse Events Based on Signs and Symptoms ................................... 47 
9.2.3. 
Adverse Events Based on Examinations and Tests ............................... 47 
9.2.4. 
Follow-up of Unresolved Adverse Events ............................................. 47 
9.2.5. 
Reporting of Serious Adverse Events .................................................... 48 
9.2.6. 
Reporting of Suspected Unexpected Serious Adverse Reactions.......... 48 


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9.3. 
Pregnancy and Pregnancy Outcome .................................................................... 49 
10. Study Management .......................................................................................................... 50 
10.1. Pre-study Activities .............................................................................................. 50 
10.2. Monitoring of the Study ....................................................................................... 50 
10.3. Source Data .......................................................................................................... 51 
10.4. Audit and Inspection ............................................................................................ 51 
10.5. Study Agreements ................................................................................................ 51 
11. Data Management ............................................................................................................ 52 
11.1. Case Report Form ................................................................................................ 52 
11.2. Provider of Data Management ............................................................................. 52 
11.3. Coding .................................................................................................................. 52 
11.4. Handling of External Data ................................................................................... 52 
12. Statistical Methods ........................................................................................................... 53 
12.1. Analysis Sets ........................................................................................................ 53 
12.1.1. Full Analysis Set .................................................................................... 53 
12.1.2. Per Protocol Analysis Set ...................................................................... 53 
12.1.3. Safety Analysis Set ................................................................................ 53 
12.1.4. Pharmacokinetic Analysis Set ............................................................... 53 
12.2. Subject characteristics .......................................................................................... 54 
12.2.1. Subject disposition ................................................................................. 54 
12.2.2. Demographics and Other Baseline Characteristics................................ 54 
12.2.3. Recent and Concomitant Medication..................................................... 54 
12.2.4. Exposure and Compliance ..................................................................... 54 
12.3. Statistical Analysis of Endpoints ......................................................................... 54 
12.3.1. Primary efficacy endpoint...................................................................... 54 
12.3.2. Reduction of total serum IgG ................................................................ 55 
12.3.3. Detectable intact IgG on a Western blot ................................................ 55 
12.3.4. Donor specific antibodies (DSA) .......................................................... 55 
12.3.5. Kidney function ..................................................................................... 55 
12.3.6. Signs of transplant glomerulopathy 180 days post treatment ................ 55 
12.3.7. Number of sessions with PE for 180 days ............................................. 55 
12.3.8. Number of patients with resolution of AMR at day 180 ....................... 55 
12.3.9. The number of patients with graft failure at day 180 ............................ 56 
12.3.10. Patient survival at day 180 ..................................................................... 56 
12.3.11. Pharmacokinetic .................................................................................... 56 
12.3.12. Pharmacodynamics ................................................................................ 56 
12.3.13. Analysis of Adverse Events ................................................................... 56 
12.3.13.1. Pre-treatment Adverse Events ................................................. 56 
12.3.13.2. Treatment Emergent Adverse Events ...................................... 56 
12.3.13.3. Post-treatment Emergent Adverse Events ............................... 57 
12.3.14. Analysis of Other Safety Variables ....................................................... 57 
12.3.15. Immunogenicity ..................................................................................... 57 


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12.4. Determination of Sample Size ............................................................................. 57 
13. Changes in Study Conduct or Planned Analyses ............................................................. 58 
13.1. Protocol Amendment(s) ....................................................................................... 58 
13.2. Protocol Deviations .............................................................................................. 58 
13.3. Statistical Analysis Plan ....................................................................................... 58 
13.4. Premature Termination or Suspension of the Study ............................................ 58 
14. Reporting and Publication ................................................................................................ 59 
14.1. Clinical Study Report ........................................................................................... 59 
14.2. Confidentiality and Data Ownership .................................................................... 59 
14.3. Publications .......................................................................................................... 59 
14.3.1. Publication Policy .................................................................................. 59 
14.4. Public disclosure .................................................................................................. 59 
15. Ethical and Regulatory Aspects ....................................................................................... 60 
15.1. Ethical Conduct of the Study ............................................................................... 60 
15.2. Liabilities and Insurance ...................................................................................... 60 
15.3. Independent Ethics Committee(s) and Institutional Review Boards ................... 60 
15.4. Regulatory Authority(ies) .................................................................................... 60 
15.5. Subject Information and Informed Consent ......................................................... 61 
15.6. Subject Participation Card ................................................................................... 61 
15.7. Subject Confidentiality ........................................................................................ 61 
16. Archiving ......................................................................................................................... 62 
16.1. Retention of Clinical Study Site Documentation ................................................. 62 
16.2. Study Master File ................................................................................................. 62 
17. References ........................................................................................................................ 63 
18. Appendix 1 ....................................................................................................................... 64 
18.1. Protocol Amendment 03 ...................................................................................... 64 
 
LIST OF TABLES 
Table 1: 
Study flow chart imlifidase arm, Screening to End of Study ............................... 34 
Table 2: 
Study flow chart imlifidase arm, visit 2, treatment .............................................. 36 
Table 3: 
Study flow chart PE arm, Screening to End of Study .......................................... 37 
Table 4: 
Study flow chart PE arm, visit 2, treatment ......................................................... 39 
Table 5: 
Safety laboratory tests .......................................................................................... 41 
 
LIST OF FIGURES  
Figure 1: 
Overall study outline imlifidase arm .................................................................... 21 
Figure 2: 
Overall study outline PE arm ............................................................................... 22 




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PPS 
Per Protocol Analysis Set 
PQC 
Product Quality Complaint 
RA 
Regulatory Authority 
SAB 
Single Antigen Bead 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Document Verification 
SOC 
Standard of Care 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TTP 
Thrombotic Thrombocytopenic Purpura 
Tmax 
Time to maximum plasma concentration 
t1/2 
Terminal half-life 
V 
Volume 
 
 
 


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1. 
INTRODUCTION 
The company code initially used for the active substance in this project was HMED-IdeS 
(sometimes abbreviated to IdeS) and thus many reports refer to this name. 
The International Non-proprietary Name (INN) imlifidase was recently assigned for the active 
substance and this name will be used throughout this document.  
1.1. 
Background  
Patient population and unmet medical need 
Antibody Mediated Rejection (AMR) is one of the most challenging adverse events after kidney 
transplantation and despite advances in the understanding of the pathophysiological processes 
causing this reaction it remains the main cause for graft dysfunction. AMR can occur in patients 
with preexisting anti-Human Leukocyte Antigen (HLA) Donor-Specific Antibodies (DSA) or 
in patients without DSA at transplantation but who develop de novo DSA. 
Significant advances have occurred in the ability to predict patients at risk for and to diagnose 
AMR. The pathophysiology of AMR suggests a prime role for antibodies, B-cells and plasma 
cells. Recent research has indicated that B-cells and plasma cells produce DSAs that interact 
with the endothelium, which activates the cellular pathways responsible for the development of 
microcirculatory changes and tissue injury.   
Satisfying data on the effectiveness of currently available therapies is limited, and 
post-transplant AMR and chronic AMR remain significant problems (Djamali et al. 2014). 
Transplant Glomerulopathy (TG) is a known consequence of persistent DSA positivity which 
rapidly dissipates allograft function resulting in graft failure and return to dialysis with attendant 
emotional consequences for the patients and financial costs for the health care system (Gloor et 
al. 2008; Jordan et al. 2010; Lefaucheur et al. 2010; Port et al. 1993; Reinsmoen et al. 2008; 
OPTN 2012). Therapies for AMR are limited (Sellares et al. 2012). Currently used therapies 
include high dose IVIg +/- rituximab, plasma exchange (PE) with low dose IVIg +/- rituximab, 
eculizumab and a minimal experience with bortezomib. However, no therapy is currently 
approved, and patients are often treated with combination therapies that make analysis of 
efficacy of any one agent difficult. Thus, there is a large unmet clinical need for new therapies 
to prevent and treat AMR.   
Imlifidase 
Imlifidase is an IgG-degrading enzyme of Streptococcus pyogenes that cleaves all four human 
subclasses of IgG with strict specificity. Imlifidase hydrolyzes human IgG below the hinge 
region thereby generating one F(ab’)2 fragment and one Fc-fragment which does not bind to 
Fc-receptors and does not activate complement. Thus, the proteolytic activity of imlifidase on 
IgG molecules prevents IgG mediated phagocytosis, antibody-dependent cellular cytotoxicity 
and complement mediated injury (Winstedt et al. 2015; Jarnum et al. 2017). Imlifidase is highly 
specific towards IgG and other Ig molecules, i.e. IgA, IgD, IgE and IgM, are not cleaved and 
no other substrates have been identified. Apart from imlifidase restricted target specificity, the 
speed of the reaction is a major advantage of imlifidase. Within a few hours after dosing, the 


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entire pool of IgG is fully cleaved into F(ab’)2 and Fc fragments thereby creating a window 
where IgG levels are kept very low for approximately one week. 
Repeat dose toxicology studies have been performed in rabbit and dog and the no observed 
adverse effect level (NOAEL) was set to 2 mg/kg and lowest observed adverse effect level 
(LOAEL) to 20 mg/kg in both species. 
Previous clinical experience with imlifidase 
Six studies with imlifidase have been completed: 
1. First human study, to assess the safety and tolerability of the IgG cleaving enzyme from 
the 
Streptococcus 
pyogenes 
Immunoglobulin 
G 
degrading 
enzyme 
of 
(11-HMedIdeS-01, EudraCT no. 2012-000 969-21). 
2. A study to evaluate the safety and efficacy of imlifidase in Chronic Kidney Disease 
Patients (CKD) (13-HMedIdeS-02, EudraCT no. 2013-005417-13) 
3. A phase II study to evaluate the safety, tolerability, efficacy and pharmacokinetics of 
intravenous ascending doses of imlifidase in kidney transplantation in sensitized 
patients (13-HMedIdeS-03, EudraCT no. 2014-000712-34) 
4. A phase II pilot study to evaluate the safety, tolerability, efficacy, pharmacodynamics 
and pharmacokinetics of imlifidase in asymptomatic antibody-mediated thrombotic 
thrombocytopenic purpura (TTP), in patients with low ADAMTS13 (15-HMedIdeS-08, 
EudraCT no. 2016-000249-30). 
5. A phase I/II study to assess safety, tolerability and efficacy of imlifidase given 
immediately prior to kidney transplantation to reduce DSAs in highly sensitized CKD 
patients awaiting DD kidney transplantation (14-HMedIdeS-04, FDA IND 124301)  
6. A phase II study to evaluate the efficacy of imlifidase to desensitize transplant patients 
with a positive crossmatch test, the primary endpoint is conversion of a positive 
crossmatch test to negative in highly sensitized patients (15-HMedIdeS-06, FDA 
IND 128074, EudraCT no. 2016-002064-13) 
Study 11-HMedIdeS-01 was a double blind, randomized, dose escalation study in healthy 
subjects performed in Sweden. Two clinically effective doses (0.12 and 0.24 mg/kg) were 
identified and imlifidase was considered safe and well tolerated in the population. 
Study 13-HMedIdeS-02 was a Swedish single-centre, single arm, dose finding, Phase II study 
in sensitized CKD patients with the primary endpoint to find an imlifidase dosing scheme 
resulting in HLA-antibody levels acceptable for transplantation in the majority of patients. 
Patients received imlifidase infusions of 0.12 mg/kg twice, 0.25 mg/kg once, or 0.25 mg/kg 
twice. The study also assessed safety, tolerability, pharmacokinetics, and pharmacodynamics 
of imlifidase. The study did not include transplantation of the patients. However, patients were 
not removed from the transplant waitlist during the study and one patient was transplanted 
following imlifidase treatment. The efficacy objective was reached, and imlifidase was 
considered safe and well tolerated. 


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Study 13-HMedIdeS-03 was a Swedish two-centre, single arm, Phase II study to assess safety 
and efficacy of imlifidase given immediately prior to kidney transplantation to reduce DSAs in 
sensitized CKD patients awaiting deceased donor (DD) or living donor (LD) transplantation. 
The primary endpoint was safety. Ten patients (8 DD, 2 LD) were treated with single doses of 
0.25 or 0.5 mg/kg imlifidase along with standard immunosuppressive treatment, but no 
additional desensitizing agents. Imlifidase was well tolerated at both doses, efficiently reduced 
anti-HLA antibody levels, including DSA, and all 10 patients could be transplanted. 
Study 15-HMedIdeS-08 was a Phase II pilot study in UK to evaluate the safety, tolerability, 
efficacy, pharmacodynamics and pharmacokinetics of imlifidase in asymptomatic 
antibody-mediated thrombotic thrombocytopenic purpura patients with low ADAMTS13 
activity. The study was prematurely terminated due to a non-favorable risk benefit profile in 
the first two patients, presumably related to the underlying disease. The patients were dosed 
with 0.25 mg/kg imlifidase. 
Study 14-HMedIdeS-04 was an investigator-initiated phase I/II, single arm, exploratory study 
in the US.  Patients received a single dose of 0.24 mg/kg imlifidase in addition to pre-treatment 
with rituximab and IVIg. Patients were eligible for inclusion if they had a panel reactive 
antibodies (PRA)> 50% and a positive crossmatch test against their available DD or had DSA(s) 
before imlifidase treatment. The study enrolled 17 patients all being transplanted.  
Study 15-HMedIdeS-06 was a Phase II study in the US and EU. The study enrolled patients 
with DSAs and a positive crossmatch test to their available LD or DD. A total of 18 patients 
were enrolled and transplanted with a kidney from a DD (13) or LD (5). Enrolled patients were 
treated with imlifidase on day 0. In addition to imlifidase, patients were given high dose IVIg 
(2 g/kg, maximum of 140 g) on day 7 and rituximab on day 9. DSA levels were monitored pre- 
and at several time points after imlifidase dosing. Safety, including kidney function, was 
monitored at multiple time points up to 180 days after treatment. Pharmacokinetics (PK), 
Pharmacodynamics (PD) and Anti-Drug Antibody (ADA) were measured.  
Two studies with imlifidase are ongoing: 
1. A phase II study to evaluate the efficacy and safety of imlifidase in anti-GBM disease 
(Glomerular Basement Membrane/Goodpasture’s disease) with adverse renal prognosis 
(15-HMedIdeS-10, EudraCT no. 2016-004082-39) 
2. A prospective, observational long-term follow up study of patients treated with 
imlifidase prior to kidney transplantation (17-HMedIdeS-14, FDA IND 128074) 
Study 15-HMedIdeS-10 is an ongoing investigator initiated multi-centre, open-label Phase II 
study conducted in EU. The study will enroll 15 patients. Imlifidase 0.25 mg/kg is given IV 
over 30 min to patients with severe anti-GBM disease on background of standard care 
consisting of pulse methylprednisolone, oral prednisolone/prednisone and intravenous 
cyclophosphamide combined with PE. 
Study 17-HMedIdeS-14 is an ongoing, five year, follow up, observational study. Up to 46 
subjects who have participated in previous studies, received imlifidase and been transplanted 
will be enrolled. 


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1.2. 
Study Design and Dose Rationale   
Antibodies to HLA antigens have a strong correlation with allograft injury and loss. More than 
5000 renal allografts are lost each year in the U.S., approximately 75-80% due to antibody 
mediated injury (Loupy et al. 2012). Clearly, the most important way to approach antibody 
mediated allograft injury is through the development of antibody-targeted therapies. This would 
address all pathogenic mechansisms associated with alloantibodies and allow grafts to continue 
functioning for much longer periods of time. Successful treatment would improve the length 
and quality of life of allograft recipients and reduce costs to the health care system. 
This is a randomized, open-label, multi-centre study, designed to investigate the safety and 
efficacy of imlifidase compared with PE, in removing anti-HLA antibodies to treat active or 
chronic active AMR post-transplant. Imlifidase at 0.25 and 0.50 mg/kg have been demonstrated 
to be safe and effective in removing IgG antibodies including DSAs in patients awaiting kidney 
transplantation. 
20 subjects will be randomized to receive a single dose of 0.25 mg/kg imlifidase. High dose 
IVIg will be given on day 4 (this may be given over 2 days) and then a single dose of rituximab 
5 days after completion of the IVIg infusion.  
10 subjects will be randomized to be treated with PEs. 5-10 sessions of PE will be performed 
at the discretion of the investigator. Immunoadsorption (IA) may replace PE, at the 
investigator’s discretion. Subjects in the PE arm will be treated with high dose IVIg on the last 
day of PE (may be given over 2 days as judged by the investigator) followed by a single dose 
of rituximab given 5 days after completion of the IVIg infusion. 
1.3. 
Benefit/Risk Aspects 
Subjects in this study may benefit from being treated with imlifidase to resolve early graft 
rejection. The potential benefit of imlifidase compared to currently used methods, e.g. PE, is 
the efficacious and immediate removal of DSAs. It is anticipated that a faster DSA removal 
will result in less damage to the allograft and thus a better outcome for the patient. If imlifidase 
fails to remove DSAs to satisfactory levels or if the DSAs rebound, the patient will be treated 
with PE and/or other standard of care (SOC) treatments, as judged by the investigator. SOC 
treatment can be initiated at any point for patients in the treatment arm if needed. The decision 
to initiate other SOC treatments will normally be based on DSA rebound. Since DSA is 
monitored frequently, signs of antibody rebound will be detected early and appropriate 
treatment initiated immediately. Thus, it is anticipated that there will be no risk that the patient 
does not receive the best available treatment. 
Since imlifidase effectively removes the IgG pool, there may be an increased risk of infection. 
To minimize the risk for bacterial infections all subjects included in the study will receive 
prophylactic antibiotics. Subjects will be closely monitored for infections and 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. Subjects will be screened for SARS-CoV-2 and 
subjects with a positive test will not be included in the study. As SARS-CoV-2-naïve subjects 


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do not have any IgG antibodies towards the virus, and since imlifidase does not prevent IgG 
synthesis, administration of imlifidase is not considered to have any  impact on patient safety 
should the subject subsequently become infected with SARS-CoV-2. 
Although samples for analysis of ADA will be taken at screening, it is not possible to wait for 
the sample to be analyzed before inclusion in the study as this would delay the treatment and 
thus have a serious impact on patient outcome.  
As for all biologics, there is a risk of infusion reactions associated with imlifidase treatment. 
Three non-serious and one serious infusion related reactions regarded as related to treatment 
have occurred in 114 subjects receiving imlifidase. Signs and symptoms associated with 
infusion related reactions included, but were not limited to dyspnoea, pharyngeal oedema, sinus 
tachycardia, chest discomfort and flushing. To mitigate the risk of infusion related reactions, 
all subjects receive glucocorticoid and antihistamine treatment prior to dosing and are closely 
monitored during the infusions.  
In vitro studies have revealed that imlifidase cleaves biologics originating from rabbit and 
human IgG including; thymoglobulin, IVIg, basiliximab, alemtuzumab, rituximab, 
adalimumab, denosumab, belatacept and etanercept. The optimal interval between imlifidase 
administration and these biologics has not been tested (2018-003R).  
The rationale for the 3-day window between imlifidase and IVIg dosing is aimed to prevent 
cleavage of the IVIg based on the pharmacokinetic and pharmacodynamic profiles of 
imlifidase. In one of the clinical studies (14-HMedIdeS-04), alemtuzumab was given four days 
post dosing of imlifidase and in one clinical study (15-HMedIdeS-06), IVIg was given seven 
days post dosing of imlifidase.  
Adverse events after administration of IVIg do occur but are seldom serious. There is a very 
small risk of anaphylaxis, often in subjects with severe IgA deficiency. Other reported side 
effects include headache, myalgia, transient hypotension and flushing (all of which can be 
corrected by slowing the infusion rate), meningism, aseptic meningitis, skin reactions 
(especially eczema), neutropenia, worsening of renal failure, and thromboembolic events 
(DVT, MI and stroke) attributable to hyperviscosity (Hughes et al. 2014).  
As an extra safety measure for women of child bearing potential, the requirement for highly 
effective contraception is part of the inclusion criteria for this study. Additionally, a pregnancy 
test will be performed at the screening visit to ensure the patient is not pregnant. 
The principal investigators will make sure that sufficient facilities and procedures are available 
to handle emergency situations during the study. 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. 
A guidance for the investigator and Reference Safety Information regarding imlifidase can be 
found in the Investigator’s Brochure. 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of this study is to: 
• Investigate the efficacy of imlifidase compared with PE in removal of DSA in patients 
who are experiencing an active or chronic active AMR episode after kidney 
transplantation 
2.1.2. 
Secondary Objectives 
Secondary objectives of this study are to: 
• Evaluate DSA levels up to 180 days after treatment 
• Evaluate HLA-antibodies levels up to 180 days after treatment 
• Evaluate the overall kidney function up to 180 days after treatment 
• Investigate the occurrence of AMR up to 180 days after treatment 
• Investigate the safety and tolerability of imlifidase compared to PE in patients 
experiencing active or chronic active AMR episodes 
• Evaluate the number of PE-sessions needed 
• Evaluate the pharmacokinetics, pharmacodynamics and immunogenicity of imlifidase 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary endpoint of this study is: 
• Maximum reduction in mean DSA level at any time point during the 5 days following 
the  start of treatment  
2.2.2. 
Secondary Endpoints 
Secondary endpoints of this study are: 
• DSA levels up to 180 days after treatment 
• HLA-antibodies levels up to 180 days after treatment 
• Kidney function change from baseline (at screening) as evaluated by eGFR, P-creatinine 
and albumin/creatinine ratio in urine up to 180 days after treatment  
• Proportion of subjects with graft loss within 180 days of treatment 
• Signs of transplant glomerulopathy 180 days post treatment 
• Change from baseline (at screening) in histopathology per Banff Criteria at 29 and 180 
days 


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• Change from baseline (at screening) in mRNA levels in kidney biopsies evaluated by 
at 29 and 180 days from baseline. If kidney biopsy is performed before 
screening, mRNA levels will be evaluated on day 29 and day 180 (no baseline will be 
available) 
• Safety parameters (AEs, safety laboratory tests, vital signs and ECG) 
• Type, frequency and intensity of adverse events  
• Number of sessions with PE 
• Total Serum IgG levels over time 
• Presence of intact IgG on SDS-page/Western blot until start of IVIg treatment 
• DSA functionality determined by C1q or C3d analysis pre- and post-treatment 
• PK profile of imlifidase (Cmax, Tmax, t½, AUC, CL, V) 
• Presence of ADA (anti-imlifidase IgG)  
 
 
 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design  
This is a randomized, open label, multi-centre, study with an active control. The study will 
primarily examine the reduction in mean levels of DSA after treatment with imlifidase 
compared to PE in patients diagnosed with active or chronic active AMR according to Banff 
2017 criteria (Haas et al. 2018), including presence of DSA(s). A total of 30 male and/or female 
patients will be included in the study.   
The randomization will be 2:1. 20 subjects will receive a single dose of 0.25 mg/kg imlifidase 
and 10 subjects will be treated with 5-10 sessions of PEs. High dose IVIg followed by a single 
dose of rituximab will be given after treatments with imlifidase and PE. For doses, see 
Section 5. Other treatments and/or procedures for AMR can be used as required at the 
investigator’s discretion. SOC treatment can be initiated at any point for patients in the 
treatment arm if needed as judged by the investigator. The decision to initiate other SOC 
treatments will normally be based on DSA rebound. Since DSA is monitored frequently, signs 
of antibody rebound will be detected early and appropriate treatment initiated immediately. 
The duration of the hospitalization for subjects in the imlifidase  arm will be at least  2 days. 
In the control arm, the duration of the hospital stay will  follow standard of care at each study 
site.  
Presence of DSA will be assessed pre-dose and at multiple times during the study. Protocol 
biopsies will be performed at screening, and on day 29 and day 180 after first day of treatment 
to assess changes in allograft histopathology and mRNA levels. . If kidney biopsy is performed 
within 5 days prior to screening it will not have to be repeated at screening visit  and mRNA 
levels will be measured on day 29 and day 180. In addition, kidney function will be followed 
by plasma or serum creatinine measurements, eGFR calculations and albumin/creatinine ratio 
in urine during the full study period. 
The study outline is summarized in Figure 1 (imlifidase) and Figure 2 (PE) below. 
Figure 1: 
Overall study outline imlifidase arm 
 
 


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Figure 2: 
Overall study outline PE arm 
 
 
Safety parameters (safety laboratory tests, vital signs and ECG) as well as kidney function and 
AEs will be monitored up to 180 days after start of treatment.  
3.1.1. 
Follow-up Procedures 
The subjects will be followed until 180 days after start of treatment. Subjects who lose their 
graft during the course of the study will remain in the study and be followed according to the 
study protocol and clinical practice at the site. 
After study completion, all study subjects will be followed regularly by the nephrologist or 
transplant surgeons according to each centre’s follow-up routines for transplanted subjects. The 
frequency of outpatient visits will be adjusted individually to the state of patient health and 
transplant function.   
3.1.2. 
Safety Review Committee  
A Safety Review Committee (SRC) will be established to evaluate safety and tolerability data. 
The committee will meet 14 days after the first patient has received the first treatment to 
evaluate available safety and tolerability data. If no clinically significant changes are identified, 
the second and third subject will be dosed and evaluated following the same schedule.  After  6 
and 11 imlifidase-treated subjects have completed visit 8 (day 29) the committee will meet 
again. Evaluation of data will include subjects from both treatment arms (i.e., imlifidase and 
PE). The SRC will meet on an ad hoc basis if any important safety issue arises anytime during 
the conduct of the study. The SRC will consist of at least 3 physician members: a drug safety 
physician, and two consultants, all independent to Hansa Biopharma. Other internal and 
external experts will be invited to attend the meetings if any issue arises that require additional 
expertise. A working procedure for the SRC will be described in an SRC charter.  
3.2. 
Study timeline 
The expected study start is Q1 2019 with 12 months recruitment and 6 months follow up for 
included subjects. The recruitment period has been extended to 35 months. 
3.3. 
Planned number of study sites and subjects 
This is a multi-centre study. Approximately 14 sites, in US, Europe and Australia, will be 
included. A total of 30 male and/or female subjects will be enrolled in the study. 


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3.4. 
End-of-Study 
The planned end-of-study is defined as last subject last visit. Hansa Biopharma will ensure that 
an end-of-study notification is submitted to the concerned Regulatory Authority (RA) and 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) according to local 
requirements. 
For procedures in case of premature termination or suspension of the Study, see Section 13.4. 
 
 


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4. 
STUDY POPULATION 
4.1. 
Selection Criteria 
To be eligible for the study, subjects must meet all inclusion criteria and no exclusion criteria. 
If a subject has been screened and meets all inclusion and no exclusion criteria but does not 
receive imlifidase and a new AMR occurs, the subject may be rescreened. 
4.2. 
Inclusion Criteria 
1. Signed Informed Consent obtained before any study-related procedures 
2. Willingness and ability to comply with the protocol 
3. Male and/or female donor kidney recipients age ≥18 years at the time of screening 
4. Presence of DSA(s) 
5. Meet the Banff 2017 criteria for active or chronic active AMR 
6. At least 25% rise in serum creatinine compared to last individual value taken prior to 
the AMR. Patients with delayed graft function and AMR within 10 days after transplant 
(confirmed by kidney biopsy) can be included regardless of serum creatinine level 
7. Women of child-bearing potential willing or able to use at least one highly effective 
contraceptive method throughout the study. In the context of this study, an effective 
method is defined as those which result in low failure rate (i.e. less than 1% per year) 
when used consistently and correctly such as:  
• combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation  
o oral  
o intravaginal  
o transdermal  
• progestogen-only hormonal contraception associated with inhibition of 
ovulation  
o oral  
o injectable  
o implantable  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomised partner 
• true abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (such as calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception] 
8. Men willing to use double-barrier contraception from the first day of treatment until at 
least 2 months after the dose of imlifidase, if not abstinent 


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4.3. 
Exclusion Criteria 
1. Previous treatment with imlifidase 
2. Previous high dose IVIg treatment (2 g/kg) within 28 days prior to inclusion 
3. Lactating or pregnant females 
4. Significantly abnormal general serum screening lab results judged inappropriate for 
inclusion in the study by the investigator   
5. Intake of other investigational drugs within 5 half-lives (or similar) of the product prior to 
inclusion 
6. Clinically relevant active infection(s) as judged by the investigator 
7. Any condition that in the opinion of the investigator could increase the subject’s risk by 
participating in the study such as severe immune deficiency and severe cardiac insufficiency 
(New York Heart Association (NYHA) Class IV) or severe uncontrolled heart disease  
8. Known allergy/sensitivity to imlifidase, IVIg and/or rituximab and the respective excipients 
9. Patient unable to tolerate treatment with plasmapheresis or immunoadsorption, as judged 
by the investigator 
10. Unsuitable to participate in the study for any other reason as judged by the investigator 
11. Positive PCR test for SARS-CoV-2 virus infection. 
12. Current diagnosis or history of thrombotic thrombocytopenic purpura (TTP), or known 
familial history of TTP 
4.4. 
Method of Assigning Subjects to Treatment Groups 
At the screening visit, study subjects will be identified by a site-specific screening identification 
number. The lowest available site-specific subject number will be allocated, when the subject 
has fulfilled the eligibility criteria. The subjects will be randomized to imlifidase or PE 
treatment in a 2:1 ratio according to a computer-generated randomisation list created by the 
CRO. Block randomisation will be used.  
4.5. 
Discontinuation of Subjects  
The subjects have the right to withdraw from the study at any time for any reason, without the 
need to justify their decision. However, the investigator should record the reason for the 
subject’s withdrawal, if possible. The investigator also has the right to withdraw subjects. In 
either event, the investigator must notify monitor. 
A subject that prematurely discontinues participation must, if possible, be called in for a last 
visit and undergo the assessments and procedures scheduled for the end of study follow up visit. 
Even if the subject is not able to attend, the End of Trial Form in the eCRF must be completed. 
Subjects who, for a medical reason, cannot comply with the protocol procedures will be 
followed by best procedure to retrieve safety and efficacy data. 


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Minor infusion-related reactions have been observed in some patients receiving imlifidase for 
other indications. These are usually mild and include chest discomfort, flushing, pharyngeal 
oedema and dyspnea. More severe reactions can occur. 
If a minor infusion-related reaction (CTCAE grade 1 or 2) is suspected the infusion should be 
temporarily stopped and the patient should be observed for clinical signs of allergic reactions. 
If a significant infusion-related reaction or anaphylactic reaction occurs (CTCAE grade 3 or 
higher) then the imlifidase therapy should be discontinued immediately.  
The patient should be treated by the investigator according to local practice for an allergic 
reaction or a severe allergic reaction/anaphylaxis, respectively. If the symptoms resolve, the 
infusion can be resumed. If the symptoms persist or worsen then the drug infusion should not 
be restarted. 
5. 
STUDY TREATMENTS 
5.1. 
Investigational Medicinal Product 
Imlifidase is provided as a freeze-dried powder for concentrate for solution for infusion, 11 mg 
per vial. After reconstitution with sterile water for injection, the concentrate contains 10 mg/mL 
imlifidase. The concentrate will be added to 50 mL sodium chloride 9 mg/mL (0.9 %) solution 
for infusion and administered as an infusion. 
The excipients are: mannitol, polysorbate 80, Tris (tris(hydroxymethyl)aminomethane) buffer 
and EDTA. The excipients are all of pharmacopoeial quality.   
Imlifidase for infusion will be prepared by the pharmacist or study nurse and the administration 
will be performed by the study nurse or physician at site. Details on preparation, labelling, 
administration and accountability of imlifidase are described in the pharmacy manual that will 
be provided to the site and pharmacy prior to inclusion of the first subject.  
One intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes, will be given 
to subjects randomized to receive imlifidase.  
5.1.1. 
Conditions for Storage and Use 
Vials with imlifidase should be stored in a refrigerator at +2°C to +8°C. 
The solution for infusion should be stored at +2°C to +8°C, protected from light. The solution 
should be used within 12 hours. The solution should be placed in room temperature 
approximately 30 minutes before administration.   
The investigator will ensure that the Investigational Medicinal Product (IMP) always will be 
stored in appropriate conditions in a secure location. The storage compartment will be 
monitored regularly, and the temperature documented. 
5.1.2. 
Packaging and labelling 
Packaging and labelling of the IMP will be performed in accordance with Good Manufacturing 
Practice (GMP) and national regulatory requirements.  


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5.2. 
Control treatment 
The control treatment in this study is PE which is a treatment with no active substance and thus 
not an IMP. PE will be prepared and performed according to the standard of care at each site. 
5-10 sessions of PE will be performed.  
5.3. 
Non-Investigational Medicinal Product(s)  
Non-Investigational Medicinal Products (NIMPs) will be sourced from the investigational site 
pharmacy supply. Essential information about the NIMPs is to be found in the latest versions 
of respective Summary of Product Characteristics.  
The subjects will be treated with the following NIMPs (other treatments may be used as 
required at the investigator’s discretion): 
Prophylactic antibiotic (all subjects): 
All subjects will receive a standard regimen of antibiotics according to local clinical practice, 
starting before the first treatment and continuing until IgG levels return to acceptable values, as 
judged by the investigator.   
Premedication (imlifidase arm): 
All subjects in the imlifidase arm, will be given antihistamine (orally) as pretreatment before 
imlifidase infusion. 
Treatment schedule for steroid dosing (all subjects): 
Day 1: 
Methylprednisolone 500 mg as premedication before treatment 
Day 2-3: 
Methylprednisolone 500 mg daily 
Day 4: 
Prednisolone/prednisone 60 mg 
Day 5: 
Prednisolone/prednisone 50 mg 
Day 6: 
Prednisolone/prednisone 40 mg 
Day 7: 
Prednisolone/prednisone 30 mg 
Day 8: 
Prednisolone/prednisone 20 mg will continue daily for 1 week, followed by 10 mg 
daily for 1 week and thereafter 5 mg daily throughout the study 
Treatment with IVIg (all subjects) 
Imlifidase arm: subjects will be given a high dose of IVIg (2 g/kg BW, maximum of 140 g), 
on day 4 (may be given over 2 days, as judged by the investigator). If a subject in this arm has 
to be treated with PE for medical reasons, IVIg will be given after the last session of PE. 
PE arm: a high dose of IVIg (2 g/kg BW, maximum of 140 g) will be given after the last 
session of PE (may be given over 2 days, as judged by the investigator). 
Treatment with Rituximab (all subjects) 


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A single dose of rituximab, 375 mg/m2, will be given to all subjects 5 days after completion of 
the IVIg infusion. 
Rituximab requires use of contraception for 12 months after treatment. Women of childbearing 
potential will be encouraged to continue using highly effective contraceptive method for at least 
6 months after end of study. 
5.3.1. 
Conditions for Storage and Use 
The investigator will ensure that the NIMPs will be stored in appropriate conditions, according 
to labels, in a secure location with controlled access. The storage compartment shall be 
monitored regularly, and the temperature shall be documented. 
5.4. 
Blinding 
This is an open-label study. Due to the nature of the control treatment, blinding of the control 
treatment is not feasible. 
5.5. 
Compliance, Accountability and Destruction of IMP(s) and NIMP(s) 
5.5.1. 
Compliance 
The administration of all medication (including investigational products) will be done by 
trained study personnel and must be recorded in the appropriate sections of the eCRF. All 
investigational treatments must also be documented in the accountability logs. Treatment 
compliance will be assured by supervised administration of the investigational product by the 
investigator or delegate. The dose, date and time of administration of the investigational product 
will be checked by the monitor at monitoring visits. 
5.5.2. 
Accountability and Destruction of IMP(s) and NIMP(s) 
It is the principal investigator’s/institution’s responsibility to establish a system for handling 
study treatments, including investigational medicinal products, to ensure that: 
1. Deliveries are correctly received by a responsible person (e.g. pharmacist or 
designated study personnel) 
2. Deliveries are recorded 
3. All IMP and NIMPs are handled and stored safely and properly 
4. The IMP provided for this study will be used only as directed in the study protocol 
5. The study personnel will account for all drugs dispensed and returned. Any 
discrepancies must be documented, investigated and appropriately resolved 
6. The study pharmacist will maintain and keep the total accountability records. At the 
end of the study, the pharmacist will return all unused IMPs to Hansa Biopharma for 
destruction after it has been checked by monitor. The used IMP vials will be 
accounted for and destructed at site, after control by monitor. 


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5.6. 
Product Quality Complaints 
A PQC is a reported defect related to the identity, quality, durability, reliability, safety, 
effectiveness, or performance of a product after it is released for distribution and/or usage. The 
defect can be related to the product itself or to the product’s label, delivery system, or 
packaging. Examples of PQCs include but are not limited to contamination, label errors, and 
delivery system failures.  
Hansa Biopharma must be made aware of any PQCs as soon as possible on the day of detection. 
Hansa Biopharma will assess the impact of the reported defect and take any necessary 
precautions to ensure the safety of the study subjects and the credibility of the study results. 
PQCs should be reported using the IMP Issue form to ensure that all relevant information is 
captured. 
5.7. 
Concomitant Medication(s) and Therapy 
Maintenance immunosuppression such as tacrolimus, mycophenolate mofetil, cyclosporine A, 
prednisolone and others are prescribed at the discretion of the treating physician or 
investigator according to SOC. These drugs can be used the same day as the infusion of 
imlifidase and be continued during the treatment of AMR. No specific maintenance 
immunosuppressive treatment in addition to what the patient already has is needed within the 
study.  
Other concomitant medication and/or other therapy considered necessary for the patient’s 
welfare may be given at the discretion of the investigator. All concomitant medication and other 
therapy, including i.e., premedication, prophylactic antibiotics, steroids and PE, must be 
recorded on the concomitant medication page in the CRF throughout the study, beginning from 
screening to end of study. Recorded information will include indication, name of drug or 
therapy, dose (if available), route of administration and start and stop date.  
 
 


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6. 
STUDY PROCEDURES 
6.1. 
Study Visits  
For each subject, the duration of the study, including the screening period and the follow-up 
visit will not exceed 7 months.  
AEs and concomitant medication and treatment will be collected throughout the study and are 
not specified for each visit. 
PE-arm: high dose IVIg will be given after the last session of PE. Since the number of sessions 
with PE may be different between subjects and thus not given at a specific visit and will not be 
described below. Samples for DSA and PD will be taken 24 hours after the last session of PE. 
A PD sample will be taken prior to and after (may be the day after) completion of high dose 
IVIg. If there are scheduled PD samples at these time points, no extra samples are needed. 
Rituximab will be given 5 days after completion of the IVIg infusion. 
6.1.1. 
Visit 1 (screening) 
Subjects will be informed about the study, the anticipated benefits and theoretical risks, in 
writing and verbally and sign the inform consent form.  
The screening visit will include to the following: 
• Signing of informed consent form by subject  
• Demographics (age, sex and race) 
• Number of pregnancies (if applicable) 
• Medical/surgical history, including transplantation and previous AMR(s) 
• The 3 latest creatinine values prior to the current AMR will be collected. The 
latest value will be used as baseline value for inclusion 
• Physical examination 
• Height and weight 
• Vital signs (blood pressure, pulse rate, respiratory frequency, and body 
temperature) 
• PCR test for SARS-CoV-2 virus 
• Pregnancy test (serum) 
• ECG 
• Safety laboratory tests (Table 5) 
• Urine sample for measurement of albumin/creatinine ratio 
• DSA sample will be collected  


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• Kidney biopsy will be performed. Kidney biopsy performed within standard of 
care and 5 days prior to screening can be used for inclusion and does not need  
to be repeated at screening. 
• Sample for ADA (IgE) (no need to wait for result before start of treatment) 
• Check of inclusion and exclusion criteria 
• Randomisation to treatment arm 
6.1.2. 
Visit 2 (treatment), Day 1-5 
The following activities and assessments will be performed on day 1, prior to start of treatment 
with imlifidase or PE: 
• Blood pressure, pulse rate and respiratory frequency, and body temperature 
• Baseline samples for DSA, PK, PD, and ADA (IgG) will be collected prior to 
start of treatment 
• P-creatinine  
• Urine sample for measurement of albumin/creatinine ratio 
Imlifidase arm: Methylprednisolone, antihistamine and antibiotic prophylaxis will be 
administered before the imlifidase infusion. 
PE arm: Methylprednisolone and antibiotic prophylaxis will be administered before the first 
treatment.  
Treatment with antibiotics will continue until IgG levels return to acceptable values as judged 
by the investigator. Methylprednisolone will be administered according to treatment schedule, 
see Section 5.3. 
The following activities will be performed after the start of treatment: 
• Blood pressure and pulse rate will be monitored at 2, 6, 24, 48, 72, and 96 hours 
• Respiratory frequency and body temperature will be monitored at 24, 48, 72, 
and 96 hours 
• Safety laboratory tests (Table 5) will be collected at 24, 48, 72, and 96 hours 
• Urine sample for measurement of albumin/creatinine ratio at 24, 48, 72, and 96 
hours. 
• Imlifidase arm: Samples for PK will be collected at 30 minutes and 1 hour 
• Samples for DSA, PK and PD will be collected at 2 and 6 hours 
• Samples for DSA, PK, PD and ADA (IgG) will be collected 24 hours after 
treatment. 
• Samples for DSA, PK and PD will be collected at  48, 72, and 96 hours. The 
72-hour sample must be taken prior to high dose IVIg is given in the imlifidase 
arm   


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Imlifidase arm: High dose IVIg will be given on day 4 (at least 72 hours after the imlifidase 
infusion). Dose may be given over 2 days as judged by the investigator.   
6.1.3. 
Visit 3, Day 6 
The following activities and assessments will be performed: 
• Blood pressure, pulse rate and body temperature will be monitored  
• Safety laboratory tests (Table 5) will be collected 
• Samples for DSA, PK and PD will be collected 
• Urine sample for measurement of albumin/creatinine ratio 
6.1.4. 
Visit 4, Day 8 
The following activities and assessments will be performed: 
• Blood pressure, pulse rate and body temperature will be monitored  
• Safety laboratory tests (Table 5) will be collected 
• Urine sample for measurement of albumin/creatinine ratio 
• Samples for DSA, PK, PD and ADA (IgG) will be collected   
6.1.5. 
Visit 5, Day 11 (+/- 2 days)  
The following activities and assessments will be performed: 
• Blood pressure, pulse rate and body temperature will be monitored  
• Safety laboratory tests (Table 5) will be collected 
• Urine sample for measurement of albumin/creatinine ratio 
• Samples for DSA, PK, PD and ADA (IgG) will be collected 
Imlifidase arm: Rituximab will be given 5 days after the completion of the IVIg infusion   
6.1.6. 
Visit 6, Day 15 (+/- 2 days) 
The following activities and assessments will be performed: 
• Blood pressure, pulse rate and body temperature will be monitored  
• Safety laboratory tests (Table 5) will be collected 
• Urine sample for measurement of albumin/creatinine ratio 
• Samples for DSA, PK, PD and ADA (IgG) will be collected   
6.1.7. 
Visit 7, Day 22 (+/- 3 days) 
The following activities and assessments will be performed: 
• Blood pressure, pulse rate and body temperature will be monitored 
• Safety laboratory tests (Table 5) will be collected 


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• Urine sample for measurement of albumin/creatinine ratio 
• Samples for DSA, PD and ADA (IgG) will be collected 
6.1.8. 
Visit 8, day 29 (+/- 3 days) 
The following activities and assessments will be performed: 
• Blood pressure, pulse rate and body temperature will be monitored  
• Safety laboratory tests (Table 5) will be collected 
• Urine sample for measurement of albumin/creatinine ratio  
• Kidney biopsy will be performed 
• Samples for DSA, PD and ADA (IgG) will be collected 
• Austria only, pregnancy test (serum) 
6.1.9. 
Visit 9, Day 64 (+/- 7 days) and Visit 10, Day 90 (+/- 7 days) 
The following activities and assessments will be performed: 
• Blood pressure, pulse rate and body temperature will be monitored  
• Safety laboratory tests (Table 5) will be collected 
• Urine sample for measurement of albumin/creatinine ratio 
• Samples for DSA, PD and ADA (IgG) will be collected  
• Austria only, pregnancy test (serum) 
6.1.10. 
Visit 11 (follow up, end of study), day 180 (+/- 14 days) 
The following activities and assessments will be performed: 
• Physical examination 
• Blood pressure, pulse rate and body temperature will be monitored 
• Safety laboratory tests (Table 5) will be collected 
• ECG 
• Pregnancy test (serum) 
• Urine sample for measurement of albumin/creatinine ratio 
• Kidney biopsy will be performed 
• Samples for DSA, PD and ADA (IgG) will be collected 














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7. 
STUDY ASSESSMENTS  
When different assessments are scheduled at the same time according to the flow chart, samples 
for DSA, PK and PD should be prioritized to be taken at the exact time point. Exact time points 
must be entered into the eCRF. All sampling, shipping and analysing of laboratory samples will 
be detailed in the laboratory manual. 
7.1. 
Assessments related to endpoints 
Samples for DSAs and pharmacodynamics (PD) will be collected at multiple time points as 
indicated in the study flowcharts (Table 1, Table 2, Table 3 and Table 4). DSAs will be 
identified by each site using HLA profile data from the donor and the patient together with 
Single Antigen Bead (SAB) analysis data obtained at baseline. 
7.1.1. 
Determination of donor specific antibodies  
Samples for determination of DSAs and HLA-antibodies will be analyzed in a single antigen 
bead assay (HLA-SAB) as well as in functional assay e.g. C1q or C3d assay. These assays allow 
determination of the mean fluorescence intensity (MFI) of antibodies in subject serum reacting 
to an array of individual HLA immobilized to beads. Analyses of HLA antibodies, including 
DSA, will be performed centrally. The date and actual time of collection of each sample will 
be recorded in the eCRF. DSAs for each patient will be identified by respective site. DSAs 
collected in standard of care at other timepoints will also be recorded in the eCRF 
DSA taken at screening will also be analysed at the local lab at each site, in addition to centrally, 
for determination of presence of DSA(s) for inclusion.  
7.1.2. 
Pharmacodynamics  
Samples for the determination of IgG levels in serum (PD) qualitative analysis of IgG-
fragments will be taken at the times presented in the study flow chart (Table 1, Table 2, Table 3 
and Table 4). The date and actual time of collection of each sample will be recorded in the 
eCRF. Samples for determination of IgG levels in serum will be analysed with a validated 
electrochemiluminescence based immunoassays using the MSD (Meso Scale Diagnostic) 
technology. Full details of the analytical method used, and the analysis results will be detailed 
in a separate bioanalytical report. IgG-fragments will be analysed by SDS-PAGE and Western 
blot, using antibodies directed to human IgG fragments.  
7.1.3. 
Kidney function as evaluated by eGFR, P-creatinine and albumin/creatinine 
ratio in urine 
Evaluation of kidney function based on P-creatinine analysis and calculation of filtration rate 
(eGFR) using MDRD GFR Equation. Calculation of eGFR will be done directly in the eCRF. 
Albumin/creatinine ratio in urine will be performed at the time points indicated in the study 
flowcharts (Table 1, Table 2, Table 3 and Table 4). Creatinine values collected in standard of 
care at other timepoints will also be recorded in the eCRF. 


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7.1.4. 
Kidney biopsy 
Kidney biopsies collected at screening or within 5 days prior to screening, on day 29 and day 
180 will be assessed according to the Banff 2017 (Haas et al. 2018) criteria, by a local 
pathologist. In addition, a piece of tissue from the kidney biopsy will be evaluated on the basis 
of microarray mRNA measurement using the 
 
 a central diagnostic system. If the initial kidney biopsy is performed  prior to 
screening and signed informed consent, mRNA levels will be evaluated on day 29 and day 180. 
If kidney biopsies are performed at any other time points, if judged necessary by the PI, reports 
from those will be collected and documented in the eCRF. 
7.1.5. 
Pharmacokinetics 
Samples for determination of concentrations of imlifidase in serum will be taken at the times 
presented in the study flow charts (Table 1, Table 2, Table 3 and Table 4). The actual date and 
time of collection of each sample will be recorded in the eCRF. Samples will be analyzed by a 
validated electrochemiluminescence based immunoassay using the MSD technology. Full 
details of the analytical method used, and the analysis results will be detailed in a separate 
bioanalytical report.  
7.1.6. 
Immunogenicity 
Samples for the determination of ADA IgE and ADA IgG levels in serum will be taken at the 
times presented in the study flow charts (Table 1, Table 2, Table 3 and Table 4). The date and 
time of collection of each sample will be recorded in the eCRF. Samples will be analysed for 
anti-imlifidase IgE and IgG, using a customized validated imlifidase ImmunoCAP test. Full 
details of the analytical method used, and the analysis results will be detailed in a separate 
bioanalytical report. 
7.2. 
Safety Assessments related to Endpoints 
7.2.1. 
Safety Laboratory 
The following blood samples will be taken at screening and time points specified in flow charts, 
Table 1, Table 2, Table 3 and Table 4. Other samples may be taken at the investigator’s 
discretion. 
Table 5: 
Safety laboratory tests 
Clinical chemistry* 
Hematology 
Coagulation 
P-IgG  
B-Hemoglobin 
PT (INR) 
P-Alkaline phosphatase (ALP) 
B-Differential analysis of leucocytes 
P-APTT 
P-Alanine aminotransferase (ALT) 
B-Thrombocytes 
 
P-Aspartate aminotransferase (AST) 
 
P-Bilirubin, total  
P-Glucose 


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Table 5: 
Safety laboratory tests 
Clinical chemistry* 
Hematology 
Coagulation 
P-Sodium 
P-CRP 
P-Albumin  
P-Urea 
P-Triglycerides 
P-Creatinine 
P-Creatinine phosphokinase 
* May be taken as serum samples if that is standard procedure at the local lab 
 
7.2.2. 
Physical Examination  
A complete physical examination will be performed at time points indicated in the study flow 
charts (Table 1 and Table 3) and include an assessment of the following: general appearance, 
head and neck, lymph nodes, abdomen, musculo-skeletal, cardiovascular, respiratory and gross 
neurological examination. The physical examination shall be performed by an investigator. 
7.2.3. 
Vital Signs 
Blood pressure, pulse rate, respiratory frequency and body temperature will be measured at 
time points indicated in the study flowchart (Table 1, Table 2, Table 3 and Table 4). 
Systolic and diastolic blood pressure will be measured after the subject has been in supine 
position for at least 5 minutes. All recordings will be performed using validated standard 
equipment. Clinically significant abnormal findings will be reported as AEs. 
7.2.4. 
ECG 
ECG, according to standard procedure at the clinic, will be taken after 10 minutes’-rest at time 
points indicated in the study flowchart (Table 1 and Table 3). Additional ECGs may be 
performed by the Investigator for safety reasons. 
The Investigator or designee will evaluate whether the ECG is normal or abnormal and whether 
it is clinically significant, if abnormal. Clinically significant abnormal findings will be reported 
as AEs.  
7.2.5. 
Adverse Events  
AEs will be recorded during the study period, from obtaining the informed consent to the end 
of study. For further information on definitions and reporting of AEs, see Section 9. 


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7.3. 
Other Assessments 
7.3.1. 
Demographics and Baseline Data 
Information about gender, race, age at inclusion, weight and height will be collected at the 
screening visit for each subject. Measurements should be taken without shoes. Medical history 
will be recorded at screening. 
7.3.2. 
Pregnancy Test 
Serum -hCG will be determined for all female subjects at screening, and at the end of study 
visit, using validated standard methods. 
ONLY FOR AUSTRIA; in accordance with Austrian Medicinal Products Act, women of 
childbearing potential must perform a pregnancy test monthly during the study. At timepoints 
with no scheduled study visit, a pregnancy test in urine may be performed at home and result 
checked at the following visit. 
7.3.3. 
Concomitant medication and other treatments 
Concomitant medication and other treatments (including PE) will be recorded throughout the 
study. 
7.3.4. 
Analysis of SARS-CoV-2 virus 
PCR testing for SARS-CoV-2 virus will be performed at screening. 
 
 


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8. 
BIOLOGICAL SAMPLING PROCEDURES 
8.1. 
Handling, Storage and Destruction of Biological Samples 
Safety samples will be disposed after analyses according to local laboratory practice. 
Biological blood samples collected for central analysis may be stored by the sponsor for a 
maximum of 5 years after completion of the study report.  
Details on handling of biological samples are described in the laboratory manual that will be 
provided to the site prior to inclusion of the first subject.  
8.2. 
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 
subjects while in storage at the centre until shipment and keeps documentation of receipt of 
arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed. 
Hansa Biopharma keeps oversight of the entire life cycle through internal procedures, 
monitoring of study sites and auditing of external laboratory providers. 
8.3. 
Withdrawal of Informed Consent for Biological Samples 
If a subject withdraws consent to the use of biological samples, the samples will be 
disposed/destructed, if not already analysed and documented. 
The principal investigator: 
• Will ensure that subject withdrawal of informed consent is notified immediately to 
Hansa Biopharma. 
• Will ensure that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed/destructed and the action documented. 
• Will ensure the local 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. 
Hansa Biopharma ensures the central 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, Hansa Biopharma will retain 
the results and associated data for regulatory reasons, but these will not be used in any 
subsequent analyses. 


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9. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
9.1. 
Definitions 
9.1.1. 
Adverse event 
An 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 ECGs).  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered as the AE rather than the procedure itself.  
In case of a fatality, the cause of death is considered as the AE, and the death is considered as 
its outcome. 
9.1.2. 
Serious adverse event 
An SAE is an AE or suspected adverse reaction (SAR) that is considered "serious" if, in the 
view of either the investigator or Hansa Biopharma, it results in any of the following outcomes: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
Life-threatening event: An AE or suspected adverse reaction is considered "life-threatening" 
if, in the view of either the investigator or Hansa Biopharma, its occurrence places the subject 
or subject at immediate risk of death. It does not include an AE 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. 


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Hospitalisation: Admittance to an emergency room for observation without being admitted to 
the hospital may be considered to be an AE but is not considered as an SAE. However, 
complications that occur during hospitalization are AEs, and if a complication prolongs 
hospitalization, the event is considered serious. 
9.2. 
Collection and Recording of Adverse Events 
In clinical studies, an AE/SAE can occur at any time after signing of the informed consent until 
the end of the study, including run-in or washout periods, even if no study treatment has been 
administered, e.g., an AE can be related to a procedure in the protocol.  
AEs will therefore be collected on the AE CRF from the time of signing of the informed consent 
and throughout the study including the follow-up period.  
AEs can be collected by: 
• The subject’s response to questions about his/her health (a standard non-leading 
question such as “Have you had any health problems since you were last 
asked/your last visit?”) 
• Symptoms spontaneously reported by the subject 
• Investigations and examinations where the findings are assessed by the 
investigator to be clinically significant changes or abnormalities 
• Other information relating to the subject’s health becoming known to the 
investigator (e.g. hospitalisation) 
9.2.1. 
Variables 
The following variables will be recorded in the CRF for each AE; description of the AE, the 
date and time (if applicable) when the AE started and stopped, severity based on Common 
Terminology Criteria for AEs grading (CTCAE v.4.03) whether the AE is serious or not, 
causality assessment, action taken and outcome.   
9.2.1.1. 
Causality Assessment  
For each reported AE, the investigator will make an assessment of the relationship of the event 
to study procedures and/or IMP using the following criteria. 
• Unrelated:  applicable to an AE that occurs when the subject was not exposed to 
study treatment or another cause is obvious. 
• Unlikely to be related:  applicable to an AE that meets the following criteria 
• Does not follow a reasonable temporal sequence from study drug dosing 
• May readily have been produced by the subject’s clinical state, environmental, 
or toxic factors, or other therapy administered to the subject 
• Possibly related:  applicable to AEs where connection with dosing of study drug 
appears unlikely but cannot be ruled out.  Applicable to AEs where: 


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• It follows a reasonable temporal sequence dosing with study drug 
• It follows a known pattern of response to study drug dosing (based on animal 
studies) 
• Probably related:  applicable to AEs that are considered, with a high degree of 
certainty, to be related to the study drug.  Applicable to AEs where 
• It follows a reasonable temporal sequence study drug dosing 
• It cannot be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy 
• It follows a known pattern of response to study drug dosing (based on animal 
studies). 
• For SAEs, causal relationship will also be assessed for any study procedure.  
9.2.2. 
Adverse Events Based on Signs and Symptoms 
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. 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. 
9.2.3. 
Adverse Events Based on Examinations and Tests 
If lab values are judged as clinically significant and/or a treatment has been given, they will be 
captured as AEs and if SAE criteria are fulfilled they will also be SAEs. 
If vital signs are judged as clinically significant and/or require a treatment, then they will be 
captured as AEs and if SAE criteria are 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 are 
fulfilled they will also be SAEs. 
Wherever possible the reporting investigator uses the clinical, rather than the laboratory term 
(e.g., anaemia versus low haemoglobin value). 
9.2.4. 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the subject’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 subject is known, unless the subject is documented as “lost to follow-up”. All 
SAEs and AEs leading to discontinuation should be followed until the event resolves or 
stabilizes.  


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Reasonable attempts to obtain this information must be made and documented. Hansa 
Biopharma retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
9.2.5. 
Reporting of Serious Adverse Events 
All SAEs have to be reported, whether or not considered related to the investigational product, 
or to the study procedure(s), on a separate SAE form. In the AE form, it will be added that the 
AE is considered serious. SAEs will be recorded from the time of informed consent.  
An assigned contract research organisation (Primevigilance) will be responsible for reporting 
all SAEs to RAs in accordance with ICH GCP and local regulations. Hansa Biopharma or the 
study monitor will be responsible for reporting to IECs/IRBs.  
As soon as the investigator is aware of a potential SAE he/she should contact Primevigilance 
by e-mail and 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, subject number, birth date, 
description of the SAE and a preliminary assessment of causality.  
Contact Information to Primevigilance: 
 
  
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform Hansa 
Biopharma, the monitor, and Primevigilance 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 Hansa Biopharma 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 Hansa Biopharma and Primevigilance. 
9.2.6. 
Reporting of Suspected Unexpected Serious Adverse Reactions  
SUSARs must be reported to RAs. A suspected serious adverse reaction is any SAE for which 
there is a reasonable possibility that the investigational product caused the AE. A serious 
adverse reaction is considered "unexpected" if it is not listed in the reference safety information 
section of the investigator brochure or is not listed at the specificity or severity that has been 
observed. 
SUSARs with an outcome of death or which are life threatening must be reported to the relevant 
RAs within 7 calendar days, all other SUSARs must be submitted within 15 calendar days. The 
SUSAR reporting procedures are detailed in the study Safety Management Plan. This plan is 
an agreement between Hansa Biopharma and Primevigilance. Hansa Biopharma will notify the 
appropriate RA(s) and all participating study investigators of any SUSARs on an expedited 
basis and in accordance with applicable regulations. In addition, Hansa Biopharma is 


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responsible for informing all investigators in all other ongoing studies involving imlifidase 
about all SUSARs.  
It is the responsibility of the site investigator to promptly notify the IEC/IRB and other 
appropriate institutional regulatory bodies of all SUSARs received involving risk to human 
subjects as per their applicable requirements. 
9.3. 
Pregnancy and Pregnancy Outcome 
Pregnancy is an exclusion criterion and a pregnancy test is performed at the screening visit and 
at the last study visit.  
If a subject becomes pregnant during the follow up phase of the study, the subject will continue 
in the study according to study protocol, if possible. A Pregnancy Report Form must be sent by 
the investigator to Primevigilance at the latest within two weeks 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 
subject has completed or discontinued the study. Primevigilance 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 Hansa Biopharma and will be handled as a SAE. 
Spontaneous abortions, congenital abnormalities/birth defects are always considered to be 
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 Hansa Biopharma (or designee).  
 
 


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10. 
STUDY MANAGEMENT 
10.1. Pre-study Activities 
Before the first subject is enrolled into the study, it may be necessary for a representative of 
Hansa Biopharma to visit the investigational study site for a pre-study visit to: 
• Determine the adequacy of the facilities to give Hansa Biopharma information about 
whether the study centre has knowledge, enough time, a sufficient subject pool, and 
sufficient training to manage the study in a good way in terms of subject inclusion, 
subject 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 Hansa 
Biopharma or its representatives.  
Before the first subject is entered into the study, a Hansa Biopharma 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) utilized 
at a site initiation visit. 
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). 
10.2. Monitoring of the Study 
During the study, a Hansa Biopharma 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, ICH GCP, data are 
being accurately and timely recorded in the CRFs, and IMP accountability checks are 
being performed. 
• Perform SDV (a comparison of the data in the CRFs with the subject’s medical 
records at the hospital or practice, and other records relevant to the study) including 
verification of informed consent of participating subjects.  
• If a subject withdraws informed consent to the use of their biological samples; ensure 
this is reported to Hansa Biopharma and biological samples are identified, 
disposed/destructed accordingly, and the action is documented, and reported to the 
subject. 


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Hansa Biopharma and its representatives will be available between visits if the investigator(s) 
or other staff at the centre need information and advice about the study conduct. Details about 
monitoring are specified in a study specific monitoring plan. 
10.3. Source Data  
Source data is defined in ICH GCP. Except for SAEs, which must always be source data 
verified, the extent to which SDV will be carried out must be decided, specified and detailed in 
the Monitoring Plan. For all data recorded, the source document must be defined in a source 
document agreement at each study site. There must only be one source defined at any time for 
any data elements. Source data for randomization will be located in the eCRF. 
10.4. Audit and Inspection 
The investigator will make all the study-related source data and records available at any time 
to Quality Assurance auditor(s) mandated by Hansa Biopharma, or to domestic/foreign 
regulatory inspectors or representatives from IECs/IRBs who may audit/inspect the study. 
The main purposes of an audit or inspection are to assess compliance with the study protocol 
and the principles of ICH GCP and all other relevant regulations. 
The subjects must be informed by the investigator and in the Informed Consent Documents that 
authorised Hansa Biopharma representatives and representatives from RAs and IECs/IRBs may 
wish to inspect their medical records. During audits/inspections the auditors/inspectors may 
copy relevant parts of the medical records. No personal identification apart from the 
screening/randomisation number will appear on these copies. 
The investigator should notify Hansa Biopharma without any delay of any inspection by a RA 
or IEC/IRB. 
10.5. 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 Hansa Biopharma and the principal investigator must be in place before 
any study-related procedures can take place, or subjects be enrolled. 
 
 


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11. 
DATA MANAGEMENT 
11.1. Case Report Form 
An eCRF system provided by a CRO will be used for data capture. The system is validated and 
access at all levels to the system is granted/revoked following Hansa Biopharma and vendor 
procedures, in accordance with regulatory and system requirements. 
After the study database is declared clean and released to the statistician, a final copy of the 
database will be stored at Hansa Biopharma. The investigator will also receive a copy of the 
study site’s final and locked data (including audit trail, meta-data and queries) as write-
protected PDF-files produced by the CRO. The PDF-files will be stored on a CD/DVD and will 
be provided to the investigator before access to the eCRF is revoked. 
11.2. Provider of Data Management 
All data management procedures will be outsourced to a CRO. Activities will be specified in a 
Data Management Plan prepared by the CRO and reviewed and approved by Hansa Biopharma. 
The plan will be issued before data collection begins and will describe all functions, processes 
and specifications for data collection, cleaning and validation. 
11.3. Coding 
For medical coding of AEs, medical/surgical history, including transplantation history, and 
concomitant medication the most recent versions of the Medical Dictionary for Regulatory 
Activities (MedDRA) and WHO Drug will be used at study closure (unless decided otherwise 
by Hansa Biopharma).  
The coding will be outsourced to a CRO. All coding performed will be approved by Hansa 
Biopharma prior to study closure/database lock. 
11.4. Handling of External Data 
Handling of external data received by Hansa Biopharma from vendors will be performed in a 
secure environment and according to a pre-defined Data Transfer Specification. 
 
 


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12. 
STATISTICAL METHODS  
The statistical analyses will be outsourced to a CRO. Prior to clean file, a Statistical Analysis 
Plan (SAP) with details on statistical analysis and data presentation will be established. No 
formal statistical hypothesis testing will be performed in this study.  
Summary tables will in general be presented by treatment and total unless this is not appropriate 
for specific tables. Mean figures will similarly be presented by treatment. 
Summary statistics for continuous variables will in general be presented as n, arithmetic mean, 
standard deviation, median, minimum and maximum. When continuous data are recorded at 
different time points absolute values at each time point and, if relevant, changes from baseline 
may be presented.  
For categorical data frequencies and percentages will be presented. 
Due to the exploratory nature of the study, missing data will remain missing and no 
adjustment will be implemented. 
12.1. Analysis Sets 
All enrolled and treated subjects will qualify for the Full Analysis Set (FAS), the Per Protocol 
Analysis Set (PPS), the Safety Analysis Set and the Pharmacokinetic Analysis Set (PKS). The 
decision to exclude subjects from any of the analysis sets will be taken by the clinical study 
team before database lock and documented in the database lock minutes. Further details will be 
specified in the SAP.  
12.1.1. 
Full Analysis Set  
The FAS will include all treated subjects for whom relevant post baseline efficacy and safety 
data have been collected. 
12.1.2. 
Per Protocol Analysis Set 
The PPS will include all subjects in the FAS who are not excluded because of important non-
compliance that will affect the efficacy data such as admission criteria, protocol deviations or 
other non-compliance.  
12.1.3. 
Safety Analysis Set 
The safety analysis set comprises all treated subjects.  
12.1.4. 
Pharmacokinetic Analysis Set 
The PKS will be defined by the PK analyst taking admission criteria, protocol deviations and 
other non-compliance into consideration. 


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12.2. Subject characteristics 
The demographics and other baseline characteristics will be summarised and listed using 
descriptive techniques.  
12.2.1. 
Subject disposition 
The subject disposition will present number of subjects as enrolled, completed, withdrawn 
overall and by reason for withdrawal and finally by each of the analysis set.  
12.2.2. 
Demographics and Other Baseline Characteristics 
The subject’s demographics and other baseline characteristics will be summarised and listed. 
12.2.3. 
Recent and Concomitant Medication 
Recent and concomitant medication will be summarised by anatomical therapeutic chemical 
(ATC) code. In addition, listings with ATC code and generic drug name will be prepared.  
12.2.4. 
Exposure and Compliance 
Exposure will be tabulated and listed.  
12.3. Statistical Analysis of Endpoints 
12.3.1. 
Primary efficacy endpoint 
The primary endpoint is the maximum reduction in DSA (MFI sum for relevant DSAs) at any 
time point during the 5 days  following the start of treatment. A subject will have at least one 
DSA and a DSA is considered relevant if it is at least 1000 MFI pre-dose. The reduction is 
derived as follows: 
1) Calculate the reduction (%) in sum of DSAs as 100*(DSA0 – DSAt)/DSA0 for each 
subject and time point. Only DSAs with a pre-dose MFI of 1000 or more will be 
included in the calculations  
2) Find the time point with maximum reduction within 5 days for each subject 
3) The maximum reduction per subject will give a single value as the primary endpoint 
for the subject 
Where DSAt is the analysis result in total MFI for relevant DSAs at time t. 
Due to the exploratory nature of this study, no formal hypothesis will be tested. The difference 
in reduction between the two treatments will be presented with 95% CI. Each subject will be 
given equal weight in the calculation of the treatment difference irrespective of number of DSAs 
for the subjects. 
A summary table showing the proportion of reduction of DSAs calculated per subject will also 
be presented.  


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12.3.2. 
Reduction of total serum IgG 
The total serum IgG is measured by the PD assay. A binary endpoint is defined as ‘Yes’ if the 
subject minimum IgG value at any timepoint during the 5 days following the start of treatment 
is less than 5% of baseline. The proportion of subjects with a positive reduction will be 
summarized in a table. The difference in proportion between treatments will be presented with 
a 95% CI. 
12.3.3. 
Detectable intact IgG on a Western blot 
An endpoint is defined as reached for a subject if no detectable intact IgG is found by the SDS-
PAGE/Western blot assay at any time point over 180 days following treatment. The proportion 
of subjects who reached the endpoint will be summarized in a table. The difference in 
proportion between treatments will be presented with a 95% CI. 
12.3.4. 
Donor specific antibodies (DSA) 
DSAs will be measured using HLA-SAB assay and a functional assay e.g. C1q or C3d assay. 
MFI levels will be listed per subject and time point. Spaghetti plots will show the DSA level 
versus time for each subject. A mean plot by treatment and time point will be presented. 
Finally, a listing with all DSA by subject and time point will be prepared.  
In addition, subject listings of MFI values for all HLA will be presented. 
12.3.5. 
Kidney function  
The kidney function will be evaluated by the parameters eGFR, P-creatinine and 
albumin/creatinine ratio in urine and biopsies. The laboratory parameters will be summarised 
as part of the safety data tabulation. Derivation of eGFR will be detailed in the SAP. 
Kidney biopsies will be assessed according to the Banff (2017) criteria pre-dose and at day 29 
and 180. The biopsy data will be summarised by treatment and listed.  In addition, 
 
 
 will be summarised. 
12.3.6. 
Signs of transplant glomerulopathy 180 days post treatment 
Possible transplant glomerulopathy 180 days post treatment will be tabulated by treatment and 
presented by listings. 
12.3.7. 
Number of sessions with PE for 180 days 
The number of PE sessions for 180 days will be summarized by treatment and listed. 
12.3.8. 
Number of patients with resolution of AMR at day 180 
The number of patients with resolution of AMR at day 180 will be tabulated by treatment and 
listed. 


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12.3.9. 
The number of patients with graft failure at day 180 
The number of patients with graft failure at day 180 will be summarized by treatment and listed. 
12.3.10. 
Patient survival at day 180 
The patient survival on day 180 will be tabulated and listed. 
12.3.11. 
Pharmacokinetic 
Imlifidase concentrations will be summarised by time point for the imlifidase treatment group 
and presented as spaghetti plots and mean plots. 
PK variables (Cmax, Tmax, t½, AUC, CL, and V) are calculated and will be summarized using n, 
arithmetic and geometric mean, standard deviation, coefficient of variation (CV), minimum, 
median, and maximum. For the terminal half life, the harmonic mean will also be presented. 
12.3.12. 
Pharmacodynamics 
Pharmacodynamics data (total serum IgG) will be summarized by time point. In addition, data 
on total serum IgG will be presented by mean and spaghetti plots. Finally, data will be listed. 
SDS PAGE and Western blot results will be presented by time point. 
12.3.13. 
Analysis of Adverse Events 
AEs will be coded according to the latest version of the MedDRA. All data will be listed by 
patient. Only treatment emergent AEs will be presented in summary tables. Separate data listing 
will be provided for AEs that are defined as pre-treatment or post-treatment emergent. 
12.3.13.1. Pre-treatment Adverse Events 
An AE that starts after the subject signed the Informed Consent Form and prior to the first dose 
of IMP. 
12.3.13.2. Treatment Emergent Adverse Events 
A treatment emergent adverse event is any adverse event occurring after the administration of 
the IMP and within the time of residual drug effect, or a pre-treatment adverse event or 
pre-existing medical condition that worsens in intensity after administration of the IMP and 
within the time of residual drug effect. 
The time of residual drug effect is the estimated period after the administration of the IMP, 
where the effect of the product is still considered to be present based on pharmacokinetic, 
pharmacodynamic or other substance characteristics. The residual drug effect is generally 
accepted to be 5 times the terminal half-life. The terminal half-life of imlifidase is expected to 
be within the range of approx. 100 hours, i.e. in this study the residual drug effect is likely to 
be well within the 29 Day assessments. All AEs occurring up to Day 29 are regarded as 
treatment emergent. 


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12.3.13.3. Post-treatment Emergent Adverse Events 
A post-treatment emergent adverse event is any adverse event occurring after the time of 
residual drug effect of the IMP, i.e. between the end of the treatment period, visit 8, and the 
follow-up visit 11. 
12.3.14. 
Analysis of Other Safety Variables 
The clinical safety laboratory tests, vital signs, and ECG parameters will be summarised for 
both absolute values and changes from baseline. Values outside the reference ranges will be 
flagged in listings. 
12.3.15. 
Immunogenicity 
Anti-imlifidase antibody data will be summarized by time point and presented using listings. 
12.4. Determination of Sample Size 
Due to the exploratory nature of the study, there is no formal statistical hypothesis. The 
difference between treatments for the reduction of DSA will however be presented with 95% 
confidence interval. A sample size of 20 imlifidase and 10 PE subjects is proposed.  
In two previous imlifidase studies, 14-HMedIdeS-04 and 15-HMedIdeS-06, the IgG reduction 
for 5 days was 90% and 93% respectively. The corresponding standard deviations are 6% and 
4% respectively. Assuming a similar variability in the PE treatment arm, the expected width of 
the 95% CI for the difference in DSA reduction will be around 8% point. This supports that 
20+10 patients are appropriate. 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. 
 
 


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13. 
CHANGES IN STUDY CONDUCT OR PLANNED ANALYSES 
Any changes and deviations to plans described in the protocol and in the SAP must be 
documented. 
13.1. Protocol Amendment(s) 
Any change to this protocol will be documented in a protocol amendment, issued by Hansa 
Biopharma, and agreed upon by the investigator and Hansa Biopharma prior to its 
implementation. Protocol Amendments and documents updated as a result of the Protocol 
Amendment must not be implemented until all approvals (IEC/IRB and RAs, if applicable) 
have been obtained. 
Changes to the protocol to eliminate immediate hazard(s) to study subjects may be implemented 
prior to IEC(s)/IRB(s) and RA approval. 
13.2. Protocol Deviations 
Under working conditions, deviations from the protocol may occur. If deviations from the 
protocol occur, the investigator must inform the monitor, and the implications of the deviation 
must be reviewed, discussed and documented on the Protocol Deviation Form. Deviation 
reports and supporting documentation will be kept in the investigator site file and the study 
master file. 
13.3. Statistical Analysis Plan 
Any changes to the SAP will be described in the Clinical Study Report and/or in the Statistical 
Report. 
13.4. Premature Termination or Suspension of the Study 
If the study is prematurely terminated or suspended for any reason, the investigator/institution 
should promptly inform the subjects and should assure appropriate therapy and follow-up. 
If the investigator terminates or suspends a study without prior agreement of Hansa Biopharma, 
the investigator should inform the Institution where applicable. The investigator/institution 
should promptly inform Hansa Biopharma and should provide Hansa Biopharma with a detailed 
written explanation of the termination or suspension. If Hansa Biopharma terminates or 
suspends a Study, the investigator should promptly inform the Institution where applicable. In 
both cases Hansa Biopharma will promptly inform the RA and IEC/IRB and provide them with 
a detailed written explanation of the termination or suspension. 
If the RA or IEC/IRB terminates or suspends its approval/favourable opinion of a study, Hansa 
Biopharma should inform the investigators and institutions (where applicable) and provide 
them with a detailed written explanation of the termination or suspension. 


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14. 
REPORTING AND PUBLICATION 
14.1. Clinical Study Report 
The results from this study will be reported in a clinical study report (CSR) within one year 
after end of study (see section 4.6). This will be prepared by Hansa Biopharma and submitted 
for comments and signature to the coordinating (signatory) investigator(s). 
14.2. Confidentiality and Data Ownership 
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 Biopharma. The investigator and any 
other persons involved in the study will protect the confidentiality of the proprietary 
information belonging to Hansa Biopharma. 
14.3. Publications  
14.3.1. 
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 Biopharma.  
Any external CRO or laboratory involved in the conduct of this study has no publication rights 
regarding the study. 
14.4. Public disclosure 
The study will be registered in a public clinical trials registry i.e. the U.S. National Institutes of 
Health register ClinicalTrials.gov and EU Clinical Trials Register if the study is conducted in 
Europe. 
 
 


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15. 
ETHICAL AND REGULATORY ASPECTS 
15.1. Ethical Conduct of the Study 
This study will be conducted in accordance with ICH GCP, the approved protocol and 
applicable regulatory requirements.  
The responsibilities of Hansa Biopharma, the monitor and the investigator are defined in the 
ICH GCP guideline and applicable regulatory requirements in the country where the study takes 
place.   
15.2. Liabilities and Insurance 
Hansa Biopharma is, as sponsor, responsible for ensuring appropriate general/product liability 
insurance and, as required in accordance with applicable laws and regulations, country-specific 
liability insurance coverage for claims made by a study subject for injury arising from the 
subject’s participation in the study. 
15.3. Independent Ethics Committee(s) and Institutional Review Boards  
All ethical and regulatory approvals must be available before a subject is exposed to any study-
related procedure, including screening tests for eligibility. 
According to applicable regulatory requirements Hansa Biopharma will: 
• obtain approval from or notify the relevant IEC(s)/IRB(s) of the protocol, any 
amendments, the Subject Information Sheet/Informed Consent Form and any 
advertisements etc. 
• send periodic updates to the IEC(s)/IRB(s) if applicable 
• provide investigator(s) with an accurate and complete record of all submissions to the 
local IEC/IRB. The copies should be filed in the investigator file. 
Hansa Biopharma will keep an updated list of submission and approval dates of all documents 
submitted to IEC(s)/IRB(s). 
15.4. Regulatory Authority(ies) 
According to applicable regulatory requirements Hansa Biopharma will send required 
documents to the RAs. Hansa Biopharma will keep an updated list of submission and approval 
dates of all documents submitted to RAs. 
Before initiating the clinical study, the Sponsor (or the sponsor and the investigator, if required 
by the applicable regulatory requirement(s)) should submit any required application(s) to the 
appropriate authority(ies) for review, acceptance, and/or permission (as required by the 
applicable regulatory requirement(s)) to begin the study. Any notification/submission should 
be dated and contain sufficient information to identify the protocol. 


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15.5. Subject Information and Informed Consent 
Before any study-related activities and in agreement with applicable regulatory requirements, 
the investigator must give the subject oral and written information about the study in a form 
that the subject can understand. Investigator must ensure that the subject is fully informed about 
the aims, procedures, potential risks, any discomforts and expected benefits of the Study. Before 
consenting, the subject must be left with ample time to consider and to pose questions. 
It must be emphasised that participation is voluntary and that the subject has the right to 
withdraw from the Study at any time without prejudice. 
The original, signed Informed Consent Forms must be kept in the Investigator File.  
The subject will receive a copy of the Subject Information and his/her signed Informed Consent 
Form. 
If new information becomes available that may be relevant to the study subject’s willingness to 
continue participation in the study, a new Subject Information and Informed Consent Form will 
be forwarded to the IEC(s)/IRB(s) (and RAs, if required). The study subjects will be informed 
about this new information and re-consent will be obtained. 
15.6. Subject Participation Card 
The subject will be provided with a subject participation card bearing the following 
information: 
• That he/she is participating in a clinical study (incl. study code) 
• That he/she has been treated with the study drug 
• The name and phone number of the investigator  
The subject will be asked to keep the subject participation card in their possession at all times 
during the study and to return it at the last study visit, if applicable. 
Include statement whether each subject’s primary care physician will be notified of their 
participation in the study by the investigator, if the subject agrees. 
15.7. Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
Hansa Biopharma and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of Hansa Biopharma. 


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The study monitor or other authorized representatives of Hansa Biopharma may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this 
study. The clinical study site will permit access to such records. 
16. 
ARCHIVING 
16.1. Retention of Clinical Study Site Documentation 
The investigator is responsible for maintaining all the 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 25 years 
[or longer if so required by local law] after the completion or discontinuation of the study, if 
no further instructions are given by Hansa Biopharma. 
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and 
anonymous CRF/eCRF data for Hansa Biopharma. The investigator must arrange for the 
retention of this Subject Identification Log and signed Informed Consent Documents for at least 
25 years [or longer if so required by local law] after the completion or discontinuation of the 
study. 
No study site document may be destroyed without prior written agreement between the 
investigator and Hansa Biopharma. Should the investigator elect to assign the study documents 
to another party, or move them to another location, Hansa Biopharma must be notified. If the 
investigator retires and the documents can no longer be archived by the site, Hansa Biopharma 
can arrange having the Investigator File archived at an external archive. 
16.2. Study Master File 
Hansa Biopharma will archive the Study Master File in accordance with ICH GCP and 
applicable regulatory requirements. 


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17. 
REFERENCES 
Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and 
management of antibody-mediated rejection: current status and novel approaches. Am 
J Transplant. 2014;14:255-71. 
Gloor J, Cosio F, Lager DJ, Stegall MD. The spectrum of antibody-mediated renal allograft 
injury: implications for treatment. Am J Transplant. 2008;8:1367-73. 
Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, et al. The Banff 2017 
Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated 
rejection, antibody-mediated rejection, and prospects for integrative endpoints for 
next-generation clinical trials. Am J Transplant. 2018;18:293-307. 
Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre 
syndrome. Cochrane Database Syst Rev. 2014:CD002063. 
Jarnum S, Runstrom A, Bockermann R, Winstedt L, Crispin M, Kjellman C. Enzymatic 
Inactivation of Endogenous IgG by IdeS Enhances Therapeutic Antibody Efficacy. 
Mol Cancer Ther. 2017;16:1887-97. 
Jordan SC, Reinsmoen N, Peng A, Lai CH, Cao K, Villicana R, et al. Advances in diagnosing 
and managing antibody-mediated rejection. Pediatr Nephrol. 2010;25:2035-45. 
Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, et al. Preexisting donor-
specific HLA antibodies predict outcome in kidney transplantation. J Am Soc 
Nephrol. 2010;21:1398-406. 
Loupy A, Hill GS, Jordan SC. The impact of donor-specific anti-HLA antibodies on late 
kidney allograft failure. Nat Rev Nephrol. 2012;8:348-57. 
OPTN. Organ Procurement and Transplantation Network. Scientific Registry of Transplant 
Recipients. 2012 Annual Data Report. (OPTN). optn.transplant.hrsa.gov/ 2012. 
Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K. Comparison of survival probabilities 
for dialysis patients vs cadaveric renal transplant recipients. JAMA. 1993;270:1339-
43. 
Reinsmoen NL, Lai CH, Vo A, Cao K, Ong G, Naim M, et al. Acceptable donor-specific 
antibody levels allowing for successful deceased and living donor kidney 
transplantation after desensitization therapy. Transplantation. 2008;86:820-5. 
Sellares J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, et al. Understanding the 
causes of kidney transplant failure: the dominant role of antibody-mediated rejection 
and nonadherence. Am J Transplant. 2012;12:388-99. 
Winstedt L, Jarnum S, Nordahl EA, Olsson A, Runstrom A, Bockermann R, et al. Complete 
removal of extracellular IgG antibodies in a randomized dose-escalation Phase I study 
with the bacterial enzyme IdeS - a novel therapeutic opportunity. PLoS One. 
2015;10:e0132011. 
 
 
 


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18. 
APPENDIX 1 
18.1. Protocol Amendment 03