Clinical trial NCT03943589
Conditions: Guillain-Barré Syndrome (GBS)
Sponsor: Hansa Biopharma AB
Start date: 2019-11-12; Completion date: 2024-02-27
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study participants are patients which have been diagnosed with Guillain-Barré Syndrome (GBS) and are planned to receive treatment with intravenous immunoglobulin (IVIg). IVIg is a standard of care treatment for GBS patients. The patients in this study will be treated with the study medicine imlifidase on day 1, and with IVIg on days 3-7.

The purpose of this study is to investigate the safety and effectiveness of imlifidase in patients diagnosed with GBS.

Detailed description:
This is an open-label, single arm, multi-centre, phase II study of imlifidase in combination with standard care IVIg in patients with GBS.

The study will recruit approximately 30 patients who are eligible for IVIg treatment based on current practice (i.e. GBS disability score \>3 and within 10 days of onset of weakness). All patients will receive imlifidase (Day 1) prior to standard care IVIg.

There is growing body of evidence suggesting that GBS is an antibody-mediated disorder. In addition to supportive care, IVIg and Plasma Exchange (PE) are the two main immunological treatment options aimed at attenuating the autoreactive humoral immune response. Imlifidase is an IgG degrading enzyme with strict specificity. The hypothesis is that reduction of pathological antibodies may result in aborted progression, quicker recovery and less severe disease.

Arms: arm 1: One (1) dose of imlifidase, 0.25 mg/kg, will be administered IV over 30 minutes, Day 1.

IVIg, 0.4 g/kg, will be administered for 5 consecutive Days, starting on Day 3 at least 48 h after imlifidase administration.
Interventions: intervention 1: Imlifidase
Intervention descriptions: intervention 1: All subjects will receive imlifidase (Day 1) prior to standard care IVIg

Protocol documents:
Prot_000.pdf: 
Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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CONFIDENTIAL 
 
 
 
Clinical Study Protocol 
 
An open-label, single arm, multi-centre, phase II study investigating safety, 
tolerability, efficacy, pharmacodynamics and pharmacokinetics of 
imlifidase (IdeS) in patients with Guillain-Barré Syndrome (GBS), in 
comparison with matched control patients 
 
Clinical Study Protocol No.: 
15-HMedIdeS-09 
Investigational Medicinal Product: 
Imlifidase 
Phase: 
II 
EudraCT Number: 
2018-001059-12 
Name and Address of Sponsor: 
Hansa Biopharma AB 
P.O. Box 785 
SE-220 07 Lund 
Sweden 
 
 
 
 
 
 
This confidential document is the property of Hansa 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: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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Synopsis 
Name of Sponsor/Company 
Hansa Biopharma AB (hereafter referred to as Hansa Biopharma) 
Title of the study 
An open-label, single arm, multi-centre, phase II study investigating safety, tolerability, efficacy, 
pharmacodynamics and pharmacokinetics of imlifidase (IdeS) in patients with Guillain-Barré 
Syndrome (GBS), in comparison with matched control patients 
Co-ordinating Investigator 
 
Study Site(s) 
Approximately 10 to 15 sites in Europe will be included 
Planned Study Period 
First subject first visit: Q4 2019 
Expected last subject last visit: Q2 2024 
Clinical Phase  
Phase II 
Background and Scientific Justification for Conducting the Study 
Guillain-Barré Syndrome is an acute, paralyzing, inflammatory disease of the peripheral nervous 
system usually preceded by an infection or other immune stimulation that induces an aberrant 
autoimmune response targeting peripheral nerves and their spinal roots. It is the most frequent 
cause of acute neuromuscular weakness in the Western world and can occur at any age. GBS is a 
rapidly progressive disorder often leading to a severe paralysis of the arms and legs. Most GBS 
patients have sensory disturbance (tingling or numbness or ataxia) and pain, and some patients 
have double vision or problems with swallowing. GBS may also paralyse the respiratory 
muscles, leading to intensive care unit admission and mechanical ventilation. The cause of GBS 
is believed to be anti-nerve autoantibody induction by infections that frequently precede the onset 
of disease. 
After onset, GBS patients have highly varying prognoses. Despite modern care, the mortality rate 
is 3-5%. Two thirds of the patients have severe symptoms resulting in their inability to walk 
unaided, and 20-30% require mechanical ventilation for a period ranging from weeks to months. 
Progression of weakness in GBS is usually rapid and reaches a nadir within 4 weeks in the 
majority of patients, but many develop their maximum deficit within 2 weeks. Even with 
subsequent recovery from the acute condition, many patients suffer from long-term 
complications, leaving 20% unable to walk after 6 months. 
To treat GBS, both general medical care and immunological treatment are recommended. 
Supportive care, including monitoring of respiratory function by frequent measurement of vital 
capacity and other clinical outcomes, is needed to prevent or to manage complications. 
Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) are the two main treatment 
options aimed at attenuating the autoreactive humoral immune response. A review performed in 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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2014 showed that IVIg and PE were equally effective in treating GBS and the frequency of 
adverse events was similar with either treatment. Unlike many other neurological conditions with 
an autoimmune basis, patients with GBS do not respond to corticosteroids. 
Although both IVIg and PE are effective treatments for GBS, many patients still have a severe 
disease course and residual deficits, including weakness, sensory signs, fatigue, and pain. 
Moreover, many patients remain otherwise disabled or severely fatigued. Three to 6 years after 
onset, the residual damage arising from GBS still has a great impact on quality of life and the 
ability to perform activities. 
In addition, the clinical response to IVIg varies among patients. About 8-16% of GBS patients 
deteriorate after a standard course of IVIg treatment, even after initial improvement. Therefore, 
there is a great medical need for a more effective treatment of patients with GBS, in particular for 
patients with a severe disease course and poor prognosis. 
Imlifidase is an immunoglobulin G-degrading enzyme derived from Streptococcus pyogenes that 
with strict specificity cleaves all four human subclasses of IgG. Imlifidase cleaves human IgG 
below the hinge region thereby generating one F(ab’)2 fragment and one Fc-fragment which does 
not bind to Fc-receptors and does not activate complement. 
In addition to safety and tolerability, this study is designed to evaluate the efficacy of intravenous 
dosing of imlifidase in GBS subjects. Pharmacokinetics (PK) and pharmacodynamics (PD) will 
be determined. 
The hypothesis is that the reduction in pathological IgG antibodies may translate into aborted 
progression, quicker recovery and less severe disease as compared to standard treatment.  
Objectives 
The objectives of this study are to: 
• Assess safety and tolerability of imlifidase in combination with standard IVIg treatment 
in GBS subjects  
• Evaluate pharmacokinetics of imlifidase 
• Evaluate pharmacodynamic profile of imlifidase 
• Evaluate immunogenicity of imlifidase 
• Evaluate efficacy of imlifidase in subjects with GBS 
• Evaluate quality of life after imlifidase treatment in subjects with GBS 
• Evaluate healthcare resource utilization after imlifidase treatment in subjects with GBS 
• Evaluate the contribution of a dose of imlifidase on outcomes with respect to severity of 
symptoms and recovery time through a comparison with an externally matched cohort of 
GBS subjects   
• Evaluate the effect of imlifidase on exploratory biomarkers 
Endpoints 
The following endpoints will be evaluated: 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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• Type, frequency and intensity of Adverse Event (AE) / Serious Adverse Event (SAE) and 
change from baseline in parameters of clinical laboratory tests, vital signs and 
Electrocardiograms (ECG) 
• Efficacy as assessed by: 
° Proportion of subjects with improvement of one or more grades in disability outcome 
(on the 6-point GBS disability score [DS]) over time  
° Proportion of subjects with improvement of two or more grades in disability outcome 
(on the 6-point GBS DS) over time 
° Proportion of subjects with improvement of three or more grades in disability outcome 
(on the 6-point GBS DS) over time 
° Change in GBS DS over time 
° Proportion of subjects able to walk unaided (GBS DS ≤ 2) over time 
° Time to improvement by at least one, two and three grade(s) on the GBS DS 
° Time to walk independently (GBS DS ≤ 2) 
° Time to run (GBS DS ≤ 1) 
° Proportion of subjects that reach GBS DS ≤ 1 by week 26 
° Proportion of subjects with an increase from baseline in R-ODS scale by at least 6 
points on the centile metric score over time 
° Proportion of subjects with all R-ODS items above 0 at week 26 
° Proportion of subjects requiring mechanical ventilation support (GBS DS 5) 
° Days on mechanical ventilation  
° Days in hospital and in an ICU 
° Changes in MRC sum score over time 
• Pharmacokinetics (PK) parameters Cmax, area under the curve (AUC), tmax, t½, V, clearance 
(CL) of imlifidase 
• Pharmacodynamics (PD) effect on IgG following administration of imlifidase 
• Pharmacodynamics (PD) effect on identified autoantibodies following administration of 
imlifidase 
• Presence of anti-imlifidase antibodies (ADA) 
• Quality of Life as measured by EurQol EQ-5D Health Questionnaire at 4 weeks and later 
Exploratory Endpoint 
• Biomarker evaluation (analysis of anti-ganglioside antibodies and neurofilament light chain 
levels) 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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Methodology 
 
This is an open-label, single arm, multi-centre, phase II study of imlifidase in combination with 
standard care IVIg in subjects within 10 days of onset of GBS.  
The study will recruit approximately 30 subjects with GBS eligible for IVIg treatment based on 
current practice (i.e. GBS disability score >3 at time of screening for enrolment and within 10 
days of onset of weakness). All subjects will receive imlifidase (Day 1) prior to standard care 
IVIg. 
Data from each subject enrolled in this study will, if feasible, be compared with a matched 
external control group from the IGOS database (International Guillain-Barré Syndrome Outcome 
Study, ClinicalTrials.gov Identifier: NCT01582763). If such an indirect comparison study is 
feasible, details pertaining to the comparison will be outlined in a separate non-interventional 
study protocol.  
A Safety Review Committee (SRC) will be established to evaluate safety and tolerability data. 
The Committee will meet after the first subject has completed study visit 6 (Day 29); thereafter 
the SRC will meet after 3, 7 and 12 subjects have completed visit 6 (Day 29). A final SRC 
meeting will be held at the end of the study. The SRC will schedule a meeting as soon as possible 
if an important safety issue arises anytime during the conduct of the study. The SRC will 
comprise of 3 independent physicians. Internal and external experts will be invited to attend the 
meetings on an ad hoc basis, if any issue arises that requires additional expertise. A working 
procedure for the SRC will be described in an SRC Charter. 
Study Procedures/Assessments 
Subjects will be followed clinically on days 1-8, 15, 29, 57, 92 and 180 days after imlifidase 
infusion and additionally with a 360-day telephone contact to assess GBS DS, R-ODS, capture 
health status in a questionnaire, and AEs. 
Disability scores to assess disability status and capture activities and social participation will be 
evaluated during the study. Blood sampling for safety, pharmacokinetics, and pharmacodynamics 
will be collected at multiple time points during the study and the subjects will be closely 
monitored after infusion with imlifidase.  
Safety parameters will be measured up to day 180. Concomitant medication will be recorded 
throughout the study. 
Reporting of adverse events will be done from signing of informed consent and throughout the 
study.  


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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After study completion, all study subjects will be followed up regularly according to clinical 
practice at the site in question.  
Number of subjects 
Approximately 30 adult males or females will be included in the study. 
Diagnosis and criteria for inclusion/exclusion  
Inclusion criteria 
1. Signed Informed Consent obtained before any study-related procedures. 
2. Willingness and ability to comply with the protocol. 
3. Male or female aged ≥18 years at the time of screening. 
4. GBS diagnosed according to National Institute of Neurological Disorders and Stroke 
(NINDS) diagnostic criteria (Asbury et al. 1990). 
5. Onset of weakness due to GBS is not more than 10 days prior to screening. 
6. Unable to walk unaided for >10 meters (grade ≥3 on GBS DS). 
7. IVIg treatment being considered. 
8. Women of child-bearing potential willing or able to use at least one highly effective 
contraceptive method from the day of treatment until at least 6 months after the dose of 
imlifidase if not abstinent. In the context of this study, an effective method is defined as 
those which result in low failure rate (i.e. less than 1% per year) when used consistently 
and correctly.  
9. Men willing to use double-barrier contraception from the day of treatment until at least 
2 months after the dose of imlifidase if not abstinent. 
Exclusion criteria 
1. Previous treatment with imlifidase. 
2. Previous IVIg treatment within 28 days prior to imlifidase treatment.  
3. Subjects who are being considered for, or already on, PE. 
4. Women of childbearing potential who are not willing to use contraception from the 
screening visit until at least 180 days following imlifidase dosing. 
5. Breastfeeding or pregnancy. 
6. Clinical evidence of a polyneuropathy of another cause e.g. diabetes mellitus (except mild 
sensory), alcoholism, vitamin deficiency, or porphyria. 
7. Known selective IgA deficiency. 
8. Hypersensitivity to IVIg or to any of the excipients.  
9. Immunosuppressive treatment (e.g. azathioprine, cyclosporine, mycofenolatemofetil, 
tacrolimus, sirolimus or >20 mg prednisolone daily) during the last month. 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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10. Subject known to have a severe concurrent disease, e.g. malignancy, severe 
cardiovascular disease or severe chronic obstructive pulmonary disease (COPD). 
11. Any condition that in the opinion of the investigator could increase the subject’s risk by 
participating in the study or confound the outcome of the study. 
12. Known mental incapacity or language barriers precluding adequate understanding of the 
Informed Consent information and the study activities. 
13. Subjects with clinical signs of ongoing infection. 
14. Subjects who have received other investigational drugs within 5 half-lives prior to 
imlifidase dosing. 
15. Present or history of thrombotic thrombocytopenic purpura (TTP), or known familial 
history of TTP. 
16. Positive PCR test for SARS-CoV-2 virus infection. 
A subject will be withdrawn from the study if more than 12 days elapse between the onset of 
weakness and planned imlifidase administration, thus preventing that the administration of IVIg 
after imlifidase administration would be later than 14 days after onset of weakness. 
Investigational Medicinal Product(s) 
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 of 0.25 mg/kg. 
Non-IMP 
IVIg is currently the standard of care and will be administered for 5 consecutive days at 0.4 g/kg, 
starting on Day 3. At least 48 hours after imlifidase dosing and within 14 days of onset of 
weakness. 
Methylprednisolone and antihistamine are administered according to the clinical practice at each 
site prior to infusion of imlifidase in order to decrease the risk infusion reaction.  
Duration of treatment  
All subjects will receive a single intravenous infusion of imlifidase over 30 minutes. 
Statistical methods 
Number of subjects 
No formal sample size calculations have been performed for this study. Approximately 
30 evaluable subjects are considered sufficient to provide adequate information about the safety 
and efficacy. 
Efficacy evaluation 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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The clinical outcome of the GBS patients treated with imlifidase and IVIg will be presented 
using descriptive statistics. In addition, a comparison to an externally matched cohort of GBS 
subjects treated with IVIg (IGOS database) will, if feasible, be conducted to evaluate the efficacy 
of imlifidase plus IVIg in combination. If such an indirect comparison study is feasible, details 
pertaining to the comparison will be outlined in a separate non-interventional study protocol.   
Safety evaluation 
Safety data will be presented by descriptive statistics. 
 
 
 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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CONFIDENTIAL 
 
 
Protocol Revision History including Summary of Changes 
Protocol 
Version 
Date 
Including 
Amendment 
Type and No. 
Overall Rationale for Changes 
9.0 
27-JUN-2023 
 
Non-substantial 
amendment 
No. 08 
The planned comparison to an externally matched 
cohort of GBS subjects will be outlined in a 
separate non-interventional study protocol. This 
change leads to modifications to some of the 
objectives and endpoints in the protocol.  
Additional baseline and disease characteristic data 
will be collected from subject’s medical records. 
8.0 
13-DEC-2022 
Non-substantial 
amendment 
No. 07 
(No updated 
protocol 
version) 
Extension of timeline for study completion. 
Number of study sites included in the trial 
updated. 
8.0 
27-JUN-2022 
Non-substantial 
amendment 
No. 06 
(No updated 
protocol 
version) 
Extension of timeline for study completion. 
8.0 
31-JAN-2022 
Substantial 
amendment 
No. 05 
The knowledge of the safety of imlifidase has 
increased since study initiation and the safety 
surveillance is standardised across studies. GBS is 
an acute illness with a well-established standard 
of care including a close monitoring of the 
patients. It is therefore considered appropriate to 
lower the amount of data to be collected in the 
trial focusing on data needed for the evaluation of 
safety and disease response to imlifidase 
treatment. This will make the trial more feasible 
to perform and free resources for patient care.  
The infusion rate of the first dose of IVIg has 
been changed to ensure administration during day 
and evening shift.  
Addition of safety sections describing overdose 
and adverse events of special interest (AESIs). 
Change in CRO responsible for SAE/SUSAR 
reporting. 
Prohibited therapies updated and clarified. 
Extension of study duration. 
7.0 
11-JUN-2021 
Non-substantial 
amendment 
No. 04 
Minor modification to the screening procedures to 
minimise the risk of unnecessary delay of GBS 
treatment 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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CONFIDENTIAL 
 
 
Protocol 
Version 
Date 
Including 
Amendment 
Type and No. 
Overall Rationale for Changes 
6.0 
09-OCT-2020 
Substantial 
amendment 
No. 03 
Request from Safety Review Committee: 
Addition of exclusion criterion 
5.0 
26-AUG-2020 
Substantial 
amendment 
No. 02 
(France only) 
Request from Regulatory Agency: 
Addition of exclusion criterion 
Addition of timeframes to administration of 
antibody-based medicinal products 
(Submitted and approved in France only) 
4.0 
14-NOV-2019 
Substantial 
amendment 
No. 01  
Change of exclusion criteria 
3.0 
13-MAR-2019 
N/A 
Updates included after input from Regulatory 
Agency 
2.0 
22-JAN-2019 
N/A 
Updates included after input from Regulatory 
Agency 
1.0 
16-NOV-2018 
N/A – Original 
Protocol 
N/A 
 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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Table of Content 
Synopsis ................................................................................................................................. 2 
Protocol Revision History including Summary of Changes ............................................. 9 
Table of Content ................................................................................................................. 11 
Abbreviations ...................................................................................................................... 16 
1. 
Introduction .......................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Scientific Rationale ................................................................................................ 19 
1.3 
Study Design and Dose Rationale .......................................................................... 20 
1.4 
Benefit/Risk Aspects .............................................................................................. 21 
2. 
Study Objectives and Endpoints ......................................................................... 23 
2.1 
Objectives ............................................................................................................... 23 
2.2 
Endpoints ............................................................................................................... 23 
2.2.1 
Exploratory Endpoint ............................................................................................. 24 
3. 
Investigational Plan .............................................................................................. 25 
3.1 
Overall Study Design ............................................................................................. 25 
3.1.1 
Screening ................................................................................................................ 25 
3.1.2 
Treatment ............................................................................................................... 25 
3.1.3 
Assessment Procedures .......................................................................................... 25 
3.2 
Safety Review Committee ..................................................................................... 26 
3.3 
Study Timeline ....................................................................................................... 26 
3.4 
Planned Number of Study Sites and Subjects ........................................................ 26 
3.5 
End-of-Study .......................................................................................................... 26 
4. 
Study Population .................................................................................................. 27 
4.1 
Selection Criteria .................................................................................................... 27 
4.2 
Inclusion Criteria .................................................................................................... 27 
4.3 
Exclusion Criteria .................................................................................................. 28 
4.4 
Method of Assigning Subjects to Treatment Groups ............................................. 28 
4.5 
Discontinuation of Subjects and Stopping Criteria ................................................ 29 
5. 
Study Treatment .................................................................................................. 30 
5.1 
Investigational Medicinal Product (IMP) .............................................................. 30 
5.1.1 
Conditions for Storage and Use ............................................................................. 30 
5.1.2 
Packaging and Labelling ........................................................................................ 30 
5.2 
Non-Investigational Medicinal Product(s) ............................................................. 30 
5.2.1 
Prophylactic Antibiotic .......................................................................................... 30 
5.2.2 
Premedication ......................................................................................................... 31 
5.2.3 
Treatment with IVIg ............................................................................................... 31 
5.2.4 
Conditions for Storage and Use ............................................................................. 31 
5.3 
Blinding .................................................................................................................. 31 
5.4 
Compliance, Accountability and Destruction of IMP(s) and NIMP(s) ................. 31 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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5.4.1 
Compliance ............................................................................................................ 31 
5.4.2 
Accountability and Destruction of IMP(s) and NIMP(s) ....................................... 32 
5.5 
Product Quality Complaints (PQC) ....................................................................... 32 
5.6 
Concomitant Medication and Therapies ................................................................ 32 
5.7 
Prohibited Therapies .............................................................................................. 33 
6. 
Study Procedures ................................................................................................. 34 
6.1 
Study Visits ............................................................................................................ 34 
6.2 
Flow Chart .............................................................................................................. 38 
7. 
Study Assessments ................................................................................................ 41 
7.1 
Assessments Related to Endpoints ......................................................................... 41 
7.1.1 
GBS Disability Score (GBS DS) ........................................................................... 41 
7.1.2 
Rasch-Built Linearly Weighted Overall Disability Scale (R-ODS) ...................... 41 
7.1.3 
Medical Research Council sum score (MRC sum score) ...................................... 41 
7.1.4 
Pharmacokinetics (PK) .......................................................................................... 42 
7.1.5 
Pharmacodynamics (PD) ........................................................................................ 42 
7.1.6 
Immunogenicity (ADA) ......................................................................................... 42 
7.1.7 
Days in Hospital and Days in an ICU .................................................................... 43 
7.1.8 
Mechanical Ventilation .......................................................................................... 43 
7.1.9 
Exploratory Biomarkers ......................................................................................... 43 
7.1.10 
EurQol EQ-5D-5L Health Questionnaire .............................................................. 43 
7.2 
Safety Assessments Related to Endpoints ............................................................. 43 
7.2.1 
Adverse Events ...................................................................................................... 43 
7.2.2 
Safety Local Laboratory ......................................................................................... 43 
7.2.3 
Physical Examination ............................................................................................. 44 
7.2.4 
Vital Signs .............................................................................................................. 44 
7.2.5 
ECG ........................................................................................................................ 45 
7.3 
Other Assessments ................................................................................................. 45 
7.3.1 
Demographics and Baseline data ........................................................................... 45 
7.3.2 
Baseline GBS Disease Information ........................................................................ 45 
7.3.3 
Serology ................................................................................................................. 45 
7.3.4 
Pregnancy Test ....................................................................................................... 45 
7.3.5 
Medical History ...................................................................................................... 46 
7.3.6 
Nerve Conduction Study (NCS) ............................................................................ 46 
7.3.7 
SARS-CoV-2 virus PCR-test ................................................................................. 46 
8. 
Biological Sampling Procedures ......................................................................... 47 
8.1 
Handling, Storage and Destruction of Biological Samples .................................... 47 
8.2 
Chain of Custody of Biological Samples ............................................................... 47 
8.3 
Withdrawal of Informed Consent for Biological Samples ..................................... 47 
9. 
Adverse Events and Serious Adverse Events .................................................... 48 
9.1 
Definitions .............................................................................................................. 48 


Hansa Biopharma AB 
Date: 27-JUN-2023 
Project: Imlifidase Other Indication 
Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
Hansa Biopharma Doc No.: 2017-238 
 
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9.1.1 
Adverse Event ........................................................................................................ 48 
9.1.2 
Serious Adverse Event ........................................................................................... 48 
9.2 
Collection and Recording of Adverse Events ........................................................ 49 
9.2.1 
Variables ................................................................................................................ 49 
9.2.1.1 Causality Assessment ............................................................................................. 49 
9.2.2 
Adverse Events Based on Signs and Symptoms .................................................... 50 
9.2.3 
Adverse Events Based on Examinations and Tests ............................................... 50 
9.2.4 
Follow-up of Unresolved Adverse Events ............................................................. 50 
9.2.5 
Reporting of Serious Adverse Events .................................................................... 50 
9.2.6 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) ........ 51 
9.3 
Pregnancy and Pregnancy Outcome ...................................................................... 52 
9.4 
Overdose ................................................................................................................ 52 
9.5 
Adverse Events of Special Interest ........................................................................ 52 
10. 
Study Management .............................................................................................. 53 
10.1 
Pre-Study Activities ............................................................................................... 53 
10.2 
Monitoring of the Study ......................................................................................... 53 
10.3 
Source Data ............................................................................................................ 54 
10.4 
Audit and Inspection .............................................................................................. 54 
10.5 
Study Agreements .................................................................................................. 54 
11. 
Data Management ................................................................................................ 55 
11.1 
Case Report Form .................................................................................................. 55 
11.2 
Provider of Data Management ............................................................................... 55 
11.3 
Coding .................................................................................................................... 55 
11.4 
Handling of External Data ..................................................................................... 55 
12. 
Statistical Methods ............................................................................................... 56 
12.1 
Analysis Sets .......................................................................................................... 56 
12.1.1 
Full Analysis Set (FAS) ......................................................................................... 56 
12.1.2 
PK/PD Analysis Set ............................................................................................... 56 
12.1.3 
Safety Analysis Set ................................................................................................ 56 
12.2 
Subject Characteristics ........................................................................................... 56 
12.2.1 
Subject Disposition ................................................................................................ 56 
12.2.2 
Demographics and Other Baseline Characteristics ................................................ 56 
12.2.3 
Recent and Concomitant Medication ..................................................................... 57 
12.2.4 
Exposure and Compliance ..................................................................................... 57 
12.3 
Statistical Analysis of Endpoints ........................................................................... 57 
12.3.1 
Analysis of Adverse Events ................................................................................... 57 
12.3.1.1 Pre-treatment Adverse Event ................................................................................. 57 
12.3.1.2 Treatment Emergent Adverse Event ...................................................................... 57 
12.3.1.3 Post-treatment Emergent Adverse Events .............................................................. 57 
12.3.2 
Overview of Treatment Emergent Adverse Events ............................................... 58 


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12.3.2.1 Incidence of Treatment Emergent Adverse Events ................................................ 58 
12.3.2.2 Serious Adverse Events, Deaths, and Other Significant Adverse Events .............. 58 
12.3.3 
Analysis of Other Safety Variables ........................................................................ 59 
12.3.3.1 Vital Signs .............................................................................................................. 59 
12.3.3.2 Clinical Chemistry, Haematology and Urinalysis .................................................. 59 
12.3.3.3 Electrocardiography ............................................................................................... 59 
12.3.4 
Efficacy .................................................................................................................. 59 
12.3.4.1 Proportion of subjects with improvement of one, two, three or more grades on 
the GBS DS ............................................................................................................ 59 
12.3.4.2 Change in GBS DS ................................................................................................ 59 
12.3.4.3 Proportion of subjects able to walk unaided (GBS DS ≤ 2) .................................. 59 
12.3.4.4 Time to improvement by at least one, two and three grade(s) on the GBS DS ..... 59 
12.3.4.5 Time to walk independently (GBS DS ≤ 2) ........................................................... 60 
12.3.4.6 Time to run (GBS DS ≤ 1) ..................................................................................... 60 
12.3.4.7 Proportion of subjects that reach GBS DS ≤ 1 by week 26 ................................... 60 
12.3.4.8 Proportion of subjects with an increase from baseline in R-ODS scale ................ 60 
12.3.4.9 Proportion of subjects with all R-ODS items above 0 at week 26 ......................... 60 
12.3.4.10 Proportion of subjects requiring mechanical ventilation support ...................... 60 
12.3.4.11 Days on mechanical ventilation ......................................................................... 60 
12.3.4.12 Days in hospital and days in an ICU ................................................................. 60 
12.3.4.13 Change in MRC sum score ................................................................................ 60 
12.3.4.14 Quality of Life – EQ-5D-5L .............................................................................. 61 
12.3.5 
Pharmacokinetics ................................................................................................... 61 
12.3.6 
Pharmacodynamics ................................................................................................ 61 
12.3.7 
Anti-drug Antibodies ............................................................................................. 61 
12.4 
Statistical Analysis of Exploratory Endpoint(s) ..................................................... 62 
12.5 
Determination of Sample Size ............................................................................... 62 
12.6 
Evaluability of Subjects for Analysis ..................................................................... 62 
13. 
Changes in Study Conduct or Planned Analyses .............................................. 63 
13.1 
Protocol Amendment(s) ......................................................................................... 63 
13.2 
Protocol Deviations ................................................................................................ 63 
13.3 
Statistical Analysis Plan ......................................................................................... 63 
13.4 
Premature Termination or Suspension of the Study .............................................. 63 
14. 
Reporting and Publication .................................................................................. 64 
14.1 
Clinical Study Report ............................................................................................. 64 
14.2 
Confidentiality and Data Ownership ...................................................................... 64 
14.3 
Publications ............................................................................................................ 64 
14.3.1 
Publication Policy .................................................................................................. 64 
14.4 
Public Disclosure ................................................................................................... 64 
15. 
Ethical and Regulatory Aspects .......................................................................... 65 


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15.1 
Ethical Conduct of the Study ................................................................................. 65 
15.2 
Liabilities and Insurance ........................................................................................ 65 
15.3 
Independent Ethics Committee(s) and Institutional Review Boards ..................... 65 
15.4 
Regulatory Authority(ies) ...................................................................................... 65 
15.5 
Subject Information and Informed Consent ........................................................... 66 
15.6 
Subject Participation Card ..................................................................................... 66 
15.7 
Subject Confidentiality .......................................................................................... 66 
16. 
Archiving ............................................................................................................... 68 
16.1 
Retention of Clinical Study Site Documentation ................................................... 68 
16.2 
Study Master File ................................................................................................... 68 
17. 
References ............................................................................................................. 69 
18. 
Attachment ........................................................................................................... 71 
18.1 
Protocol Amendment 08 ........................................................................................ 71 
List of Tables 
Table 1. Study Flow Chart ................................................................................................ 38 
 
List of Figures  
Figure 1. 
Overview of study design ............................................................................. 25 
 


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Abbreviations 
ADA 
Anti-Drug Antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AMAN 
Acute Motor Axonal Neuropathy 
AUC 
Area Under the Curve 
CKD 
Chronic Kidney Disease 
CL 
Clearance  
Cmax 
Maximum serum concentration 
CRO 
Contract Research Organisation 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
EuroQoL EQ-5D Health Questionnaire 
FAS 
Full Analysis data Set 
GBS 
Guillain-Barré Syndrome 
GBS DS 
Guillain-Barré Syndrome disability score 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IdeS 
Immunoglobulin G degrading enzyme of Streptococcus pyogenes 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IGOS 
International Guillain-Barré syndrome Outcome Study 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board  
IVIg 
Intravenous Immunoglobulin 
MedDRA 
The Medical Dictionary for Regulatory Activities 
MFS 
Miller Fisher Syndrome 
MRC 
Medical Research Council sum score 
NCS 
Nerve Conduction Studies 
NIMP 
Non-Investigational Medicinal Products 
NOAEL 
No Observed Adverse Effect Level 
PD 
Pharmacodynamics 
PE 
Plasma Exchange 
PP 
Per Protocol 
PK 
Pharmacokinetics 
PQC 
Product Quality Complaint 
PT 
Preferred Term  
RA 
Regulatory Authority 
R-ODS 
Rasch- built Overall Disability Scale 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


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SDV 
Source Document Verification 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
t½ 
Terminal half-life 
tmax 
Time to maximum plasma concentration 
TTP 
Thrombotic thrombocytopenic purpura 
V 
Distribution volume 
 
 
 


Hansa Biopharma AB 
Date: 27-JUN-2023 
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1. INTRODUCTION 
The company code initially used for the active substance in this project was HMED-IdeS 
(sometimes abbreviated to IdeS) and thus many reports refer to this name. 
The International Non-proprietary Name imlifidase was recently assigned for the active 
substance, and this name will be used in the following.  
1.1 Background  
Disease and patient population 
Guillain-Barré Syndrome (GBS) is an acute, paralyzing, inflammatory peripheral disease of 
the peripheral nervous system usually preceded by an infection or other immune stimulation 
that induces an aberrant autoimmune response targeting peripheral nerves and their spinal 
roots. It is the most frequent cause of acute neuromuscular weakness in the Western world 
and can occur at any age (Willison et al. 2016). GBS is a rapidly progressive disorder often 
leading to a severe paresis of the arms and legs. Most GBS patients also have sensory 
disturbance (tingling or numbness or ataxia) and pain, and some patients have double vision 
or problems with swallowing. GBS may also involve the respiratory muscles, leading to 
intensive care unit (ICU) admission and mechanical ventilation.  
After onset, GBS patients have highly varying prognoses. Despite modern care, the mortality 
rate is 3-5%. Two thirds of the patients have severe symptoms resulting in their inability to 
walk unaided (van Leeuwen et al. 2016), and 20-30% require mechanical ventilation for a 
period ranging from weeks to months. Progression of weakness in GBS is usually rapid and 
reaches a nadir within 4 weeks in the majority of patients, but many develop their maximum 
deficit within 2 weeks (Willison et al. 2016; van Leeuwen et al. 2016). Even with subsequent 
to recovery from the acute condition, many patients suffer from long-term complications, 
leaving 20% unable to walk after 6 months. 
There are two major GBS electrophysiological subtypes as determined by Nerve Conduction 
Studies (NCS) and Electromyography (EMG):  
• Demyelinating variant, referred to as acute inflammatory demyelinating 
polyneuropathy (AIDP) 
• Axonal variants with two major subtypes, Acute Motor Axonal Neuropathy (AMAN) 
and Acute Motor and Sensory Axonal Neuropathy (AMSAN) 
Clinically, there are multiple GBS subtypes or variants, with the best known being the Miller 
Fisher Syndrome (MFS) and the pure motor form (van den Berg et al. 2014; Willison et al. 
2016). In addition, GBS is highly variable with respect to disease severity, clinical course and 
outcome.  
Current Treatments 
To treat GBS, both general medical care and immunological treatment are indicated. 
Supportive care, including monitoring of respiratory function by frequent measurement of 
vital capacity and other clinical outcomes, is needed to prevent or to manage complications 


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(Willison et al. 2016). Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) are the 
two main treatment options aimed at attenuating the autoreactive humoral immune response. 
A Cochrane review performed in 2014 (Hughes et al. 2014), showed that IVIg and PE were 
equally effective in treating GBS, and the frequency of adverse events (AE) was similar with 
either treatment. Unlike many other neurological conditions with an autoimmune basis, 
patients with GBS do not respond to corticosteroids. 
Although both IVIg and PE are effective treatments for GBS, many patients still have a severe 
disease course and residual clinical deficits, including weakness, sensory signs, fatigue, and 
pain (van den Berg et al. 2014; Willison et al. 2016; van Leeuwen et al. 2016). Moreover, many 
patients remain otherwise disabled or severely fatigued. Three to 6 years after onset, the residual 
damage arising from GBS still has a great impact on quality of life and the ability to perform 
activities (van Doorn et al. 2010). 
In addition, the clinical response to IVIg varies among patients. About 8-16% of GBS patients 
deteriorate after a standard course of IVIg treatment, even after initial improvement (van 
Doorn et al. 2010). Therefore, there is a great medical need for a more effective treatment of 
patients with GBS, in particular for patients with a severe disease and poor prognosis 
(Walgaard et al. 2011). 
1.2 Scientific Rationale 
There is growing body of evidence to suggest that GBS is an antibody-mediated disorder in 
which complement fixing, Immunoglobulin G (IgG) 1/3 subclass, anti-ganglioside antibodies 
play a major role in the pathogenesis. These antibodies are also directed against epitopes 
present on peripheral nerves and are induced through the mechanism including molecular 
mimicry with bacterial lipo-oligosaccharides (Willison et al. 2016; Kieseier et al. 2018). The 
specificity of these antibodies largely determines the clinical spectrum (pure motor, sensory-
motor, MFS, etc.). Current research into the pathogenesis of GBS is primarily focused on 
identifying humoral immunity and downstream effector pathways, including complement 
activation.  
Imlifidase 
Imlifidase is an immunoglobulin G-degrading enzyme derived from Streptococcus pyogenes 
(IdeS) that cleaves all four human subclasses of IgG with strict specificity and comparable 
efficacy. Imlifidase cleaves human IgG below the hinge region thereby generating one F(ab’)2 
fragment and one Fc-fragment which does not bind to Fcγ-receptors and does not activate 
complement. Thus, the proteolytic activity of imlifidase on IgG molecules prevents IgG 
mediated phagocytosis, antibody-dependent cellular cytotoxicity and complement mediated 
injury (Winstedt et al. 2015; Jarnum et al. 2017). Imlifidase is highly specific towards IgG; 
other Ig molecules, i.e. IgA, IgD, IgE and IgM, are not cleaved, and no other substrates have 
been identified. In addition to the restricted target specificity of imlifidase, the speed of the 
reaction is a major advantage of the substance. Within a few hours after dosing, the entire 
intra- and extravascular pool of IgG is fully cleaved into F(ab’)2 and Fc fragments, thereby 
creating a window where IgG levels are kept very low, lasting for approximately one week. It 
is therefore hypothesised that imlifidase can rapidly and efficiently deplete the autoreactive 
IgG pool in GBS patients, thereby interrupting the disease process. 


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Using sera from 15 patients diagnosed with GBS or MFS it was demonstrated that imlifidase 
efficiently cleaved IgG and blocked complement activation mediated by anti-ganglioside IgG 
antibodies (Takahashi et al. 2015).  
Furthermore, treatment with imlifidase in a rabbit model of AMAN significantly reduced the 
disruption of Nav channels as well as activated C3 deposition at the anterior spinal root nodes 
of Ranvier. The clinical recovery of AMAN rabbits was significantly promoted, and there 
were significantly lower frequencies of axonal degeneration in anterior spinal roots of AMAN 
rabbits. The data support that imlifidase treatment reduces the anti-ganglioside IgG-mediated 
impairment in peripheral nerves (Wang et al. 2017). 
Six studies with imlifidase have been completed, one in healthy subjects as well as four in 
sensitized chronic kidney disease (CKD) subjects and one in asymptomatic antibody-
mediated thrombotic thrombocytopenic purpura (TTP) subjects. 
Two studies with imlifidase are ongoing, one investigator-initiated phase II study to evaluate 
the efficacy and safety of imlifidase in anti-GBM disease (Glomerular Basement 
Membrane/Goodpasture’s disease) with adverse renal prognosis and one prospective, 
observational long-term follow up study of patients treated with imlifidase prior to kidney 
transplantation. 
1.3 Study Design and Dose Rationale  
This is an open-label, single-arm, multi-center, phase II study of imlifidase added to standard 
care IVIg in subjects within 10 days of onset of GBS.  
Approximately 30 subjects will be included in this study.  
In addition to safety and tolerability, another objective of the proposed study is efficacy. 
Other objectives include pharmacokinetics (PK) and pharmacodynamics (PD). 
Eligible subjects must have been diagnosed with GBS and be unable to walk unaided for 
>10 meters (grade ≥3 on Guillain-Barré Syndrome disability score (GBS DS)). Onset of 
weakness should be within 10 days before inclusion. 
Healthy subjects have been dosed with 0.01-0.24 mg/kg, and patients up to 2 x 0.25 and 1 x 
0.5 mg/kg of imlifidase. Rapid and complete cleavage of IgG to F(ab’)2 and Fc fragments was 
demonstrated at a dose of 0.25 mg/kg. In this study, each patient will receive one dose of 
0.25 mg/kg imlifidase administered as an intravenous infusion over 30 minutes on Day 1. 
A standard 5-day IVIg regimen (0.4 g/kg/day for 5 consecutive days) will be initiated at least 
48 hours after imlifidase dosing. As subjects will be included and dosed with imlifidase 
within 12 days of onset of weakness, IVIg treatment will be initiated in all subjects within 
14 days from onset of weakness which is within the time frame for which standard treatment 
has been shown to have a beneficial effect on the outcome (Hughes et al. 2014).  
Based on the current knowledge, including experience from completed and ongoing clinical 
studies, it is expected that imlifidase will degrade IgG into F(ab’)2 and Fc fragments across all 
compartments allowing a rapid and potent inactivation of any pathological GBS auto-
antibodies. This may in turn prevent irreversible nerve damage. 




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C, and HIV, and subjects having clinical signs of ongoing infection will be excluded from the 
study. Subjects will also be screened for SARS-CoV-2, and subjects with a positive test will 
not be included in the study. As SARS-CoV-2-naïve subjects do not have any IgG antibodies 
towards the virus, and since imlifidase does not prevent IgG synthesis, administration of 
imlifidase is not considered to have any impact on patient safety should the subject 
subsequently become infected with SARS-CoV-2. As IVIg treatment will be started at least 
48 hours post dosing of imlifidase, normal IgG levels are expected to be restored shortly after 
and minimize the risk of infection. 
In a previous study with imlifidase in patients with TTP, 2 patients developed rash and 
arthralgia, with one of the subjects experiencing fever as well. The sponsor cannot exclude 
that the underlying disease of TTP was a factor in the development of serum sickness in these 
patients since none of 27 other subjects treated with imlifidase without concomitant 
immunosuppression showed signs of serum sickness. Of note is that at the time of these 
events only very low levels of imlifidase were left in circulation, not sufficient to form 
immune complexes with Anti-Drug Antibody (ADA). Serum sickness has not been observed 
in toxicology studies. 
The rationale for at least 48 hours between imlifidase and IVIg dosing is based on the 
pharmacokinetic and pharmacodynamic profiles of imlifidase. In addition, in one clinical 
study (14-HmedIdeS-04) alemtuzumab was given four days post dosing of imlifidase, and in 
another clinical study (15-HmedIdeS-06) IVIg was given seven days post dosing of 
imlifidase. As there is no data supporting initiation of IVIg treatment earlier than 48 hours 
post imlifidase dosing, a subject who deteriorates very quickly during the first 24 hours after 
imlifidase administration may be treated with PE to remove any remaining imlifidase before 
initiating IVIg treatment according to standard of care. This decision is made at the discretion 
of the investigator. 
The subjects will be closely monitored for all adverse events. The principal investigators will 
make sure that sufficient facilities and procedures are available to handle emergency 
situations including unexpected adverse reactions during the study. Furthermore, all subjects 
will be included in a long-term safety follow-up approximately 12 months after dosing. 
Adverse events after administration of IVIg do occur but are seldom serious. There is a very 
small risk of anaphylaxis, often in subjects with severe IgA deficiency. Other reported side 
effects include headache, myalgia, nausea, transient hypotension and flushing (all of which 
can be corrected by slowing the infusion rate), meningism, aseptic meningitis, skin reactions 
(especially eczema), neutropenia, worsening of renal failure, and thromboembolic events 
(Deep vein thrombosis (DVT), Myocardial Infarction (MI) and stroke) attributable to 
hyperviscosity (Hughes et al. 2014). To reduce the risk of thromboembolic events patients 
will be managed according to standard of care for GBS, i.e. patients who are unable to walk 
independently will receive subcutaneous low-molecular-weight heparin. 
A guidance for the investigator and Reference Safety Information regarding imlifidase can be 
found in the Investigator’s Brochure. 
 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Objectives 
The objectives of this study are to: 
• Assess safety and tolerability of imlifidase in combination with standard IVIg 
treatment in GBS subjects  
• Evaluate pharmacokinetics of imlifidase 
• Evaluate pharmacodynamics profile of imlifidase 
• Evaluate immunogenicity of imlifidase 
• Evaluate efficacy of imlifidase in subjects with GBS 
• Evaluate quality of life after imlifidase treatment in subjects with GBS 
• Evaluate healthcare resource utilization after imlifidase treatment in subjects with 
GBS 
• Evaluate the contribution of a dose of imlifidase on outcomes with respect to severity 
of symptoms and recovery time through a comparison with an externally matched 
cohort of GBS subjects   
• Evaluate the effect of imlifidase on exploratory biomarkers 
2.2 Endpoints 
The following endpoints will be evaluated: 
• Type, frequency and intensity of AE / Serious Adverse Event (SAE) and change from 
baseline in parameters of clinical laboratory tests, vital signs and Electrocardiograms 
(ECG) 
• Efficacy as assessed by: 
° 
Proportion of subjects with improvement of one or more grades in disability 
outcome (on the 6-point GBS DS) over time 
° 
Proportion of subjects with improvement of two or more grades in disability 
outcome (on the 6-point GBS DS) over time  
° 
Proportion of subjects with improvement of three or more grades in disability 
outcome (on the 6-point GBS DS) over time 
° 
Change in GBS DS over time 
° 
Proportion of subjects able to walk unaided (GBS DS ≤ 2) over time 
° 
Time to improvement by at least one, two and three grade(s) on the GBS DS 
° 
Time to walk independently (GBS DS ≤ 2)  


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° 
Time to run (GBS DS ≤ 1) 
° 
Proportion of subjects that reach GBS DS ≤ 1 by week 26 
° 
Proportion of subjects with an increase from baseline in R-ODS scale by at least 
6 points on the centile metric score over time 
° 
Proportion of subjects with all R-ODS items above 0 at week 26 
• Proportion of subjects requiring mechanical ventilation support (GBS DS 5) 
° 
Days on mechanical ventilation  
° 
Days in hospital and in an ICU 
° 
Changes in MRC sum score over time 
• Pharmacokinetics (PK) parameters maximum serum concentration (Cmax), area under 
the curve (AUC), time to maximum plasma concentration (tmax), terminal half-life (t½), 
V, clearance (CL), of imlifidase 
• Pharmacodynamics (PD) effect on IgG following administration of imlifidase 
• Pharmacodynamics (PD) effect on identified autoantibodies following administration 
of imlifidase  
• Presence of anti-imlifidase antibodies (ADA)  
• Quality of Life as measured by EurQol EQ-5D Health Questionnaire at 4 weeks and 
later 
2.2.1 Exploratory Endpoint 
• Biomarker evaluation (analysis of anti-ganglioside antibodies and neurofilament light 
chain levels) 
 


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3. INVESTIGATIONAL PLAN 
3.1 Overall Study Design  
 
 
Figure 1. 
Overview of study design 
 
 
This is an open-label, single arm, multi-centre, phase II study of imlifidase in combination 
with standard care IVIg in subjects within 10 days of onset of GBS.  
A detailed analysis plan is contained in the Statistical Analysis Plan (SAP). Data from each 
subject enrolled in this study will, if feasible, be compared with an external control group 
consisting of matched subjects from the IGOS database (Jacobs et al. 2017) (International 
Guillain-Barré Syndrome Outcome Study, ClinicalTrials.gov Identifier: NCT01582763). If 
such an indirect comparison study is feasible, details pertaining to the comparison will be 
outlined in a separate non-interventional study protocol. 
3.1.1 Screening 
The study will recruit approximately 30 subjects with GBS eligible for IVIg treatment based 
on current practice (i.e. GBS disability score >3 at time of screening for enrolment and within 
10 days of onset of weakness). Any male or female subject aged ≥18 years who presents with 
symptoms of GBS will be evaluated for eligibility to enter the study.  
3.1.2 Treatment 
All subjects will receive imlifidase (Day 1) prior to standard care IVIg (see Section 5.2). 
Scores to assess disability status and capturing activities and social participation will be 
evaluated. Blood samples for safety, pharmacokinetics, and pharmacodynamics will be 
collected, and subjects will be closely monitored after infusion with imlifidase. 
3.1.3 Assessment Procedures 
The subjects will be followed clinically on Days 1-8, 15, 29, 57, 92 and 180 days after 
imlifidase infusion and additionally with a 360-day telephone contact to assess GBS DS, 
R-ODS, capture health status in a questionnaire and AEs. 
After study completion, all study subjects will be followed up regularly according to clinical 
practice at the site in question.  


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3.2 Safety Review Committee 
A Safety Review Committee (SRC) will be established to evaluate safety and tolerability data. 
The Committee will meet after the first subject has completed study visit 6 (Day 29) 
thereafter the SRC will meet after 3, 7 and 12 subjects have completed visit 6 (Day 29). A 
final SRC meeting will be held at the end of the study. The SRC will schedule a meeting as 
soon as possible if an important safety issue arises anytime during the conduct of the study. 
The SRC will comprise of 3 independent physicians. Internal and external experts will be 
invited to attend the meetings on an ad hoc basis, if any issue arises that requires additional 
expertise. A working procedure for the SRC will be described in an SRC Charter. 
3.3 Study Timeline 
The expected study start is Q4 2019. Expected last subject last visit is Q2 2024 including 
recruitment and 12 months follow up for included subjects.  
3.4 Planned Number of Study Sites and Subjects 
This is a multi-center study. Approximately 10 to 15 sites in Europe will be included. 
Approximately 30 adult male or female subjects will be enrolled in the study. 
3.5 End-of-Study 
The planned end-of-study is defined as the last telephone contact has been completed (visit 10). 
Hansa Biopharma will ensure that an end-of-study notification is submitted to the concerned 
Regulatory Authority (RA) and Independent Ethics Committee (IEC)/ Institutional Review 
Board (IRB) according to local requirements. 
For procedures in case of premature termination or suspension of the study, see Section 13.4. 
 


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4. STUDY POPULATION 
4.1 Selection Criteria 
To be eligible for the study, subjects must meet all inclusion criteria and no exclusion criteria. 
Those subjects who pass the screening phase of the study will receive imlifidase. Imlifidase 
administration will commence as soon as possible after consent is obtained (within 24 hours) 
and within 12 days of onset of weakness due to GBS.   
4.2 Inclusion Criteria 
1. Signed Informed Consent obtained before any study-related procedures. 
2. Willingness and ability to comply with the protocol. 
3. Male or female aged ≥18 years at the time of screening. 
4. GBS diagnosed according to National Institute of Neurological Disorders and Stroke 
(NINDS) diagnostic criteria (Asbury et al. 1990). 
5. Onset of weakness due to GBS is not more than 10 days prior to screening. 
6. Unable to walk unaided for >10 meters (grade ≥3 on GBS DS). 
7. IVIg treatment being considered. 
8. Women of child-bearing potential willing or able to use at least one highly effective 
contraceptive method from the day of treatment until at least 6 months after the dose 
of imlifidase if not abstinent. In the context of this study, an effective method is 
defined as those which result in low failure rate (i.e. less than 1% per year) when used 
consistently and correctly such as:  
• combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation  
° 
oral  
° 
intravaginal  
° 
transdermal  
• progestogen-only hormonal contraception associated with inhibition of ovulation  
° 
oral  
° 
injectable  
° 
implantable  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS)  
• bilateral tubal occlusion  
• vasectomized partner 
• true abstinence: When this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (such as calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 


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9. Men willing to use double-barrier contraception from the day of treatment until at 
least 2 months after the dose of imlifidase if not abstinent. 
4.3 Exclusion Criteria 
1. Previous treatment with imlifidase. 
2. Previous IVIg treatment within 28 days prior to imlifidase treatment.  
3. Subjects who are being considered for, or already on, PE. 
4. Women of childbearing potential who are not willing to use contraception from the 
screening visit until at least 180 days following imlifidase dosing. 
5. Breastfeeding or pregnancy. 
6. Clinical evidence of a polyneuropathy of another cause e.g. diabetes mellitus (except 
mild sensory), alcoholism, vitamin deficiency, or porphyria. 
7. Known selective IgA deficiency. 
8. Hypersensitivity to IVIg or to any of the excipients 
9. Immunosuppressive treatment (e.g. azathioprine, cyclosporine, mycofenolatemofetil, 
tacrolimus, sirolimus or >20 mg prednisolone daily) during the last month. 
10. Subject known to have a severe concurrent disease, e.g. malignancy, severe 
cardiovascular disease and severe chronic obstructive pulmonary disease (COPD). 
11. Any condition that in the opinion of the investigator could increase the subject’s risk 
by participating in the study or confound the outcome of the study. 
12. Known mental incapacity or language barriers precluding adequate understanding of 
the Informed Consent information and the study activities. 
13. Subjects with clinical signs of ongoing infection. 
14. Subjects should not have received other investigational drugs within 5 half-lives prior 
to imlifidase dosing. 
15. Present or history of thrombotic thrombocytopenic purpura (TTP), or known familial 
history of TTP. 
16. Positive PCR test for SARS-CoV-2 virus infection. 
A subject will be withdrawn from the study if more than 12 days elapse between the onset of 
weakness and planned imlifidase administration, thus preventing that the administration of 
IVIg after imlifidase administration would be later than 14 days after onset of weakness. 
4.4 Method of Assigning Subjects to Treatment Groups 
Not applicable since this is a single-arm, non-randomised study. 


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4.5 Discontinuation of Subjects and Stopping Criteria  
A subject will be withdrawn from the study if more than 12 days elapse between the onset of 
weakness and planned imlifidase administration. 
The subjects have the right to withdraw from the study at any time for any reason without the 
need to justify their decision. However, the investigator should record the reason for the 
subject’s withdrawal, if possible. The investigator also has the right to withdraw subjects. In 
either event, the investigator must notify Monitor.  
Minor infusion-related reactions have been observed in some patients receiving imlifidase for 
other indications. These are usually mild and include chest discomfort, flushing, pharyngeal 
oedema and dyspnea. More severe reactions can occur. 
If a minor infusion-related reaction (Common Terminology Criteria for Adverse Events 
(CTCAE) grade 1 or 2) is suspected the infusion should be temporarily stopped and the 
patient should be observed for clinical signs of allergic reactions. If a significant infusion-
related reaction or anaphylactic reaction occurs (CTCAE grade 3 or higher) then the 
imlifidase therapy should be discontinued immediately.  
The patient should be treated by the investigator according to local practice for an allergic 
reaction or a severe allergic reaction/anaphylaxis, respectively. If the symptoms resolve, the 
infusion can be resumed. If the symptoms persist or worsen, then the drug infusion should not 
be restarted. 
A subject that prematurely discontinues participation must, if possible, be called in for a last 
visit and undergo the assessments and procedures scheduled for visit 9 (180 days after 
treatment with imlifidase). Even if the subject is not able to attend, the End-of-Study Form in 
the electronic Case Report Form (eCRF) must be completed. Subjects who for a medical 
reason cannot comply with the protocol procedures will be followed by best procedure to 
retrieve safety and efficacy data. 
Subjects withdrawn from the study before visit 6 (29 days after treatment with imlifidase) 
may be replaced, not using the same subject number, in order to reach approximately 
30 evaluable subjects.  


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5. STUDY TREATMENT 
5.1 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. 
The excipients are: mannitol, polysorbate 80, Tris (tris(hydroxymethyl)aminomethane) buffer 
and ethylenediaminetetraacetic acid (EDTA). The excipients are all Pharmacopoeial quality. 
Imlifidase for infusion will be prepared by the pharmacist or study nurse and the 
administration will be performed by the study nurse or physician at site. Details on 
preparation, labelling, administration and accountability of imlifidase are described in the 
pharmacy manual that will be provided to the site and pharmacy prior to inclusion of the first 
subject.  
All subjects will receive an intravenous dose of imlifidase, 0.25 mg/kg, administered over 
30 minutes. 
5.1.1 Conditions for Storage and Use 
The vials with imlifidase should be stored in a refrigerator at +2°C to +8°C.  
For information on preparation, storage and use of the solution for infusion it is referred to the 
Pharmacy Manual.  
The investigator will ensure that the medicinal products always will be stored in appropriate 
conditions in a secure location. The storage compartment shall be monitored regularly, and 
the temperature shall be documented. 
5.1.2 Packaging and Labelling 
Packaging and labelling of the medicinal products will be performed in accordance with Good 
Manufacturing Practice (GMP) and national regulatory requirements.  
5.2 Non-Investigational Medicinal Product(s) 
Non-Investigational Medicinal Products (NIMPs) will be sourced from the investigational site 
pharmacy supply. Essential information about the NIMPs is to be found in the latest version 
of respective Summary of Product Characteristics. 
The subjects will be treated with the following NIMPs (other treatments may be used as 
required at the investigators discretion):  
5.2.1 Prophylactic Antibiotic  
Since imlifidase effectively removes the IgG pool, there may be an increased risk of infection. 
To minimize the risk for bacterial infections all study subjects will receive prophylactic 
antibiotics for 14 days (e.g. phenoxymethylpenicillin (1 g ×1 orally), amoxicillin (500 mg ×1 


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orally) or ciprofloxacin (500 mg ×1 orally); in case of penicillin allergy clindamycin (300 mg 
×1 orally) can be given). Subjects will be closely monitored for infections and instructed to 
contact the principal investigator immediately if they have any signs of infection. 
5.2.2 Premedication 
Premedication with methylprednisolone (1 mg/kg, max 100 mg, iv) and antihistamine 
(chlorphenamine maleate 10 mg orally, or an equipotent antihistamine) will be administered 
before imlifidase infusion to prevent/minimise risk of infusion reactions. 
5.2.3 Treatment with IVIg 
All subjects will receive standard care with IVIg infusion (0.4 g IVIg/kg for consecutive 
5 days (total dose 2 g/kg) intravenously, starting on Day 3, ≥48 hours after end of imlifidase 
administration and within 14 days of onset of weakness. 
First dose will be given by starting with a slow infusion rate over 2 hours (at a maximum rate 
of 0.55 mg/kg/min). If the infusion is well tolerated the infusion rate of the first infusion can 
be increased according to the site’s standard of care for the rest of the infusion. The 
consecutive doses should follow the site standard of care practice. 
The participation in the study will delay the commencement of standard IVIg treatment by at 
least 48 hours. If a subject deteriorates very quickly during the first 24 hours after imlifidase 
administration, the subject may be treated with PE to manage the rapid progression of GBS to 
remove any remaining imlifidase before initiating IVIg treatment according to standard of 
care. This decision is made at the discretion of the investigator. The subjects will continue in 
the study according to study schedule.  
Premedication if any before first IVIg dose will be given to the subjects according to local 
clinical standard. 
5.2.4 Conditions for Storage and Use 
The investigator will ensure that the NIMPs will be stored in appropriate conditions, 
according to labels, in a secure location with controlled access. The storage compartment 
shall be monitored regularly, and the temperature shall be documented. 
5.3 Blinding 
Blinding is not relevant since this is an open-label study, and all subjects will receive the 
same dose of IMP. 
5.4 Compliance, Accountability and Destruction of IMP(s) and NIMP(s) 
5.4.1 Compliance 
The administration of all medication (including investigational products) will be done by 
trained study personnel and must be recorded in the appropriate sections of the eCRF. All 


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investigational treatments must also be documented in the accountability logs. Treatment 
compliance will be assured by supervised administration of the investigational product by the 
investigator or delegate. The dose, date and time of administration of the investigational 
product will be checked by the monitor at monitoring visits. 
5.4.2 Accountability and Destruction of IMP(s) and NIMP(s) 
It is the principal investigator’s/institution’s responsibility to establish a system for handling 
study treatments, including investigational medicinal products, to ensure that: 
1. Deliveries are correctly received by a responsible person (e.g. pharmacist or 
designated study personnel). 
2. Deliveries are recorded. 
3. All IMP and NIMPs are handled and stored safely and properly. 
4. The IMP and NIMP provided for this study will be used only as directed in the study 
protocol. 
5. The study personnel will account for all drugs dispensed and returned. Any 
discrepancies must be documented, investigated and appropriately resolved. 
6. The study pharmacist will maintain and keep the total accountability records. At the 
end of the study, the pharmacist will return all unused IMPs to Klifo for destruction 
after it has been checked by monitor unless otherwise agreed with Hansa Biopharma. 
The used IMP vials will be accounted for and destructed at site, after control by 
monitor.  
5.5 Product Quality Complaints (PQC) 
A PQC is a reported defect related to the identity, quality, durability, reliability, safety, 
effectiveness, or performance of a product after it is released for distribution and/or usage. 
The defect can be related to the product itself or to the product’s label, delivery system, or 
packaging. Examples of PQCs include but are not limited to contamination, label errors, and 
delivery system failures.  
Hansa Biopharma must be made aware of any PQCs as soon as possible on the day of 
detection. Hansa Biopharma will assess the impact of the reported defect and take any 
necessary precautions to ensure the safety of the study subjects and the credibility of the study 
results. PQCs should be reported using the IMP Issue form to ensure that all relevant 
information is captured. 
5.6 Concomitant Medication and Therapies  
Concomitant medication and/or other therapy considered necessary for the subject’s welfare 
may be given at the discretion of the investigator. All concomitant medication and other 
therapy, including e.g. premedication, prophylactic antibiotics and PE, must be recorded on 


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the concomitant medication page in the eCRF throughout the study, beginning from screening 
to end of study. Treatments up to 30 days prior to screening will be recorded in the eCRF. 
Recorded information will include indication, name of drug, dose (if available), route of 
administration and start and stop date. 
5.7 Prohibited Therapies 
Imlifidase specifically cleaves all subclasses of human and rabbit IgG. As a consequence, 
medicinal products based on human or rabbit IgG may be inactivated if given in connection 
with imlifidase. For this reason the following restrictions apply: 
• intravenous immunoglobulin (IVIg) should not be administered within 48 hours 
following imlifidase administration 
• alemtuzumab, adalimumab, basiliximab, denosumab, etanercept, and rituximab should 
not be administered within 4 days following imlifidase administration 
• rabbit anti-human thymocyte globulin (rATG) and belatacept should not be 
admininstred within 1 week following imlifidase administration 
Of note, equine anti-thymocyte globulin and eculizumab are not cleved by imlifidase and no 
time interval applies if any of these drugs should be considered necessary for the subject’s 
welfare. 
No report of AEs related to incompatibilities with administration of biologics concomitantly 
with imlifidase has been reported to date. 


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6. STUDY PROCEDURES 
6.1 Study Visits 
The total duration of the study, including screening, follow-up visits and long-term follow up 
will not exceed 13 months. The flow chart for patients enrolled in the study is presented in 
Table 1. 
Visit 1, screening of subject, and visit 2 may be performed at the same day. Assessments 
included in both visits will then only be performed once, except for GBS disability score that 
will be assessed again at visit 2 if more than 24 hours elapse between screening and dosing.  
Imlifidase administration will be commenced as soon as possible after confirmed eligibility 
(within 24 hours).  
AEs and concomitant medication and other treatments will be collected throughout the study 
and are not specified for each visit. 
The following GBS disease baseline characteristics will be collected whenever first available: 
GBS variant, GBS subtypes and cranial nerve involvement.  
Comorbidities affecting mobility and/or respiration will be collected as part of medical 
history. 
Information on days on mechanical ventilation, days in hospital, days in an ICU and reason 
for ICU admittance will be collected from screening to Day 180.  
 
Visit 1, Screening 
All subjects considered for the study will be informed about the study the anticipated benefits 
and theoretical risks verbally and in writing and must give their written consent before 
screening or any other study procedure is performed.  
The screening visit will include to the following: 
• Signing of Informed Consent form  
• Demographics (age, sex and race) 
• Medical history (including symptom onset time) 
• Physical examination  
• Vital signs (blood pressure & pulse, respiratory frequency, oxygen saturation, body 
temperature) 
• Height and weight 
• Serology (HIV, Hep B and C)  
• Evaluation of SARS-CoV-2 virus PCR-test analysis performed at hospital admission 
or later  


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• Pregnancy test (serum) 
• Safety local laboratory (Clinical Chemistry, Haematology and Urinalysis) 
• GBS DS, MRC sum score and R-ODS scale 
• Concomitant medication 
• Check of inclusion and exclusion criteria 
 
Visit 2 (Imlifidase treatment), Day 1 and Day 2 
The following activities and assessments will be performed on Day 1, prior to dosing with 
imlifidase: 
• Vital signs (blood pressure & pulse, respiratory frequency, oxygen saturation, and 
body temperature) 
• Safety local laboratory (Clinical Chemistry, Haematology, and Urinalysis)  
• PD and ADA 
• Exploratory biomarkers 
• GBS DS only if more than 24 hours have elapsed between screening and dosing 
Premedication prior to dosing with imlifidase: 
Methylprednisolone and antihistamine, see Section 5.2.2. 
Predose prophylactic antibiotic treatment: 
Antibiotics for prophylaxis will be administered to all subjects according to Section 5.2.1. 
Treatment with antibiotics will start before imlifidase administration and continue for 
14 days. 
Imlifidase dosing: 
All subjects will receive an intravenous infusion of imlifidase (0.25 mg/kg) over 30 minutes. 
The following activities and assessments will be performed on Day 1 after start of 
imlifidase: 
• The subjects should be observed for 2 hours after end of imlifidase infusion. 
• Vital signs (blood pressure & pulse, respiratory frequency, oxygen saturation, and 
body temperature) at 1 and 2 h after end of imlifidase infusion. 
The following activities should be done at Day 2: 
• Safety local laboratory (Clinical Chemistry, Haematology, and Urinalysis) 
• PD and ADA within 24 hours after start of imlifidase infusion 
• Exploratory biomarkers within 24 hours after start of imlifidase infusion 
• GBS DS and MRC sum score 


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Visit 3 (IVIg treatment), Day 3-7 
All subjects will receive standard care IVIg infusion starting Day 3, at least 48 hours after end 
of the imlifidase infusion (0.4 g IVIg/kg for 5 days [total dose 2 g/kg]), see Section 5.2.3 for 
details on infusion rate etc.   
The following activities and assessments will be performed in the morning before start of 
IVIg infusion: 
• Safety local laboratory (Clinical Chemistry, Haematology, and Urinalysis), Day 3  
• PD and ADA, Day 3  
• Exploratory biomarkers, Day 3  
• GBS DS and MRC sum score Days 3, 4, 5, 6 and 7  
 
Visit 4, Day 8 (+2 days) 
The following activities and assessments will be performed: 
• Vital signs (blood pressure & pulse, respiratory frequency, and oxygen saturation) 
• Safety local laboratory (Clinical Chemistry, Haematology, and Urinalysis) 
• PD and ADA 
• Exploratory biomarkers 
• GBS DS, R-ODS, and MRC sum score  
• EurQol EQ-5D Health Questionnaire 
 
Visit 5, Day 15 (±2 days) 
The following activities and assessments will be performed: 
• Vital signs (blood pressure & pulse, respiratory frequency, and oxygen saturation) 
• Safety local laboratory (Clinical Chemistry, Haematology, and Urinalysis) 
• PD and ADA 
• Exploratory biomarkers  
• NCS (optional) 
• GBS DS, R-ODS and MRC sum score 
• EurQol EQ-5D Health Questionnaire 
 


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Visit 6, Day 29 (±3 days) 
The following activities and assessments will be performed: 
• Vital signs (blood pressure & pulse, respiratory frequency, and oxygen saturation)  
• Safety local laboratory (Clinical Chemistry, Haematology, and Urinalysis) 
• ADA  
• Exploratory biomarkers 
• NCS (optional) 
• GBS DS, R-ODS and MRC sum score  
• EurQol EQ-5D Health Questionnaire 
 
Visit 7, Day 57 (±4 days) and Visit 8, Day 92 (±4 days) 
The following activities and assessments will be performed: 
• ADA  
• Exploratory biomarkers 
• GBS DS, R-ODS and MRC sum score  
• EurQol EQ-5D Health Questionnaire 
 
Visit 9, Day 180 (+14 days) 
The last on-site visit will be performed 180 days after infusion of imlifidase.  
The following activities and assessments will be performed: 
• Physical examination  
• Pregnancy test (serum) 
• ADA 
• Exploratory biomarkers 
• GBS DS, R-ODS and MRC sum score  
• EurQol EQ-5D Health Questionnaire 
• Confirm that the diagnosis is still GBS (yes/no), if no, specify which primary 
diagnosis the patient has been given 
 








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7. STUDY ASSESSMENTS  
All sampling, shipping and analysing of laboratory samples will be detailed in the laboratory 
manual.  
7.1 Assessments Related to Endpoints 
7.1.1 GBS Disability Score (GBS DS) 
The GBS DS will be assessed at all visits for all subjects. GBS DS is a widely accepted and 
easily obtainable scoring system to assess disability status of GBS subjects. 
The score is as follows: 
0 = Healthy 
1 = Minor symptoms and capable of running (subjects must be asked to run) 
2 = Able to walk independently 10 meters or more but unable to run 
3 = Able to walk more than 10 meters across an open space with help 
4 = Bedridden or chair bound 
5 = Needing mechanical ventilation 
6 = Dead 
7.1.2 Rasch-Built Linearly Weighted Overall Disability Scale (R-ODS) 
R-ODS will be assessed at Screening, Days 8, 15, 29, 57, 92, 180, and 360 for all patients. 
R-ODS is a linearly weighted disease specific scale, which captures activities and social 
participation limitation in patients with immune-mediated neuropathies, including GBS (van 
Nes et al. 2011). The final questionnaire comprises 24 items ranging from ability to read a 
book or newspaper (as the easiest item to accomplish) to ability to run (most difficult item to 
accomplish).  
The response options for each item are: 
0 = Not possible  
1 = Possible with effort  
2 = Easy to perform  
The obtained raw summed score is subsequently translated to a convenient centile metric 
ranging from 0 (most severe disability) to 100 (no disability at all) that can be analysed in an 
analysis of covariance model (ANCOVA) model. 
7.1.3 Medical Research Council sum score (MRC sum score) 
MRC will be assessed at all visits except for Days 1 and 360 for all patients. 
The MRC sum score is widely used to assess the motor impairment in subjects with 
peripheral neuropathies. It is a sum score of power in six muscle groups on each side 


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(abduction of arm, flexion of forearm, extension of the wrist, hip flexion, and extension of 
knee and dorsal flexion of the foot). The sum of these scores ranges from 0 (total paralysis) to 
60 (normal power). It gives very valuable information about the muscle strength, especially 
when patient in bed bound and ventilated (Kleyweg et al. 1991). Change in MRC sum score 
helps in identification of GBS patients with treatment related fluctuation or exacerbation.  
The individual MRC grades are defined as follows: 
0 = No visible contraction 
1 = Visible contraction without movement of the limb 
2 = Movement of the limb but not against gravity 
3 = Movement against gravity (almost full range) 
4 = Movement against gravity and resistance 
5 = Normal 
7.1.4 Pharmacokinetics (PK) 
No PK sampling will be done after Protocol Ver. 8.0 is approved unless PK sampling has 
been initiated to a patient in accordance with previous version of the protocol. If so collection 
of PK samples should continue for a full PK profile. 
7.1.5 Pharmacodynamics (PD) 
Samples for the determination of IgG levels in serum (PD) will be taken during study as 
described below. The date and actual time of collection of each sample will be recorded in the 
eCRF. Full details of the analytical method used will be detailed in a separate bioanalytical 
report and the analysis results will be collected in the clinical database. 
Samples for PD determination will be taken: 
• Day 1: predose 
• Day 2: within 24 hours after start of imlifidase administration 
• Day 3: before start of IVIg 
• Days 8 and 15 
7.1.6 Immunogenicity (ADA) 
Samples for the determination of anti-drug antibody (ADA) levels in serum will be taken 
during study as described below. The date and time of collection of each sample will be 
recorded in the eCRF.
 
 Full details of the analytical method used, and the analysis results will be 
detailed in a separate bioanalytical report. 
Serum samples for the determination of ADA levels will be taken: 
• Day 1: predose 
• Day 2: within 24 hours after start of imlifidase administration 


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• Day 3: before start of IVIg 
• Days 8, 15, 29, 57, 92 and 180 
7.1.7 Days in Hospital and Days in an ICU 
Number of days in hospital and number of days in ICU from screening up until Day 180 will 
be collected. Reason for admittance to ICU will be collected as: worsening of GBS, study 
procedure/according to site standard practice, infection or other. 
7.1.8 Mechanical Ventilation 
Number of days on mechanical ventilation from screening up until Day 180 will be collected.  
7.1.9 Exploratory Biomarkers 
Blood samples for exploratory biomarkers including autoantibodies and other inflammatory 
factors will be collected:  
• Day 1: predose 
• Day 2: within 24 hours after start of imlifidase administration 
• Day 3: before start of IVIg 
• Days 8, 15, 29, 57, 92, and 180 
7.1.10 EurQol EQ-5D-5L Health Questionnaire 
EQ-5D-5L is a standardised measure of health status developed to provide a simple, generic 
measure of health for clinical and economic appraisal. The EQ-5D-5L consists of a 
descriptive system and an EQ Visual Analogue scale (EQ VAS) and EQ-5D-5L is designed 
for self-completion by respondents. The questionnaire is cognitively undemanding and taking 
only a few minutes to complete. EQ-5D-5L will be completed by the participating subjects at 
Days 8, 15, 29, 57, 92, 180, and 360. 
7.2 Safety Assessments Related to Endpoints 
7.2.1 Adverse Events 
AEs will be recorded during the study period, from obtaining the informed consent until 
end-of-study visit 10. For further information on definitions and reporting of AEs and SAEs, 
see Section 9. 
7.2.2 Safety Local Laboratory 
Blood samples for safety laboratory evaluations of clinical chemistry and haematology 
parameters will be collected during study as described below. Actual sampling time will be 
recorded. Clinically significant abnormal findings will be reported as AEs. Findings at the 


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screening visit will be recorded in the medical history section in the eCRF. Clinical chemistry 
and haematology will be analysed locally. 
Urine samples for safety evaluations will be taken as described below. Samples will be 
measured with dipstick and analysed locally. In case of abnormal results, a microscopic test 
will be measured. 
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.  
The following parameters will be collected: 
• Clinical chemistry: 
o P-alanine aminotransferase (ALT), P-gamma glutamyl transferase, P-alkaline 
phosphate, P-bilirubin total, P-creatinine, P-potassium, P-albumin, P-calcium, 
P-immunoglobulin G (IgG) 
• Haematology: 
o B-haemoglobin, B-haematocrit, B-white blood cell count, 
B-neutrophils (absolute count), B-lymphocytes (absolute count), 
B-eosinophiles (absolute count), B-platelet count 
• Urinalysis(dipstick): 
o U-glucose, U-haemoglobin, U-protein, U-pH 
Time of collection: 
• All the above analyses: 
o At screening within 7 days prior to inclusion 
o Day 1: Prior to imlifidase administration 
o Days 2, 3 (prior to IVIg infusion), 8, 15 and 29  
7.2.3 Physical Examination  
A complete physical examination will be performed at screening and Day 180 (visit 9) and 
include an assessment of the following: general appearance, head and neck, lymph nodes, 
abdomen, musculo-skeletal, cardiovascular, respiratory and gross neurological examination. 
The physical examination shall be performed by an investigator. 
7.2.4 Vital Signs 
Blood pressure, pulse rate, respiratory frequency, oxygen saturation and body temperature 
will be assessed at: 
• Screening  


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• Day 1: 
o Predose 
o 1 and 2 hours after end of imlifidase dosing  
• Days 8, 15, and 29 (all except body temperature) 
At Day 1 the subject will be observed for 2 hours after end of imlifidase infusion, longer if 
medically indicated. If the subject is without infusion related symptoms and vital signs are 
normal the observation period ends 2 hours after end of infusion. 
Systolic and diastolic blood pressure will be measured after the subject has been in supine 
position for at least 5 minutes. All recordings will be performed using validated standard 
equipment. Clinically significant abnormal findings will be reported as AEs. 
7.2.5 ECG 
No ECGs will be collected. 
7.3 Other Assessments 
7.3.1 Demographics and Baseline data 
Information about gender, race and age at inclusion, weight and height will be collected at the 
screening visit for each subject. Measurements should be taken without shoes and overcoat.  
7.3.2 Baseline GBS Disease Information  
The following information will be collected when first available: 
• GBS variant (pure motor GBS, pharyngeal-cervical-branchial weakness, Miller Fisher 
syndrome [no limb weakness], Miller Fisher-GBS overlap syndrome, pure sensory 
GBS, ataxic form, other) 
• Cranial nerve involvement  
• Electrophysiology classification of subtypes (acute motor axonal neuropathy 
[AMAN], acute inflammatory demyelinating neuropathy [AIDP], unresponsive 
nerves, responsive nerves but not classifiable [equivocal], normal).   
7.3.3 Serology 
Determination of HIV-1 and HIV-2 antibodies, hepatitis B surface-antigen and hepatitis C 
virus antibodies will be performed at screening.  
7.3.4 Pregnancy Test 
Serum β-hCG will be determined for all female subjects at screening and on Day 180 (visit 9), 
using validated standard methods.  


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7.3.5 Medical History 
Information regarding medical history will be collected at the screening visit for each subject 
and recorded in the eCRF. Medical history will include information regarding any 
comorbidities affecting mobility and/or respiration.   
7.3.6 Nerve Conduction Study (NCS) 
If assessed, nerve conduction study (NCS) will be measured at Days 15 and 29. NCS is 
performed using standard techniques at least on one side of the body. The skin temperature 
should be controlled and maintained between 32 °C and 34 °C. The NCS includes median, 
ulnar, peroneal, and tibial motor responses and superficial radial, and sural sensory responses. 
The median nerve is stimulated at the wrist, antecubital fossa, and responses are recorded over 
the abductor pollicis brevis. The ulnar nerve is stimulated at the wrist, below the elbow, and 
responses are recorded over the abductor digiti minimi. The peroneal nerve is stimulated at 
the ankle, fibular head, and responses are recorded over the extensor digitorum brevis. The 
tibial nerve is stimulated at the ankle and popliteal fossa, and responses are recorded over the 
abductor hallucis. Measurements include distal latency, negative peak duration, baseline-to-
peak amplitude, conduction velocity, and minimum F-wave latencies. To define conduction 
block (CB), we used the consensus criteria of the American Association of Electrodiagnostic 
Medicine (Olney et al. 2003). 
7.3.7 SARS-CoV-2 virus PCR-test 
At the screening visit an evaluation of the result of the SARS-CoV-2 virus PCR-test, 
performed at hospital admission or later, will be done. 


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


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9. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
9.1 Definitions 
9.1.1 Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product. Relationship to the study drug will be 
deemed as not related, unlikely, possible or probable. An undesirable medical condition can 
be symptoms (e.g., nausea and chest pain), signs (e.g., tachycardia and enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings and 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. 
9.1.2 Serious Adverse Event 
An SAE is an AE or suspected adverse reaction that is considered "serious" if, in the view of 
either the investigator or Hansa Biopharma, it results in any of the following outcomes: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalisation or prolongation of existing hospitalisation 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, 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. 
Hospitalisation: Admittance to an emergency room for observation without being admitted 
to the hospital may be considered to be an AE but is not considered as an SAE. However, 
complications that occur during hospitalization are AEs, and if a complication prolongs 
hospitalisation, the event is considered serious. 


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The death of a subject is per se not an event but an outcome, but the cause of the death is. 
9.2 Collection and Recording of Adverse Events 
In clinical studies, an AE/SAE can occur at any time after signing of the informed consent 
until the end of the study, including run-in or washout periods, even if no study treatment has 
been administered, e.g., an AE can be related to a procedure in the protocol.  
AEs will therefore be collected on the AE eCRF from the time of signing of the informed 
consent and throughout the study including the follow-up period.  
Adverse events can be collected by: 
• The subject’s response to questions about his/her health (a standard non-leading 
question such as “Have you had any health problems since you were last 
asked/your last visit?”) 
• Symptoms spontaneously reported by the subject 
• Investigations and examinations where the findings are assessed by the 
investigator to be clinically significant changes or abnormalities 
• Other information relating to the subject’s health becoming known to the 
investigator (e.g. hospitalisation) 
9.2.1 Variables 
The following variables will be recorded in the eCRF 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. 4.03) whether the AE is serious 
or not, causality assessment, action taken and outcome.   
9.2.1.1 Causality Assessment  
For each reported AE the investigator will make an assessment of the relationship of the event 
to study procedures and/or IMP using the following criteria. 
• Unrelated: applicable to an AE that occurs when the subject was not exposed to study 
treatment or another cause is obvious. 
• Unlikely to be related: applicable to an AE that meets the following criteria 
• Does not follow a reasonable temporal sequence from study drug dosing 
• May readily have been produced by the subject’s clinical state, environmental, 
or toxic factors, or other therapy administered to the subject 
• Possibly related: applicable to AEs where connection with dosing of study drug 
appears unlikely but cannot be ruled out.  Applicable to AEs where 
• It follows a reasonable temporal sequence dosing with study drug 
• It follows a known pattern of response to study drug dosing (based on previous 
studies) 


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• Probably related: applicable to AEs that are considered, with a high degree of 
certainty, to be related to the study drug.  Applicable to AEs where 
• It follows a reasonable temporal sequence study drug dosing 
• It cannot be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy 
• It follows a known pattern of response to study drug dosing (based on previous 
data). 
• For SAEs causal relationship will also be assessed for any study procedure.  
9.2.2 Adverse Events Based on Signs and Symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) rather than 
recording a list of signs and symptoms, for example: congestive heart failure rather than low 
ejection fraction. However, if a diagnosis is known and there are other signs or symptoms that 
are not generally part of the diagnosis, the diagnosis and each sign or symptom not part of the 
diagnosis will be recorded separately, for example: congestive heart failure and conjunctivitis. 
9.2.3 Adverse Events Based on Examinations and Tests 
If lab values are judged as clinically significant and/or a treatment has been given, they will 
be captured as AEs and if SAE criteria are fulfilled they will also be SAEs.  
If vital signs are judged as clinically significant and/or require a treatment, then they will be 
captured as AEs and if SAE criteria are fulfilled they will also be SAEs. 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE and if SAE 
criteria is fulfilled they will also be SAEs. 
Wherever possible the reporting investigator uses the clinical, rather than the laboratory term 
(e.g., anaemia versus low haemoglobin value). 
9.2.4 Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the investigator until stabilization, for as long as medically indicated or the overall clinical 
outcome of the subject is known, unless the subject is documented as “lost to follow-up”. All 
SAEs and AEs leading to discontinuation should be followed until the event resolves or 
stabilizes.  
Reasonable attempts to obtain this information must be made and documented. Hansa 
Biopharma retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
9.2.5 Reporting of Serious Adverse Events 
All SAEs must be reported, whether considered related to the investigational product, or to 
the study procedure(s), on a separate SAE form. In the Adverse Event form, it will be added 
that the AE is considered serious. SAEs will be recorded from the time of informed consent.  


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An assigned Contract Research Organisation (CRO),
, will be responsible for 
reporting all SAEs to RA in accordance with International Conference on Harmonisation 
(ICH) Good Clinical Practice (GCP), the Detailed guidance on the collection, verification and 
presentation of adverse event/reaction reports arising from clinical trials on medicinal 
products for human use (‘CT-3’), and local regulations. Hansa Biopharma or
 will be 
responsible for reporting to IEC/IRBs.  
As soon as the investigator is aware of a potential SAE he/she should contact 
 
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, subject 
number, and birth date, description of the SAE and a preliminary assessment of causality.  
 
Contact Information: 
CRO: 
 
e-mail: 
  
 
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 Hansa Biopharma and monitor of any follow-up information on a previously reported 
SAE immediately but no later than within 24 hours of when he or she becomes aware of it. 
The monitor or Hansa Biopharma will advise the investigator/study site personnel how to 
proceed. 
The SAE reporting procedures are detailed in the study specific Safety Management Plan. 
This plan is an agreement between Hansa Biopharma and
. 
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 investigational product caused the adverse event. A serious adverse reaction is considered 
"unexpected" if it is not listed in the reference safety information section of the investigator 
brochure or is not listed at the specificity or severity that has been observed. 
SUSARs with an outcome of death or 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. 
 will be responsible for ensuring reporting all SUSARs to RAs in 
accordance with ICH GCP, CT-3, and local regulations.  
The CRO managing the trial sites is responsible for informing all participating trial 
investigators and ethics committees 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. The SUSAR reporting procedures are detailed in the study Safety 


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Management Plan. This plan is an agreement between the Hansa Biopharma, and 
.  
9.3 Pregnancy and Pregnancy Outcome 
Pregnancy is an exclusion criterion and a pregnancy test are performed at the screening visit 
and prior to infusion of the imlifidase. A pregnancy test is also performed at visit 9.  
If a subject becomes pregnant after receiving the dose of imlifidase, the subject will continue 
in the study according to study protocol, if possible. A Pregnancy Report Form must be sent 
by the investigator to 
 at the latest within two weeks of learning of the 
pregnancy. The outcome of all pregnancies (spontaneous miscarriage, elective termination, 
normal birth or congenital abnormality) will be followed up on the Pregnancy Report Form 
even after the subject has completed or discontinued the study. 
 will follow up 
on pregnancy outcome 4 weeks after the projected due date.  
Pregnancy itself is not considered an AE or SAE, but any event occurring during pregnancy 
that meets serious criteria must be reported to Hansa Biopharma and will be handled as a 
SAE. Spontaneous abortions, congenital abnormalities/birth defects are always considered to 
be SAEs and will be reported and followed up in accordance with other SAEs. Any SAE 
occurring as a result of a post-study pregnancy and considered reasonably related to the study 
drug by the investigator will be reported to Hansa Biopharma (or designee).  
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 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 
• An overdose without associated symptoms is only reported in the patient file 
9.5 Adverse Events of Special Interest 
The following events will be assessed as adverse events of special interest (AESI): 
• Infusion-related reactions that occurs within 48 hours of imlifidase treatment 
• All AEs 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 imlifidase administration  
All events (irrespective of severity) that results in interruption of imlifidase dose should be 
reported within 24 hours as described for SAEs (see Section 9.2.5). 


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10. STUDY MANAGEMENT 
10.1 Pre-Study Activities 
Before the first subject is enrolled into the study, it may be necessary for a representative of 
Hansa Biopharma to visit the investigational study site for a pre-study visit to: 
• Determine the adequacy of the facilities to give Hansa Biopharma information about 
whether the study centre has knowledge, enough time, a sufficient subject pool, and 
sufficient training to manage the study in a good way in terms of subject inclusion, 
subject handling, data and overall study management. 
• Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities regarding protocol adherence and the responsibilities of Hansa 
Biopharma or its representatives.  
Before the first subject is entered into the study, a Hansa Biopharma representative will 
review and discuss the requirements of the clinical study protocol and related documents with 
the investigational staff and train them in any study specific procedures and system(s) utilized 
at a site initiation visit. 
The principal investigator will ensure that appropriate training relevant to the study is given to 
all staff, and that any new information relevant to the performance of this study is forwarded 
to the staff involved. 
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
10.2 Monitoring of the Study 
During the study, a Hansa Biopharma representative will have regular contacts with the study 
site, including visits to: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, ICH GCP, data are 
being accurately and timely recorded in the eCRFs, and IMP accountability checks are 
being performed. 
• Perform Source Data Verification (SDV) (a comparison of the data in the eCRFs with 
the subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating subjects.  
• If a subject withdraws informed consent to the use of their biological samples; ensure 
this is reported to Hansa Biopharma and biological samples are identified, 
disposed/destructed accordingly, and the action is documented, and reported to the 
subject. 


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


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11. DATA MANAGEMENT 
At clean file, data from visit 1 to 9 will be evaluated and reported in the Clinical Study Report 
(CSR). Data from visit 10  will be reported separately as an addendum to the CSR.  
11.1 Case Report Form 
An eCRF system provided by a CRO will be used for data capture. The system is validated 
and access at all levels to the system is granted/revoked following Hansa Biopharma and 
vendor procedures, in accordance with regulatory and system requirements. 
After the study database is declared clean and released to the statistician, a final copy of the 
database will be stored at Hansa Biopharma. The investigator will also receive a copy of the 
study site’s final and locked data (including audit trail, 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 or other applicable media and will be provided to the investigator before access to 
the eCRF is revoked. 
11.2 Provider of Data Management 
All data management procedures will be outsourced to a CRO. Activities will be specified in 
a Data Management Plan prepared by the CRO and reviewed and approved by Hansa 
Biopharma. The plan will be issued before data collection begins and will describe all 
functions, processes and specifications for data collection, cleaning and validation. 
11.3 Coding 
For medical coding of AEs, medical history and concomitant medication the most recent 
versions of the Medical Dictionary for Regulatory Activities (MedDRA) and World Health 
Organization (WHO) Drug Dictionary will be used at study closure (unless decided otherwise 
by Hansa Biopharma).  
The coding will be outsourced to a CRO. All coding performed will be approved by Hansa 
Biopharma prior to study closure/database lock. 
11.4 Handling of External Data 
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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12. STATISTICAL METHODS  
The detailed analysis plan is contained in the SAP. The statistical analyses will be outsourced 
to a CRO. Prior to database lock, a SAP with details on statistical analysis and data 
presentation will be written. No formal statistical hypothesis testing will be performed in this 
study.  
The data from the clinical assessments, including demographics and other baseline 
characteristics, will be summarised and listed by time point using descriptive techniques. 
Summary statistics (n, arithmetic mean, standard deviation, median, minimum and maximum 
values) will be presented for continuous variables (absolute values at each time point and, if 
relevant, changes from baseline) and counts and, if relevant, percentages will be presented for 
categorical variables.  
12.1 Analysis Sets 
Compliance and all baseline characteristics (demographics, GBS disease information, medical 
history, prior and concomitant medication, and physical examination) will be presented for all 
analysis sets. 
12.1.1 Full Analysis Set (FAS) 
The FAS comprises data from all dosed subjects having a confirmed GBS diagnosis, i.e., 
subjects having change in diagnosis during the course of the study will be excluded. The FAS 
will be used for presentation  of efficacy endpoints. 
12.1.2 PK/PD Analysis Set 
The PK/PD analysis data set comprises data from all dosed subjects, with at least one PK or 
PD data point available post-baseline. The PK/PD analysis set will be used for presentation of 
pharmacokinetic and pharmacodynamic endpoints.  
12.1.3 Safety Analysis Set 
The safety analysis set comprises all treated subjects and will be used for presentation of safety 
endpoints. 
12.2 Subject Characteristics 
12.2.1 Subject Disposition 
The subject disposition will present number of subjects as enrolled, completed, withdrawn 
overall and by reason for withdrawal and finally by each of the analysis sets. The number of 
subjects screened but not found eligible will be stated in the trial report but otherwise not 
accounted for. Subjects enrolled but not dosed will be regarded as screening failures. 
12.2.2 Demographics and Other Baseline Characteristics 
The subject demographics and other baseline characteristics will be listed and summarised. 


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12.2.3 Recent and Concomitant Medication 
Recent and concomitant medication will be summarised by anatomical therapeutic chemical 
(ATC) code and generic drug name. 
12.2.4 Exposure and Compliance 
Exposure and compliance will be calculated per subject and listed. 
12.3 Statistical Analysis of Endpoints 
No formal statistical hypothesis testing will be performed in the study.  
12.3.1 Analysis of Adverse Events 
AEs will be coded according to the latest version of the MedDRA. All data will be listed by 
subject. Only treatment emergent AEs will be presented in summary tables. Separate data 
listing will be provided for AEs that are defined as pre-treatment or post-treatment emergent. 
12.3.1.1 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. 
12.3.1.2 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 after the administration of the IMP, 
where the effect of the product is still considered to be present based on pharmacokinetic, 
pharmacodynamic or other substance characteristics. The residual drug effect is generally 
accepted to be 5 times the terminal half-life. The terminal half-life of imlifidase is expected to 
be within the range of approx. 100 hours, i.e. in this study the residual drug effect is likely to 
be well within the Day 29 assessments, but since this is the first administration of imlifidase 
to GBS subjects, all AEs occurring up to Day 29 are regarded as treatment emergent. 
12.3.1.3 Post-treatment Emergent Adverse Events 
A post-treatment emergent adverse event is any adverse event occurring after the time of 
residual drug effect of the IMP, i.e. between the end of the treatment period visit 6 and 
visit 10. 


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12.3.2 Overview of Treatment Emergent Adverse Events 
A treatment emergent AE summary table will be presented. The table will include, the 
number of subjects reporting an AE, the percentage of subjects with an AE and the number of 
events reported, for the following categories: 
• All AEs 
• Severe AEs 
• SAEs 
• Adverse Drug Reactions (ADR) 
• AEs leading to withdrawal 
• Deaths 
ADRs are defined as events that are considered to be possibly or probably related to IMP as 
judged by the Investigator. 
12.3.2.1 
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 subjects reporting 
an AE, the percentage of subjects (%) 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 
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”. 
12.3.2.2 
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. 


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12.3.3 Analysis of Other Safety Variables  
12.3.3.1 Vital Signs 
Vital signs will be presented by assessment (time) for each parameter and summarised, 
including absolute change and percentage change from treatment period baseline. Shift tables 
will be presented from baseline to end of residual drug effect, i.e. Day 29. Any changes from 
normal/low to high or from normal/high to low during these periods will be counted as a shift 
and will be summarised. 
12.3.3.2 Clinical Chemistry, Haematology and Urinalysis 
Clinical chemistry, haematology and urinalysis parameters will be presented in the same way 
as the vital sign parameters. 
12.3.3.3 Electrocardiography 
ECGs will be categorised as “normal”, “abnormal, not clinically significant”, or “abnormal, 
clinically significant” (as judged by the Investigator) and listed by subject. 
12.3.4 Efficacy 
The clinical outcome of the GBS subjects treated with imlifidase and IVIg will be presented 
as outlined below and as further described in the SAP. Additional analyses, such as a 
comparison with a matched external control group will be outlined in a separate non-
interventional study protocol and corresponding SAP.  
12.3.4.1 Proportion of subjects with improvement of one, two, three or more grades on 
the GBS DS 
The proportion of subjects with improvement of at least one, two or three grades, 
respectively, on the GBS DS will be presented using descriptive statistics by time point. 
12.3.4.2 Change in GBS DS 
Actual values and changes from baseline will be presented using descriptive statistics by time 
point. 
12.3.4.3 Proportion of subjects able to walk unaided (GBS DS ≤ 2)  
Proportion of subjects able to walk unaided (GBS DS ≤ 2) will be presented using descriptive 
statistics by time point.  
12.3.4.4 Time to improvement by at least one, two and three grade(s) on the GBS DS  
Time to improvement by at least one, two and three grade(s), respectively, on the GBS DS 
will be presented using Kaplan-Meier curves. 


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Final Version: 9.0 Incl. Amend 08 
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12.3.4.5 Time to walk independently (GBS DS ≤ 2) 
Time to walk independently (GBS DS ≤ 2) will be presented using Kaplan-Meier curves. 
12.3.4.6 Time to run (GBS DS ≤ 1) 
Time to run (GBS DS ≤ 1) will be presented using Kaplan-Meier curves. 
12.3.4.7 Proportion of subjects that reach GBS DS ≤ 1 by week 26 
Proportion of subjects that reach GBS DS ≤ 1 by week 26 will be presented using descriptive 
statistics. 
12.3.4.8 Proportion of subjects with an increase from baseline in R-ODS scale 
Proportion of subjects with an increase from baseline in R-ODS scale by at least 6 points on 
the centile metric score will be presented using descriptive statistics by time point. Actual 
values and change from baseline will be presented using descriptive statistics by time point. 
12.3.4.9 Proportion of subjects with all R-ODS items above 0 at week 26 
Proportion of subjects with all R-ODS items above 0 at week 26 will be presented using 
descriptive statistics. 
12.3.4.10 Proportion of subjects requiring mechanical ventilation support 
Proportion of subjects requiring mechanical ventilation support (GBS DS 5) will be presented 
using descriptive statistics by time point. 
12.3.4.11 Days on mechanical ventilation  
Days on mechanical  ventilation will be presented using descriptive statistics. 
12.3.4.12 Days in hospital and days in an ICU   
Days in hospital, days in an ICU and reason for admittance to ICU will be presented using 
descriptive statistics. 
12.3.4.13 Change in MRC sum score 
Actual values and changes from baseline will be presented using descriptive statistics by time 
point. 


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Final Version: 9.0 Incl. Amend 08 
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12.3.4.14 Quality of Life – EQ-5D-5L  
Change in quality of life EQ-5D-5L score will be presented using descriptive statistics by 
time point. 
12.3.5 Pharmacokinetics 
The PK parameters will be calculated using the software WinNonlin® (Pharsight Corporation, 
US). Non-compartmental analysis (NCA) or compartment calculations will be used for PK 
evaluation. Actual sampling time points relative to dosing will be used in the PK calculations 
for each patient and on the individual plots of plasma concentration versus time.  
Plasma concentration values below lower limit of quantification (LLOQ) and missing values 
(e.g. no blood sample collected, or no value obtained at analysis) will be excluded from the 
PK parameter calculation.  
PK parameters will be estimated based on measurements of the plasma concentration-time 
data of imlifidase, and the following parameters will be estimated (but not limited to), if 
possible: AUC, %AUCextrap, Cmax, tmax, t½, CL, Vz.  
PK parameters will be presented with number of measurements, number of missing data, 
mean, standard deviation, median, minimum, maximum, geometric mean. For t½, the 
harmonic mean will be listed instead of the geometric mean. For tmax the geometric mean and 
the CV% will be omitted. 
12.3.6 Pharmacodynamics 
The PD data will be summarised and presented graphically as mean profiles and by patient 
profiles.  
The SDS-PAGE bioanalytical report will include a qualitative description of results, and the 
outcome will be scored according to the following, listed, and summarised:  
  
  
  
  
  
  
The relationship between imlifidase concentration and IgG cleavage will be presented 
graphically. 
12.3.7 Anti-drug Antibodies 
Presence of ADAs will be presented using descriptive statistics by time point. 


Hansa Biopharma AB 
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12.4 Statistical Analysis of Exploratory Endpoint(s) 
Exploratory biomarkers will be presented by descriptive statistics. 
12.5 Determination of Sample Size 
No formal sample size calculations have been performed for this study. Approximately 
30 evaluable subjects are considered sufficient to provide adequate information about the 
safety and efficacy. 
12.6 Evaluability of Subjects for Analysis 
Major protocol violations such as significant non-compliance or other serious unforeseen 
violations deemed to invalidate the data collected for the purposes of the study may lead to 
exclusion of the data from analysis. In case of minor protocol violations, data will not be 
excluded from the data analysis. The rating of protocol violations in ‘minor’ and ‘major’ will 
be decided on the basis of a review of the data before declaration of ‘clean file’ and database 
lock. 
 


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


Hansa Biopharma AB 
Date: 27-JUN-2023 
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Final Version: 9.0 Incl. Amend 08 
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14. REPORTING AND PUBLICATION 
14.1 Clinical Study Report 
The main analyses for the clinical study report (CSR) will be based on all data when all 
patients have had visit 9 (Day 180). Data from visit 10 (Day 360) will be reported as an 
addendum to the CSR. The full CSR including addendum will be available within one year 
after end of study (for definition see Section 3.5).  
14.2 Confidentiality and Data Ownership 
Any confidential information relating to the IMP or the study, including any data and results 
from the study will be the exclusive property of Hansa Biopharma. The investigator and any 
other persons involved in the study will protect the confidentiality of the proprietary 
information belonging to Hansa Biopharma. 
14.3 Publications  
14.3.1 Publication Policy 
At the end of the study, one or more manuscripts for joint publication will be prepared in 
collaboration between the investigator(s) offered authorship and Hansa Biopharma.  
Any external CRO or laboratory involved in the conduct of this study has no publication 
rights regarding the study. 
14.4 Public Disclosure 
The study will be registered in a public clinical trials registry e.g. the U.S. National Institutes 
of Health register ClinicalTrials.gov and EU Clinical Trials Register. 
 


Hansa Biopharma AB 
Date: 27-JUN-2023 
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Final Version: 9.0 Incl. Amend 08 
Clinical Study Protocol No.: 15-HMedIdeS-09 
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15. ETHICAL AND REGULATORY ASPECTS 
15.1 Ethical Conduct of the Study 
This study will be conducted in accordance with ICH GCP, approved protocol and any 
amendment and applicable regulatory requirements.  
The responsibilities of Hansa Biopharma, the monitor and the investigator are defined in the 
ICH GCP guideline and applicable regulatory requirements in the country where the study 
takes place.  
15.2 Liabilities and Insurance 
Hansa Biopharma is, as sponsor, responsible for ensuring appropriate general/product liability 
insurance and, as required in accordance with applicable laws and regulations, country-
specific liability insurance coverage for claims made by a study subject for injury arising from 
the subject’s participation in the study. 
15.3 Independent Ethics Committee(s) and Institutional Review Boards  
All ethical and regulatory approvals must be available before a subject is exposed to any study-
related procedure, including screening tests for eligibility. 
According to applicable regulatory requirements Hansa Biopharma will: 
• obtain approval from or notify the relevant (IECs) of the protocol, any amendments, 
the Subject Information Sheet/Informed Consent Form and any advertisements etc. 
• send periodic updates to the IEC(s) if applicable 
• provide investigator(s) with an accurate and complete record of all submissions to the 
local IEC. The copies should be filed in the investigator site file. 
Hansa Biopharma will keep an updated list of submission and approval dates of all documents 
submitted to IEC(s). 
15.4 Regulatory Authority(ies) 
Before initiating the clinical study, Hansa Biopharma and the investigator, if required by the 
applicable regulatory requirement(s), should submit any required application to the 
appropriate Regulatory Authorities (RA) for review, acceptance, and/or permission (as 
required by the applicable regulatory requirement(s) to begin the study. Any 
notification/submission should be dated and contain sufficient information to identify the 
protocol. 
Hansa Biopharma will keep an updated list of submission and approval dates of all documents 
submitted to RAs. 


Hansa Biopharma AB 
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15.5 Subject Information and Informed Consent 
Before any study-related activities and in agreement with applicable regulatory requirements, 
the investigator must give the subject oral and written information about the study in a form 
that the subject can understand. Investigator must ensure that the subject is fully informed 
about the aims, procedures, potential risks, any discomforts and expected benefits of the 
study. Before consenting, the subject must be left with ample time to consider and to pose 
questions. 
It must be emphasised that participation is voluntary and that the subject has the right to 
withdraw from the study at any time without prejudice. 
In cases where the subject is deemed to have capacity, but physical disability prevents them 
from signing the personal consent form, the procedure for information and consent will be 
followed in compliance with local regulations, which could involve a designated authorised 
person to consent on behalf of the subject. 
The original, signed Informed Consent Forms must be kept in the investigator site file.  
The subject will receive a copy of the Subject Information and his/her signed Informed 
Consent Form. 
If new information becomes available that may be relevant to the study subject’s willingness 
to continue participation in the study, a new Subject Information and Informed Consent Form 
will be forwarded to the IEC(s)/IRB(s) (and RAs, if required). The study subjects will be 
informed about this new information and re-consent will be obtained. 
15.6 Subject Participation Card 
The subject will be provided with a subject participation card bearing the following 
information: 
That he/she is participating in a clinical study (incl. study code). 
That he/she has been treated with study drug. 
The name and phone number of the investigator (could be phone number to the department of 
the investigator, when used in emergency situations). 
The subject will be asked to keep the subject participation card in their possession at all times 
during the study and to return it at the last study visit, if applicable. 
Include statement whether each subject’s primary care physician will be notified of their 
participation in the study by the investigator, if the subject agrees. 
15.7 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
Hansa Biopharma and their agents. This confidentiality is extended to cover testing of 


Hansa Biopharma AB 
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biological samples and genetic tests in addition to the clinical information relating to 
participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party without prior written approval of Hansa Biopharma. 
The study monitors, or other authorized representatives of Hansa Biopharma may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects 
in this study. The clinical study site will permit access to such record. 


Hansa Biopharma AB 
Date: 27-JUN-2023 
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16. ARCHIVING 
16.1 Retention of Clinical Study Site Documentation 
The investigator is responsible for maintaining all the records, which enable the conduct of 
the study at the site to be fully understood, in compliance with ICH GCP. The study 
documentation including all the relevant correspondence should be kept by the investigator 
for at least 25 years or longer if so required by local law after the completion or 
discontinuation of the study, if no further instructions are given by Hansa Biopharma. 
The investigator is responsible for the completion and maintenance of the confidential subject 
identification code which provides the sole link between named subject source records and 
anonymous eCRF data for Hansa Biopharma. The investigator must arrange for the retention 
of this Subject Identification Log and signed Informed Consent Documents for at least 
25 years or longer if so required by local law after the completion or discontinuation of the 
study. 
No study site document may be destroyed without prior written agreement between the 
investigator and Hansa Biopharma. Should the investigator elect to assign the study 
documents to another party, or move them to another location, Hansa Biopharma must be 
notified. If the investigator retires and the documents can no longer be archived by the site, 
Hansa Biopharma can arrange having the investigator site file archived at an external archive. 
16.2 Study Master File 
Hansa Biopharma will archive the Study Master File in accordance with ICH GCP and 
applicable regulatory requirements. 
 


Hansa Biopharma AB 
Date: 27-JUN-2023 
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Final Version: 9.0 Incl. Amend 08 
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17. REFERENCES 
 
Asbury, A. K., and D. R. Cornblath. 1990. 'Assessment of current diagnostic criteria for 
Guillain-Barre syndrome', Ann Neurol, 27 Suppl: S21-4. 
Hughes, R. A., A. V. Swan, and P. A. van Doorn. 2014. 'Intravenous immunoglobulin for 
Guillain-Barre syndrome', Cochrane Database Syst Rev: CD002063. 
Jacobs, B. C., B. van den Berg, C. Verboon, G. Chavada, D. R. Cornblath, K. C. Gorson, T. 
Harbo, H. P. Hartung, R. A. C. Hughes, S. Kusunoki, P. A. van Doorn, H. J. Willison, 
and Igos Consortium. 2017. 'International Guillain-Barre Syndrome Outcome Study: 
protocol of a prospective observational cohort study on clinical and biological 
predictors of disease course and outcome in Guillain-Barre syndrome', J Peripher 
Nerv Syst, 22: 68-76. 
Jarnum, S., A. Runstrom, R. Bockermann, L. Winstedt, M. Crispin, and C. Kjellman. 2017. 
'Enzymatic Inactivation of Endogenous IgG by IdeS Enhances Therapeutic Antibody 
Efficacy', Mol Cancer Ther, 16: 1887-97. 
Kieseier, B. C., E. K. Mathey, C. Sommer, and H. P. Hartung. 2018. 'Immune-mediated 
neuropathies', Nat Rev Dis Primers, 4: 31. 
Kleyweg, R. P., F. G. van der Meche, and P. I. Schmitz. 1991. 'Interobserver agreement in the 
assessment of muscle strength and functional abilities in Guillain-Barre syndrome', 
Muscle Nerve, 14: 1103-9. 
Olney, R. K., R. A. Lewis, T. D. Putnam, J. V. Campellone, Jr., and Medicine American 
Association of Electrodiagnostic. 2003. 'Consensus criteria for the diagnosis of 
multifocal motor neuropathy', Muscle Nerve, 27: 117-21. 
Takahashi, R., and N. Yuki. 2015. 'Streptococcal IdeS: therapeutic potential for Guillain-
Barre syndrome', Sci Rep, 5: 10809. 
Walgaard, C., H. F. Lingsma, L. Ruts, P. A. van Doorn, E. W. Steyerberg, and B. C. Jacobs. 
2011. 'Early recognition of poor prognosis in Guillain-Barre syndrome', Neurology, 
76: 968-75. 
van den Berg, B., C. Walgaard, J. Drenthen, C. Fokke, B. C. Jacobs, and P. A. van Doorn. 
2014. 'Guillain-Barre syndrome: pathogenesis, diagnosis, treatment and prognosis', 
Nat Rev Neurol, 10: 469-82. 
van Doorn, P. A., K. Kuitwaard, C. Walgaard, R. van Koningsveld, L. Ruts, and B. C. Jacobs. 
2010. 'IVIG treatment and prognosis in Guillain-Barre syndrome', J Clin Immunol, 30 
Suppl 1: S74-8. 
van Leeuwen, N., H. F. Lingsma, A. M. Vanrolleghem, M. C. Sturkenboom, P. A. van Doorn, 
E. W. Steyerberg, and B. C. Jacobs. 2016. 'Hospital Admissions, Transfers and Costs 
of Guillain-Barre Syndrome', PLoS One, 11: e0143837. 
van Nes, S. I., E. K. Vanhoutte, P. A. van Doorn, M. Hermans, M. Bakkers, K. Kuitwaard, C. 
G. Faber, and I. S. Merkies. 2011. 'Rasch-built Overall Disability Scale (R-ODS) for 
immune-mediated peripheral neuropathies', Neurology, 76: 337-45. 
Wang, Y., Q. Shi, H. Lv, M. Hu, W. Wang, Q. Wang, B. Qiao, G. Zhang, Z. Lv, C. Kjellman, 
S. Jarnum, L. Winstedt, Y. Zhang, J. Wen, Y. Hao, and N. Yuki. 2017. 'IgG-degrading 
enzyme of Streptococcus pyogenes (IdeS) prevents disease progression and facilitates 
improvement in a rabbit model of Guillain-Barre syndrome', Exp Neurol, 291: 134-40. 
Willison, H. J., B. C. Jacobs, and P. A. van Doorn. 2016. 'Guillain-Barre syndrome', Lancet, 
388: 717-27. 


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Winstedt, L., S. Jarnum, E. A. Nordahl, A. Olsson, A. Runstrom, R. Bockermann, C. 
Karlsson, J. Malmstrom, G. S. Palmgren, U. Malmqvist, L. Bjorck, and C. Kjellman. 
2015. 'Complete Removal of Extracellular IgG Antibodies in a Randomized Dose-
Escalation Phase I Study with the Bacterial Enzyme IdeS - A Novel Therapeutic 
Opportunity', PLoS One, 10: e0132011. 
 
 


Hansa Biopharma AB 
Date: 27-JUN-2023 
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18. ATTACHMENT  
18.1 Protocol Amendment 08 
 
 

SAP_001.pdf: 
Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
15-HMedIdeS-09   
Statistical analysis plan 
Page 1 of 35
 
F504-0-1-9 
 
 
 
Statistical analysis plan 
 
 
An open-label, single arm, multi-centre, phase II study investigating safety, 
tolerability, efficacy, pharmacodynamics and pharmacokinetics of imlifidase 
(IdeS) in patients with Guillain-Barré Syndrome (GBS), in comparison with 
matched control patients 
 
 
Sponsor: 
Hansa Biopharma AB 
P.O. Box 785  
SE-220 07 Lund  
Sweden 
Contract research organisation: 
 
Sponsor protocol number: 
15-HMedIdeS-09 
EudraCT number: 
2018-001059-12 
ClinicalTrials.gov number: 
NCT03943589 
Universal trial number (UTN): 
Not applicable 
Investigational product name: 
Imlifidase 
Development phase:  
II 
Date of final SAP: 
21-FEB-2024 
 


Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
15-HMedIdeS-09   
Statistical analysis plan 
Page 2 of 35
 
F504-0-1-9 
Signature page 
Author 
 
 
Sponsor approval 
 
 
 
 
 
 
Date  
(dd-Mmm-yyyy) 
 
Signature 
 
 
                                     
 
 
Title: Biostatistician 
 
 
 
 
 
 
 
Date  
(dd-Mmm-yyyy) 
 
Signature 
 
 
                                                   
 
 
Title: Senior Medical Director 
 
 
 
 
 
 
 
 
 
 
 
 
Date  
(dd-Mmm-yyyy) 
 
Signature 
 
 
  
 
 
Title: Manager, Biostatistics 


Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
15-HMedIdeS-09   
Statistical analysis plan 
Page 3 of 35
 
F504-0-1-9 
Table of contents 
Signature page ........................................................................................................... 2 
Table of contents ........................................................................................................ 3 
List of abbreviations and definition of terms ......................................................... 5 
1 
Introduction ........................................................................................................ 6 
1.1 
Study objectives and endpoints ....................................................................................... 6 
1.1.1 
Objectives ........................................................................................................... 6 
1.1.2 
Endpoints ........................................................................................................... 7 
2 
Study design ...................................................................................................... 10 
2.1 
Overview of study procedures ....................................................................................... 10 
2.2 
Determination of sample size ........................................................................................ 11 
2.3 
Blinding ......................................................................................................................... 11 
2.4 
Data pre-processing ....................................................................................................... 11 
3 
Analysis sets ...................................................................................................... 12 
3.1 
Full analysis set ............................................................................................................. 12 
3.2 
PK/PD analysis set ........................................................................................................ 12 
3.3 
Safety analysis set ......................................................................................................... 12 
4 
Statistical analyses and presentation of data ................................................. 13 
4.1 
General considerations .................................................................................................. 13 
4.1.1 
Data presentation .............................................................................................. 13 
4.1.2 
Baseline definition ........................................................................................... 13 
4.1.3 
Data imputation ................................................................................................ 13 
4.2 
Subject disposition ........................................................................................................ 15 
4.3 
Protocol deviations ........................................................................................................ 15 
4.4 
Demographics and other baseline characteristics .......................................................... 15 
4.5 
Compliance and exposure ............................................................................................. 17 
4.6 
Subgroups ...................................................................................................................... 17 
4.7 
Efficacy analysis ........................................................................................................... 17 
4.7.1 
GBS Disability Score (GBS DS) ..................................................................... 17 
4.7.2 
Rasch-Built Linearly Weighted Overall Disability Scale (R-ODS) ................ 18 
4.7.3 
Medical Research Council sum score (MRC sum score) ................................ 19 
4.7.4 
Ventilator support, days in hospital and days in an ICU ................................. 20 
4.7.5 
EurQol EQ-5D-5L Health Questionnaire ........................................................ 21 
4.8 
Safety ............................................................................................................................. 21 


Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
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Statistical analysis plan 
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F504-0-1-9 
4.8.1 
Adverse events ................................................................................................. 21 
4.8.2 
Other safety endpoints ..................................................................................... 23 
4.9 
Other endpoints ............................................................................................................. 24 
4.9.1 
Anti-ganglioside antibodies ............................................................................. 24 
4.9.2 
Pharmacokinetics and Pharmacodynamics ...................................................... 25 
4.9.3 
Pregnancy test .................................................................................................. 26 
4.9.4 
Nerve conduction study (NCS) ........................................................................ 26 
4.9.5 
SARS-CoV-2 virus PCR-test ........................................................................... 26 
5 
Interim analyses ............................................................................................... 27 
6 
Deviations from protocol analysis .................................................................. 28 
7 
Quality control.................................................................................................. 29 
8 
Layout of output ............................................................................................... 30 
9 
Appendixes ........................................................................................................ 31 
9.1 
Appendix 1 - Modified Erasmus GBS outcome score (mEGOS) score calculation ..... 31 
9.2 
Appendix 2 - Centile metric score calculated for the R-ODS ....................................... 32 
9.3 
Appendix 3 - Vital Sign Parameters Normal Ranges .................................................... 34 
10 Change log ........................................................................................................ 35 
 
 


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List of abbreviations and definition of terms  
ADA 
Anti-Drug Antibody  
ADaM 
Analysis data model 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest  
AUC 
Area under the concentration versus time curve 
BP 
Blood pressure 
CI 
Confidence interval 
CL 
Clearance of imlifidase 
Cmax 
Maximum observed concentration 
CSR 
Clinical Study Report 
ECG 
Electrocardiography 
EQ-5D-5L 
EuroQoL EQ-5D Health Questionnaire  
FAS 
Full analysis set 
GBS 
Guillain-Barré Syndrome  
GBS DS 
Guillain-Barré Syndrome disability score  
ICU 
Intensive Care Unit  
IdeS 
Immunoglobulin G degrading enzyme of Streptococcus pyogenes  
IMP 
Investigational medicinal product 
IVIg 
Intravenous Immunoglobulin  
LLOQ 
Lower limit of quantification 
mEGOS 
Modified Erasmus GBS Outcome Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRC  
Medical Research Council sum score  
NCS 
Nerve Conduction Studies  
PD 
Pharmacodynamics  
PE 
Plasma Exchange  
PK 
Pharmacokinetics 
PKPDAS 
PK/PD analysis set 
PT 
Preferred term 
R-ODS 
Rasch-built Overall Disability Scale  
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SE 
Standard error 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
Tmax 
Time of observed Cmax 
t½  
Half-life 
V 
Volume of central compartment 
Vss 
Volume of distribution at steady-state 
Vz 
Volume of distribution during the elimination phase 


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1 
Introduction 
Guillain-Barré Syndrome (GBS) is an acute, paralyzing, inflammatory disease of the peripheral 
nervous system usually preceded by an infection or other immune stimulation that induces an 
aberrant autoimmune response targeting peripheral nerves and their spinal roots. GBS is a rapidly 
progressive disorder often leading to a severe paralysis of the arms and legs. Most GBS patients 
have sensory disturbance (tingling or numbness or ataxia) and pain, and some patients have 
double vision or problems with swallowing. GBS may also paralyse the respiratory muscles, 
leading to intensive care unit admission and mechanical ventilation.  
After onset, GBS patients have a mortality rate of 3-5%. Two thirds of the patients have severe 
symptoms resulting in their inability to walk unaided, and 20-30% require mechanical ventilation 
for a period ranging from weeks to months. Progression of weakness in GBS is usually rapid and 
reaches a nadir within 4 weeks in patients, but the majority develop their maximum deficit within 
2 weeks.  
To treat GBS, both general medical care and immunological treatment are recommended. 
Intravenous Immunoglobulin (IVIg) and Plasma Exchange (PE) are the two main treatments. 
Imlifidase is an immunoglobulin G-degrading enzyme derived from Streptococcus pyogenes that 
with strict specificity cleaves all four human subclasses of IgG. Imlifidase cleaves human IgG 
below the hinge region thereby generating one F(ab’)2 fragment and one Fc-fragment which does 
not bind to Fc-receptors and does not activate complement.  
This study is designed to evaluate the safety, tolerability, and efficacy of intravenous dosing of 
imlifidase in GBS subjects. Additionally, pharmacokinetics (PK) and pharmacodynamics (PD) 
will be assessed.   
In addition, a comparison to an externally matched cohort of GBS subjects treated with IVIg 
(IGOS database) will, if feasible, be conducted to evaluate the efficacy of imlifidase plus IVIg in 
combination. If such an indirect comparison study is feasible, details pertaining to the comparison 
will be outlined in a separate non-interventional study protocol.   
This document presents the planned statistical analyses for Hansa Biopharma AB, study 
15-HMedIdeS-09: An open-label, single arm, multi-centre, phase II study investigating safety, 
tolerability, efficacy, pharmacodynamics and pharmacokinetics of imlifidase (IdeS) in patients 
with Guillain-Barré Syndrome (GBS), in comparison with matched control patients. 
This statistical analysis plan is based on the trial protocol version 7.0 (dated 11JUN2021), version 
8.0 (dated 31JAN2022) and version 9.0 (dated 27JUN2023).  
In case of deviations from the SAP, explanations will be provided in the Clinical Study Report 
(CSR). 
 
1.1 Study objectives and endpoints 
1.1.1 
Objectives 
The objectives of this study are to:  
• 
Assess safety and tolerability of imlifidase in combination with standard IVIg treatment in 
GBS subjects  


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• 
Evaluate pharmacokinetics of imlifidase  
• 
Evaluate pharmacodynamic profile of imlifidase  
• 
Evaluate immunogenicity of imlifidase  
• 
Evaluate efficacy of imlifidase in subjects with GBS  
• 
Evaluate quality of life after imlifidase treatment in subjects with GBS 
• 
Evaluate healthcare resource utilization after imlifidase treatment in subjects with GBS 
• 
Evaluate the contribution of a dose of imlifidase on outcomes with respect to severity of 
symptoms and recovery time through a comparison with an externally matched cohort of 
GBS subjects   
• 
Evaluate the effect of imlifidase on exploratory biomarkers. 
 
1.1.2 
 Endpoints 
1.1.2.1 
Efficacy 
The efficacy endpoints are the following: 
• 
GBS Disability Score (DS):  
o Proportion of subjects with improvement of one or more grades in disability 
outcome (on the 6-point GBS DS) over time (i.e., at all post-baseline visits)  
o Proportion of subjects with improvement of two or more grades in disability 
outcome (on the 6-point GBS DS) over time (i.e., at all post-baseline visits)  
o Proportion of subjects with improvement of three or more grades in disability 
outcome (on the 6-point GBS DS) over time (i.e., at all post-baseline visits) 
o Change in GBS DS over time (i.e., at all post-baseline visits) 
o Proportion of subjects able to walk unaided (GBS DS ≤ 2) over time (i.e., at all 
post-baseline visits)  
o Time (days) to improvement by at least one, two and three grade(s) on the GBS 
DS  
o Time (days) to walk independently (GBS DS ≤ 2) 
o Proportion of subjects that reach GBS DS ≤ 1 by week 26 
o Time (days) to run (GBS DS ≤ 1) 
• 
Rasch-built Overall Disability Scale (R-ODS): 
o Proportion of subjects with an increase from baseline in R-ODS scale by at 
least 6 points on the centile metric score over time (i.e., at all post-baseline 
visits) 
o Proportion of subjects with all R-ODS items above 0 at week 26 
• 
Change in MRC sum score over time (i.e., at all post-baseline visits). 
• 
Ventilation support (GBS DS 5): 


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o Proportion of subjects requiring mechanical ventilation support (GBS DS 5) 
(i.e., at all visits) 
o Time (days) on mechanical ventilation  
• 
Time (days) in hospital and in an ICU  
• 
Quality of life as measured by EurQol EQ-5D Health Questionnaire (EQ-5D-5L) at 4 
weeks and later. 
 
1.1.2.2 
Safety 
Safety will be assessed by: 
• 
Adverse events: 
• 
All AEs  
• 
TEAEs 
• 
Severe AEs (AEs having CTCAE grade ≥ 3) 
• 
SAEs  
• 
Adverse Drug Reactions (ADR) defined as TEAEs related to study treatment (Possibly 
or Probably Related AEs)  
• 
AEs leading to withdrawal  
• 
Deaths  
• 
Adverse events of special interest (AESI), defined as  
• 
Infusion-related reactions that occurs within 48 hours of imlifidase treatment  
• 
All AEs 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 imlifidase administration  
 
• 
Presence of anti-imlifidase antibodies (ADA) 
 
• 
Laboratory tests:  
o Clinical chemistry:  
P-alanine aminotransferase (ALT), P-gamma glutamyl transferase, P-alkaline 
phosphate, P-bilirubin total, P-creatinine, P-potassium, P-albumin, P-calcium, 
P-immunoglobulin G (IgG)  
o Haematology:  
B-haemoglobin, B-haematocrit, B-white blood cell count, B-neutrophils (absolute 
count), B-lymphocytes (absolute count), B-eosinophiles (absolute count), 
B-platelet count  
o Urinanalysis:  
U-glucose, U-haemoglobin, U-protein, U-pH, U-urobilinogen, U-protein, U-
ketone, U-bilirubin.   
 
• 
Vital signs (Blood pressure, pulse rate, respiratory frequency, oxygen saturation and body 
temperature) 


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• 
Physical examination (include an assessment of the following: general appearance, head 
and neck, lymph nodes, abdomen, musculo-skeletal, cardiovascular, respiratory and gross 
neurological examination) 
 
• 
Electrocardiography (ECG) (categorised as “normal”, “abnormal, not clinically 
significant”, or “abnormal, clinically significant”, as judged by the Investigator), only 
collected up to protocol version 7.0 (inclusive). 
 
1.1.2.3 
Pharmacokinetics (PK) and Pharmacodynamics (PD) 
PD and PK will additionally be evaluated as endpoints: 
• 
PK parameters maximum serum concentration (Cmax), area under the curve (AUC), time to 
maximum plasma concentration (tmax), terminal half-life (t½), V, clearance (CL), of 
imlifidase  
 
• 
PD effect on IgG following administration of imlifidase 
 
• 
PD effect on identified autoantibodies regarded as GBS disease specific following 
administration of imlifidase.  
To note, identification of post-infusion antibodies is described in section 1.1.2.4. 
 
1.1.2.4 
Exploratory Endpoint  
Biomarker assessment (analysis of anti-ganglioside antibodies and neurofilament light chain 
levels) will be evaluated as an exploratory endpoint. 


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2 
Study design 
The study is an open-label, single arm, multi-centre, phase II study of imlifidase in combination 
with standard care IVIg in subjects within 10 days of onset of GBS.  
The study will recruit approximately 30 subjects (adult males or females) with GBS eligible for 
IVIg treatment based on current practice (i.e. GBS disability score ≥3 at time of screening for 
enrolment and within 10 days of onset of weakness).  
Data from each subject enrolled in this study will, if feasible, be compared with an external 
control group consisting of matched subjects from the IGOS database (International Guillain-
Barré Syndrome Outcome Study, ClinicalTrials.gov Identifier: NCT01582763). If such an indirect 
comparison study is feasible, details pertaining to the comparison will be outlined in a separate 
non-interventional study protocol. This data will be handled according to a separate SAP. 
 
2.1 Overview of study procedures 
All subjects will receive imlifidase (Day 1) prior to standard of care IVIg. Disability scores to 
assess disability status and capture activities and social participation will be evaluated. Blood 
samples for safety, pharmacokinetics, and pharmacodynamics will be collected, and subjects will 
be closely monitored after infusion with imlifidase. 
Subjects will be followed clinically on days 1-8, 15, 29, 57, 92 and 180 days after imlifidase 
infusion and additionally with a 360-day telephone contact to assess GBS DS, R-ODS, capture 
health status in a questionnaire, and AEs.  
Safety parameters will be measured up to Day 180. Concomitant medication will be recorded 
throughout the study.  
Reporting of adverse events will be done from signing of informed consent and throughout the 
study.  
After study completion, all study subjects will be followed up regularly according to clinical 
practice at the site in question.  
 
Figure 1. Overview of study 
 
 
The planned tests are summarised in the Study Flow Chart Table outlined in the study protocol. 
Note, schedule of Study Flow Chart (i.e., assessments and procedures) may change between 
protocol versions, please refer to corresponding schedule relevant for each protocol version. 


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2.2 Determination of sample size 
No formal sample size calculations have been performed for this study. Approximately 30 
evaluable subjects will be enrolled and are considered sufficient to provide adequate information 
about the safety and efficacy. 
2.3 Blinding 
Blinding is not relevant since this is an open-label study, and all subjects will receive a dose of 
imlifidase, 0.25mg/kg.  
2.4 Data pre-processing 
Difference between the value at each assessment and value at baseline for the efficacy parameters 
as an absolute change and percentage change will be calculated as:  
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥= 𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥−𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏.  
 
𝐶𝐶ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 % 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥= 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥
𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
∙100. 
 
The proportion of subjects with improvement since baseline at each visit will be calculated as: 
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥= 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏
. 
 
Mean difference from baseline to each visit will be calculated as: 
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥= 𝑠𝑠𝑠𝑠𝑠𝑠 𝑜𝑜𝑜𝑜 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑥𝑥
. 
 
 


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F504-0-1-9 
3 
Analysis sets 
3.1 Full analysis set 
The full analysis set (FAS) consists of data from all dosed subjects having a confirmed GBS 
diagnosis, i.e., subjects re-evaluated and having change in diagnosis (incorrectly diagnosed with 
GBS at study entry) will be excluded.  
The FAS will be used for presentation of efficacy endpoints. 
3.2 PK/PD analysis set 
The PK/PD analysis set (PKPDAS) comprises data from all dosed subjects, with at least one PK 
or PD data point available post-baseline.  
The PK/PD analysis set will be used for presentation of pharmacokinetic and pharmacodynamic 
endpoints. 
3.3 Safety analysis set  
All treated subjects are included in the safety analysis set (SAF). 
The safety analysis set will be used for presentation of safety endpoints. 


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4 
Statistical analyses and presentation of data  
4.1 General considerations 
In general, FAS, PKPDAS and SAF will be used for presentation of all baseline characteristics 
(demographics, GBS disease information, medical history, prior and concomitant medication, and 
physical examination), FAS will be used for efficacy endpoints, SAF will be used for exposure 
and compliance and safety endpoints and PKPDAS will be used for pharmacokinetic and 
pharmacodynamic endpoints. 
Listings to be presented for all subjects, if not otherwise specified in the corresponding TFL shell. 
4.1.1 
Data presentation  
No statistical testing will be performed. Results from analyses will be presented with estimates 
and 95% confidence intervals (CIs). For log-transformed analyses, the anti-log transformation will 
be applied before presentation. 
No adjustments for multiple testing will be done, since no statistical testing will be performed. 
Numerical data will be presented in summary tables by number of subjects, arithmetic mean, 
median, standard deviation (SD), minimum and maximum. When numerical data are recorded at 
different time points, absolute values at each time point and changes from baseline may be 
presented in the summary tables. 
Categorical data will be presented by number and percent of subjects as well as number of events 
(where applicable).  
Summaries and analysis of data will in general be presented for all subjects included in the 
analysis set, unless otherwise specified in the output shell. 
All data will be listed by subject and time point (if applicable).  
4.1.2 
Baseline definition  
Baseline value is defined as the last non-missing assessment before the subjects start on the 
treatment. Change from baseline will be calculated as the difference between values for a given 
timepoint after baseline and baseline values (timepoint after baseline value minus baseline value). 
If the post-baseline value or baseline value are missing, then the change from baseline will also be 
missing. 
4.1.3 
Data imputation 
In general, missing data will remain as missing and the missing values will not be imputed. There 
are some exceptions described below. 
Dates for adverse event and concomitant medication 
Missing or partial start dates for AEs and concomitant medication data will be handled in the 
following way: 


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• If the start date is totally missing, the date will still be missing. 
• If the start date is partial where only month and year are given, then the two cases are 
considered: 
1. If the available partial date (month and year) is before the month and year of treatment 
start date, then the AE/medication will be considered as pre-treatment and the date will 
be imputed as the end date of the month. 
2. If the available partial date does not indicate that the AE/medication has started before 
the treatment start, then the AE/medication will be considered as treatment 
emergent/concomitant or post-treatment emergent, as follows: 
• If month is same as month of treatment start date or the month right after the month 
of treatment start date, then the AE is treatment emergent. 
• Else if month is after month of treatment start date, then the AE is post-treatment 
emergent. 
• For medications, if the available partial date does not indicate that the medication 
has started before the treatment start, then it will be considered as concomitant. 
The date will be imputed as the start (1st) of the month (if the month and year is after 
the month and year of the treatment start date) or treatment start date (if the month and 
year is same as month and year of the treatment start date). 
• If the start date is partial where only the year is given, then the two cases are considered: 
3. If the available partial date (year) is clearly before the year of treatment start date, then 
the start date is imputed as last day of the year (i.e. 31 December).  
4. If the available partial date (year) is equal to or after the year of treatment start date, 
then the start date will be imputed as start of the year (1st January YYYY) (if the year 
is not same as that of the treatment start date) or treatment start date (if the year is 
same as the treatment start date). 
• For the partial end dates, similar procedure will be used as for the start dates. The only 
difference is the imputation for missing days and months. Missing days is imputed to the 
end of the month (instead of the start of the month) or at the date of study 
discontinuation/completion, whichever occurs first. If only year is available, the end date 
is set to 31st December YYYY or at the date of study discontinuation/completion, 
whichever occurs first. It will be checked that the imputed end dates fall after the 
corresponding start dates. 
All completely missing end dates will be missing. 
The partial dates as reported will be presented in the listings. The imputed dates purpose is for 
deriving the corresponding flags for relation to start/end of IMP (e.g. TEAE flagging) and study 
days, when applicable. 
 


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4.2 Subject disposition 
Subjects enrolled but not dosed will be regarded as screening failures. 
Subjects screened but not found eligible will be stated in the trial report but otherwise not 
accounted for. 
A table will present the subject disposition as number of subjects screened, enrolled, GBS not 
confirmed at 6 months, GBS not confirmed at 12 months, screen failures, completed (6 months 
follow-up visit and 12 months follow-up visit, respectively), withdrawn overall and by reason for 
withdrawal and by subjects in each of the analysis sets. 
 
4.3 Protocol deviations  
Deviations from the protocol, as continuously tracked by investigator and sponsor, will be 
classified as ‘minor’ or ‘major’. The final classification of the deviations will be done before the 
database lock. 
All protocol deviations will be summarised with frequency and percentage for each category of 
protocol deviation, for both FAS and safety analysis sets. The protocol deviations will also be 
listed by subject. 
 
4.4 Demographics and other baseline characteristics 
The demographics are age at screening date, sex, and race. 
Medication will be classified according to WHODrug Global B3 dictionary version 2018Q3. 
Summary tables will be performed for: 
• Demographics (including age (years), sex, race, height, weight and BMI before IMP 
intake) 
• Medical history or concomitant illness as reported at study entry  
• Baseline GBS characteristics and GBS symptoms, including:  
o Presence of diarrhoea (<4 weeks from screening) 
o Onset of weakness due to GBS 
o Days from onset of weakness until imlifidase administration 
o GBS variant type at screening 
o Electrophysiology classification of subtype the subject has according to JJ Sejver 
et al. (Vaccine 2011; 29: 599-612) 
o Status of cranial involvement 
o Medical history of disease affecting mobility (yes/no) 


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o Medical history of disease affecting respiration (yes/no) 
• Pre-medication to prevent/minimise risk of infusion reactions (methylprednisolone and 
antihistamine or an equipotent antihistamine) before imlifidase infusion 
• Medication to minimise the risk for bacterial infections (prophylactic antibiotics), 
summarizing all prophylactic antibiotics the subjects had during the first 14 days after 
imlifidase administration (including prophylactic antibiotics given in day before imlifidase 
administration and in same day as the imlifidase administration).  
• Prior medication, summarizing all medications the subjects had before the study (prior to 
start of study treatment)  
• Concomitant medication, summarizing all medications the subjects had throughout the 
study (following start of study treatment), considering the following tables: 
o All concomitant medications 
o Concomitant medication during Day 1 – 29 
o Concomitant medications during Day 30 – End of study 
Note: prior and concomitant medication will exclude ‘Pre-medication to prevent/minimise risk of 
infusion reactions before imlifidase infusion’ and ‘Medication to minimise the risk for bacterial 
infections’. 
Listings will be provided including the values for each subject of:  
• Subject disposition (enrolled, completed, withdrawn (reason for withdrawal) for each 
analysis set (FAS, SAF and PKPDAS). 
• Demographics (including age (years), sex, race) 
• Medical history as reported at study entry (system organ class (SOC) and preferred term 
(PT)) 
• GBS disease information at study entry 
• Baseline GBS characteristics 
• Pre-medication to prevent/minimise risk of infusion reactions (methylprednisolone and 
antihistamine or an equipotent antihistamine) before imlifidase infusion  
• Prophylactic antibiotics (flag in if during the first 14 days after imlifidase treatment). 
• Prior medication (anatomical therapeutic chemical (ATC) code and generic drug name) 
• Concomitant medication (anatomical therapeutic chemical (ATC) code and generic drug 
name) 
• Serology (HIV-1 and HIV-2 antibodies, hepatitis B surface-antigen and hepatitis C virus 
antibodies performed at screening) 
 




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     6 = Dead 
Summary statistics will be presented in tables for the actual values and absolute change from 
baseline by time point. Also, shift tables will be presented to show the change from baseline as 
compared to post-baseline visits for the GBS DS. 
In addition, the number and percentages of subjects with improvement of at least one, two or three 
grades, respectively, on the GBS DS will be presented by time point. 
Similarly, the number and percentage of subjects able to walk unaided (GBS DS ≤ 2) and run 
(GBS DS ≤ 1), respectively, will be presented by time point.  
Lastly, the following Kaplan-Meier analysis summary tables and plots will be presented: 
• Time to improvement by at least one grade on the GBS DS  
• Time to improvement by at least two grades on the GBS DS  
• Time to improvement by at least three grades on the GBS DS  
• Time to walk independently (GBS DS ≤ 2) 
• Time to run (GBS DS ≤ 1) 
Study end/discontinuation will be considered as censoring for subjects that do not have the event. 
In addition, the survival function will start at 0, since all these are “positive” events. 
For each endpoint two separate Kaplan-Meier plots will be presented, one up to Day 29  
(collected part of Visit 6) and one up to Day 360 (collected as part of Visit 10), including the 
subjects at risk at specific timepoints. Also censored observations will be marked as such on the 
plot. 
The summary tables for the corresponding Kaplan-Meier analysis will include the following for 
specific timepoints up to Day 360: subjects at risk, number of subjects with events, censored 
observations, proportion estimates and associated pointwise 95% confidence interval (CI). 
A separate table will present the number of subjects included in the analysis with corresponding 
number of events, number of censored observations and summary statistics for the time to event 
(minimum, maximum, median and associated 95% CI, quartiles). 
Additionally, a swimmer plot will be created to show change in GBS DS over time up to Day 92 
(collected as part of Visit 8). Subjects will be shown as rows on y-axis, time on x-axis, each 
subject having a bar that is coloured according to latest GBS DS.  
 
4.7.2 
Rasch-Built Linearly Weighted Overall Disability Scale (R-ODS) 
The response options for each item of the Rasch-Built Linearly Weighted Overall Disability Scale 
(R-ODS) used for the efficacy endpoints will be assessed for all subjects as per the schedule of 
assessments. The final questionnaire comprises 24 items ranging from ability to read a book or 
newspaper (as the easiest item to accomplish) to ability to run (most difficult item to accomplish). 
The response options for each item are: 
     0 = Not possible  


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     1 = Possible with effort  
     2 = Easy to perform 
The obtained raw summed score is subsequently translated to a convenient centile metric ranging 
from 0 (most severe disability) to 100 (no disability at all), as described in Appendix 2, which will 
be used for summary statistics and analyses. To note, the centile metric will be calculated only if 
all 24 items have data, otherwise this will be missing. 
Summary statistics will be presented in tables for the actual values and absolute change from 
baseline by time point for the centile metric.  
In addition, the number and percentages of subjects with an increase from baseline in R-ODS 
scale by at least 6 points on the centile metric score will be presented using descriptive statistics 
by time point. 
Similarly, the number and percentages of subjects with all R-ODS items above 0 at week 26 will 
be presented. 
 
4.7.3 
Medical Research Council sum score (MRC sum score) 
The Medical Research Council sum score (MRC sum score) used for the efficacy endpoints will 
be assessed for all subjects as per the schedule of assessments. It is a sum score of power in six 
muscle groups on each side (summing all the obtained scores of each muscle groups on each 
side). The sum of these scores ranges from 0 (total paralysis) to 60 (normal power). The 
individual MRC grades are defined as: 
     0=No visible contraction    
           1=Visible contraction without movement of the limb 
           2=Movement of the limb but not against gravity 
           3=Movement against gravity (almost full range) 
           4=Movement against gravity and resistance 
           5=Normal 
Summary statistics will be presented in tables for the actual values and absolute change from 
baseline for MRC sum score by time point. MRC sum score will be calculated only if all 12 
scores of each muscle groups on each side have data, otherwise this will be missing. 
In addition, representing proximal and distal muscles outcomes, summary statistics (both actual 
values and absolute change from baseline) will be presented for the following four subgroups of 
the MRC score (sub-scores), calculated as an average of the included items, by time point:  
• abduction of arm + flexion of forearm for both sides  
• extension of the wrist for both sides 
• hip flexion + extension of knee at both sides 
• dorsal flexion of the foot for both sides 


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Sub-scores including one muscle group will be calculated if both sides have scores, sub-scores 
including two muscle groups will be calculated if both muscle groups have scores from at least 
one side. This does mean that the MRC sum score may be missing even though some sub-scores 
are calculated (due to available data for the scores in particular muscle groups). 
Individual subject plots will be created showing both MRC sub-scores and GBS DS over time up 
to Day 92 (collected as part of Visit 8). The graph will show time since imlifidase administration 
on x-axis, MRC sub-scores over time will be represented as a line, GBS DS as a bar coloured 
according to latest GBS DS. Additional events of interest will be included on the plot: onset date 
of worsening of GBS (captured as AE: any AE with reporter term stating 'FACIAL PARALYSIS', 
or AE coded preferred term of 'Neuropathy peripheral' or 'Respiratory failure' with corresponding 
reported term suggesting worsening/deterioration of GBS), start and stop dates for ICU 
admission(s).   
 
4.7.4 
Ventilator support and days in hospital and days in an ICU 
The number and percentage of subjects requiring mechanical ventilation support (GBS DS 5) will 
be presented by time point. 
In addition, summary statistics will be presented in three separate tables for the number of days on 
mechanical ventilation and number of days in hospital and in an ICU. The number of days in an 
ICU is a subset of number of days in hospital. 
The total number of days on mechanical ventilation and total number of days in hospital and in an 
ICU will be calculated for each subject considering the following formula: 
Total number of days on mechanical ventilator = Sum of [(End date of mechanical 
ventilation – Start date of mechanical ventilation) + 1] 
Total number of days in hospital = Sum of [(End date in hospital – Start date in hospital) + 
1] 
Total number of days in an ICU = Sum of [(End date in an ICU – Start date in an ICU) + 
1], 
including each period the subject was on mechanical ventilator in hospital and in an ICU between 
administration of IMP to Day 180. As periods can overlap (new period starting at the same date 
that previous period ended) it will be ensured that no day is counted twice.  
Also, the number and percentage of subjects that were at ICU or on mechanical ventilator at time 
of imlifidase administration will be presented in a separate table on the FAS, part of the baseline 
characteristics section. 
Details about the mechanical ventilation support, hospital admission and days in an ICU will be 
presented in separate listings. 
 


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4.7.5 
EurQol EQ-5D-5L Health Questionnaire 
Quality of Life is used for assessment of efficacy and is measured by EuroQol EQ-5D Health 
Questionnaire. The EQ-5D-5L consists of 5 individual items (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) and an EQ Visual Analogue scale (EQ VAS) and EQ-5D-5L 
is designed for self-completion by respondents. EQ-5D-5L will be completed by the participating 
subjects as per the schedule of assessments. 
Summary statistics will be presented in a table for the VAS score by time point. Also, all 
individual items will be summarized using frequency counts and associated percentages for all 
time points in a separate table.  
 
4.8 Safety  
Safety data will be presented by descriptive statistics in tables and in listings for each subject. 
Safety parameters will be evaluated for the safety analysis data set.  
4.8.1 
Adverse events 
According to the protocol, an AE is defined as the development of an undesirable medical 
condition or the deterioration of a pre-existing medical condition following or during exposure to 
a pharmaceutical product, whether or not considered causally related to the product. Relationship 
to the study drug will be deemed as not related, unlikely, possible or probable. An undesirable 
medical condition can be symptoms (e.g., nausea and chest pain), signs (e.g., tachycardia and 
enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings and 
electrocardiograms).  
A pre-treatment adverse event is any untoward medical occurrence arising or observed between 
signing of informed consent and administration of the IMP. 
A treatment emergent adverse event (TEAE) is any AE occurring after the start of administration 
of the IMP and within the time of residual drug effect, or a pre-treatment AE or pre-existing 
medical condition that worsens in intensity after start of administration of the IMP and within the 
time of residual drug effect.  
The time of residual drug effect is the estimated period after the administration of the IMP, where 
the effect of the product is still considered to be present based on pharmacokinetic, 
pharmacodynamic or other substance characteristics. The residual drug effect is generally 
accepted to be 5 times the terminal half-life. The terminal half-life of imlifidase is expected to be 
within the range of approx. 100 hours, i.e. in this study the residual drug effect is likely to be well 
within the Day 29 assessments, but since this is the first administration of imlifidase to GBS 
subjects, all AEs occurring up to Day 29 are regarded as treatment emergent. 
A Serious Adverse Event (SAE) is defined as an AE which fulfills any of the following: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 


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• 
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. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE, but not the procedure itself. 
The following events will be assessed as adverse events of special interest (AESI):  
• 
Infusion-related reactions that occurs within 48 hours of imlifidase treatment  
• 
All AEs 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 imlifidase administration  
 
AEs will be coded according to Medical Dictionary for Regulatory Activities (MedDRA) version 
21.1. 
 
Summary tables will be presented for all AEs and TEAEs, respectively. For each of the AE 
categories below, the number of subjects reporting an AE, the percentage of subjects with an AE 
and the number of events reported:  
• 
All AEs  
• 
TEAEs 
• 
All non-TEAEs divided in pre- and post-TEAE 
• 
AEs having CTCAE grade ≥ 3  
• 
TEAEs having CTCAE grade ≥ 3  
• 
All non-TEAE having CTCAE grade ≥ 3 divided in pre- and post-TEAE 
• 
SAEs 
• 
Serious TEAEs  
• 
Adverse Drug Reactions (ADR) defined as TEAEs related to study treatment (i.e., 
Possibly or Probably Related AEs) 
• 
AEs leading to withdrawal  
• 
TEAEs leading to withdrawal  
• 
AEs leading to death 
• 
AEs of special interest (AESI). 
 
Summary tables will be prepared for the incidence of all AEs and TEAEs, respectively, by 
MedDRA System Organ Class (SOC) and Preferred Term (PT), presenting number of subjects 
reporting an AE, the percentage of subjects (%) with an AE and the number of events reported. 
Summary tables will be prepared for:  
• 
All AEs by SOC and PT  
• 
All TEAEs by SOC and PT  
• 
All pre-TEAEs by SOC and PT  


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• 
All post-TEAEs by SOC and PT  
• 
AEs by SOC, PT and causality (related/not-related)  
• 
TEAEs by SOC, PT and causality (related/not-related) 
• 
Pre-TEAE by SOC, PT and causality (related/not-related) 
• 
Post-TEAE by SOC, PT and causality (related/not-related) 
• 
AEs by SOC, PT and intensity 
• 
TEAEs by SOC, PT and intensity 
• 
Pre-TEAE by SOC, PT and intensity 
• 
Post-TEAE by SOC, PT and intensity 
• 
TEADRs by SOC and PT  
• 
Post-Treatment emergent ADRs by SOC and PT  
• 
TEADRs by SOC and PT and intensity  
• 
Post-Treatment emergent ADR by SOC, PT and 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 will be taken to be 
severe, if seriousness is missing, the AE will be considered as an SAE and if the outcome is 
missing and no date of outcome is present, the outcome is regarded as “not yet recovered”. 
Listing will be provided for: 
• 
All AEs  
• 
TEAEs 
• 
Pre-treatment AEs  
• 
Post-treatment emergent AEs 
• 
AEs having CTCAE grade ≥ 3 divided in Pre-TEAE, TEAE and Post-TEAEs 
• 
SAEs divided in Pre-TEAE, TEAE and Post-TEAEs 
• 
Adverse Drug Reactions (ADR) divided in TEAE and Post-TEAEs 
• 
AEs leading to withdrawal divided in Pre-TEAE, TEAE and Post-TEAEs 
• 
Deaths (ie AEs leading to death) divided in Pre-TEAE, TEAE and Post-TEAEs 
• 
Adverse events of special interest (AESI) divided in TEAE and Post-TEAEs 
 
4.8.2 
Other safety endpoints 
4.8.2.1 
Anti-imlifidase antibodies (ADA) 
Presence of anti-imlifidase antibodies (ADA) will be assessed. The long-term effect of treatment 
will be evaluated by presenting summary statistics for each time point, for antibodies anti-
imlifidase IgG (ADA) values. A listing will also present the ADA results collected over time by 
time point. 
Antibodies anti-imlifidase IgG (ADA) values below lower limit of quantification (LLOQ) will be 
imputed using the limit itself. 
Boxplots corresponding to the ADA results collected over time will be presented by time point. 
Also, individual plots will be presented for each subject to show the ADA results over time point 
in two separate set of plots: one up to Day 29 (collected part of Visit 6) and one up to Day 180 
(collected part of Visit 9). 


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4.8.2.2 
Vital signs 
Vital signs will be presented by visit (i.e., time point) for each parameter and summarised, 
including absolute change from baseline. Shift tables will be presented from baseline to all 
planned time points until end of residual drug effect, i.e. Day 29. Any changes from normal/low to 
high or from normal/high to low during these periods will be counted as a shift and will be 
summarised. The results will be flagged as Low (L)/High (H) as per the criteria defined in 
Appendix 3. 
In addition, separate listings containing vital signs data will be presented by subject. 
The vital signs assessment part of visit 3, 7 and 9 has only been collected up to protocol version 
7.0 (inclusive). Results from these visits will only be presented in the listing. 
4.8.2.3 
Clinical Chemistry, Haematology and Urinalysis 
Laboratory tests will be summarised and presented in tables similarly as the vital signs 
parameters. In addition, shift tables for normal, abnormal and not clinically significant, abnormal 
and clinically significant results will be presented for all clinical chemistry and haematology 
laboratory parameters from baseline to all planned time points until end of residual drug effect, 
i.e. Day 29. Similar shift tables will be presented also for urinalysis parameters from baseline to 
all planned time points until end of residual drug effect, i.e. Day 29. Listings containing 
laboratory test data will be presented by subject. Abnormal clinically significant values will be 
flagged in listings. 
The safety laboratory assessment part of visit 7 and 9 has only been collected up to protocol 
version 7.0 (inclusive). Results from these visits will only be presented in the listings. 
4.8.2.4 
Electrocardiography (ECG) 
ECGs will be categorised as “normal”, “abnormal, not clinically significant”, or “abnormal, 
clinically significant” (as judged by the Investigator) and listed by subject. 
4.8.2.5 
Physical examination 
A complete physical examination will be performed at screening and Day 180 (visit 9). The 
physical examination will be listed by subject. 
 
4.9 Other endpoints 
4.9.1 
Anti-ganglioside antibodies 
Biomarker assessment (analysis of anti-ganglioside antibodies and neurofilament light chain 
levels) will be evaluated as an exploratory endpoint.  
Pre-dose samples will be screened for anti-ganglioside antibodies and presented in a table as 
positive or negative. The anti-ganglioside antibodies data will be listed by subject.  


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Neurofilament light chain levels will be summarized in a table and presented in a listing by 
subject. In addition, neurofilament light chain levels will be presented both as mean plot and 
individual subject plots to show the change over time.  
Moreover, a separate plot will show anti-ganglioside antibodies titers per subject over time up to 
Day 92 (collected as part of Visit 8) together with the swimmer plot of the GBS disability scores 
and the subgroup MRC scores on FAS.   
 
4.9.2 
Pharmacokinetics and Pharmacodynamics 
PK sampling has only been done up to protocol version 7.0 (inclusive). If PK sampling were 
initiated in accordance with the previous version of the protocol after Protocol Version 8.0 was 
approved, collection of PK samples were to continue for the full imlifidase PK profile. 
Plasma concentrations of imlifidase will be summarized with number of measurements, number 
below LLOQ, number of missing data, mean, standard deviation, median, minimum, maximum, 
geometric mean and CV (%) by time points and presented graphically as mean profiles and by 
subject profiles. No formal analysis of “outliers” is planned. If the actual time differs more than 
20% from the nominal time for a value, that value will not be included in the figure for the mean 
concentrations. 
Plasma concentrations will be presented both as mean plot (both in linear and log-scale) and 
individual subject plots to show the change over time. 
Pharmacokinetics (PK) parameters will be estimated based on measurements of the plasma 
concentration-time data of imlifidase. The following parameters will be estimated, if possible, but 
not limited to:  
• 
Maximum serum concentration (Cmax) 
• 
Area under the curve (AUC) 
• 
Time to maximum plasma concentration (tmax) 
• 
Terminal half-life (t½) 
• 
Distribution volume (Vz)  
• 
Volume of distribution, steady state (Vss) 
• 
Volume of central compartment (V) 
• 
Clearance (CL) of imlifidase.  
PK parameters will be presented with number of measurements, number of missing data, mean, 
standard deviation, median, minimum, maximum, geometric mean and CV(%). For t½, the 
harmonic mean will be considered instead of the mean and geometric mean. For tmax only the 
median, minimum and maximum will be presented.  
Plasma concentration values below lower limit of quantification (LLOQ) will be imputed as 0 for 
descriptive statistics, LLOQ/2 in plots and excluded from PK parameter calculations. Missing 
values (e.g. no blood sample collected, or no value obtained at analysis) will not be imputed for 
plasma concentrations descriptive statistics or PK parameter calculations. 
In addition, the PK concentrations and PK parameters will be presented in separate listings by 
subject. 


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Pharmacodynamics (PD) will be assessed by: 
• 
Effect on IgG following administration of imlifidase  
• 
Effect on identified autoantibodies following administration of imlifidase.  
• 
IgG fragment analysis using SDS-PAGE 
 
The IgG below LLOQ will be imputed using the limit itself for the summary statistics and the 
plots. 
The IgG data will be summarised in tables and presented graphically as mean profiles. Individual 
data will be plotted over time.  
Anti-ganglioside autoantibodies titer data results of Negative will be imputed to 500 for the 
summary statistics and the plots. 
Anti-ganglioside autoantibodies titer data will be summarised in tables and presented graphically 
over time as mean profiles for each ganglioside antibody and in a mean summary graph with all 
anti-ganglioside antibodies, if data allows. Individual data will be plotted over time. 
IgG and identified autoantibodies will additionally be presented in listings. 
SDS-PAGE score data of intact IgG, scIgG and IgG fragments in serum will be presented by 
subjects and summarised by time point in a table. 
4.9.3 
Pregnancy test  
Serum β-hCG will be determined for all female subjects at screening and on Day 180 (visit 9). All 
pregnancy test results will be presented in a listing by subject. 
4.9.4 
Nerve conduction study (NCS) 
Nerve conduction study (NCS) might be measured at Days 15 and 29. NCS is performed using 
standard techniques at least on one side of the body. 
The NCS assessments details will be included only in the SDTM datasets (ie will not be presented 
in the TFLs). 
4.9.5 
SARS-CoV-2 virus PCR-test 
At the screening visit an evaluation of the result of the SARS-CoV-2 virus PCR-test, performed at 
hospital admission or later, will be done. 
SARS-CoV-2 virus PCR-test assessments details will be presented in a listing by subject. 
 


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5 
Interim analyses 
No interim analyses are planned. 
The main analyses for the CSR will be based on all data up to and including visit 9 (Day 180). To 
note, at time of the main analysis some subjects will have also the visit 10 (Day 360) performed, 
ie will have completed the study. All data available at time of database lock will be included in 
the main analyses, meaning that some subjects will have completed the study. 
Remaining data from visit 10 (Day 360) will be included in an addendum to the CSR. 


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6 
Deviations from protocol analysis 
The following changes have been considered in current SAP as compared to study protocol: 
• Minor wording on the FAS definition as compared to protocol. Change has been made in 
order to make the definition clearer. 
• Percentage change from baseline summaries will be not presented for the vital signs and 
laboratory assessment results (ie clinical chemistry, haematology and urinalysis). 
• The main analyses for the CSR will be based on all data included in the database at time of 
database lock, including visit 10 (Day 360) data for subjects that reached that stage (ie 
completed the study). 
 
 


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7 
Quality control 
ADaM data sets will be based on the SDTM data sets. The programming of the ADaM datasets 
will be performed in SAS and QC of the programs will include  
• Independent code review 
• QC of SDTM input data vs output in ADaM or listings 
Tables, listings and figures (TLF) will be created by SAS programs and based on the ADaM data 
sets. To note, if only listings are planned to be presented on a particular data (ie no tables and 
figures) then that can be created using the SDTM data sets. 
The programming of TLFs will be reviewed by an independent person. 
SAS Viya version 3.5 or later, will be used for data handling and presentation. 
 


Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
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Statistical analysis plan 
Page 30 of 35
 
F504-0-1-9 
8 
Layout of output 
The output will follow
 standard output templates. Tables, figures and listings will be 
prepared as individual RTF (Rich text format) files. Separate Word documents will be created for 
tables (called 14.x), figures (called 14.x), and listings (called 16.x) respectively. 
Margins and font will be chosen to respect the requirements for filing with EMA (European 
medicines agency) and FDA (the US Food and drug administration).  
In the page header of each table/listing, a table/listing number followed by the title of the 
table/listing will be presented. After the title line, optional sub-title or population information can 
be presented. Footnotes will be put in the footer at the bottom of the page.  
SAS program name, name of output file, location of files and date of creation of each 
table/listing/figure will appear below the output. Page number will appear on the top right corner 
and sponsor name and status (draft/final) on the top left of the header of each page for each 
table/listing/figure.  
In a listing, in the case that a subject’s record has been continued to the next page, an appropriate 
identification (e.g., the subject ID number) must be presented at the beginning of that page. 
 
 
 




Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
15-HMedIdeS-09   
Statistical analysis plan 
Page 32 of 35
 
F504-0-1-9 
 
9.2 Appendix 2 - Centile metric score calculated for the R-ODS  
The following nomogram allows the translation of raw sum scores of the final R-ODS 
(range 0 to 48) to logits or to a centile metric score with values ranging from 0 (most 
severe activity and social participation restrictions) to 100 (no activity and social 
participation limitations). Rasch analysis calculates the corresponding logits and centile 
metric.  
 
R-ODS summed 
raw score 
Rasch person 
location 
(logits) 
centile metric 
0 
-6.95 
0 
1 
-6.03 
6 
2 
-5.36 
11 
3 
-4.87 
14 
4 
-4.48 
16 
5 
-4.14 
19 
6 
-3.84 
21 
7 
-3.57 
22 
8 
-3.32 
24 
9 
-3.09 
26 
10 
-2.87 
27 
11 
-2.66 
28 
12 
-2.46 
30 
13 
-2.26 
31 
14 
-2.07 
32 
15 
-1.88 
34 
16 
-1.70 
35 
17 
-1.52 
36 
18 
-1.33 
37 
19 
-1.15 
39 
20 
-0.97 
40 
21 
-0.79 
41 
22 
-0.61 
42 
23 
-0.42 
43 
24 
-0.24 
45 
25 
-0.05 
46 
26 
0.14 
47 
27 
0.34 
48 
28 
0.53 
50 
29 
0.73 
51 
30 
0.94 
52 
31 
1.15 
54 
32 
1.36 
55 
33 
1.58 
57 
34 
1.81 
58 
35 
2.04 
60 
36 
2.28 
61 
37 
2.54 
63 


Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
15-HMedIdeS-09   
Statistical analysis plan 
Page 33 of 35
 
F504-0-1-9 
38 
2.80 
65 
39 
3.09 
67 
40 
3.40 
69 
41 
3.74 
71 
42 
4.11 
73 
43 
4.54 
76 
44 
5.03 
80 
45 
5.59 
83 
46 
6.25 
88 
47 
7.07 
93 
48 
8.11 
100 
 
 
 


Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
15-HMedIdeS-09   
Statistical analysis plan 
Page 34 of 35
 
F504-0-1-9 
9.3 Appendix 3 - Vital Sign Parameters Normal Ranges 
All vital signs measurement results below/above the normal range will be flagged as Low 
(L)/High (H) results, as per criteria defined below: 
Vital Sign Parameter 
Lower range 
Upper range 
Systolic Blood Pressure 
(mmHg) 
less than 120 
140 or higher 
Diastolic Blood Pressure 
(mmHg) 
less than 80 
90 or higher 
Oxygen Saturation (%) 
less than 95 
NA 
Pulse Rate (beats/min) 
less than 60 
100 or higher 
Respiratory Rate (breaths/min) 
less than 12 
20 or higher 
Body Temperature (C) 
less than 36.4 
37.8 or higher 
 


Sponsor: 
Hansa Biopharma AB 
CONFIDENTIAL 
21-FEB-2024
Study product: Imlifidase Other Indication 
 
Version 2.0 final
Study ID: 
15-HMedIdeS-09   
Statistical analysis plan 
Page 35 of 35
 
F504-0-1-9 
10 Change log 
Version 
Effective date 
Reason for revision 
1.0 
14-SEP-2023 
Finalized as v1.0. 
2.0 
21-FEB-2024 
Finalized as v2.0 (updated during main analysis).