Clinical trial NCT05049850
Conditions: Kidney Transplantation in Highly Sensitized Patients
Keywords: Highly sensitized Kidney transplantation Renal transplantation
Sponsor: Hansa Biopharma AB
Start date: 2022-12-16; Completion date: 2024-05-08
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess whether imlifidase in combination with bortezomib, belatacept, rituximab and IVIg can suppress donor specific antibodies (DSA) and the occurrence of antibody-mediated rejection (AMR) in highly sensitized patients with chronic kidney disease with a positive crossmatch towards their living donor during a period of 3 months from transplantation.

Detailed description:
Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG. Clinical studies with imlifidase have demonstrated that the treatment enables transplantation in patients otherwise highly unlikely to be transplanted, by converting a positive crossmatch to a negative.

However, as with other desensitization methods, DSA tend to reappear within weeks after treatment and transplantation, which may cause AMR and increased risk of graft loss. In this study, treatment with imlifidase in combination with approved drugs that prevent or suppress DSA rebound by targeting antibody-producing plasma-cells and their B-cell precursors is suggested. These drugs include (i) bortezomib, a proteasome inhibitor which has activity against mature plasma cells, the source of DSA, (ii) belatacept, a fusion protein which is crucial in blocking T-cell co-stimulation and which is effective in reducing de novo DSA generation in humans, (iii) rituximab, an anti-CD20 monoclonal antibody that targets B-cells and which is an immunomodulatory agent, and (iv) intravenous immunoglobulin (IVIg) which is commonly used in desensitization regimens and for the treatment of AMR.

After being informed about the study and potential risks, all patients giving written informed consent will undergo a 2-week screening period to determine eligibility for study entry. Patients who meet the eligibility requirements will then start treatment with belatacept and bortezomib about 3 weeks prior to the imlifidase infusion and transplantation. Rituximab will be initiated 8 days after transplantation and IVIg 10 days after transplantation. Induction and maintenance immunosuppression will also be administered. The patients will be hospitalized for approximately 2 weeks following transplantation and after that 9 follow-up visits to the clinic will take place up to 6 months after transplantation.

Arms: arm 1: Imlifidase is administered intravenously as one dose of 0.25 mg/kg over 15 minutes within the 24-hour period prior to transplantation. (A second dose may be given if the crossmatch test at 4 hours after the first dose remains positive.)
Interventions: intervention 1: Imlifidase
Intervention descriptions: intervention 1: Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG.

Protocol documents:
Prot_SAP_001.pdf: 
Hansa Biopharma AB 
Date: 23Jun2022 
Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
Confidential 
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Clinical Trial Protocol 
An open label, phase II study to investigate DSA rebound in patients with a 
positive crossmatch, made transplantable with imlifidase  
Clinical Trial Protocol No.: 
NCT Number:
Protocol version and date: 
Revision history: 
Investigational Medicinal Product: 
Phase: 
Proposed indication: 
Principal investigator: 
EudraCT Number: 
IND Number: 
Name and Address of Sponsor: 
18-HMedIdeS-16
05049850
v. 4.0, 23JUN2022
N/A
Imlifidase
2
Kidney transplantation in highly sensitized 
patients
Vasishta Tatapudi
N/A
128074
Hansa Biopharma AB
P.O. Box 785
SE-220 07 Lund
Sweden
This confidential document is the property of Hansa Biopharma 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: 23Jun2022 
Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
 
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Signature page 
This clinical trial protocol, identified by the version and date above, is approved by: 
 
Senior Medical Director, Hansa Biopharma AB 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
 
 
 
 
 
 
 
 
Signatory Principal Investigator 
 
Vasishta Tatapudi, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
 
 
 
 
 


Hansa Biopharma AB 
Date: 23Jun2022 
Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
 
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Investigators and Clinical Trial Administrative Structure 
Principal Investigator 
Name and title: 
Address: 
 
 
 
 
Vasishta Tatapudi, MD 
NYU Langone Health,  
550 First Avenue 
New York, NY 10016 
 
  
Sponsor’s Medical 
Expert 
Name and title: 
Address: 
 
 
 
 
 
 
Hansa Biopharma, 
Scheelevägen 22,  
P.O. BOX 785, 
SE-220 07, Lund, Sweden 
  
  
 
Contact details for all investigators responsible for conducting the trial, medically qualified 
physicians responsible for all trial site related medical decisions (if other than the 
investigators), clinical laboratories, other medical and/or technical departments and/or 
institutions involved in the trial, monitors, and relevant sponsor representatives are supplied in 
a trial contact list filed in the investigator site file/trial master file. 
 
 
 


Hansa Biopharma AB 
Date: 23Jun2022 
Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
 
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Synopsis 
Name of Sponsor/Company 
Hansa Biopharma AB (hereafter referred to as Hansa Biopharma) 
Title of the trial 
An open label, phase II study to investigate DSA rebound in patients with a positive 
crossmatch, made transplantable with imlifidase  
Co-ordinating Investigator 
Principal Investigator: Dr. Vasishta Tatapudi 
Trial Site 
One site, NYU Langone Health Transplant Institute 
Planned trial period 
First subject first visit (FSFV) Q3 2022 
Last subject last visit (LSLV) Q3 2024 
Clinical Phase  
2 
Background and Scientific Justification for Conducting the Trial 
Renal transplantation is the preferred treatment for patients with end-stage renal disease since 
it increases patient survival and quality of life and results in substantial savings in health care 
costs compared to dialysis. However, sensitization to anti-human leukocyte antigen is a 
major and often insurmountable barrier to successful kidney transplantation. Approximately 
one third of patients in the US waiting for kidney transplantation are sensitized to potential 
donor tissues, i.e. they have antibodies to human leukocyte antigen (HLA) (Iyer et al. 2013). 
Preformed donor specific antibodies (DSA) typically arise due to immunization- during 
earlier pregnancies, blood transfusions, previous transplants or infections (Stites et al. 2015; 
Thomas et al. 2015).  A patient with significant HLA antibodies to a potential donor will 
show a strong positive crossmatch to that donor and that is a contraindication to 
transplantation since it will cause immediate damage to the graft. As many as 13% of the US 
patients on the transplantation waitlist are highly sensitized, i.e. have a calculated panel 
reactive antibody (cPRA) ≥ 80% of which 7% with a cPRA 98-100% (Hart et al. 2019).  
For patients with a wide range of HLA antibodies it can be extremely difficult to find a 
compatible donor even after the implementation of the new kidney allocation system (KAS) 
in 2014. The modifications to the KAS have helped broaden access to organ transplantation 
for highly sensitized patients, however, despite the initial significant improvement in access, 
there remains a pool of highly sensitized patients with low likelihood of ever receiving an 
organ offer (Stewart et al. 2016; Schinstock et al. 2016; Stegall 2019; Schinstock et al. 2017). 
Further, an analysis of the United Network for Organ Sharing (UNOS) data 2010-2016, 
showed that for patients with cPRA ≥99.5%, the transplant rates decrease with increasing 
levels of sensitization. Recent data showed that patients with cPRA ≥99.9% constitute the 


Hansa Biopharma AB 
Date: 23Jun2022 
Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
 
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largest group in the 100% cPRA cohort (99.5-100%) and continue to have prolonged waiting 
time and the lowest rate of deceased donor (DD) transplantation (Jackson et al. 2019; 
Schinstock et al. 2019). For these highly sensitized candidates with an incompatible living 
donor, Kidney Paired Donation (KPD) program can improve the prospects of finding a 
compatible living donor but the probability of finding a match through KPD programs is 
insignificant.  
The general benefit of transplantation even with an incompatible kidney was investigated in a 
study comparing patients receiving an incompatible living donor kidney with patients staying 
on the waiting list with or without later transplantation (Orandi et al. 2016). Prior to 
transplantation the patients received perioperative desensitization therapy according to a 
protocol of the site’s own choice. The results demonstrated that receipt of a kidney transplant 
from an incompatible live donor was associated with a significant survival benefit as 
compared with the matched controls staying on the waiting list throughout the studied period, 
8 years. 
Data demonstrate that successful desensitization followed by transplantation of patients with 
DSA is clearly associated with short term and long term survival benefits compared to 
staying on dialysis (Montgomery et al. 2011; Orandi et al. 2014; Orandi et al. 2016; Vo et al. 
2013), despite a higher reported incidence of active antibody mediated rejection (AMR) 
(20% to 61%) compared to non-sensitized patients where AMR is very rare (Lefaucheur et 
al. 2008; Gloor et al. 2010; Vo, Wechsler, et al. 2008; Haririan et al. 2009; Marfo et al. 2011; 
Thielke et al. 2009; Riella et al. 2014). In addition, the patient’s quality of life is dramatically 
improved and there is substantial cost effectiveness associated with desensitization and 
transplantation compared to dialysis (Vo et al. 2013). 
There are no approved treatments for desensitization nor is there a standardized protocol for 
desensitization in the US. However, a few institutional protocols have been developed and 
tested in clinical settings (Iyer et al. 2013). All these protocols use techniques to block out 
antibodies through high-dose intravenous immunoglobulin (IVIg) or remove them by 
plasmapheresis/ immunoadsorption (IA), often combined with low-dose IVIg (Montgomery 
et al. 2000; Jordan et al. 2004). Some protocols use anti-CD20 antibodies i.e. rituximab to 
inhibit the synthesis of IgG (Vo, Lukovsky, et al. 2008). There have been no randomized 
controlled trials of these protocols. In addition, desensitization protocols are usually 
combined with induction therapy using steroids and antithymocyteglobulin (ATG) and/or 
anti-IL2R antibody (e.g. basiliximab) to prevent acute cell mediated rejections in high-risk 
patients.  
Imlifidase is an immunoglobulin G-degrading enzyme of Streptococcus pyogenes that is 
highly specific for IgG. The cleavage of IgG generates one F(ab’)2- and one homodimeric 
Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG 
 
(Vincents et al. 2004; von Pawel-Rammingen et al. 2002; Wenig et al. 2004). Clinical studies 
with imlifidase have demonstrated that the treatment enables transplantation in patients 
otherwise highly unlikely to be transplanted, by converting a positive crossmatch to a 
negative (Jordan et al. 2017; Lorant et al. 2018; Jordan et al. 2020; Lonze 2021; Schinstock 
2020). The treatment is highly efficacious as demonstrated by 100% crossmatch conversion 


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Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
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in patients treated.  Imlifidase-mediated IgG degradation constitutes a novel therapeutic 
principle for the treatment of IgG-driven human diseases. A treatment regimen allowing 
transplantation of highly sensitized patients with deceased or living donor organs, while 
keeping the occurrence of AMR at a low level, would provide an important improvement in 
the treatment of these patients.  
Preclinical studies in non-human primate models of transplantation in highly sensitized 
recipients suggest that combining co-stimulation blockade by belatacept with plasma-cell 
depleting therapy by bortezomib may durably suppress DSA and decrease the risk of AMR 
(Burghuber et al. 2019). In this trial, treatment with drugs that prevent or suppress DSA 
rebound by targeting antibody-producing plasma-cells and their B-cell precursors is 
suggested. Bortezomib is a proteasome inhibitor which has activity against mature plasma 
cells, the source of DSA. Belatacept is a fusion protein composed of the Fc-fragment of a 
human IgG1 linked to the extracellular domain of CTLA-4, which is a molecule crucial in 
blocking T-cell co-stimulation, and was shown to be effective in reducing de novo DSA 
generation in humans (Sethi et al. 2017; Vincenti et al. 2016). Rituximab, an anti-CD20 
monoclonal antibody that targets B-cells and immunomodulatory agent IVIg are commonly 
used in desensitization regimens and for the treatment of AMR (Montgomery et al. 2011; 
Orandi et al. 2014; Orandi et al. 2016; Vo et al. 2013).  
The trial will investigate whether the suggested treatment regimen can suppress DSA 
recurrence and the occurrence of AMR in highly sensitized patients with a positive 
crossmatch towards their living donor. These patients have a high unmet medical need in 
transplantation today.  
Objectives 
Primary objective 
• To evaluate DSA rebound during the first 3 months after transplantation 
 
Secondary objectives 
• To evaluate AMR frequency up to 6 months after transplantation 
• To evaluate DSA rebound up to 6 months after transplantation  
• To evaluate crossmatch conversion within 24 hours after imlifidase treatment 
• To evaluate DSA and complement binding (C1q) DSA MFI levels  
• To evaluate graft and patient survival  
• To evaluate safety parameters 
• To evaluate kidney function  
• To evaluate pharmacokinetic (PK) profile of imlifidase 
• To evaluate pharmacodynamic (PD) profile of imlifidase   


Hansa Biopharma AB 
Date: 23Jun2022 
Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
 
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• To evaluate immunogenicity profile of imlifidase (ADA) 
• To evaluate health related quality of life (HRQoL) specifically patients’ life 
participation 
 
Exploratory Objective 
 
 
 
 
 
 
  
 
  
 
 
  
Endpoints 
Primary endpoint 
• Proportion of patients with DSA rebound during the first 3 months after 
transplantation. 
 
Secondary endpoints 
• Proportion of patients with kidney biopsy proven AMR (according to Banff 2019) up 
to 6 months after transplantation (based on for cause biopsies and protocol biopsies) 
• Proportion of patient with DSA rebound up to 6 months after transplantation 
• Proportion of patients with negative flow crossmatch test within 24 hours after 
imlifidase treatment 
• Levels of DSA and complement binding(C1q) DSA MFI before imlifidase treatment 
and up to 6 months after transplantation 
• Graft survival at 6 months after transplantation 
• Patient survival at 6 months after transplantation 
• Safety parameters (AEs, clinical laboratory tests, vital signs and ECG) up to 6 months 
after transplantation  
• Kidney function assessed by creatinine, estimated glomerular filtration rate (eGFR), 
and protein/creatinine ratio in urine up to 6 months after transplantation 
• Imlifidase pharmacokinetics up to 14 days after imlifidase  
• Imlifidase pharmacodynamics up to 10 days after imlifidase  


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Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
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• Anti-drug antibodies (ADA) levels up to 6 months after imlifidase 
• Change in patient-reported life participation, as measured by the PROMIS Social 
Health domain “Ability to participate in social roles & activities, PROMIS-SF-8a”, 
from baseline to 6 months after transplantation 
 
Exploratory endpoints 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
Methodology 
This is a phase 2, single center, open label, single arm, exploratory trial. The trial will 
investigate the frequency of DSA rebound and AMR in highly sensitized kidney patients 
made transplantable with imlifidase. The primary objective is to investigate DSA rebound 
during the first 3 months after transplantation.  
The definition of rebound is the following: 
1. When the positive FCXM at screening is due to low titer, non-complement binding 
DSAs, rebound is measured as: 
a. Immuno-dominant DSA: a post-transplant MFI value that is ≥50% the pre-
imlifidase value 
OR 
b. Total DSAs: a post-transplant serum where ≥50% of the DSA prior to 
imlifidase treatment have an MFI value that is ≥50% of the pre-transplant 
MFI value AND the sum MFI must be ≥50% of the pre-transplant value  


Hansa Biopharma AB 
Date: 23Jun2022 
Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
 
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2. When the positive FCXM at screening is due to high titer, complement binding 
DSAs, rebound is measured as:  
a. Immuno-dominant DSA: a post-transplant MFI value at 1:16 dilution that is 
≥8000 MFI 
OR 
b. Total DSAs: a post-transplant 1:16 diluted serum where ≥50% of the DSA 
prior to imlifidase treatment have an MFI value that is ≥50% of the pre-
transplant MFI value AND the sum MFI must be ≥8000 
 
An HLA antibody is considered a DSA when the MFI value is at least 3000 in the serum 
analyzed prior to imlifidase treatment. Either a or b must be fulfilled for the increase in DSA 
to be defined as rebound.  
12 patients with a living donor will be included in the trial. All patients will receive high-
dose methylprednisolone as induction therapy starting on the day of transplantation and 
continued for 3 days. It will then be tapered over several days and, when applicable, 
converted to oral prednisone. Induction therapy with rATG will start 
 and be given 
on at least 3 days. Treatments to prevent rejection will be rituximab administered 
 
and high dose IVIg administered
 The treatments with belatacept and bortezomib 
will start about 3 weeks prior to transplantation. Three doses of belatacept will be 
administered at days -21, -16 and -7 and for bortezomib 4 doses (1 cycle) will be 
administered. Belatacept administration is continued after transplantation with 6 additional 
doses starting on day 6 and ending at week 13. Bortezomib administration is continued with 
2 more cycles, starting the second cycle on day 2 and the third 3 weeks later. An ECG and 
echocardiogram will be performed after each bortezomib cycle.  Maintenance 
immunosuppression therapy will be tacrolimus, mycophenolate mofetil (MMF) and 
prednisone. Tacrolimus and MMF therapies will start once the first dose of bortezomib is 
administered.  
Imlifidase is administered within the 24-hour period prior to transplantation. Prior to 
imlifidase infusion the patients will be premedicated with methylprednisolone (250 mg IV) 
and loratadine (10 mg PO) to prevent infusion reactions. The patients will be monitored for 
6 months after transplantation. The patients will be hospitalized the first 14 days (may vary 
between patients) and thereafter return for 9 planned scheduled visits (visits 13-21). 
Trial Procedures/Assessments 
At screening the following will be collected/assessed/measured; signed informed consent, 
inclusion/exclusion criteria, demography, medical and surgical history, HLA-typing, height 
and weight, vital signs (pulse, blood pressure, body temperature), concomitant medication, 
virology (hepatitis B and C, HIV, CMV, EBV and SARS-CoV-2), chemistry panel 
(including p-creatinine and eGFR), CBC with differential, coagulation, urine 
protein/creatinine ratio, crossmatch tests, and DSA. A physical examination, ECG and 
echocardiogram measurements, peripheral neuropathy assessment, a pregnancy test (women 


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Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
Hansa Biopharma Doc. No.: 2019-003 
 
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of childbearing potential) and a HRQoL assessment will be done at screening and at the last 
trial visit.  
Inclusion/exclusion criteria, medical and surgical history and concomitant medication will be 
checked prior to infusion with imlifidase. Data on donor demographics, kidney condition and 
HLA-typing will be collected. A pregnancy test will be performed unless the patient has been 
hospitalized since the screening visit. The following will be assessed/measured; vital signs, 
weight, chemistry panel (including p-creatinine/eGFR), CBC with differential, coagulation, 
urine protein/creatinine ratio, DSA, flow crossmatch tests (FCXM and if possible, CDCXM) 
and anti-imlifidase IgG antibodies. Measurements for imlifidase pharmacokinetic and 
pharmacodynamic profiles will start.  
Imlifidase will be infused IV over 15 minutes. A flow crossmatch test will be performed 1, 2, 
4 and 24 hours after the end of the infusion to confirm the conversion from a positive to a 
negative test. A second dose may be given if the crossmatch test at 4 hours after the initial 
dose remains positive. In case of a second dose additional crossmatch tests will be performed 
pre-dose and at 2 hours post dose in addition to remaining tests from the first dose.  
After imlifidase infusion the following will be assessed on repeated occasions; pulse and 
blood pressure, body temperature, chemistry panel (including p-creatinine and eGFR), CBC 
with differential, coagulation, urine protein/creatinine ration, anti-imlifidase IgG antibodies, 
DSA and complement binding (C1q) DSA
. A full pharmacokinetic and 
pharmacodynamic profile will be calculated.
 
 
 
ytomegalovirus, Epstein Barr and BK viruses will be monitored 
throughout the trial period. Adverse events and concomitant medications will be registered 
throughout the trial. 
Number of subjects 
12 patients with a living donor will be enrolled in the study. 
Diagnosis and main criteria for inclusion/exclusion 
Patients with chronic kidney disease who are eligible for transplantation. 
 
Inclusion criteria 
1. Signed Informed Consent obtained before any trial-related procedures 
2. Male or female age 18 to 70 years at the time of screening 
3. Highly sensitized patients registered on the UNOS waiting list for kidney 
transplantation, with either of the following:  
• cPRA ≥ 99.9%  


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Project: Imlifidase 
Version: 4.0 
Clinical Trial Protocol No.: 18-HMedIdeS-16 
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• cPRA ≥ 98% and have been in kidney paired donation or kidney paired exchange 
programs for at least 1 year 
4. A positive crossmatch towards a living donor 
5. Willingness and ability to comply with the protocol 
 
Exclusion criteria 
1. Previous treatment with imlifidase 
2. Previous high dose IVIg treatment (2 g/kg) within 28 days prior to imlifidase 
treatment  
3. Breast-feeding or pregnancy 
4. Women of child-bearing potential not willing or able to practice FDA-approved 
forms of contraception. Two medically acceptable methods of highly effective 
contraception must be used for the duration of the study (e.g. oral, transdermal, 
intravaginal, injectable or implantable contraceptive; intrauterine device; intrauterine 
hormone-releasing system; vasectomized partner; bilateral tubal occlusion; or double-
barrier method). For a woman to be considered postmenopausal this ascertainment 
must be made according to medical records and clinical history and may be aided by 
measurement of elevated postmenopausal serum gonadotropin levels (FSH).   
5. ABO blood group incompatible transplantations (A2 and A2B kidneys will not be 
accepted for B recipients) 
6. Positive serology for HIV  
7. Clinical signs of HBV, HCV, CMV, or EBV infection 
8. EBV seronegative or with unknown EBV serostatus 
9. Positive SARS-CoV-2 test at any time point from screening to transplantation 
10. Active tuberculosis 
11. Ongoing serious infections as judged by the investigator 
12. Severe other conditions requiring treatment and close monitoring e.g. cardiac failure 
≥ grade 4 (New York Heart Association), unstable coronary disease or oxygen 
dependent respiratory disease 
13. A history of proven hypercoagulable condition 
14. Current peripheral neuropathy of Grade 2 with pain, or Grade 3 (severe symptoms; 
limiting self-care activities of daily living) based on NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 
15. Present, or history of, thrombotic thrombocytopenic purpura (TTP) or known familial 
history of TTP 
16. Intake of investigational drugs (other than imlifidase) within 5 half-lives  
17. Contemporaneous participation in a medical device study 
18. Known allergy/sensitivity (except local reactions) to imlifidase or to any drug (or the 
excipients) specified in the protocol 


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19. Known mental incapacity or language barriers precluding adequate understanding of 
the Informed Consent information and the trial activities 
20. Inability by the judgement of the investigator to participate in the trial for any other 
reason 
Investigational Medicinal Product 
Imlifidase, is provided as a freeze-dried powder for concentrate for solution for infusion, 
11 mg/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. Imlifidase 0.25 mg/kg will be 
infused intravenously over 15 minutes.   
Duration of treatment  
Imlifidase will be administered as a single IV infusion over 15 minutes. If the first dose does 
not have sufficient effect the administration is repeated.  
Statistical methods 
This is an open-label trial, and the statistical evaluation and presentation of data will be 
descriptive by nature. Continuous variables will be summarized by number of observations 
(n), mean, median, standard deviation, minimum and maximum. Categorical variables will 
be presented by counts and percentages. In addition, the data will be presented graphically 
when relevant. 
No formal sample size calculations have been performed for this exploratory trial. The 
number of subjects enrolled is considered sufficient to provide adequate information about 
the general safety and efficacy at this stage of development.  


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Protocol Revision History including Summary of Changes 
Version 
Date 
Reason for Change 
Summary of Major Changes 
V. 1.0 
4 Feb 2020 
Original protocol  
NA 
V. 2.0 
31 Mar 2021 
Version 1 of the Clinical 
Trial Protocol was finalized 
but never implemented. 
Version 2 is the first version 
submitted to the FDA. 
 
NA 
V. 3.0 
14 Jul 2021 
Version 3 is updated after 
feedback from the FDA. 
- 
Route of administration of 
bortezomib changed from IV 
to SQ. 
- 
ECG and echocardiogram at 
screening, after each 
bortezomib cycle and end of 
trial added. 
- 
Exclusion criteria regarding 
peripheral neuropathy added. 
- 
Peripheral neuropathy 
assessment added. 
- 
Bortezomib treatment specific 
discontinuation criteria added. 
- 
Study level stopping criteria 
further clarified. 
- 
Minor typos corrected, 
clarifications added and trial 
timelines updated. 
V. 4.0 
23 Jun 2022 
Version 4 is updated before 
trial initiation 
- 
Change of Sponsor's Medical 
Expert 
- 
Change of CRO responsible 
for SAE/SUSAR reporting 
and clarification of 
responsibilities in SUSAR 
reporting 
- 
Section on adverse events of 
special interest (AESI) added 
- 
Change of guidance on donor 
SARS-CoV2 testing 
- 
Clarification of biological 
sampling procedures 
(handling, storage, and 
destruction) 


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- 
Additional timepoints for 
ADA sampling added 
- 
Minor typos corrected, 
clarifications added, and trial 
timelines updated. 
 
 
 


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Table of Content 
Signature page ...................................................................................................................... 2 
Investigators and Clinical Trial Administrative Structure .............................................. 3 
Synopsis ................................................................................................................................. 4 
Protocol Revision History including Summary of Changes ........................................... 13 
Table of Content ................................................................................................................. 15 
List of Abbreviations .......................................................................................................... 20 
1. 
Introduction .......................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Scientific Rationale ................................................................................................ 24 
1.3 
Benefit/Risk Aspects .............................................................................................. 24 
2. 
Trial Objectives and Endpoints .......................................................................... 27 
2.1 
Objectives ............................................................................................................... 27 
2.1.1 
Primary Objective .................................................................................................. 27 
2.1.2 
Secondary Objectives ............................................................................................. 27 
2.1.3 
Exploratory Objectives .......................................................................................... 27 
2.2 
Endpoints ............................................................................................................... 28 
2.2.1 
Primary endpoint .................................................................................................... 28 
2.2.2 
Secondary endpoints .............................................................................................. 28 
2.2.3 
Exploratory endpoints ............................................................................................ 28 
3. 
Investigational Plan .............................................................................................. 30 
3.1 
Overall Trial Design ............................................................................................... 30 
3.1.1 
Follow-up Procedures............................................................................................. 30 
3.1.2 
Data Safety Monitoring Board ............................................................................... 30 
3.1.3 
Trial Stopping Criteria ........................................................................................... 31 
3.1.4 
Bortezomib-Associated Discontinuation Criteria .................................................. 31 
3.1.5 
Interim Analysis ..................................................................................................... 31 
3.2 
Trial Schedule ........................................................................................................ 31 
3.3 
Planned number of trial sites and patients ............................................................. 31 
3.4 
End-of-Trial ........................................................................................................... 32 
4. 
Trial Population ................................................................................................... 33 
4.1 
Selection Criteria .................................................................................................... 33 
4.2 
Inclusion Criteria .................................................................................................... 33 
4.3 
Exclusion Criteria .................................................................................................. 33 
4.4 
Restrictions ............................................................................................................. 34 
4.4.1 
Prohibited Therapy ................................................................................................. 34 
4.5 
Method of Assigning Patients to Treatment Groups .............................................. 34 
4.6 
Discontinuation of Patients .................................................................................... 35 
5. 
Trial Treatment .................................................................................................... 36 
5.1 
Investigational Medicinal Product (IMP) .............................................................. 36 


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5.1.1 
Imlifidase ............................................................................................................... 36 
5.2 
Non-investigational medicinal products (NIMPs) ................................................. 36 
5.2.1 
Pre-medications ...................................................................................................... 36 
5.2.2 
Prophylactic antibiotic, antiviral and antifungal .................................................... 36 
5.2.3 
Belatacept ............................................................................................................... 36 
5.2.4 
Bortezomib ............................................................................................................. 37 
5.2.5 
Rituximab ............................................................................................................... 37 
5.2.6 
IVIg 37 
5.2.7 
Induction immunosuppressants .............................................................................. 37 
5.2.8 
Maintenance immunosuppressants ........................................................................ 38 
5.3 
Concomitant medications and therapies ................................................................ 38 
5.4 
Characteristics and Source of Supply .................................................................... 38 
5.4.1 
Investigational Medicinal Product ......................................................................... 38 
5.4.2 
Non-investigational medicinal products ................................................................ 38 
5.5 
Conditions for Storage and Use ............................................................................. 38 
5.5.1 
Investigational product ........................................................................................... 38 
5.5.2 
Non-investigational medicinal products ................................................................ 39 
5.6 
Packaging and Labeling ......................................................................................... 39 
5.7 
Blinding .................................................................................................................. 39 
5.8 
Compliance, Accountability and Destruction of IMP ............................................ 39 
5.8.1 
Compliance ............................................................................................................ 39 
5.8.2 
Accountability and destruction of IMP .................................................................. 39 
5.9 
Product Quality Complaints ................................................................................... 40 
6. 
Trial Procedures ................................................................................................... 41 
6.1 
Trial Visits .............................................................................................................. 41 
7. 
Trial Assessments ................................................................................................. 49 
7.1 
Assessments related to Primary Endpoint .............................................................. 49 
7.2 
Assessments related to Secondary Endpoints ........................................................ 50 
7.2.1 
Frequency of AMR ................................................................................................ 50 
7.2.2 
Proportion of patients with DSA rebound .............................................................. 50 
7.2.3 
Determination of DSA and complement binding DSA levels ............................... 50 
7.2.4 
Analysis of crossmatch tests .................................................................................. 50 
7.2.5 
Graft survival ......................................................................................................... 50 
7.2.6 
Patient survival ....................................................................................................... 51 
7.2.7 
Kidney function ...................................................................................................... 51 
7.2.8 
Pharmacokinetics ................................................................................................... 51 
7.2.9 
Pharmacodynamics ................................................................................................ 51 
7.2.10 
Immunogenicity ..................................................................................................... 51 
7.2.11 
Safety Laboratory ................................................................................................... 51 
7.2.12 
Vital Signs .............................................................................................................. 52 
7.2.13 
Adverse Events ...................................................................................................... 52 
7.2.14 
Health Related Quality of Life Questionnaires (HR-QoL) .................................... 53 
7.3 
Assessments related to Exploratory Endpoints ...................................................... 53 
 
 


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7.4 
Other Assessments ................................................................................................. 54 
7.4.1 
Physical Examination ............................................................................................. 54 
7.4.2 
ECG and Echocardiogram ..................................................................................... 54 
7.4.3 
Peripheral Neuropathy Assessment ....................................................................... 55 
7.4.4 
Viral surveillance ................................................................................................... 55 
7.4.5 
Demographics and Baseline Data .......................................................................... 55 
7.4.6 
Medical and Surgical History ................................................................................ 55 
7.4.7 
Donor data .............................................................................................................. 55 
7.4.8 
Pregnancy Test ....................................................................................................... 56 
8. 
Biological Sampling Procedures ......................................................................... 57 
8.1 
Volume of Blood .................................................................................................... 57 
8.2 
Handling, Storage and Destruction of Biological Samples .................................... 57 
8.3 
Chain of Custody of Biological Samples ............................................................... 57 
8.4 
Withdrawal of Informed Consent for Biological Samples ..................................... 57 
9. 
Adverse Events and Serious Adverse Events .................................................... 58 
9.1 
Definitions .............................................................................................................. 58 
9.1.1 
Adverse event ......................................................................................................... 58 
9.1.1.1 Pre-treatment adverse event ................................................................................... 58 
9.1.1.2 Treatment emergent adverse event ........................................................................ 58 
9.1.1.3 Post-treatment emergent adverse event .................................................................. 58 
9.1.2 
Serious adverse event ............................................................................................. 58 
9.2 
Collection and Recording of Adverse Events ........................................................ 59 
9.2.1 
Variables ................................................................................................................ 60 
9.2.1.1 Causality Assessment ............................................................................................. 60 
9.2.2 
Adverse Events Based on Signs and Symptoms .................................................... 60 
9.2.3 
Adverse Events Based on Examinations and Tests ............................................... 60 
9.2.4 
Follow-up of Unresolved Adverse Events ............................................................. 61 
9.2.5 
Reporting of Serious Adverse Events .................................................................... 61 
9.2.6 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) ........ 62 
9.3 
Adverse Events of Special Interest ........................................................................ 62 
9.4 
Overdose ................................................................................................................ 62 
9.5 
Pregnancy and Pregnancy Outcome....................................................................... 63 
10. 
Statistical Methods ............................................................................................... 64 
10.1 
Analysis Sets .......................................................................................................... 64 
10.1.1 
Full Analysis Set (FAS) ......................................................................................... 64 
10.1.2 
Safety Analysis Set................................................................................................. 64 
10.1.3 
Pharmacokinetic Analysis Set ................................................................................ 64 
10.2 
Patient characteristics ............................................................................................. 64 
10.2.1 
Patient disposition .................................................................................................. 64 
10.2.2 
Demographics and Other Baseline Characteristics ................................................ 65 
10.2.3 
Recent and Concomitant Medication ..................................................................... 65 


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10.2.4 
Exposure and Compliance ..................................................................................... 65 
10.3 
Statistical analysis of Primary Endpoint ................................................................ 65 
10.4 
Statistical analysis of Secondary Endpoints ........................................................... 65 
10.4.1 
Proportion of patients with DSA rebound .............................................................. 65 
10.4.2 
Proportion of patients with biopsy proven AMR ................................................... 65 
10.4.3 
Proportion of patients with negative crossmatch tests ........................................... 65 
10.4.4 
Measurements of DSA and complement binding (C1q) DSA levels ..................... 65 
10.4.5 
Graft survival ......................................................................................................... 65 
10.4.6 
Patient survival ....................................................................................................... 65 
10.4.7 
Kidney function ...................................................................................................... 65 
10.4.8 
Pharmacokinetics ................................................................................................... 65 
10.4.9 
Pharmacodynamic .................................................................................................. 66 
10.4.10 Anti-drug antibody level ........................................................................................ 66 
10.4.11 Health related quality of life .................................................................................. 66 
10.5 
Statistical analysis of Exploratory Endpoints ........................................................ 66 
 
 
 
 
 
 
 
 
10.6 
Safety Endpoints .................................................................................................... 67 
10.6.1 
Analysis of Adverse Events ................................................................................... 67 
10.6.1.1 Adverse Events ...................................................................................................... 67 
10.6.1.2 Overview of treatment emergent adverse events ................................................... 67 
10.6.1.3 Incidence of treatment emergent adverse events ................................................... 67 
10.6.1.4 Serious adverse events, deaths, and other significant adverse events .................... 68 
10.6.2 
Analysis of Other Safety Variables ........................................................................ 68 
10.6.2.1 Vital signs .............................................................................................................. 68 
10.6.2.2 Clinical Chemistry, Hematology, Hemostasis, and Urinalysis .............................. 68 
10.6.2.3 Electrocardiography ............................................................................................... 68 
10.7 
Determination of Sample Size ............................................................................... 68 
11. 
Trial Management ................................................................................................ 69 
11.1 
Pre-trial Activities .................................................................................................. 69 
11.2 
Monitoring of the Trial .......................................................................................... 69 
11.3 
Source Data ............................................................................................................ 70 
11.4 
Audit and Inspection .............................................................................................. 70 
11.5 
Trial Agreements .................................................................................................... 70 
12. 
Data Management ................................................................................................ 71 
12.1 
Case Report Form .................................................................................................. 71 
12.2 
Provider of Data Management ............................................................................... 71 
12.3 
Coding .................................................................................................................... 71 
12.4 
Handling of External Data ..................................................................................... 71 
13. 
Changes in Trial Conduct or Planned Analyzes ............................................... 72 
13.1 
Protocol Amendment(s) ......................................................................................... 72 


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13.2 
Protocol Deviations ................................................................................................ 72 
13.3 
Statistical Analysis Plan ......................................................................................... 72 
13.4 
Premature Termination or Suspension of the Trial ................................................ 72 
14. 
Reporting and Publication .................................................................................. 73 
14.1 
Clinical Trial Report .............................................................................................. 73 
14.2 
Confidentiality and Data Ownership ...................................................................... 73 
14.3 
Publications ............................................................................................................ 73 
14.3.1 
Publication Policy .................................................................................................. 73 
14.4 
Public disclosure .................................................................................................... 73 
15. 
Ethical and Regulatory Aspects .......................................................................... 74 
15.1 
Ethical Conduct of the Trial ................................................................................... 74 
15.2 
Liabilities and Insurance ........................................................................................ 74 
15.3 
Institutional Review Boards ................................................................................... 74 
15.4 
Regulatory Authority ............................................................................................. 74 
15.5 
Patient Information and Informed Consent ............................................................ 74 
15.6 
Patient Confidentiality ........................................................................................... 75 
16. 
Archiving ............................................................................................................... 76 
16.1 
Retention of Clinical Trial Site Documentation .................................................... 76 
16.2 
Trial Master File ..................................................................................................... 76 
17. 
List of reports ....................................................................................................... 77 
18. 
References ............................................................................................................. 78 
19. 
Appendices ............................................................................................................ 81 
 
 
 
 
List of Tables 
Table 1. 
Safety laboratory tests .................................................................................. 52 
 
List of Appendices 
Appendix 1. 
 
Appendix 2. 
 
Appendix 3. 
 
Appendix 4. PROMIS Short Form v2.0 
Appendix 5. PROMIS–29 Profile v2.1 
Appendix 6. 
 
 


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List of Abbreviations 
 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
AMR 
Antibody Mediated Rejection 
ATG 
Anti-Thymocyte globulin derived from rabbit 
AUC 
Area Under the Curve 
CD52 
Cluster of differentiation 52, or CAMPATH-1antigen 
CL 
Clearance of drug from plasma/serum 
Cmax 
Maximum Concentration 
CMR 
Cell mediated rejection 
CDC 
Complement Dependent Cytotoxicity 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Curriculum Vitae 
%CV 
Percentage Coefficient of Variation 
CMV 
Cytomegalovirus 
cPRA 
Calculated PRA 
XM 
Crossmatch 
 
 
DSA 
Donor Specific Antibodies 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EQ-5D-5L 
European Quality of Life -5 Levels 
FCXM 
Flow Cytometry Crossmatch Test 
GCP 
Good Clinical Practice 
HAR 
Hyperacute rejection 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HRQoL 
Health Related Quality of Life 
IA 
Immunoadsorption 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IL2R 
Interleukin-2 receptor 
 


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IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
IVIg 
Intravenous Immunoglobulin 
LLQ 
Lower Level of Quantification 
MedDRA 
The Medical Dictionary for Regulatory Activities 
MFI 
Mean Fluorescence Intensity 
MMDx 
Moculecular Microscope® Diagnostic System 
MMF 
Mycophenolate mofetil 
N/A 
Not Applicable 
NIMP 
Non-Investigational Medicinal Product 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PLEX 
Plasma Exchange 
POD 
Post Operative Day 
PP 
Per Protocol 
PQC 
Product Quality Complaint 
PRA 
Panel Reactive Antibody 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QA 
Quality Assurance 
RA 
Regulatory Authority 
SAB 
Single Antigen Bead 
SAB-C1q 
Anti-HLA antibodies with complement binding capacity measured with the 
SAB assay 
SAB-HLA 
Anti-HLA antibodies measured with the SAB assay 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
ScIgG 
Single-cleaved IgG 
SDS-PAGE 
Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis 
SDV 
Source Document Verification 
SOC 
System Organ Class 
SQ 
Subcutaneous 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
T1/2 
Terminal half-life 
Tmax 
Time to Maximum concentration 
UNOS 
United Network for Organ Sharing 
Vz 
Apparent Volume of distribution 
WBC 
White Blood Corpuscles  
 
Definition of Terms 
Enrolled 
When the subjects, or his/her representative, and the investigator have 
signed the informed consent form 


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1. INTRODUCTION 
1.1 Background  
Approximately one third of patients in the US waiting for kidney transplantation are 
sensitized to potential donor tissues, i.e. they have antibodies to human leukocyte antigen 
(HLA) (Iyer et al. 2013). Preformed donor specific antibodies (DSA) typically arise due to 
immunization- during earlier pregnancies, blood transfusions, previous transplants or 
infections (Stites et al. 2015; Thomas et al. 2015). A patient with significant HLA antibodies 
to a potential donor will show a strong positive crossmatch to that donor and that is a 
contraindication to transplantation since it will cause immediate damage to the graft. At 
worst, DSA can result in hyperacute rejection (HAR) beginning immediately after perfusion, 
inevitably resulting in graft loss (Kissmeyer-Nielsen et al. 1966; Patel et al. 1969). As many 
as 13% of the US patients on the transplantation waitlist are highly sensitized, i.e. a calculated 
panel reactive assay (cPRA) ≥ 80% of which 7% with a cPRA 98-100% (Hart et al. 2019). 
For patients with a wide range of HLA antibodies it can be extremely difficult to find a 
compatible donor even after implementation of the new kidney allocation system (KAS) in 
2014. The modifications to the KAS have helped broaden organ access to transplantation for 
highly sensitized patients. However, despite the initial significant improvement in access, 
there remains a pool of highly sensitized patients with low likelihood of ever receiving an 
organ offer (Stewart et al. 2016; Schinstock et al. 2016; Stegall 2019; Schinstock et al. 2017). 
Further, an analysis of the United Network for Organ Sharing (UNOS) data 2010-2016, 
showed that for patients with cPRA of ≥99.5%, the transplant rates decrease with increasing 
levels of sensitization. Recent data showed that patients with cPRA ≥99.9% constitute the 
largest group in the 100% cPRA cohort (99.5-100%) and continue to have prolonged waiting 
time and the lowest rate of deceased donor (DD) transplantation (Jackson et al. 2019; 
Schinstock et al. 2019). For these highly sensitized candidates with an incompatible living 
donor, Kidney Paired Donation (KPD) program can improve the prospects of finding a 
compatible living donor but the probability of finding a match through KPD programs is 
insignificant.  
The general benefit of transplantation even with an incompatible kidney was investigated in a 
study comparing patients receiving an incompatible living donor kidney with patients staying 
on the waiting list with or without later transplantation (Orandi et al. 2016). Prior to 
transplantation the patients received perioperative desensitization therapy according to a 
protocol of the site’s own choice. The results demonstrated that receipt of a kidney transplant 
from an incompatible live donor was associated with a significant survival benefit as 
compared with the matched controls staying on the waiting list throughout the studied period, 
8 years. 
Data demonstrate that successful desensitization followed by transplantation of patients with 
DSA is clearly associated with short term and long term survival benefits compared to staying 
on dialysis (Montgomery et al. 2011; Orandi et al. 2014; Orandi et al. 2016; Vo et al. 2013), 
despite a higher reported incidence of active antibody mediated rejection (AMR) 


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(20% to 61%) compared to non-sensitized patients where AMR is very rare (Lefaucheur et al. 
2008; Gloor et al. 2010; Vo, Wechsler, et al. 2008; Haririan et al. 2009; Marfo et al. 2011; 
Thielke et al. 2009; Riella et al. 2014). In addition, the patient’s quality of life is dramatically 
improved and there is substantial cost effectiveness associated with desensitization and 
transplantation compared to dialysis (Vo et al. 2013). 
There are no approved treatments for desensitization nor is there a standardized protocol for 
desensitization in the US. However, a few institutional protocols have been developed and 
tested in clinical settings (Iyer et al. 2013). All of these protocols use techniques to block out 
antibodies through high-dose intravenous immunoglobulin (IVIg) or remove them by 
plasmapheresis/ immunoadsorption (IA), often combined with low-dose IVIg (Montgomery et 
al. 2000; Jordan et al. 2004). Some protocols use anti-CD20 antibodies i.e. rituximab to 
inhibit the synthesis of IgG (Vo, Lukovsky, et al. 2008). There have been no randomized 
controlled trials of these protocols. In addition, desensitization protocols are usually combined 
with induction therapy using steroids and antithymocyteglobulin (ATG) and/or anti-IL2R 
antibody (e.g. basiliximab) to prevent acute cell mediated rejections in high-risk patients.  
Imlifidase is an immunoglobulin G-degrading enzyme of Streptococcus pyogenes that is 
highly specific for IgG. The cleavage of IgG generates one F(ab’)2- and one homodimeric Fc-
fragment and efficiently neutralizes Fc-mediated activities of IgG 
 (Vincents 
et al. 2004; von Pawel-Rammingen et al. 2002; Wenig et al. 2004). Clinical studies with 
imlifidase have demonstrated that the treatment enables transplantation in patients otherwise 
highly unlikely to be transplanted, by converting a positive crossmatch to a negative (Jordan 
et al. 2017; Lorant et al. 2018; Jordan et al. 2020; Lonze 2021; Schinstock 2020). The 
treatment is highly efficacious as demonstrated by 100% crossmatch conversion in patients 
treated. Imlifidase (Idefirix®) has a conditional approval in Europe for desensitization of 
highly sensitized patients prior to transplantation against a positive XM with a deceased donor 
kidney. 
However, as with other desensitization methods, DSA tend to reappear within weeks of 
imlifidase treatment and transplantation, which may cause AMR and increased risk of graft 
loss. The incidence of AMR in highly sensitized patients is 20-61%, compared with 
approximately 5% in non-sensitized patients. Imlifidase-mediated IgG degradation constitutes 
a novel therapeutic principle for the treatment of IgG-driven human diseases. A treatment 
regimen allowing transplantation of highly sensitized patients with deceased or living donor 
organs, while keeping the occurrence of AMR at a low level, would provide an important 
improvement in the treatment of these patients. 
 
Clinical studies 
Patients in transplantation studies were treated with imlifidase and all patients who received a 
clinically relevant dose were transplanted. In studies including immunologically difficult 
patients (cPRA >95%), it was shown that treatment with 1 or 2 doses of 0.25 mg/kg imlifidase 
before transplantation converted positive crossmatches into negative and was effective in 
reducing or eliminating DSAs, allowing transplantation of all treated patients. However, DSA 
rebound started after about one week in most patients leading to AMR episodes at an 


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incidence of 31%, similar to what has been reported previously with desensitized patients 
(Jordan et al. 2017; Lorant et al. 2018; Jordan et al. 2020). A treatment regimen which 
prevents or suppresses DSA rebound is likely to decrease the AMR frequency in highly 
sensitized patients with HLA antibodies.  
1.2 Scientific Rationale 
This is a phase 2, single center, open label, single arm, exploratory trial. The trial will 
investigate the DSA rebound and frequency of AMR in highly sensitized patients made 
transplantable with imlifidase. The primary objective is to investigate the DSA rebound 
during a period of 3 months from transplantation. The trial will include 12 highly sensitized 
patients on the kidney transplant list who have a positive crossmatch test towards a living 
donor and either a cPRA≥ 99.9% or have been in kidney paired donation or kidney paired 
exchange programs for at least 1 year with a cPRA ≥ 98%. These patients have a high unmet 
medical need in transplantation today and current data show that imlifidase has the potential 
to inactivate DSAs and thereby convert a positive crossmatch test into negative, allowing 
these highly sensitized patients to be transplanted.  
Preclinical studies in non-human primate models of transplantation in highly sensitized 
recipients suggest that combining co-stimulation blockade by belatacept with plasma-cell 
depleting therapy by bortezomib may durably suppress DSA and decrease the risk of AMR 
(Burghuber et al. 2019). In this trial treatment with drugs that prevent or suppress DSA 
rebound by targeting antibody-producing plasma-cells and their B-cell precursors is 
suggested. Bortezomib is a proteasome inhibitor which has activity against mature plasma 
cells, the source of DSA. Belatacept is a fusion protein composed of the Fc-fragment of a 
human IgG1 linked to the extracellular domain of CTLA-4, which is a molecule crucial in 
blocking T-cell co-stimulation, and was shown to be effective in reducing de novo DSA 
generation in humans (Sethi et al. 2017; Vincenti et al. 2016). Rituximab, an anti-CD20 
monoclonal antibody that targets B-cells and immunomodulatory agent IVIg are commonly 
used in desensitization regimens and for the treatment of AMR (Montgomery et al. 2011; 
Orandi et al. 2014; Orandi et al. 2016; Vo et al. 2013). 
This trial will investigate whether the suggested treatment regimen can suppress DSA 
recurrence and the occurrence of AMR in highly sensitized patients. 
To assess response to bortezomib and belatacept therapies, the immunological status of the 
transplant recipients will be evaluated both quantitatively and qualitatively in bone marrow 
and lymph nodes.  
1.3 Benefit/Risk Aspects 
Patients in this trial are highly sensitized and may benefit from being treated with imlifidase 
to enable kidney transplantation. The potential benefit of imlifidase over currently used 
methods for antibody removal include the extremely efficient inactivation of DSAs which 
enable desensitization even for patients that are very highly sensitized and with high antibody 
titers. The administration of the proteasome inhibitor, bortezomib, and the T-cell blocking 
monoclonal antibody, belatacept, along with the anti-CD20 monoclonal antibody rituximab, 


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and IVIg will potentially suppress DSA rebound and decrease the number of AMR episodes 
in the highly sensitized transplanted patients participating in the study.   
Since imlifidase effectively removes the IgG pool, there may be an increased risk of infection. 
Patients in this trial will receive antibiotics in connection with imlifidase treatment and 
transplantation and high dose IVIg 
 which will minimize the risk for bacterial 
infections. In addition, patients 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 if a patient shows 
signs of infection. In case of infection in a patient with low IgG plasma levels, intravenous 
immunoglobulin may be indicated.  
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 83 subjects receiving imlifidase and 1 non-serious infusion reaction in a 
subject receiving placebo. 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.  
To date, a total of 46 patients in clinical studies have been transplanted after treatment with 
imlifidase. Imlifidase was well-tolerated, with only few related adverse events (AEs) reported 
and no clinically relevant safety findings. 
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 suggested intervals between 
imlifidase administration and these biologics are presented in the Investigator’s Brochure (IB) 
for imlifidase.
 
 
 
Both IVIg and rituximab are commercially available agents that have been well studied for 
use in transplantation for treatment of AMR (Sethi et al. 2017). These agents are typically 
well tolerated but may potentially cause infusion reactions necessitating pre-medications prior 
to infusion (Vo, Lukovsky, et al. 2008).  
Belatacept is approved for prevention of rejection in renal transplant patients (Sethi et al. 
2017). A trial with 666 renal transplant patients published 2016 reveals that serious infections 
were the most common side effect in kidney transplant patients with urinary tract infections 
(UTI) dominating (Vincenti et al. 2016). Measures will be in place for early detection and 
management of UTI in trial patients. 
Bortezomib is approved for treatment of multiple myeloma and mantle cell lymphoma and 
have been studied in renal transplant patients both as a desensitization agent and for treatment 
of AMR. Recent clinical studies have suggested that bortezomib has the capability to 
downregulate circulating antibodies and treat AMR episodes (Requiao-Moura et al. 2017). 


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Most commonly reported AEs include diarrhea, thrombocytopenia and peripheral neuropathy. 
It should be noted that diarrhea is a commonly observed side effect of immunosuppressive 
drugs and that the events of thrombocytopenia and peripheral neuropathy were both 
responsive to treatment (Requiao-Moura et al. 2017). 
The effect of bortezomib and belatacept on a cellular level will be investigated through tissue 
sampling from the bone marrow and iliac lymph nodes. The biopsies, including kidney 
biopsies, are generally safe procedures and complications are rare but may include bleedings, 
infections and discomfort from the biopsy site.  
The principal investigator will ensure that sufficient facilities and procedures are available to 
handle emergency situations during the trial. The trial site has extensive experience in phase 
I/II studies within transplantation and graft rejection treatment as well as handling biological 
drugs. The site has adequate procedures in place to handle unexpected adverse reactions. 
A guidance for the investigator and Reference Safety Information can be found in the current 
version of the Investigator’s Brochure for imlifidase and in the United States Prescribing 
Information for belatacept, bortezomib, thymoglobulin, rituximab, and IVIg. The trial will be 
conducted in compliance with the protocol, Good Clinical Practice (GCP) and the applicable 
regulatory requirements. 


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2. TRIAL OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
2.1.1 Primary Objective 
• To evaluate DSA rebound during the first 3 months after transplantation  
2.1.2 Secondary Objectives  
• To evaluate AMR frequency up to 6 months after transplantation  
• To evaluate DSA rebound up to 6 months after transplantation 
• To evaluate crossmatch conversion within 24 hours after imlifidase treatment  
• To evaluate DSA and complement binding (C1q) DSA MFI levels  
• To evaluate graft and patient survival  
• To evaluate safety parameters 
• To evaluate kidney function  
• To evaluate pharmacokinetic (PK) profile of imlifidase 
• To evaluate pharmacodynamic (PD) profile of imlifidase   
• To evaluate immunogenicity profile of imlifidase (ADA)  
• To evaluate health related quality of life (HRQoL) specifically patients’ life 
participation  
2.1.3 Exploratory Objectives 
 
  
 
 
 
 
  
 
 
 
 
 


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2.2 Endpoints 
2.2.1 Primary endpoint 
• Proportion of patients with DSA rebound during the first 3 months after 
transplantation  
2.2.2 Secondary endpoints  
• Proportion of patients with kidney biopsy proven AMR (according to Banff 2019) up 
to 6 months after transplantation (based on for cause biopsies and protocol biopsies) 
• Proportion of patient with DSA rebound up to 6 months after transplantation 
• Proportion of patients with negative flow crossmatch test within 24 hours after 
imlifidase treatment 
• Levels of DSA and complement binding (C1q) DSA MFI levels before imlifidase 
treatment and up to 6 months after transplantation 
• Graft survival at 6 months after transplantation 
• Patient survival at 6 months after transplantation 
• Safety parameters (AEs, clinical laboratory tests, vital signs and ECG) up to 6 months 
after transplantation  
• Kidney function assessed by creatinine, estimated glomerular filtration rate (eGFR), 
and protein/creatinine ratio in urine up to 6 months after transplantation  
• Imlifidase pharmacokinetics up to 14 days after imlifidase  
• Imlifidase pharmacodynamics up to 10 days after imlifidase  
• Anti-drug antibodies (ADA) levels up to 6 months after imlifidase 
• Change in patient-reported life participation, as measured by the PROMIS Social 
Health domain “Ability to participate in social roles & activities, PROMIS-SF-8a”, 
from baseline to 6 months after transplantation 
2.2.3 Exploratory endpoints  
 
 
 
 
 
 
 
 
 
 


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3. INVESTIGATIONAL PLAN 
3.1 Overall Trial Design  
This is a phase 2, single center, open label, single arm, exploratory trial. The trial will 
investigate the frequency of DSA rebound and AMR in highly sensitized kidney patients 
made transplantable with imlifidase. The primary objective is to investigate DSA rebound 
during a period of 3 months from transplantation.  
12 patients with a living donor will be included in the trial. Imlifidase is administered 
preferably within the 24-hour period prior to transplantation. Prior to imlifidase infusion the 
patients will be premedicated with methylprednisolone (250 mg IV) and loratadine (10 mg 
PO) or an equipotent antihistamine. Should a second dose of imlifidase be necessary, 
premedication will be repeated. The administration of imlifidase is identified as 
.  
There will be scheduled visits prior to imlifidase infusion and transplantation, including the 
screening visit that will take place during the interval day 
. The patients will be 
hospitalized for the first 14 days after imlifidase treatment and transplantation (may vary 
between patients) and after that, a further planned clinic visits are planned 
. 
The follow-up after transplantation will be 6 months for all patients.   
The treatments with belatacept and bortezomib will start about 3 weeks prior to imlifidase 
infusion and transplantation. Three doses of belatacept will be administered with about 5 and 
9 days between the doses, and for bortezomib 4 doses (1 cycle) will be administered. 
Belatacept administration is continued post-transplantation with 6 additional doses starting on 
day 6 and ending at week 13. Bortezomib administration is continued with 2 more cycles, 
starting the second cycle on day 3 and the third 3 weeks later. ECG and echocardiogram will 
be performed after each bortezomib cycle.   
All patients will receive high-dose methylprednisolone starting on the day of transplantation, 
in the operating room, and continued for 3 days. It will then be tapered over several days and, 
when applicable, converted to oral prednisone. rATG treatment will start 
 and be 
given on at least 3 days, rituximab will be administered 
 and intravenous 
immunoglobulin 
. Maintenance immunosuppression therapy will be tacrolimus, 
mycophenolate mofetil (MMF) and prednisone. Tacrolimus and MMF therapies will start 
once the first dose of bortezomib is administered. All therapies are presented in Section 5.   
3.1.1 Follow-up Procedures 
Following trial termination approximately 6 months post-transplant, all trial patients will be 
followed up regularly and interdisciplinary by nephrologists and transplant surgeons 
according to the center’s follow-up routines for transplanted patients.  
3.1.2 Data Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will monitor participant safety data and 
evaluate the progress of the trial. The constitution, activities and reports of the DSMB shall be 
governed by the FDA’s “Guidance for Clinical Study Sponsors; Establishment and Operation 
of Clinical Study Data Monitoring Committees”. A trial specific DSMB charter will be 
available detailing the purpose of the DSMB, scope, timing of meetings, the composition, 


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roles, responsibilities, procedures and deliverables. The DSMB will be an external group of 
experts, independent of the sponsor and consist of at least three physicians of which one will 
be the DSMB chairman. This committee will convene after the first two transplants, then 
quarterly for the remainder of the trial. 
3.1.3 Trial Stopping Criteria 
The trial may be stopped prematurely if: 
1. DSMB assessments of safety findings, such as death related to treatment, graft loss, or 
any other safety concerns, justifying termination of the trial. 
2. Findings that, at the discretion of Principal Investigator and/or sponsor, indicate that 
further dosing should be stopped. 
3.1.4 Bortezomib-Associated Discontinuation Criteria 
A subject must be discontinued immediately from bortezomib treatment if she/he experiences 
any of the following:  
1. Bortezomib-associated peripheral neuropathy of Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self-care activities of daily living) based on CTCAE v5.0, that by 
the Investigator’s clinical judgement prevent further treatment. 
2. Bortezomib-associated peripheral neuropathy of Grade 4 (life-threatening 
consequences; urgent intervention indicated) based on CTCAE v5.0. 
3. Acute development or exacerbation of congestive heart failure and new onset of 
significantly decreased left ventricular ejection fraction (>15%) after bortezomib 
administration. 
4. Hematological toxicities consisting of platelet count <30×109/L or ANC <0.75×109/L, 
which does not resolve to Grade 1 or baseline after withholding bortezomib.  
If the patient experiences any of the above bortezomib associated discontinuation criteria 
prior to imlifidase treatment and transplantation, she/he will be withdrawn from the trial. 
3.1.5 Interim Analysis 
Not applicable. 
3.2 Trial Schedule 
The first patient first visit (FPFV) is planned to Q3 2022 and the trial will run for about 
2 years with a clinical report available about 1 year later. 
3.3 Planned number of trial sites and patients 
This is a single center trial performed at NYU Langone Health Transplant Institute. It is 
estimated that about 17 patients need to be screened to enroll 12 patients.  


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3.4 End-of-Trial 
The planned End-of-Trial is defined as the last patient last visit. Hansa Biopharma will submit 
to IRB according to local requirements. 
For procedures in case of premature termination or suspension of the Trial, see Section 13.4. 


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4. TRIAL POPULATION 
4.1 Selection Criteria 
If a patient has been screened and meets all inclusion criteria and no exclusion criteria but 
does not start treatments with belatacept and bortezomib according to trial schedule the 
patient may be re-screened. Patients are not allowed to be re-screened if they have received 
imlifidase, but transplantation has not been performed or if they have been 
discontinued/withdrawn due to AE(s). The re-screening procedure will be the same as the 
previous screening visit with the exception for the virology tests which do not have to be 
repeated if not more than 6 months old. Medical and surgical history and concomitant 
medication will be updated if applicable. If a patient is re-screened a new screening number 
will be issued.  
To be eligible for the trial, patients must meet all inclusion criteria and no exclusion criteria.  
4.2 Inclusion Criteria 
1. Signed Informed Consent obtained before any trial-related procedures 
2. Male or female age 18 to 70 years at the time of screening 
3. Highly sensitized patients registered on the UNOS waiting list for kidney 
transplantation, with either of the following:  
• cPRA ≥ 99.9%  
• cPRA ≥ 98% and have been in kidney paired donation or kidney paired exchange 
programs for at least 1 year 
4. A positive crossmatch towards a living donor 
5. Willingness and ability to comply with the protocol 
4.3 Exclusion Criteria 
1. Previous treatment with imlifidase 
2. Previous high dose IVIg treatment (2 g/kg) within 28 days prior to imlifidase 
treatment  
3. Breast-feeding or pregnancy 
4. Women of child-bearing potential not willing or able to practice FDA-approved forms 
of contraception. Two medically acceptable methods of highly effective contraception 
must be used for the duration of the study (e.g. oral, transdermal, intravaginal, 
injectable or implantable contraceptive; intrauterine device; intrauterine hormone-
releasing system; vasectomized partner; bilateral tubal occlusion; or double-barrier 
method). For a woman to be considered postmenopausal this ascertainment must be 
made according to medical records and clinical history and may be aided by 
measurement of elevated postmenopausal serum gonadotropin levels (FSH).   
5. ABO blood group incompatible transplantations (A2 and A2B kidneys will not be 
accepted for B recipients) 
6. Positive serology for HIV  


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7. Clinical signs of HBV, HCV, CMV, or EBV infection 
8. EBV seronegative or with unknown EBV serostatus 
9. Positive SARS-CoV-2 tests at any time point from screening to transplantation  
10. Active tuberculosis 
11. Ongoing serious infections as judged by the investigator 
12. Severe other conditions requiring treatment and close monitoring e.g. cardiac failure 
≥ grade 4 (New York Heart Association), unstable coronary disease or oxygen 
dependent respiratory disease 
13. A history of a proven hypercoagulable condition 
14. Current peripheral neuropathy of Grade 2 with pain, or Grade 3 (severe symptoms; 
limiting self-care activities of daily living) based on NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0 
15. Present, or history of, thrombotic thrombocytopenic purpura (TTP) or known familial 
history of TTP 
16. Intake of investigational drugs (other than imlifidase) within 5 half-lives  
17. Contemporaneous participation in a medical device study 
18. Known allergy/sensitivity (except local reactions) to imlifidase or to any drug (or the 
excipients) specified in the protocol 
19. Known mental incapacity or language barriers precluding adequate understanding of 
the Informed Consent information and the trial activities 
20. Inability by the judgement of the investigator to participate in the trial for any other 
reason 
4.4 Restrictions 
4.4.1 Prohibited Therapy 
High dose IVIg treatment (2 g/kg) must not be administered within 28 days prior to imlifidase 
treatment (exclusion criterion No. 2). 
Investigational drugs (other than imlifidase) must not be taken within 5 half-lives of the given 
drug (exclusion criterion No. 16). 
4.5 Method of Assigning Patients to Treatment Groups 
After the patient’s eligibility has been confirmed (fulfilled the inclusion criteria and no 
exclusion criteria) at the screening visit, the patient will be allocated a patient identification 
number (screening number). The screening number is set automatically by the electronic case 
report form (eCRF) when the patient is added to the database. When a patient is screened, 
he/she will always be assigned the lowest available screening number. 


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4.6 Discontinuation of Patients  
Patients may be discontinued from trial treatment and assessments at any time. The patients 
are free to discontinue the participation in the trial at any time and for any reason, without 
prejudice to further treatment. Patients who withdraw prior to trial treatment may be replaced.  
Patients who discontinue after trial drug administration will always be asked about the 
reason(s) for discontinuation and the presence of any AEs. The patients will be asked to allow 
follow-up for 6 months for safety measurements and at least graft and patient survival 
information even if consent is withdrawn. If a patient refuses any follow-up visit, if possible, 
the patient should undergo the assessments and procedures scheduled for the last trial visit (as 
defined in Section 6, Trial Procedures). Even if the patient is not able to attend, the End-of-
Trial Form must be completed. Patients who, for a medical reason, cannot comply with the 
protocol procedures will be followed by best procedure to retrieve safety and efficacy data. 
Patients who are treated with imlifidase but not transplanted will be handled in the same way 
as discontinued patients.  
If the trial is prematurely terminated, the sponsor will promptly inform the investigator and 
the FDA of the termination and the reason(s) for the termination. The IRB will also be 
promptly informed and provided the reason(s) for the termination either by sponsor or 
investigator, depending on local requirements. All patients, those in the trial at the time for 
termination as well as those that have completed the trial, will be informed about the trial 
termination and the reason(s) for it by the investigator. The monitor must also be informed 
about the trial termination.  


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5. TRIAL TREATMENT 
5.1 Investigational Medicinal Product (IMP) 
5.1.1 Imlifidase 
The investigational medicinal product (IMP), 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.  
Imlifidase for infusion will be prepared by the pharmacist and the administration will be 
performed by a qualified nurse at the site. Details on preparation, labeling, 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 patient. 
Imlifidase will be administered intravenously as one dose of 0.25 mg/kg over 15 minutes 
within the 24-hour period prior to transplantation. The infusion may be interrupted if needed 
and resumed. An infusion that is interrupted and then resumed will not be regarded as a 
protocol deviation. A second dose may be given if the crossmatch test at 4 hours after the first 
dose remains positive. 
5.2 Non-investigational medicinal products (NIMPs) 
5.2.1 Pre-medications 
To reduce the risk of infusion reactions all patients will receive pre-medication with a 
corticosteroid, methylprednisolone 250 mg intravenously, and an antihistamine, loratadine 
10 mg orally or an equipotent antihistamine, prior to imlifidase infusion.  
All patients will receive premedication prior thymoglobulin, IVIg, and rituximab according to 
standard of care. 
5.2.2 Prophylactic antibiotic, antiviral and antifungal 
All patients will receive standard prophylaxis for pneumocystis, CMV, and candida 
infections. Therapeutic alternatives may be used if allergies or intolerance are present. 
Prophylaxis for bacterial infections according to clinical practice will be administered prior to 
imlifidase infusion until IVIg is administered or until serum IgG level is back within normal 
range as judged by the investigator.  
5.2.3 Belatacept 
Belatacept will be provided as the commercially available product and administered 
intravenously (IV) with the dose of 10 mg/kg.  
Belatacept will be administered on days -21, -16 and -7 prior to transplantation, and after 
transplantation on days 6, 10, 22, 33, 64 and 91.  


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The belatacept dosing can be moved, interrupted or skipped for safety reasons at any time. 
This is done based on the physician’s judgement and is not considered a protocol deviation. 
However, the change must be noted in the eCRF together with the reason.  
5.2.4 Bortezomib 
Bortezomib will be provided as the commercially available product and administered 
subcutaneously (SQ) with the dose of 1.3 mg/m2.  
Bortezomib will be administered in three 21-day cycles, the first on the days -21, -18, -14, and 
-11 prior to transplantation, the second after transplantation on days 3, 6, 9, and 12, and the 
third on days 22, 25, 29, and 33.  
The bortezomib dosing can be moved, interrupted or skipped for safety reasons at any time, 
see Section 3.1.4 for bortezomib-associated discontinuation criteria. Consecutive doses should 
be separated by at least 72 hours. This is done based on the physician’s judgement and is not 
considered a protocol deviation. However, the change must be noted in the eCRF together 
with the reason.  
5.2.5 Rituximab 
Rituximab will be provided as the commercially available product and administered 
intravenously (IV) to all patients as a single dose of 375 mg/m2 
 
5.2.6 IVIg 
High dose IVIg 10% solution will be provided as the commercially available product and 
administered to all patients with the dose 2 g/kg (max 140 g for >70 kg) 
 (as a single 
dose or in divided doses administered on two consecutive days). 
5.2.7 Induction immunosuppressants 
All patients will be given the following commercially available medications: 
1. High dose corticosteroids, methylprednisolone, 1000 mg intravenously at the day of 
transplantation and 500 mg for at least 3 days. The high dose corticosteroids will then 
be tapered over several days and converted to prednisone as maintenance therapy, 
starting at 30 mg orally. 
2.  rATG (Thymoglobulin® 1.5 mg/kg) IV given over at least 3 days starting 
 
, to achieve a cumulative dose of 4.5 
mg/kg.
 
 
The induction therapy dosing can be moved, interrupted, or skipped for safety reasons at any 
time. This is done based on the physician’s judgement and is not considered a protocol 
deviation. However, the change must be noted in the eCRF together with the reason.  


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5.2.8 Maintenance immunosuppressants 
Once bortezomib is administered (3 weeks prior to transplantation), tacrolimus will be given 
with a trough goal of 8-10 ng/mL and mycophenolate mofetil 1000 mg twice daily.  
After transplantation, all patients will receive tacrolimus with a trough goal of 8-12 ng/mL, 
mycophenolate mofetil, 1000 mg twice daily, and prednisone daily, tapered from 30 mg to 
5 mg over a 3-months’ period.  
5.3 Concomitant medications and therapies  
Maintenance immunosuppressant medications and standard of care transplant therapies other 
than those described above and other concomitant medications and/or other therapies 
considered necessary for the patient’s welfare will be prescribed at the discretion of the 
investigator.  
All concomitant medications must be recorded on the concomitant medication page in the 
eCRF throughout the trial, beginning from screening to end of trial. Recorded information 
will include indication, name of drug, dose (if available), route of administration and start and 
stop date. 
5.4 Characteristics and Source of Supply 
Imlifidase will be provided by Hansa Biopharma and will be handled according to the 
principles of Good Manufacturing Practice (GMP). Hansa Biopharma will provide the 
investigational pharmacy at trial site with the drug in amounts sufficient for the trial. All 
commercially available NIMPs will be provided by the main pharmacy at the investigational 
site. 
5.4.1 Investigational Medicinal Product 
Imlifidase is supplied as a freeze-dried (lyophilized) powder for concentrate for solution for 
infusion. The excipients are mannitol, polysorbate 80, trometamol, disodium edetate dihydrate 
(EDTA) and hydrochloric acid (for pH adjustment). The excipients are all of pharmacopeial 
quality. 
5.4.2 Non-investigational medicinal products 
Non-Investigational Medicinal Products (NIMPs) will be sourced from pharmacy at the 
investigational site. Essential information about the NIMPs is to be found in the latest 
versions of respective Prescribing Information.  
5.5 Conditions for Storage and Use 
5.5.1 Investigational product 
The investigator will ensure that the IMP will be stored in appropriate conditions in a secure 
location with controlled access. The storage compartment must be monitored on a regular 
basis and the temperature documented. 
Until reconstitution imlifidase should be stored refrigerated at +5°C (±3°C) (+41.0°F 
[±37.4°F]). Reconstitution and dilution should be performed under aseptic conditions. If not 
used immediately, the solution for infusion can be kept for up to 24 hours if refrigerated 


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(+5°C (±3°C)). During this 24-hour period, the solution for infusion may be kept outside the 
refrigerator, below 25°C (+77.0°F), for a maximum of 4 hours. The solution should be stored 
protected from light. Neither powder, nor solution for infusion should be frozen. Prior to 
administration, the solution for infusion should be inspected visually for particulate matter or 
discoloration. The solution should be discarded if any particulate matter or discoloration is 
observed. The entire, fully diluted infusion should be administered with an infusion set and a 
sterile, inline, non-pyrogenic, low protein binding filter (pore size of 0.2 μm). Unused 
portions of the solution for infusion must not be re-used.  
5.5.2 Non-investigational medicinal products 
The investigator will ensure that the NIMPs will be stored according to Prescribing 
Information in a secure location with controlled access and prepared according to label. 
5.6 Packaging and Labeling 
Packaging and labeling of the IMP will be performed in accordance with GMP and national 
regulatory requirements.  
5.7 Blinding 
This is a single arm open-label trial.  
5.8 Compliance, Accountability and Destruction of IMP 
5.8.1 Compliance 
The administration of all medication will be done by a qualified nurse and must be recorded 
in the appropriate sections of the eCRF. The investigational treatment must be documented 
also in the accountability logs. Treatment compliance will be assured by supervised 
administration of the IMP by the investigator or delegate. The dose, date and time of 
administration of the IMP will be checked by the monitor at monitoring visits. 
5.8.2 Accountability and destruction of IMP 
It is the principal investigator’s/institution’s responsibility to establish a system for handling 
trial treatments, including the IMP, to ensure that: 
1. Deliveries are correctly received by a responsible person (e.g. pharmacist or 
designated trial personnel). 
2. Deliveries are recorded. 
3. The IMP is handled and stored safely and properly. 
4. The IMP provided for this trial will be used only as directed in the trial protocol. 
5. The trial personnel will account for all drugs dispensed and returned. Any 
discrepancies must be documented, investigated, and appropriately resolved. 
6. The Investigational pharmacist will maintain and keep the total accountability records. 
Used and unused IMP will be returned or destroyed according to the site’s 
Investigational Pharmacy’s SOP. 


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5.9 Product Quality Complaints 
A product quality complaint (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 related to imlifidase 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 trial subjects and the credibility of 
the trial results. PQCs should be reported using the IMP Issue form to ensure that all relevant 
information is captured. 


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6. TRIAL PROCEDURES 
6.1 Trial Visits  
For each patient the planned duration of the trial, including the screening period and the 
follow-up visit, is about 7 months. A trial flowchart is presented in Appendix 1 and the trial 
procedures/assessments are presented in Appendix 2.   
Assessments of concomitant medication and AEs will be performed at all visits throughout 
the trial.  
Visit 1, 
  
Patients will be informed about the trial, the anticipated benefits and theoretical risks, in 
writing and verbally and sign the informed consent form. The time window for the screening 
visit is 
. 
The screening visit will include the following: 
• Signing of informed consent form 
• SARS-CoV-2 test 
• Demographics (age, gender, race, height, weight) 
• Medical and surgical history (see Section 7.4.6) 
• Physical examination 
• Vital signs (blood pressure, pulse rate, body temperature) 
• Pregnancy test for women of childbearing potential 
• ECG and echocardiogram 
• Safety laboratory tests (Table 1)  
• Virus screening; HIV 1 and 2 antigen/antibody, 4th generation, Hepatitis B and 
Hepatitis C serologies, CMV and EBV serologies 
• Sampling for DSA 
• FCXM test and if possible, CDCXM test 
• Baseline peripheral neuropathy assessment  
• Inclusion and exclusion criteria 
• HRQoL questionnaires  
Visit 2, 
  
The following activities and assessments will be performed: 
 
• Small safety laboratory test; hemoglobin, leucocytes with differential count, 
CRP, creatinine/eGFR (calculated) 


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• Bone marrow biopsy and contemporaneous blood sample prior to initiating 
bortezomib and other medications  
• Start of maintenance immunosuppression prior to bortezomib and belatacept 
(tacrolimus; MMF twice daily) 
• Start of standard prophylaxis for pneumocystis, CMV, and candida infections 
prior to bortezomib when deemed medically appropriate by investigator 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
• Belatacept administered 
  
• Small safety laboratory test; hemoglobin, leucocytes with differential count, 
CRP, creatinine/eGFR (calculated) 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
  
• Small safety laboratory test; hemoglobin, leucocytes with differential count, 
CRP, creatinine/eGFR (calculated) 
• Belatacept administered 
  
• Small safety laboratory test; hemoglobin, leucocytes with differential count, 
CRP, creatinine/eGFR (calculated) 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
  
• Small safety laboratory test; hemoglobin, leucocytes with differential count, 
CRP, creatinine/eGFR (calculated) 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
• ECG and echocardiogram 
  
• Small safety laboratory test; hemoglobin, leucocytes with differential count, 
CRP, creatinine/eGFR (calculated) 
• Belatacept administered 
Visit 3,
 
 
The following activities and assessments will be performed 
 
  
• Review of inclusion/exclusion criteria 
• SARS-CoV-2 test (completed within 5 days before IMP administration) 
• Safety laboratory tests (Table 1)  


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• Pregnancy test for women of childbearing potential, unless woman has been 
hospitalized between V1 and V3 
• Review of medical/surgical history  
• Donor demographics and characteristics, donor kidney conditions and donor HLA-
typing 
• Vital signs (blood pressure, pulse rate, body temperature) 
• Weight 
• Baseline sampling for DSA, PK, PD, and ADA (IgG)  
• FCXM test and if possible, CDCXM test 
• Methylprednisolone and antihistamine will be administered prior to the imlifidase 
infusion. Antibiotic prophylaxis will start prior to imlifidase infusion and the 
treatment will continue until IVIg has been administered or until IgG levels return 
to acceptable values as judged by the investigator. Methylprednisolone will be 
administered according to treatment schedule, see Section 5.2  
• Imlifidase administered, 0.25 mg/kg  
 
The following activities will be performed 
 
 
• Blood pressure and pulse rate at 30 minutes, 1, 2, 4, 24, 48 and 72 hours 
• Body temperature at 2, 4, 24 and 48 hours 
• Safety laboratory tests (Table 1) at 2, 4, 24, 48 and 72 hours 
• Sampling for DSA at 1, 2, 4, 24 and 48 hours  
• Sampling for FCXM test at 1, 2, 4 and 24 hours. The 24-hour sample may be 
drawn between 20-24 hours post-imlifidase.  
• Sampling for PK and PD at 30 minutes, 1, 2, 4, 8, 24, 48 and 72 hours  
• Sampling for ADA (IgG) at 48 hours 
• 
 
• 
 
• 
 
• Methylprednisolone 1000 mg at day of transplantation and thereafter 500 mg daily 
for three days; POD 1-3 
• Transplantation within 24 hours from imlifidase administration  
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered on day 3 (POD 1) 
 


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If the first dose of imlifidase does not have sufficient effect (4-hour crossmatch still positive), 
a second dose of 0.25 mg/kg can be given. If a second dose is administered, 
methylprednisolone and antihistamine treatments prior to imlifidase infusion will be repeated. 
Sampling for a FCXM test will be performed prior to the second dose and at 2 hours after 
dosing. At the same time point sampling for DSA analysis will be performed. 
PK samples will be drawn just prior to the second infusion and 30 minutes after the end of the 
infusion. No other blood samples will be drawn. All subsequent samplings will follow the 
time schedules initiated after the first dosing of imlifidase.  
Visit 4, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Vital signs (blood pressure and pulse rate) 
• Sampling for DSA, PK and PD 
• Methylprednisolone administered 
• rATG administered 
Visit 5, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Vital signs (blood pressure and pulse rate) 
• Sampling for PK, PD and ADA (IgG) 
• Belatacept administered 
• rATG administered 
 
 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
Visit 6, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• rATG administered 


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Visit 7, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Vital signs (blood pressure and pulse rate) 
• Sampling for DSA, PK, PD and ADA (IgG) 
 
Visit 8, 
 
The following activities and assessments will be performed: 
• Small safety laboratory test; hemoglobin, leucocytes with differential count, CRP, 
creatinine/eGFR (calculated) 
• Rituximab administered 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
Visit 9, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Vital signs (blood pressure and pulse rate) 
• Sampling for PK, PD and ADA (IgG) 
 
• Belatacept administered 
Visit 10, 
 
The following activities and assessments will be performed: 
• High dose IVIg administered intravenously. IVIg can be split into two doses given 
over 2 days. 
Visit 11, 
  
The following activities and assessments will be performed: 
• Small safety laboratory test; hemoglobin, leucocytes with differential count, CRP, 
creatinine/eGFR (calculated)  
• Sampling for ADA (IgG) 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
• ECG and echocardiogram 


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Visit 12, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1) 
• Vital signs (blood pressure and pulse rate)  
• Sampling for DSA, PK and ADA (IgG)  
• Sampling for CMV, EBV and BKV PCRs 
Visit 13, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1) 
• Vital signs (blood pressure and pulse rate)  
• Sampling for DSA and ADA (IgG)  
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
• Belatacept administered 
Visit 14, 
  
The following activities and assessments will be performed: 
• Small safety laboratory test; hemoglobin, leucocytes with differential count, CRP, 
creatinine/eGFR (calculated) 
• Peripheral neuropathy assessment prior to bortezomib treatment  
• Bortezomib administered 
Visit 15, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Vital signs (blood pressure and pulse rate) 
• Sampling for DSA and ADA (IgG)  
• Sampling for CMV, EBV and BKV PCRs 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
• 
 


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Visit 16, 
  
The following activities and assessments will be performed: 
• Small safety laboratory test; hemoglobin, leucocytes with differential count, CRP, 
creatinine/eGFR (calculated) 
• Peripheral neuropathy assessment prior to bortezomib treatment 
• Bortezomib administered 
• Belatacept administered 
• ECG and echocardiogram 
Visit 17, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1) 
• 
  
Visit 18, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Sampling for DSA and ADA (IgG)  
• Sampling for CMV, EBV and BKV PCRs 
• Belatacept administered 
• 
 
Visit 19, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Vital signs (blood pressure and pulse rate) 
• Sampling for DSA and ADA (IgG) 
• Sampling for CMV, EBV and BKV PCRs 
• Belatacept administered 
• 
 
 
• 
 


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Visit 20, 
  
The following activities and assessments will be performed: 
• Safety laboratory tests (Table 1)  
• Sampling for DSA and ADA (IgG)  
• 
 
Visit 21, 
  
The following activities and assessments will be performed: 
• Physical examination 
• Vital signs (blood pressure and pulse rate) 
• Body temperature 
• ECG and echocardiogram 
• Safety laboratory tests (Table 1)  
• Peripheral neuropathy assessment  
• Sampling for DSA and ADA (IgG)  
• Sampling for CMV, EBV and BKV PCRs 
• Pregnancy test for women of child-bearing potential 
• 
 
 
• Quality of Life as measured by 
 PROMIS-SF-8a patient questionnaires  
• 
 
 


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7. TRIAL ASSESSMENTS  
The trial assessments are described in the sections below and the timing of these assessments 
are detailed in the trial schedule of events (Appendix 2). The PK sampling must occur as 
close to the scheduled time as possible. To achieve this, other assessments scheduled at the 
same time may be initiated prior to the time point. The timing priority order at each timepoint 
is: 
1. Blood samples for PK and PD 
2. Blood samples for DSA, and FCXM test and if possible, CDCXM 
3. Vital signs 
4. Safety laboratory 
5. Additional laboratory samples 
Whenever possible, all blood and urine samples should be collected in the morning prior to 
administration of any medication. 
7.1 Assessments related to Primary Endpoint 
The primary endpoint is the proportion of patients with DSA rebound during the first 
3 months after transplantation. The definition of rebound is the following (Appendix 3): 
1. When the positive FCXM at screening is due to low titer, non-complement binding 
(C1q-negative) DSAs, rebound is measured as: 
a. Immuno-dominant DSA: a post-transplant MFI value that is ≥50% the pre-
imlifidase value 
OR 
b. Total DSAs: a post-transplant serum where ≥50% of the DSA DSA prior to 
imlifidase treatment have an MFI value that is ≥50% of the pre-transplant MFI 
value AND the sum MFI must be ≥50% of the pre-transplant value  
2. When the positive FCXM at screening is due to high titer, complement binding (C1q-
positive) DSAs, rebound is measured as:  
a. Immuno-dominant DSA: a post-transplant MFI value at 1:16 dilution that is 
≥8000 MFI 
OR 
b. Total DSAs: a post-transplant 1:16 diluted serum where ≥50% of the DSA 
prior to imlifidase treatment have an MFI value that is ≥50% of the pre-
transplant MFI value AND the sum MFI must be ≥8000 
 
An HLA antibody is considered a DSA when the MFI value is at least 3000 in the serum 
analyzed prior to imlifidase treatment. Either a or b must be fulfilled for the increase in DSA 
to be defined as rebound.  


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7.2 Assessments related to Secondary Endpoints 
7.2.1 Frequency of AMR  
The proportion of patients with biopsy proven AMR will be calculated at the following time 
points: 
• During the first 3 months after transplantation (for-cause and protocol biopsy) 
• From transplantation up to 6 months (for-cause and protocol biopsies) 
 
All biopsies will be evaluated according to Banff 2019 (Loupy et al. 2020). The biopsies will 
be performed and evaluated at the site. The date of collection of the biopsies, result of the 
biopsies and the Banff scores will be entered in the eCRF together with the contemporaneous 
DSA measurements performed locally. Contemporaneous kidney function parameters will 
also be collected/calculated in connection with the AMR (p-creatinine/eGFR).  
AMR findings from the kidney biopsies will be reported as AEs/SAEs.  
7.2.2 Proportion of patients with DSA rebound 
The proportion of patients with DSA rebound up to 6 months after transplantation will be 
calculated. The DSA rebound definition is presented in Section 7.1.  
7.2.3 Determination of DSA and complement binding DSA levels  
Samples for determination of anti-HLA-antibodies, titer and complement (C1q) binding 
DSAs will be analyzed centrally, in immunoglobulin (Ig) G single antigen solid-phase 
immunoassay for antibodies to HLA class I and class II (SAB-HLA, C1qScreen, One 
Lambda), to obtain full antibody profiles. The assay allows determination of the mean 
fluorescence intensity (MFI) of antibodies in patient serum reacting to an array of individual 
HLA immobilized to beads. DSAs will be identified by the site using HLA profile data from 
the donor and the patients obtained at the screening visit, together with the SAB analysis data. 
DSAs and HLA-mismatches between donor and patients will be entered in the eCRF.   
The levels of anti-HLA specific DSA will be evaluated at several timepoints from the 
screening visit and throughout the trial. In addition, C1q and titers will be analyzed if an MFI 
level of a DSA is high enough to result in a meaningful analysis (Tambur et al. 2015; Zeevi et 
al. 2013). All subjects will be analyzed for both titers and C1q pre-imlifidase treatment 
regardless of MFI level.   
7.2.4 Analysis of crossmatch tests 
Two crossmatch tests will be performed, flow cytometry (FCXM) and complement dependent 
cytotoxicity (CDC). CDC will only be performed at the screening visit and prior to imlifidase 
dosing, if it is possible. The test(s) will be performed locally.  
7.2.5 Graft survival  
Graft survival 6 months after transplantation, death censored, will be calculated. 


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7.2.6 Patient survival 
Patient survival 6 months after transplantation will be calculated. 
7.2.7 Kidney function  
Evaluation of kidney function will be based on p-creatinine and eGFR according to the 
modification of diet in renal disease (MDRD) equation: 
eGFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
African American) (conventional units) 
The ratio protein/creatinine in urine will also be measured unless patients are anuric. The 
kidney function variables will be analyzed locally.  
7.2.8 Pharmacokinetics 
Determination of concentrations of imlifidase in serum will be analyzed centrally 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. The actual date and time of collection of each sample will be recorded in 
the eCRF.  
7.2.9 Pharmacodynamics  
The IgG levels in serum (pharmacodynamics) will be analyzed centrally by a validated 
electrochemiluminescence based immunoassays using the MSD (Meso Scale Diagnostic) 
technology. Full details of the analytical method and the analysis results will be detailed in a 
separate bioanalytical report. IgG-fragments will be analyzed by protein electrophoresis. The 
sampling date and time will be recorded in the eCRF.  
7.2.10 Immunogenicity 
Determination of anti-drug antibodies (ADA) will be analyzed centrally. Determination of 
anti-imlifidase IgG concentration in serum will be performed using a customized 
ImmunoCAP. Anti-imlifidase IgG will be analyzed throughout the trial. Full details of the 
analytical method used, and the analysis results will be detailed in a separate bioanalytical 
report.   
7.2.11 Safety Laboratory 
The blood samples for determination of clinical chemistry (plasma), hematology (whole 
blood), coagulation (plasma) and urine analysis are presented in Table 1.  


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Table 1. 
Safety laboratory tests  
Clinical chemistry  
Hematology 
Coagulation Urine 
IgG, total 
Hemoglobin 
PT-INR 
Protein/creatinine ratio 
(unless anuric) 
Alkaline phosphatase  
Leucocytes, 
total  
APTT 
 
Alanine aminotransferase 
Thrombocytes  
 
Aspartate aminotransferase 
Differential 
analysis of 
leucocytes 
 
 
Bilirubin, total 
 
 
 
Glucose, fasting 
 
 
 
Sodium 
 
 
 
C-reactive protein (CRP) 
 
 
 
Albumin 
 
 
 
Triglycerides 
 
 
 
Creatinine  
 
 
 
eGFR (calculated from 
creatinine by MDRD 
formula) 
 
 
 
 
A small safety laboratory test will be performed and analyzed prior to administration of 
bortezomib and/or belatacept: hemoglobin, leukocytes with differential count, CRP, 
creatinine/eGFR (calculated).  
All safety samples listed in Table 1 (including small safety laboratory test kit) will be 
analyzed locally at the hospital laboratory. The investigator will review the laboratory results 
and evaluate and document whether the results are normal or abnormal and whether abnormal 
results are non-clinically or clinically significant. Clinically significant abnormal findings will 
be reported as AEs.  
7.2.12 Vital Signs 
Blood pressure, pulse rate, and body temperature will be measured at several time points 
throughout the trial. 
Systolic and diastolic blood pressure will be measured after the patient has been in supine 
position for at least 5 minutes. All recordings will be performed using validated standard 
equipment. Clinically significant abnormal findings will be reported as AEs. 
7.2.13 Adverse Events  
See Section 9. 


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7.2.14 Health Related Quality of Life Questionnaires (HR-QoL) 
At the screening visit and at the last visit, visit 21, the following patient questionnaire will be 
used to assess life participation; PROMIS Social Health domain “Ability to participate in 
social roles & activities, PROMIS-SF-8a” (PROMIS Short Form v2.0) (Appendix 4). The 
guideline for the questionnaire will be followed. 
7.3 Assessments related to Exploratory Endpoints 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4 Other Assessments 
7.4.1 Physical Examination  
A complete physical examination will be performed at the first and last trial visits 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. The results will be reported as 
normal or abnormal in the eCRF. Abnormal findings will be assessed as clinically significant 
or not clinically significant. Clinically significant abnormal findings will be reported as AEs. 
7.4.2 ECG and Echocardiogram 
ECG according to standard procedure at the clinic, will be measured after 10 minutes’-rest at 
the first and the last trial visit. ECG and echocardiogram will be measured after each 
completed bortezomib cycle. Additional ECGs and echocardiograms may be performed by 
the Investigator for safety reasons. 


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The Investigator or designee will evaluate whether the ECG and echocardiogram is normal or 
abnormal and whether it is clinically significant, if abnormal. Clinically significant abnormal 
findings will be reported as AEs.  
7.4.3 Peripheral Neuropathy Assessment 
Peripheral motor neuropathy and peripheral sensory neuropathy will be assessed by the 
Investigator at screening and prior to each bortezomib infusion and graded using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The Investigator or 
designee will evaluate the Grade and whether any change in Grade is clinically significant. 
Clinically significant Grades will be reported as AEs and evaluated for trial stopping criteria. 
7.4.4 Viral surveillance 
Virus screening performed at the screening visit will be HIV 1 and 2 antigen/antibody, 4th 
generation, Hepatitis B and Hepatitis C serologies, CMV and EBV serologies and a SARS-
CoV-2 test. The SARS-CoV-2 test will be repeated prior to administration of imlifidase. 
During the trial CMV, EBV and BKV PCRs will be performed for early diagnosis of viral 
activations/reactivations and early treatment. Extra samples should be taken if indicated. At 
screening, results not older than 6 months can be used. 
7.4.5 Demographics and Baseline Data 
Information about gender, race, age at inclusion, weight and height will be collected at the 
screening visit and the weight will be measured again prior to imlifidase administration. 
Measurements should be taken without shoes. Body Mass Index will be calculated from the 
height and the weight. 
7.4.6 Medical and Surgical History 
Medical and surgical history will be recorded at screening visit, including blood group, 
female history of pregnancy, previous transplantation(s) including all previous donor HLA-
type (if available), previous analyzed DSAs, relationship with donor, previous desensitization 
therapies prior to transplantations, time on dialyses pre- and post-transplantations including 
the present, number of dialyses and number of transfusions within the year of current 
transplantation. HLA-typing of the patient will be performed (complete genotyping; 11 loci; 
A, B, C, DRB1, DRB3/4/5, DQA, DQB, DPA, DPB), and historical calculated PRA 
collected. Clinically significant findings at the screening visit will be documented as Medical 
History in the eCRF.  
7.4.7 Donor data 
Donor demographics and characteristics will be collected as well as donor HLA-typing 
(complete genotyping; 11 loci; A, B, C, DRB1, DRB3/4/5, DQA, DQB, DPA, DPB) and 
kidney condition. Data collection will include the following: demographics (age, gender, 
race), body measurements (weight, height), history of hypertension and diabetes (including 
HbA1c), serum creatinine, HCV screen, CMV and EBV serostatus, blood group, risk 
evaluation of donor, surgical complications, acute kidney injury including acute hemodialysis, 
kidney biopsy performed (date, time and information from the biopsy report). Other data than 
the ones listed here may be collected depending on donor/kidney condition. Total cold 


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ischemia time (if applicable), warm ischemia time (if applicable), whether machine perfusion 
has been used, will also influence the condition of the kidney and will be documented in the 
eCRF.  
All intended donors must be tested for SARS-CoV-2 as soon as possible in accordance with 
the latest version of the “Summary of Current Evidence and Information – Donor SARS-
CoV-2 Testing & Organ Recovery from Donors with a History of COVID-19” by the OPTN 
Ad Hoc Disease Transmission Advisory Committee (DTAC) (Summary of Evidence and 
Information: SARS-CoV-2 (hrsa.gov))a. 
All data collected will be de-identified. The reason for collecting these data is to evaluate the 
conditions of the donated kidney, which may impact the kidney function, possible rejection 
episodes and severity and graft survival after transplantation. 
7.4.8 Pregnancy Test 
Serum β-hCG will be determined for all females of childbearing potential at screening, at 
visit 3 unless the woman has been hospitalized between visit 1 and 3 and at the last visit, 
using validated standard methods. 
 
 
a  The document is updated quarterly by DTAC (COVID-19 - OPTN (hrsa.gov) and 
https://optn.transplant.hrsa.gov/media/kkhnlwah/sars-cov-2-summary-of-evidence.pdf). 


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8. BIOLOGICAL SAMPLING PROCEDURES 
8.1 Volume of Blood 
The total blood volume obtained will be about 850 mL over 6 months. 
8.2 Handling, Storage and Destruction of Biological Samples 
Locally analyzed samples will be discarded immediately after analysis according to local 
laboratory practice. 
Blood, urine, and kidney biopsy samples collected for central analysis will be stored coded by 
the sponsor or by the sponsors contracted laboratory, until completion of the trial report. 
Residual biological specimen will then be discarded or anonymized so that they cannot be 
linked to the patient any longer. Kidney biopsies/stained glass will be sent back to the hospital 
or will be anonymized. Biobank/data protection and local legislation will be adhered to. 
Anonymized samples will be used for methodology development. 
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 patient.  
8.3 Chain of Custody of Biological Samples 
A full chain of custody will be maintained for all samples until they are anonymized. 
The principal investigator will have the responsibility to keep full traceability of collected 
biological samples from the patients while in storage at the site until shipment, and keep 
documentation of receipt of arrival. 
The sample receiver will keep full traceability of the samples while in storage during the 
study until used, discarded or anonymized. 
Hansa Biopharma will keep oversight of the entire life cycle through internal procedures, 
monitoring of trial sites and auditing of external laboratory providers. 
8.4 Withdrawal of Informed Consent for Biological Samples 
If a patient withdraws consent to the use of biological samples during the study, all samples 
that has not yet been analyzed will be discarded. 
 


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9. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
9.1 Definitions 
9.1.1 Adverse event 
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. 
Relationship to the trial drug will be deemed as not related, unlikely related, possibly related 
or probably related. An undesirable medical condition can be symptoms (e.g., nausea and 
chest pain), signs (e.g., tachycardia and enlarged liver) or the abnormal results of an 
investigation (e.g., laboratory findings and electrocardiograms).  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered as the AE rather than the procedure itself.  
In case of a fatality, the cause of death is considered as the AE, and the death is considered as 
its outcome. 
9.1.1.1 Pre-treatment adverse event 
A pre-treatment adverse event is any untoward medical occurrence arising or observed 
between signing of informed consent and administration of the IMP. 
9.1.1.2 Treatment emergent adverse event 
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 
of time 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 of imlifidase is governed by the PD effect and return of IgG, which 
starts 1-2 weeks after treatment. Since the IgG levels are not immediately back to normal, the 
time of residual drug effect is set to 30 days. 
9.1.1.3 Post-treatment emergent adverse event 
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 residual drug effect period and the 
end-of-trial visit. 
9.1.2 Serious adverse event 
A serious adverse event (SAE) is an AE or suspected adverse reaction (SAR) that is 
considered "serious" if, in the view of either the investigator or Hansa Biopharma, it results in 
any of the following outcomes: 
• Results in death 
• Is immediately life-threatening 


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• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above. Examples of 
such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
Life-threatening event: An adverse event or suspected adverse reaction is considered "life-
threatening" if, in the view of either the investigator or Hansa Biopharma, its occurrence 
places the patient or subject at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused 
death.   
Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
Hospitalization: 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 trial, including run-in or washout periods, even if no trial 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 trial including the follow-up period.  
Adverse events can be collected by: 
• The patient’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 patient 
• Investigations and examinations where the findings are assessed by the 
investigator to be clinically significant changes or abnormalities 
• Other information relating to the patient’s health becoming known to the 
investigator (e.g. hospitalization) 


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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 Adverse Events grading (CTCAE v.5.0) 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 trial procedures and/or IMP using the following criteria. 
• Not related:  applicable to an AE that occurs when the patient was not exposed to trial 
treatment or another cause is obvious. 
• Unlikely related:  applicable to an AE that meets the following criteria 
o Does not follow a reasonable temporal sequence from trial drug dosing 
o May readily have been produced by the patient’s clinical state, environmental, 
or toxic factors, or other therapy administered to the subject 
• Possibly related:  applicable to AEs where connection with dosing of trial drug 
appears unlikely but cannot be ruled out.  Applicable to AEs where: 
o It follows a reasonable temporal sequence dosing with trial drug 
o It follows a known pattern of response to trial drug dosing  
• Probably related:  applicable to AEs that are considered, with a high degree of 
certainty, to be related to the trial drug.  Applicable to AEs where 
o It follows a reasonable temporal sequence trial drug dosing 
o It cannot be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
o It follows a known pattern of response to trial drug dosing. 
• For SAEs causal relationship will also be assessed for any trial 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 considered as SAEs.  
If vital signs are judged as clinically significant and/or require a treatment they will be 
captured as AEs and if SAE criteria are fulfilled, they will also be considered as SAEs. 


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Findings from the kidney biopsies (AMR, CMR) will be captured as AEs and if SAE criteria 
are fulfilled, they will also be considered as SAEs. 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE and if SAE 
criteria is fulfilled, they will also be considered as SAEs. 
Wherever possible the reporting investigator uses the clinical term, rather than the laboratory 
term (e.g., anemia versus low hemoglobin value). 
9.2.4 Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the patient’s last AE assessment in the trial are followed up by 
the investigator until stabilization, for as long as medically indicated or until the overall 
clinical outcome of the patient is known, unless the patient is documented as “lost to 
follow-up”. All SAEs and AEs leading to discontinuation should be followed until the event 
resolves or stabilizes.  
Reasonable attempts to obtain this information must be made and documented. Hansa 
Biopharma retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the trial, if judged necessary. 
9.2.5 Reporting of Serious Adverse Events 
SAEs will be recorded from the time of informed consent. 
All SAEs have to be reported, whether or not considered related to the investigational 
product, or to the trial procedure(s), on a separate safety form. It will be recorded in the AE 
module of the eCRF that the AE is considered serious.  
An assigned contract research organization (CRO), PrimeVigilance, will be responsible for 
the SAE handling in accordance with International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) and applicable regulations.  
As soon as the investigator is aware of a potential SAE he/she should contact PrimeVigilance 
by e-mail and in any case no later than 24 hours after the knowledge of such a case. At the 
time of initial reporting the investigator must provide as a minimum requirement, patient 
number, birth date, description of the SAE and a preliminary assessment of causality.  
 
Contact Information: 
CRO: 
PrimeVigilance  
 
  
 
For fatal or life-threatening adverse events where important or relevant information is 
missing, active follow-up is undertaken immediately. Investigators or other site personnel 
inform 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. 


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The SAE reporting procedures are detailed in the trial 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)  
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 IMP caused the adverse event. A serious adverse reaction is considered "unexpected" if it 
is not listed in the reference safety information section of the investigator brochure or is not 
listed at the specificity or severity that has been observed. 
SUSARs with an outcome of death or 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.  
PrimeVigilance will be responsible for ensuring reporting of all SUSAR to RA in accordance 
with ICH GCP and local regulations. The CRO managing the trial sites, VCLS – Voisin 
Consulting Life Sciences, is responsible for informing all participating trial investigators of 
any SUSAR on an expedited basis and in accordance with applicable regulations.  
In addition, Hansa Biopharma is responsible for ensuring information about all SUSAR to all 
investigators, IRB, and ethics committees, as applicable, in all other ongoing studies 
involving imlifidase. In US, it is the responsibility of the site investigator to promptly notify 
the IRB and other appropriate institutional regulatory bodies of all SUSAR received involving 
risk to human subjects as per their applicable requirements. 
The SUSAR reporting procedures are detailed in the trial Safety Management Plan. This plan 
is an agreement between Hansa Biopharma and PrimeVigilance.  
9.3 Adverse Events of Special Interest 
The following events will be assessed as AESI: 
• infusion-related reactions that occurs within 48 hours of imlifidase treatment 
• all events resulting in interruption (pause and/or discontinuation) of imlifidase dose 
(exempted are all interruptions due to problems with e.g. infusion line or pump) 
• severe or serious infections within 30 days after transplantation 
Events resulting in interruption of the imlifidase dose should be reported within 24 hours, as 
described for SAEs in section 9.2.5, and submitted to the sponsor using a safety form. 
9.4 Overdose 
An overdose is a dose in excess of the dose specified in the protocol. There are no data on 
overdosing of imlifidase. There is no known antidote, but depletion of IgG can be restored 
with intravenous immunoglobulin (IVIg). In the event of an overdose the patient should be 
monitored closely and treated symptomatically. This should be recorded as follows:  
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF 


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• An overdose without associated symptoms is only reported in the patient file 
The actual dose administered must be reported in the appropriate module of the eCRF. 
9.5 Pregnancy and Pregnancy Outcome 
Pregnancy is an exclusion criterion, and a pregnancy test is performed at the screening visit 
and prior to infusion of the IMP unless the patient has been hospitalized between the 
screening visit and the infusion. A pregnancy test is also performed at the last trial visit.  
If a patient becomes pregnant during the follow up phase of the trial, the patient will continue 
in the trial according to the trial 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 patient has completed or discontinued the trial. 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-trial pregnancy and considered possibly or probably related to 
the trial drug by the investigator will be reported to Hansa Biopharma (or designee). 


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10. 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 trial. The statistical analyzes will 
include descriptive statistics reflecting the explorative nature of the trial. 
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 trial, missing data will remain missing and no substitution 
of missing data will be performed. 
Patients treated with imlifidase but not transplanted will be included in the safety analysis set 
but not in the full analysis set. These patients will be included in the patient disposition 
presentation.  
10.1 Analysis Sets 
The analysis sets used in the trial are defined below. The decision to exclude patients from 
any of the analysis sets for reasons not covered by the definition will be taken by the clinical 
trial team before database lock and documented in the database lock minutes. Further details 
will be specified in the SAP. 
10.1.1 Full Analysis Set (FAS) 
The FAS will be used to present efficacy endpoints and include all imlifidase treated patients 
who were transplanted. 
10.1.2 Safety Analysis Set 
The safety analysis set comprises of all patients treated with at least one dose of imlifidase, 
belatacept and/or bortezomib and will be used in all presentations of safety data. 
10.1.3 Pharmacokinetic Analysis Set 
The Pharmacokinetic analysis set will be defined by the PK analyst taking admission criteria, 
protocol deviations, and other non-compliance into consideration.  
10.2 Patient characteristics 
The data from the clinical assessments, including demographics and other baseline 
characteristics, will be summarized and listed for each time point using descriptive statistics.  
10.2.1 Patient disposition 
The patient disposition will present number of patients as screened, enrolled, exposed, 
transplanted, completed, withdrawn overall and by reason for withdrawal and finally by each 
of the analysis set.  


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10.2.2 Demographics and Other Baseline Characteristics 
The patient’s demographics and other baseline characteristics will be summarized and listed.  
10.2.3 Recent and Concomitant Medication 
Recent and concomitant medication will be summarized by anatomical therapeutic chemical 
(ATC) code. In addition, listings with ATC code and generic drug name will be prepared. 
10.2.4 Exposure and Compliance 
Exposure of imlifidase will be tabulated and listed.  
10.3 Statistical analysis of Primary Endpoint 
Patients with DSA rebound will be listed and summarized from the time of transplantation up 
to 3 months after transplantation.  
10.4 Statistical analysis of Secondary Endpoints 
10.4.1 Proportion of patients with DSA rebound 
Patients with DSA rebound will be listed and summarized from the time of transplantation up 
to 6 months after transplantation.  
10.4.2 Proportion of patients with biopsy proven AMR 
Patients with AMR will be listed and summarized from the time of transplantation up to 3 
months and up to 6 months after transplantation.  
10.4.3 Proportion of patients with negative crossmatch tests  
Results of crossmatch tests (FCXM) will be listed by patient and summarized. 
10.4.4 Measurements of DSA and complement binding (C1q) DSA levels 
All DSA and complement binding (C1q) DSA MFI values before and after imlifidase 
administration will be summarized by patient and time point and presented as listings.  
10.4.5 Graft survival 
Graft survival will be listed by patient and summarized by end of trial.  
10.4.6 Patient survival 
Patient survival is listed by patient and summarized by end of trial.  
10.4.7 Kidney function 
Kidney function assessed by p-creatinine, eGFR and urine protein/creatinine levels will be 
listed by patient and time point and summarized. 
10.4.8 Pharmacokinetics 
The PK analysis will be performed by Hansa Biopharma. The PK parameters will be 
calculated by non-compartmental analysis (NCA) or compartmental analysis using the 
software WinNonlin® (Pharsight Corporation, US). Actual sampling time points relative to 
dosing will be used for the calculations and on the individual plots of plasma concentration 
versus time. Plasma concentration values below LLQ and missing values (e.g. no blood 


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sample collected or no value obtained at analysis) will be excluded from the calculations. 
Values below LLQ will be represented by ‘0’ (zero) in the arithmetic 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, Vz.  
PK parameters will be presented with number of measurements, number of missing data, 
arithmetic mean, standard deviation, %CV (arithmetic), median, minimum, maximum, 
geometric mean, and %CV (geometric mean). For t½, the harmonic mean will be listed instead 
of the arithmetic and geometric means, and for tmax only the median, minimum, and 
maximum will be presented. 
10.4.9 Pharmacodynamic 
Concentration of IgG will be listed by patient and timepoint and summarized. Scoring of IgG 
fragments will be listed by patient and timepoint and summarized. 
10.4.10 Anti-drug antibody level 
Concentration of anti-imlifidase antibodies will be listed by patient and timepoint and 
summarized. 
10.4.11 Health related quality of life 
HRQoL endpoint is change in patient-reported life participation, as measured by the PROMIS 
Social Health domain “Ability to participate in social roles & activities, PROMIS-SF-8a”, 
from baseline to 6 months after transplantation. HRQoL will be evaluated in the FAS by 
patient questionnaire PROMIS “Ability to participate in social roles activities, PROMIS-SF-
8a” at the screening visit and at the last trial visits (Visit 21). The HRQoL measurements will 
be summarised descriptively. 
10.5 Statistical analysis of Exploratory Endpoints 
 
 
 
 
 
   
  


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10.5.4 Health Related Quality of Life 
 
  
 
10.6 Safety Endpoints 
10.6.1  Analysis of Adverse Events 
10.6.1.1 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. 
10.6.1.2 
Overview of treatment emergent adverse events 
A treatment emergent AE summary table will be presented. The table will include, the 
number of patients reporting an AE, the percentage of patients with an AE and the number of 
events reported, for the following categories: 
• All AEs 
• Severe AEs 
• SAEs 
• Adverse drug reactions 
• AEs leading to withdrawal 
• Deaths 
Adverse drug reactions (ADRs) are defined as events that are considered to be possibly or 
probably related to IMP as judged by the Investigator. 
10.6.1.3 Incidence of treatment emergent adverse events 
Summary tables will be prepared for the incidence of treatment emergent AEs by MedDRA 
system organ class (SOC) and preferred term (PT), presenting number of patients reporting an 
AE, the percentage of patients (%) with an AE and the number of events reported. Summary 
tables will be prepared for: 
• All treatment emergent AEs by SOC and PT 
• AEs by causality 
• AEs by intensity 
• ADRs by SOC and PT 
• ADRs by intensity 
Missing values will be treated as missing except for causality, intensity, seriousness and 
outcome of an AE, in which case, a “worst case” approach will be taken. Thus, if causality is 
missing, the AE will be regarded as related to the IMP, if intensity of the AE is missing, it 


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will be taken to be severe, if seriousness is missing, the AE will be considered to be an SAE 
and if the outcome is missing and no date of outcome is present, the outcome is regarded as 
“not yet recovered”. 
10.6.1.4 Serious adverse events, deaths, and other significant adverse events 
Separate listings will be provided for SAEs, deaths, and other significant AEs if any such 
event occurs. 
10.6.2 Analysis of Other Safety Variables  
10.6.2.1 Vital signs 
Vital signs will be listed by patient and time for each parameter and summarized.  
10.6.2.2 Clinical Chemistry, Hematology, Hemostasis, and Urinalysis 
Clinical chemistry, hematology, hemostasis and urinalysis parameters will be presented in the 
same way as the vital sign parameters.  
10.6.2.3 Electrocardiography  
ECG’s will be categorized as “normal”, “abnormal and not clinically significant”, “abnormal 
and clinically significant” (as judged by the investigator) and summarized. ECG and 
echocardiogram results will be listed by patient and abnormal values will be flagged.  
10.7 Determination of Sample Size 
Due to the exploratory nature of the trial, there is no formal statistical hypothesis. The 
evaluation of DSA rebound will be descriptive. A sample size of 12 patients is considered 
sufficient to provide adequate information for the purpose to the trial.  


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11. TRIAL MANAGEMENT 
11.1 Pre-trial Activities 
Before the first subject is enrolled into the trial, it may be necessary for a representative of 
Hansa Biopharma to visit the investigational trial site for a pre-trial visit to: 
• 
Determine the adequacy of the facilities to give Hansa Biopharma information 
about whether the trial center has knowledge, enough time, a sufficient patient 
pool, and sufficient training to manage the trial in a good way in terms of patient 
inclusion, patient handling, data and overall trial management. 
• 
Discuss with the investigator(s) (and other personnel involved with the trial) their 
responsibilities with regards to protocol adherence and the responsibilities of 
Hansa Biopharma or its representatives.  
Before the first patient is entered into the trial, a Hansa Biopharma representative will review 
and discuss the requirements of the clinical trial protocol and related documents with the 
investigational staff and also train them in any trial specific procedures and system(s) utilized 
at a site initiation visit. 
The principal investigator will ensure that appropriate training relevant to the trial is given to 
all staff, and that any new information relevant to the performance of this trial is forwarded to 
the staff involved. 
The principal investigator will maintain a record of all individuals involved in the trial 
(medical, nursing and other staff). 
11.2 Monitoring of the Trial 
During the trial, a Hansa Biopharma representative will have regular contacts with the trial 
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 Source Data Verification (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 trial) including verification of informed consent of participating 
subjects.  
• 
If a patient 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 
patient. 


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Hansa Biopharma and the monitor will be available between visits if the investigator(s) or 
other staff at the center need information and advice about the trial conduct. Details about 
monitoring are specified in a trial specific monitoring plan. 
11.3 Source Data 
Except for SAEs, which must always be 100% 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 data must be defined in a source data agreement. There must only be one 
source defined at any time for any data elements. 
The investigator will make all the trial-related source data and records available at any time to 
Quality Assurance (QA) auditor(s) mandated by Hansa Biopharma, or to domestic/foreign 
regulatory inspectors or representatives from IRBs who may audit/inspect the trial and to 
permit trial-related monitoring. 
11.4 Audit and Inspection 
The investigator(s)/institution will permit trial-related monitoring, sponsor audit(s), IRB/IEC 
audit(s)/inspection(s), regulatory audit(s)/inspection(s), providing direct access to source 
data/documents. The investigator(s)/institution will give permission to examine, analyze, 
verify, and reproduce any records and reports that are important to evaluation of a clinical 
trial. Any party (e.g. domestic/foreign regulatory authority, sponsor’s monitors and auditors) 
with direct access should take all reasonable precautions within the constraints of the 
applicable regulatory requirements to maintain the confidentiality of patients’ identities and 
sponsor’s proprietary information.   
The purpose of an audit/inspection is to systematically and independently examine all trial-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, GCP, 
guidelines of the International council for Harmonisation (ICH), and any applicable 
regulatory requirements including the Declaration of Helsinki. 
The patients must be informed by the investigator and in the Informed Consent Documents 
that authorized 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/subject number will appear on these copies. 
The investigator must notify Hansa Biopharma without any delay of any inspection by a RA 
or IEC/IRB. 
11.5 Trial Agreements 
The principal investigator must comply with all the terms, conditions, and obligations of the 
clinical trial agreement for this trial. In the event of any inconsistency between this clinical 
trial protocol and the clinical trial agreement, the clinical trial protocol will prevail. 
Agreements between Hansa Biopharma and the principal investigator must be in place before 
any trial-related procedures can take place, or subjects be enrolled. 


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12. DATA MANAGEMENT 
12.1 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 trial database has been 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 trial site’s final and locked data (including audit trail, electronic signature, 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. 
12.2 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. 
12.3 Coding 
For medical coding of AEs, medical history and concomitant medication the most recent 
versions of the Medical Dictionary for Regulatory Activities (MedDRA) and WHO Drug 
Dictionary will be used at trial 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 trial closure/database lock. 
12.4 Handling of External Data 
If central laboratories or other external data transfers from vendors to Hansa Biopharma will 
be transmitted, it will be performed in a secure environment according to a Data Transfer 
Specification. 


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13. CHANGES IN TRIAL CONDUCT OR PLANNED ANALYZES 
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 (IRB and RA, if applicable) have 
been obtained. 
Changes to the protocol to eliminate immediate hazard(s) to trial patients may be 
implemented prior to IRB 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 trial 
master file. 
13.3 Statistical Analysis Plan 
A statistical analysis plan will be prepared and finalized before the database lock. Any 
changes to the SAP will be described in the Clinical Trial Report and/or in the Statistical 
Report. 
13.4 Premature Termination or Suspension of the Trial 
If the trial is prematurely terminated or suspended for any reason, the investigator/institution 
should promptly inform the patients and should assure appropriate therapy and follow-up. 
If the investigator terminates or suspends a trial 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 Trial, the investigator should promptly inform the Institution where applicable. 
In both cases Hansa Biopharma will promptly inform the RA and IRB and provide them with 
a detailed written explanation of the termination or suspension. 
If the RA terminates or suspends its approval/favorable opinion of a trial, 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 Trial Report 
The results from this trial will be reported in a clinical trial report (CSR) within one year after 
end of trial. The report will be submitted for comments and signature to the coordinating 
(signatory) investigator. 
14.2 Confidentiality and Data Ownership 
Any confidential information relating to the IMP or the trial, including any data and results 
from the trial will be the exclusive property of Hansa Biopharma. The investigator and any 
other persons involved in the trial 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 trial, one or more manuscripts for joint publication may be prepared in 
collaboration between the investigator and Hansa Biopharma. Hansa and the investigator may 
publish on the trial progress and outcomes of the trial once both parties have reviewed the 
potential manuscripts and agree on authorship prior to any submissions or publications. 
Any external CRO or laboratory involved in the conduct of this trial has no publication rights 
regarding the trial. 
14.4 Public disclosure 
The trial will be registered in a public clinical trials registry i.e. the US National Institutes of 
Health register ClinicalTrials.gov. 


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15. ETHICAL AND REGULATORY ASPECTS 
15.1 Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that have their origins in 
the World Medical Association Declaration of Helsinki, Ethical Principles for Medical 
Research Involving Human Subjects, Brazil 2013 in compliance with the approved protocol 
and applicable regulatory requirements.  
The responsibilities of the sponsor, the monitor and the investigator are defined in the ICH-
GCP consolidated guideline (E6 R2) and applicable regulatory requirements in the country 
where the trial takes place. The investigator is responsible for adhering to the ICH-GCP 
responsibilities of investigators. 
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 trial patient for injury arising from 
the patient’s participation in the trial. 
15.3 Institutional Review Boards  
All ethical and regulatory approvals must be available before a subject is exposed to any trial-
related procedure, including screening tests for eligibility. 
According to applicable regulatory requirements Hansa Biopharma will: 
• obtain approval from or notify the relevant IRB of the protocol, any amendments, the 
Patient Information Sheet/Informed Consent Form and any advertisements etc. 
• send periodic updates to the IRB if applicable 
• provide investigator(s) with an accurate and complete record of all submissions to the 
local 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 IRB. 
15.4 Regulatory Authority 
According to applicable regulatory requirements Hansa Biopharma will send required 
documents to the RA. Hansa Biopharma will keep an updated list of submission and approval 
dates of all documents submitted to RA. 
15.5 Patient Information and Informed Consent 
Before any trial-related activities and in agreement with applicable regulatory requirements, 
the investigator must give the patient oral and written information about the trial in a form 
that the patient can understand. The Investigator must ensure that the patient is fully informed 
about the aims, procedures, potential risks, any discomforts and expected benefits of the Trial. 
Before consenting, the patient must be left with ample time to consider and to pose questions. 


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It must be emphasized that participation is voluntary and that the patient has the right to 
withdraw from the Trial at any time without prejudice. 
The original, signed Informed Consent Forms must be kept in the Investigator File.  
The patient will receive a copy of the Patient Information and his/her signed Informed 
Consent Form. 
If new information becomes available that may be relevant to the trial patient’s willingness to 
continue participation in the trial, a new Subject Information and Informed Consent Form will 
be forwarded to the IRB (and RA, if required). The trial patients will be informed about this 
new information and re-consent will be obtained. 
15.6 Patient Confidentiality 
Patient 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 patient. 
The trial protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the trial or the data will be released to any 
unauthorized third party without prior written approval of Hansa Biopharma. 
The trial 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 patients 
in this trial. The clinical trial site will permit access to such records. 


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16. ARCHIVING 
16.1 Retention of Clinical Trial Site Documentation 
The investigator is responsible for maintaining all the records, which enable the conduct of 
the trial at the site to be fully understood, in compliance with ICH-GCP. The trial 
documentation including all the relevant correspondence should be kept by the investigator 
for at least 25 years or longer if required by local law after the completion or discontinuation 
of the trial, if no further instructions are given by Hansa Biopharma. 
The investigator is responsible for the completion and maintenance of the confidential patient 
identification code which provides the sole link between named patient source records and 
anonymous eCRF data for Hansa Biopharma. The investigator must arrange for the retention 
of this Patient Identification Log and signed Informed Consent Documents for at least 25 
years or longer if required by local law after the completion or discontinuation of the trial. 
No trial site document may be destroyed without prior written agreement between the 
investigator and Hansa Biopharma. Should the investigator elect to assign the trial 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 Trial Master File 
Hansa Biopharma will archive the Trial Master File in accordance with ICH-GCP and 
applicable regulatory requirements. 


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17. LIST OF REPORTS 
 
 


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18. REFERENCES 
 
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immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA 


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antibodies by IdeS (imlifidase) in chronic kidney disease patients. Am J Transplant. 
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benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med. 
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et al. Eculizumab and splenectomy as salvage therapy for severe antibody-mediated 
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Stites E, Le Quintrec M, Thurman JM. The complement system and antibody-mediated 
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intravenous immune globulin for desensitization during renal transplantation. N Engl J 
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proteinase with unique specificity for immunoglobulin G. EMBO J. 2002;21:1607-15. 
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anti-HLA antibody at high titer is complement binding and associated with increased 
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Transplant. 2013;32:98-105. 
 
 


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19. APPENDICES 
 
 


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