Clinical trial NCT04875975
Conditions: Leucine-Rich Glioma Inactivated 1 Autoimmune Encephalitis
Keywords: Leucine-Rich Glioma Inactivated 1 Autoimmune Encephalitis Phase 2 Rozanolixizumab
Sponsor: UCB Biopharma SRL
Start date: 2021-09-27; Completion date: 2024-04-26
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess the efficacy of rozanolixizumab as measured by seizure freedom, change in cognitive function, use of rescue medication, onset of seizure freedom and to assess safety and tolerability.

Detailed description:

Arms: arm 1: Participants will be randomized to receive a predefined dose of rozanolixizumab. arm 2: Participants will be randomized to receive a dose of placebo.
Interventions: intervention 1: Rozanolixizumab intervention 2: Placebo
Intervention descriptions: intervention 1: * Pharmaceutical form: Solution for infusion
* Route of administration: Subcutaneous use

Subjects will receive rozanolixizumab in a pre-specified sequence during the Treatment Period. intervention 2: * Pharmaceutical form: Solution for infusion
* Route of administration: Subcutaneous use

Subjects will receive placebo in a pre-specified sequence during the Treatment Period.

Protocol documents:
Prot_000.pdf: 
UCB 
 
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Clinical Study Protocol Amendment 6 
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Page 1 of 154 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER, PHASE 2 STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF 
ROZANOLIXIZUMAB IN ADULT STUDY PARTICIPANTS WITH 
LEUCINE-RICH GLIOMA INACTIVATED 1 AUTOIMMUNE 
ENCEPHALITIS 
 
PROTOCOL AIE001 AMENDMENT 6 
PHASE 2 
 
SHORT TITLE: 
A Phase 2 study evaluating the efficacy and safety of rozanolixizumab in participants with 
leucine-rich glioma inactivated 1 autoimmune encephalitis 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
Eudra CT Number: 
2019-004778-25 
IND Number: 
157206 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
 
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Clinical Study Protocol Amendment 6 
Rozanolixizumab 
AIE001 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Type of amendment 
Amendment 6 
18 Jul 2023 
Substantial 
Amendment 5 
09 Feb 2023 
Substantial 
Amendment 4 
19 Oct 2022 
Substantial 
Amendment 3 
14 Jan 2022 
Substantial 
Amendment 2a 
07 Sep 2021 
Substantial  
Amendment 1/Addendum C (CN) 
21 Jun 2021 
Not applicable 
Amendment 1/Addendum C (IT) 
24 May 2021 
Not applicable 
Amendment 1/Addendum B (DE) 
17 May 2021 
Not applicable 
Amendment 1/Addendum A (UK) 
26 Feb 2021 
Not applicable 
Amendment 1 
04 Dec 2020 
Substantial 
Original Protocol 
31 Jul 2020 
Not applicable 
a Protocol Amendment 2 was not submitted to all regulatory authorities prior to submission of Protocol 
Amendment 3. Details of the changes between Protocol Amendment 1 and Protocol Amendment 2 are provided in 
Section 10.11. 
Amendment 6 (date: 18 Jul 2023)  
Overall Rationale for the Amendment 
The overall rationale for the amendment is to address a request from FDA to re-introduce certain 
safety assessments to support the safety profile of rozanolixizumab in a new population. Since 
Amendment 5, there has been no change in the benefit/risk profile of rozanolixizumab. 
Minor grammatical, editorial, and formatting changes have also been made for clarification 
purposes only. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.3 Schedule of activities 
3 Objectives and 
Endpoints 
8.9.1 Immunology 
9.4.2.4 Immunological 
analyses 
10.2 Appendix 2 Clinical 
laboratory tests 
Endpoints, procedures, and text 
relating to the assessment of serum 
 concentrations re-
instated as per Protocol 
Amendment 3. 
As per FDA request. 
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18 Jul 2023 
Clinical Study Protocol Amendment 6 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
4.1 Overall design 
6.8 Treatment after the 
end of the study 
Protocol sections updated with part or 
all of the following text: Study 
participants who complete the 24-
week Treatment Period and require 
further treatment may have the option 
to access rozanolixizumab via another 
clinical study or an access program, if 
available, as per local laws and 
regulations. Study participants 
continuing with rozanolixizumab must 
complete an End of Treatment Visit 
and be transitioned to 
rozanolixizumab provided by those 
alternative options without undergoing 
SFU or EOS Visits. 
To facilitate plans for optional 
post-trial access to 
rozanolixizumab, where 
applicable. 
1.3 Schedule of activities 
5.2 Exclusion criteria 
7.1.2 Permanent 
discontinuation due to 
other AEs 
10.2 Appendix 2 Clinical 
laboratory tests 
The IGRA TB test was re-instated as a 
Screening procedure as per Protocol 
Amendment 4, with exclusion 
criterion #11 updated to exclude 
participants with a positive TB test at 
Screening unless the positive test 
result is related to adequately treated 
latent TB infection. 
Footnote j of Table 1-1 updated to 
include a cross-reference to 
Section 10.12.  
Protocol updated to indicate that 
participants with LTBI at Screening 
can be randomized after undergoing 
4 weeks of TB prophylactic treatment. 
Exclusion criterion #12 re-instated to 
that used in Protocol Amendment 4 to 
exclude participants with LTBI 
(unless prophylaxis initiated 4 weeks 
prior to first dose of IMP) and 
participants with current or a history 
of NTM infection (unless fully 
recovered). 
Section 7.1.2 updated to state that 
participants who develop active TB, 
LTBI, or NTM infection must be 
permanently discontinued from IMP.  
As per FDA request. 
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18 Jul 2023 
Clinical Study Protocol Amendment 6 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
Vital sign assessments re-instated at 
Week 17 and Week 21 (Visits 22 and 
26) and removed from Week 22 
(Visit 27). 
Correction. 
5.2 Exclusion criteria 
Exclusion criterion #6 re-instated as 
per Protocol Amendment 4. 
As per FDA request. 
5.2 Exclusion criteria 
Exclusion criterion #8b (previously 
#8a) updated to exclude participants 
with a serious infection 6 weeks prior 
to the first dose of IMP. 
As per FDA request. 
5.2 Exclusion criteria 
Exclusion criterion #15 (excluding 
participants with an 
 deficiency) 
re-instated as per Protocol 
Amendment 4.  
As per FDA request. 
6.5.2 Prohibited prior and 
concomitant treatments 
(medications and 
therapies) 
Any use of cyclophosphamide prior to 
the Baseline visit is prohibited (re-
instatement of Protocol Amendment 4 
timeframe) 
As per FDA request. 
7.1.2 Permanent 
discontinuation due to 
other AEs 
The phrase ‘and move to the Safety 
Follow-up Period’ was removed as the 
procedure is better described in 
Section 7.1. 
For clarity. 
8 Study assessments and 
procedures 
Text in penultimate paragraph updated 
to indicate that unscheduled 
assessments (as well as unscheduled 
visits) can be performed at the 
investigator’s discretion. 
To remind investigators that 
safety assessments can be 
performed if required. 
9.3 Planned 
efficacy/outcome analyses 
Text describing the additional 
adjustments to be made to the 
statistical modelling to accommodate 
prior disease-related therapies has 
been removed from Section 9.3. 
Details of subgroup analyses 
based on prior treatment will be 
provided in the SAP. 
9.3.2 Secondary efficacy 
analysis 
Clarified that there are 4 alpha-
controlled secondary endpoints 
As per FDA request. 
9.3.3.2 Seizure control 
Added text that defines seizure count 
categories. 
For clarity. 
10.3 Appendix 3: Adverse 
Events – Definitions and 
Procedures for Recording, 
Evaluating , Follow-up 
and Reporting 
Text added to remind investigators 
that safety reporting requirements for 
the TB are provided in Section 10.12 
For clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.12.2 Screening Period 
10.12.3 Physical 
examination 
10.12.4 Interferon gamma 
release assay (IGRA) 
10.12.5 Practical steps 
10.12.7 Latent TB 
10.12.8 Active TB 
Text revised to require participants 
with LTBI undergo 4 weeks (instead 
of 1 week) of TB prophylactic 
treatment prior to randomization. 
The removal of the possibility for 
participants to remain receiving IMP 
in the event of a new diagnosis of 
LTBI. 
To align with changes made in 
the body of the protocol. 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
US and Canada: +1 800 880 6949 or +1 866 890 3175 
Email 
Global: DS_ICT@ucb.com (for interventional clinical studies) 
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Clinical Study Protocol Amendment 6 
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TABLE OF CONTENTS 
SERIOUS ADVERSE EVENT REPORTING .......................................................................... 6 
1 
PROTOCOL SUMMARY ............................................................................................... 12 
1.1 
Synopsis ....................................................................................................................... 12 
1.2 
Schema ......................................................................................................................... 18 
1.3 
Schedule of activities ................................................................................................... 19 
1.3.1 
Additional study assessments .............................................................................. 28 
2 
INTRODUCTION ........................................................................................................... 29 
2.1 
Study rationale ............................................................................................................. 30 
2.2 
Background .................................................................................................................. 31 
2.3 
Benefit/Risk Assessment ............................................................................................. 32 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 33 
4 
STUDY DESIGN ............................................................................................................. 36 
4.1 
Overall design .............................................................................................................. 36 
4.2 
Scientific rationale for study design ............................................................................ 37 
4.3 
Justification for dose .................................................................................................... 39 
4.3.1 
Justification for IgG target ................................................................................... 40 
4.4 
End of study definition................................................................................................. 41 
5 
STUDY POPULATION .................................................................................................. 41 
5.1 
Inclusion criteria .......................................................................................................... 41 
5.2 
Exclusion criteria ......................................................................................................... 43 
5.3 
Lifestyle restrictions..................................................................................................... 45 
5.3.1 
Meals and dietary restrictions .............................................................................. 45 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 46 
5.3.3 
Activity ................................................................................................................ 46 
5.4 
Screen failures .............................................................................................................. 46 
6 
STUDY TREATMENTS ................................................................................................. 46 
6.1 
Treatments administered .............................................................................................. 46 
6.2 
Preparation, handling, storage, and accountability requirements ................................ 47 
6.2.1 
Drug accountability ............................................................................................. 48 
6.3 
Measures to minimize bias: randomization and blinding ............................................ 48 
6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 49 
6.3.1.1 
Maintenance of study treatment blind ....................................................... 49 
6.3.1.2 
Breaking the treatment blind in an emergency situation ........................... 50 
6.4 
Treatment compliance .................................................................................................. 50 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 50 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 50 
6.5.2 
Prohibited prior and concomitant treatments (medications and therapies).......... 51 
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6.5.3 
Rescue medication ............................................................................................... 53 
6.6 
Dose modification ........................................................................................................ 53 
6.7 
Criteria for study hold or dosing stoppage ................................................................... 53 
6.8 
Treatment after the end of the study ............................................................................ 53 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 53 
7.1 
Discontinuation of study medication ........................................................................... 53 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 54 
7.1.2 
Permanent discontinuation due to other AEs ....................................................... 54 
7.1.3 
Permanent discontinuation due to absence or loss of clinical benefit ................. 55 
7.1.4 
Temporary discontinuation of IMP ..................................................................... 55 
7.2 
Participant discontinuation/withdrawal from the study ............................................... 56 
7.2.1 
Study withdrawal criteria ..................................................................................... 57 
7.3 
Lost to follow up .......................................................................................................... 57 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 57 
8.1 
Efficacy assessments .................................................................................................... 59 
8.1.1 
Assessment of seizures ........................................................................................ 59 
8.1.2 
Assessment of Cognitive Function: Repeatable Battery for the Assessment of 
Neuropsychological Status .................................................................................. 60 
8.1.3 
Assessment of Disability: Modified Rankin Scale .............................................. 60 
8.1.4 
Patient-reported outcomes ................................................................................... 60 
8.1.4.1 
36-item Short Form Survey ....................................................................... 61 
8.1.4.2 
EuroQol-5D-5L ......................................................................................... 61 
8.1.5 
Clinical Global Impression of Severity ............................................................... 61 
8.2 
Safety assessments ....................................................................................................... 61 
8.2.1 
Physical examination ........................................................................................... 62 
8.2.2 
Neurological examination .................................................................................... 62 
8.2.3 
Vital signs ............................................................................................................ 62 
8.2.4 
Electrocardiogram ................................................................................................ 63 
8.2.5 
Magnetic resonance imaging ............................................................................... 63 
8.2.6 
Clinical safety laboratory assessments ................................................................ 63 
8.2.7 
Suicidal risk monitoring ...................................................................................... 63 
8.3 
Adverse events and serious adverse events ................................................................. 64 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 64 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 64 
8.3.3 
Follow-up of AEs and SAEs ................................................................................ 64 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 65 
8.3.5 
Pregnancy ............................................................................................................ 65 
8.3.6 
Adverse events of special interest ........................................................................ 65 
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8.3.7 
Adverse events of special monitoring .................................................................. 66 
8.3.8 
Anticipated serious adverse events ...................................................................... 66 
8.3.9 
COVID-19 vaccination ........................................................................................ 66 
8.4 
Safety signal detection ................................................................................................. 67 
8.5 
Treatment of overdose ................................................................................................. 67 
8.6 
Pharmacokinetics and immunogenicity ....................................................................... 67 
8.7 
Genetics........................................................................................................................ 68 
8.8 
Pharmacodynamics ...................................................................................................... 68 
8.9 
Biomarkers ................................................................................................................... 68 
8.9.1 
Immunology ......................................................................................................... 69 
8.10 
Medical resource utilization and health economics ..................................................... 70 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 70 
9.1 
Definition of analysis sets ............................................................................................ 70 
9.2 
General statistical considerations ................................................................................. 70 
9.3 
Planned efficacy/outcome analyses ............................................................................. 71 
9.3.1 
Primary efficacy analysis ..................................................................................... 71 
9.3.1.1 
Seizure freedom ......................................................................................... 71 
9.3.2 
Secondary efficacy analysis ................................................................................. 73 
9.3.2.1 
Change in cognitive function: RBANS ..................................................... 74 
9.3.2.2 
Change in overall disability: mRS ............................................................. 76 
9.3.2.3 
Use of rescue medication due to an absence or loss of clinical benefit .... 78 
9.3.2.4 
Time to first occurrence of seizure freedom ............................................. 80 
9.3.3 
Exploratory efficacy analyses .............................................................................. 80 
9.3.3.1 
Time to seizure freedom maintenance (TTSFM) ...................................... 80 
9.3.3.2 
Seizure control ........................................................................................... 81 
9.3.3.3 
Duration of seizure-free period ................................................................. 81 
9.3.3.4 
Change in RBANS domain scores ............................................................ 81 
9.3.3.5 
Ranked outcome from the integrated score ............................................... 82 
9.3.3.6 
Values and changes in participant and clinician-reported HRQoL 
assessments ................................................................................................ 82 
9.3.4 
Withdrawals from the study ................................................................................. 82 
9.4 
Planned safety and other analyses................................................................................ 83 
9.4.1 
Safety analyses ..................................................................................................... 83 
9.4.2 
PK and immunogenicity analyses ........................................................................ 83 
9.4.2.1 
Rozanolixizumab ....................................................................................... 83 
9.4.2.2 
Immunogenicity analysis ........................................................................... 83 
9.4.2.3 
Pharmacodynamic analyses ....................................................................... 84 
9.4.2.4 
Immunological analyses ............................................................................ 84 
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9.5 
Handling of protocol deviations................................................................................... 84 
9.6 
Handling of dropouts or missing data .......................................................................... 84 
9.7 
Planned interim analysis and data monitoring ............................................................. 84 
9.8 
Determination of sample size ....................................................................................... 84 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 86 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ......................... 86 
10.1.1 
Regulatory and ethical considerations ................................................................. 86 
10.1.2 
Financial disclosure ............................................................................................. 87 
10.1.3 
Informed consent process .................................................................................... 87 
10.1.4 
Data protection ..................................................................................................... 88 
10.1.5 
Committees structure ........................................................................................... 88 
10.1.6 
Data quality assurance ......................................................................................... 88 
10.1.7 
Apps ..................................................................................................................... 89 
10.1.8 
Source documents ................................................................................................ 90 
10.1.9 
Study and Site Closure ......................................................................................... 90 
10.1.10 
Publication Policy ................................................................................................ 91 
10.2 
Appendix 2: Clinical Laboratory Tests ........................................................................ 91 
10.3 
Appendix 3: Adverse Events – Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ............................................................................................ 93 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ....... 98 
10.5 
Appendix 5: Genetics ................................................................................................. 100 
10.6 
Appendix 6: Liver Safety – Suggested Actions and Follow-up Assessments ........... 101 
10.7 
Appendix 7: Medical Device AEs, Adverse Device Effects, SAEs and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.................................................................................................................... 104 
10.8 
Appendix 8: Rapid Alert Procedures ......................................................................... 105 
10.9 
Appendix 9: Country-specific Requirements............................................................. 106 
10.10 Appendix 10: Abbreviations and Trademarks ........................................................... 107 
10.11 Appendix 11: Protocol Amendment History ............................................................. 111 
10.12 Appendix 12: Assessment and Management of Tuberculosis and Tuberculosis Risk 
Factors ........................................................................................................................ 140 
10.12.1 
TB definitions .................................................................................................... 140 
10.12.2 
Screening Period ................................................................................................ 140 
10.12.3 
Physical Examination ........................................................................................ 141 
10.12.4 
Interferon gamma release assay (IGRA) ........................................................... 141 
10.12.5 
Practical steps .................................................................................................... 141 
10.12.6 
IGRA Test Conversion ...................................................................................... 143 
10.12.7 
Latent TB ........................................................................................................... 143 
10.12.8 
Active TB ........................................................................................................... 144 
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10.12.9 
Safety Reporting Requirements ......................................................................... 144 
10.13 Appendix 13: Management of AESM ....................................................................... 145 
10.14 Appendix 14: Management of Infections and Hypogammaglobulinemia ................. 148 
10.15 Appendix 15: Management of Infusion Reactions or Hypersensitivity Reactions .... 149 
REFERENCES ...................................................................................................................... 151 
SPONSOR DECLARATION ................................................................................................ 154 
 
LIST OF TABLES 
Table 1-1: 
Schedule of Activities ...................................................................................... 19 
Table 1-2: 
Additional study assessments .......................................................................... 28 
Table 6-1: 
Study medications administered ...................................................................... 47 
Table 6-2: 
Prohibited concomitant treatments and treatment-free period for 
exclusionary immunosuppressants, biologics, and other therapies prior to 
Baseline Visit ................................................................................................... 52 
Table 8-1: 
Anticipated SAEs for LGI1 AIE population .................................................... 66 
Table 9-1: 
Estimands for the primary efficacy endpoint ................................................... 72 
Table 9-2: 
Estimands for the secondary efficacy endpoint: RBANS ................................ 74 
Table 9-3: 
Estimands for the mRS improvement efficacy endpoint ................................. 77 
Table 9-4: 
Estimands for the secondary efficacy endpoint: absence or loss of clinical 
benefit - use of rescue medication ................................................................... 78 
Table 9-5: 
Estimands for the secondary efficacy endpoint: TTFSF.................................. 80 
Table 9-6: 
Study operating characteristics ........................................................................ 86 
Table 10-1: 
Decision tree for IGRA TB results at Screening or before entering a study . 142 
Table 10-2: 
Suggested management guidelines at site for infusion reactions or 
anaphylaxis .................................................................................................... 149 
 
LIST OF FIGURES 
Figure 7-1: 
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm ....... 54 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: A randomized, double-blind, placebo-controlled, multicenter, Phase 2 study to 
evaluate the efficacy, safety, and pharmacokinetics of rozanolixizumab in adult study 
participants with leucine-rich glioma inactivated 1 autoimmune encephalitis 
Short title: A Phase 2 study evaluating the efficacy and safety of rozanolixizumab in 
participants with leucine-rich glioma inactivated 1 autoimmune encephalitis 
Rationale: Autoimmune encephalitis (AIE) is a group of disorders where the immune system 
causes inflammation of the brain, leading to debilitating neurological and psychiatric symptoms. 
There are currently no approved treatments for AIE. Leucine-rich glioma inactivated 1 AIE 
(LGI1 AIE) has a distinct clinical presentation and has been identified as a variant that may be 
suitable for immunotherapy, and therefore for treatment with rozanolixizumab, which blocks the 
activity of neonatal Fc receptor (FcRn), accelerates the catabolism of antibodies and reduces the 
concentration of immunoglobulin (Ig) G. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
• To assess the efficacy of 
rozanolixizumab as measured 
by seizure freedom 
• Seizure freedom (defined by 28 consecutive days of 
no seizures) maintained until the end of the Treatment 
Period (Week 25) 
Secondary 
• To assess the efficacy of 
rozanolixizumab as measured 
by a change in cognitive 
function 
• Change from Baseline in Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS) 
total scale index score at the end of the Treatment 
Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab on study 
participants’ overall disability 
• Proportion of participants with a favorable outcome in 
the Modified Rankin Scale (mRS) during the 
Treatment Period, where favorable outcome is 
defined as no worsening for participants with a 
Baseline mRS score of ≤1 or improvement of 
≥1 point for participants with a Baseline mRS score 
of ≥2 
• To assess the efficacy of 
rozanolixizumab as measured 
by use of rescue medication 
• Use of rescue medication due to an absence or loss of 
clinical benefit during the Treatment Period 
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Objectives 
Endpoints 
• To assess the efficacy of 
rozanolixizumab as measured 
by the onset of seizure 
freedom 
• Time to first occurrence of seizure freedom (TTFSF) 
defined by the number of days after randomization to 
the first day of the first 28 consecutive days without 
seizures during the Treatment Period 
• To assess the safety and 
tolerability of 
rozanolixizumab 
• Incidence of treatment-emergent adverse events 
(TEAEs) during the study 
Exploratory 
• To assess the time of onset of 
efficacy of rozanolixizumab 
for the subgroup of study 
participants who achieve the 
primary endpoint as measured 
by the onset of seizure 
freedom 
• Time to achieving seizure freedom (defined by 
28 consecutive days of no seizures) maintained until 
the end of the Treatment Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab as measured 
by seizure control 
• ‘Good’ or ‘Moderate’ seizure control maintained over 
a period of 4 consecutive weeks until the end of the 
Treatment Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab as measured 
by a change in cognitive 
function (domains of RBANS) 
• Change from Baseline in the domain scores of 
RBANS (immediate memory; 
visuospatial/constructional; delayed memory; 
language; and attention) during the Treatment Period 
• To assess the efficacy of 
rozanolixizumab using an 
integrated ranked analysis of 
combined clinical and 
functional outcome measures 
• Ranked outcome derived from the combined 
integrated analysis of clinical and functional 
assessments (including mRS, seizure freedom, and, 
cognitive function) at the end of the Treatment Period 
(Week 25) 
• To assess the safety and 
tolerability of 
rozanolixizumab 
• Change from Baseline in vital signs and laboratory 
results during the study 
• To assess the 
pharmacodynamic (PD) effect 
of rozanolixizumab as 
measured by the total IgG 
concentrations in serum 
• Value and change (absolute and percentage) from 
Baseline in serum total IgG and IgG subclass 
concentrations during the study 
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Objectives 
Endpoints 
• To assess the PD effect of 
rozanolixizumab as measured 
by LGI1 autoantibody levels 
using the flow cytometry 
LGI1 quantitative assay 
• Value and change from Baseline in LGI1 
autoantibody serum levels during the Treatment 
Period 
• Value and change from Baseline in LGI1 
autoantibody cerebrospinal fluid (CSF) levels during 
the Treatment Period (for consenting participants) 
• To evaluate the effects of 
rozanolixizumab on patient-
reported health-related quality 
of life (HRQoL) 
• Value and change from Baseline in the 36-item Short 
Form Survey (SF-36) Physical Component Summary 
(PCS) score, Mental Component Summary (MCS) 
score, and individual domain scores during the 
Treatment Period 
• Value and change from Baseline in the EuroQol-5D-
5L (EQ-5D-5L) during the Treatment Period 
• Value and shift from Baseline in Clinical Global 
Impression of Severity (CGI-S) during the Treatment 
Period 
• To evaluate the effects of 
rozanolixizumab on 
healthcare resource utilization 
(HCRU) 
• Disease-related hospitalizations (number, duration) 
• To assess the pharmacokinetic 
(PK) characteristics of 
rozanolixizumab 
• Plasma concentration of rozanolixizumab during the 
Treatment Period 
• To evaluate the impact of 
concomitant antiepileptic 
drugs (AEDs) on 
rozanolixizumab plasma 
levels  
• Plasma concentration of rozanolixizumab during the 
Treatment Period 
• To evaluate the incidence and 
emergence of antidrug 
antibody (ADA) of 
rozanolixizumab and impact 
on PK and PD 
• ADA status 
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Objectives 
Endpoints 
• To evaluate the effects of 
rozanolixizumab on the 
concentration of total protein, 
albumin, 
 and 
serum and plasma 
complement levels 
• Values and change from Baseline in total protein, 
albumin, and serum immunoglobulin concentrations 
(
 during the Treatment Period  
• Values and change from Baseline in serum 
complement levels (
), and plasma 
complement levels (
) in case of infusion 
or hypersensitivity reaction 
• To assess exploratory 
biomarkers 
• Deoxyribonucleic acid (DNA), ribonucleic acid 
(RNA), and genetic analysis that may be measured to 
understand the cause and appropriate treatment of 
LGI1 AIE 
• Exploratory biomarkers such as but not limited to 
 
 
• Proteins and metabolite changes may be measured to 
understand the cause, progression, and appropriate 
treatment of LGI1 AIE 
 
Overall Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 2-arm, repeat dose 
study to evaluate the efficacy, safety, and PK of rozanolixizumab for the treatment of LGI1 AIE. 
Approximately 68 adult study participants with LGI1 AIE with onset of disease symptoms 
between 0 to 12 months prior to study entry, as assessed by the investigator, will be randomized 
to receive rozanolixizumab 
 or placebo, administered by subcutaneous (sc) infusion at 
 intervals for 24 weeks. A Treatment Period of 24 weeks has been selected to ensure a 
sufficient time period to evaluate a difference between rozanolixizumab and placebo in key 
symptoms of the disease. The primary objective of the study is to assess the efficacy of 
rozanolixizumab as measured by seizure freedom. 
Down titration of steroids will begin after at least 3 days on the initial high dose corticosteroids 
(based on the decision of the investigator).  
The study participants will be stratified at randomization by: 
• Time from disease symptom onset (≤6 months or >6 months from disease symptom onset) 
• Cognitive function (RBANS score of ≤85 or >85) 
After the initial 5 investigational medicinal product (IMP) administrations have been performed 
at the clinic (if applicable), the study participant may have the opportunity to be treated at home 
by a visiting healthcare practitioner. 
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Although the use of rescue medication is allowed at any time during the study, the use of rescue 
medications should be delayed, if clinically feasible, for at least 4 weeks following the initiation 
of study treatment. Study participants who require use of rescue medication will discontinue 
blinded treatment and complete the assessments for the Early Discontinuation (EDisc) Visit. 
Following this, the selection of an appropriate rescue medication will be made at the 
investigators discretion, and the study participant will enter the Safety Follow-Up (SFU) Period. 
Unscheduled study visits are permitted for any study participant including those study 
participants who have initiated rescue medication. 
An Independent Data Monitoring Committee (IDMC) will be established for the study to 
monitor the emerging safety data within the clinical study on a periodic basis. 
Number of Participants 
To account for an expected 10% dropout rate within each treatment arm, approximately 
68 participants will be randomly assigned to study treatment arms such that approximately 
60 evaluable study participants complete the study. 
Treatment Groups and Duration 
The maximum study duration per study participant is upto 38 weeks. There are 3 study periods: 
• Screening Period: Eligibility will be assessed during the Screening Period of up to 42 days. If 
a study participant becomes seizure free as a result of steroid treatment, the participant may 
still be randomized in the study, providing the prior occurrence of seizures is well 
documented. 
Following screening and completion of the Baseline assessments, treatment will be initiated 
in study participants who are deemed appropriate for initiation or re-initiation of high dose 
corticosteroids (500 to 1000mg methylprednisolone [MP] equivalent /day) based on clinical 
symptoms and history, or who have initiated corticosteroids within 42 days prior to 
randomization at a dose of 500 to 1000mg MP equivalent/day. Corticosteroids can be 
initiated prior to the start of the Screening Period, however, the study participant must be 
randomized within 42 days of corticosteroids initiation. If the study participant has initiated a 
steroid taper, the study participant cannot receive oral steroids at a dose lower than 40mg/day 
when randomized. Study participants receiving a steroid dose of 60mg/day, 50mg/day or 
40mg/day at the time of randomization, will have to maintain that dose for 7 days (±2 days), 
14 days (±2 days) or 21 days(±2 days), respectively, before resuming 
 down-titration 
steps. Each subsequent down-titration step will last for 7 days (±2 days; see Section 1.2). For 
those participants that have not initiated a steroid taper, the down-titration of the oral steroid 
dose will begin after at least 3 days on the initial high dose corticosteroids, as per 
investigator’ discretion. 
• Treatment Period: Participants who have been confirmed eligible will be randomized in a 
1:1 ratio to receive rozanolixizumab 
 or placebo at 
 intervals over a 24-week 
Treatment Period. Initially, study participants will receive rozanolixizumab or placebo in 
addition to intravenous (iv) or oral steroids that will be tapered as described in Section 1.2. 
• Safety Follow-Up Period: Study participants who complete the 24-week Treatment Period or 
prematurely discontinue IMP, as well as study participants who receive rescue medication 
during the 24-week Treatment Period will undergo the End of Treatment (EOT) Visit/EDisc 
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Visit and enter the SFU Period. At 4 weeks after the final dose, study participants will 
undergo a SFU phone call, and at 8 weeks after the final dose, study participants will undergo 
the End of Study (EOS) Visit. 
Study participants who complete the 24-week Treatment Period and require further treatment 
may have the option to access rozanolixizumab via another clinical study or an access program, 
if available, as per local laws and regulations. Study participants continuing with 
rozanolixizumab must complete an End of Treatment Visit and be transitioned to 
rozanolixizumab provided by those alternative options without undergoing SFU or EOS Visits. 
 
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1.2 
Schema 
 
EDisc=early discontinuation; EOT=end of treatment; EOS=end of study; MP=methylprednisolone; SFU=safety follow-up; W=Week 
Note: Rozanolixizumab or placebo will be initiated in study participants who are deemed appropriate for initiation or re-initiation of corticosteroids based on 
clinical symptoms and history, or have initiated corticosteroids within 42 days prior to randomization at a dose of 500 to 1000mg MP equivalent/day. Study 
participants will be administered rozanolixizumab or placebo in addition to iv or oral steroids that will be tapered. The dotted line indicates the period in which 
each down-titration step may occur. 
Note: Visit 17 and Visit 18 were removed in Protocol Amendment 4 and Visit 4 was removed in Protocol Amendment 5; however, the Visits were not 
renumbered. 
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1.3 
Schedule of activities 
The Schedule of Activities is provided in Table 1-1. Visit 32 (Week 25) is designated as the EOT Visit however, study participants 
that undergo early discontinuation will undergo these assessments as part of the EDisc Visit, which may occur at any week of 
Treatment Period. Study participants who undergo the EDisc Visit should then follow the same temporal schedule for subsequent 
visits (ie, complete the SFU phone call and EOS Visit at 3 and 7 weeks after the EDisc Visit, respectively). 
Some study-specific investigations may not be conducted according to the study protocol during a pandemic or other exceptional 
circumstances due to the need to implement safety measures and guidance from regulatory authorities (see Section 8 for further 
information). 
 
 
Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verification of 
inclusion/ 
exclusion 
criteria 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizatio
n 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full 
neurological 
examination & 
full PEf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Brief 
neurological 
examination & 
brief PEf 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
LGI1 
detection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
withdrawal 
criteria  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
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Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSg 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
General 
medical/ 
procedure 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Pregnancy test 
(serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine)h  
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
O 
FSH testi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
chemistryo, 
urinalysis 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
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Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
testing (HIV, 
Hepatitis B 
and Hepatitis 
C) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IGRA TB testj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital signsk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
Record AE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record prior 
and 
concomitant 
(including 
rescue) 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Clinical Study Protocol Amendment 6 
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Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
sampling for 
PK of RLZm 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
O 
Blood 
sampling for 
DNA and 
RNA analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Serum 
complement 
 and 
plasma 
complement 
n 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgGo,p 
X 
X 
 
X 
X 
X 
X 
-/X/- 
X 
-/X/- 
X 
-/X/- 
X 
-/X/- 
X 
 
X 
 
 
 
X 
 
X 
O 
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Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgG subclasses  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
LGI1 IgG 
(total and 
subclasses) 
serum 
quantification 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
Anti-drug 
antibodiesq 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
CSF sample 
collection for 
LGI1r 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O 
 
 
 
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Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
sampling for 
exploratory 
biomarker 
analysiss 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Seizure 
evaluationt 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Provide 
seizure diary 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
resource 
utilization 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RBANSv 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
O 
mRSw 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
O 
CGI-Sv 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
O 
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Table 1-1: 
Schedule of Activities 
Period 
Scra 
Treatment Period (24 Weeks) 
EOT/EDisc 
SFU 
EOS 
Unsch 
Visit type 
S 
S 
THb 
S 
S 
S 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
S 
THc 
THc 
THc 
THc 
THc 
S 
Td 
S 
S 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
O 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
O 
MRI scanu 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ADA=antidrug antibody; AE=adverse event; BL=Baseline (predose); BP=blood pressure; 
 
 CGI-S=Global Impression of Disease Severity; CSF=cerebrospinal fluid; C-SSRS=Columbia Suicide Severity Rating Scale; CT=computed tomography; 
Disc.=discontinuation; DNA=deoxyribonucleic acid; ECG=electrocardiogram; EDisc=Early Discontinuation Visit; EOS=end of study; EOT=end of treatment; EQ-5D-5L=EuroQol-5D-5L; FSH=follicle 
stimulating hormone; GI=gastrointestinal; HIV=human immunodeficiency virus; Ig=immunoglobulin; IGRA=interferon-gamma release assay; IMP=investigational medicinal product; IRT=interactive 
response technology; IVMP=intravenous methylprednisolone; LGI1=leucine-rich glioma inactivated 1; MRI=magnetic resonance imaging; mRS=Modified Rankin Scale; No.=number; O=optional; 
PD=pharmacodynamic; PE=physical examination; Per.=Period; PK=pharmacokinetic(s); Proc.=Procedure; RBANS=Repeatable Battery for the Assessment of Neuropsychological Status; 
RLZ=rozanolixizumab; RNA=ribonucleic acid; S=site visit; Scr=Screening; SFU=Safety Follow-up; SF-36=36-item Short Form Survey; T=telephone call; TB=tuberculosis; TH=telephone call and 
home visit; Unsch=Unscheduled Visit 
a Recording of seizures will be initiated and conducted on each day of Screening. These daily seizure recordings will be used to calculate the Baseline seizure frequency.  
b The study participant will be telephoned by a qualified site personnel and be assessed for AEs, concomitant medications, withdrawal criteria, and the seizure diary. A healthcare professional will also 
visit the study participant at their home to collect PK samples. Alternately, the visit can be conducted at the site as deemed necessary by site personnel and/or the study participant. There should be at 
least 1 day between visits. 
c Visits may be performed by a healthcare professional visiting the study participant at their home. During the home visit, a qualified site personnel will assess AEs, concomitant medications, 
withdrawal criteria, and the seizure diary by telephone call prior to IMP administration. Alternately, the visits can be conducted at the site as deemed necessary by site personnel and/or the study 
participant. Feasibility of IMP dosing in a home setting must be confirmed before the visit is conducted. 
d During the SFU phone call, the qualified site personnel will assess AEs, concomitant medications, and evaluation of seizure diary by telephone. 
e For eligibility criteria, the laboratory and body weight data from Screening will be used. However, the urine pregnancy test at Visit 2 also must be negative for eligibility. 
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f A brief PE can also be performed on the occurrence of an AE. A full or brief PE should include evaluation for medical history and for signs and symptoms of latent or active TB and for risk factors for 
exposure to TB at the following time points: Screening, Baseline, W13, W21, EDisc if applicable and EOS (see Section 10.12). A full neurological examination should also be performed for any study 
participant who experiences severe and/or serious headache and for study participants with suspected aseptic meningitis. For details of the assessments included in these examinations see Section 8.2.1 
(description of full and brief PE), and Section 8.2.2 (description of full and brief neurological examination).  
g A full C-SSRS assessment will be performed only when the study participant has a positive response to the suicidal ideation query. If a study participant has active suicidal ideation as confirmed by 
the answer ‘Yes’ to Question 4 or Question 5 of the C-SSRS assessments, the study participant will be excluded or withdrawn from the study and immediately referred to a mental healthcare 
professional. 
h A urine pregnancy test will be performed using a dipstick test; a positive urine pregnancy test must be confirmed using a serum pregnancy test. The serum pregnancy test must be negative before 
dosing. 
i The FSH test will only be performed to confirm menopausal status in female study participants (as applicable). 
j The IGRA test will be performed by a local laboratory. Study participant should not be dosed in case of any positive IGRA or 2 indeterminate IGRAs until the study participant has been evaluated by 
a TB specialist. Further details are provided in Section 10.12.  
k Vital signs comprise systolic and diastolic BP, pulse rate, and temperature.  
l The interval between administration of 2 consecutive rozanolixizumab doses should be 7 ±2 days. On dosing days for the first 2 weeks (Visit 2 and Visit 5), a 4-hour post-dose observation will be in 
place. Assuming the first 2 doses were well tolerated, on dosing days in Week 3, 4, and 5 (Visit 6, Visit 7, and Visit 8), a 1-hour post dose observation will be in place. Assuming the first 5 doses were 
well tolerated, on subsequent weeks, a 15-minute post-dose observation will be in place. Following a missed dose due to temporary IMP discontinuation, a 1-hour observation will be in place for the 
first 2 doses followed by a 15 minute observation per above. The minimum post dose observation time frame may be extended at the discretion of the investigator or study nurse at home dosing visits. 
These recommendation are applicable for dosing at site and at home except where specified. 
m At Visits 2, 8, 12, 16, 22, and 29, blood samples for PK will be obtained predose. At nondosing Visits 3, 30, 31, and 32, samples will be obtained once during the visit. 
n Serum and plasma complements are to be obtained predose at Baseline (Day 1) for all study participants. 
o Ad hoc assessments of IgG and albumin can be performed to monitor the recovery of IgG and albumin levels, or for random sampling of study participants to maintain the blind. These results will be 
reviewed by the unblinded medical monitor only (Section 7.1.4). 
p For Visits 9–11, Visits 13–15, Visits 19–21, and Visits 23–25, samples for total IgG assessments are only required to be taken at the middle visit (ie, Visits 10, 14, 20, and 24). In the table, the samples 
required at these visits are described as ‘-/X/-’ representing no sample (-)/sample (X)/no sample (-). 
q For study participants who withdraw from the study, a sample should be taken for ADA analysis upon his/her EDisc Visit. A Screening sample will be taken for the purpose of assay parameter 
characterization (eg, setting ADA cut points and PK selectivity assessments).  
r This optional CSF sample will be used to test for LGI1 autoantibodies using an independent research-use only, quantitative assay (flow cytometry LGI1 assay). Further details are provided in 
Section 8.9. 
s Exploratory biomarker samples will be taken predose at Baseline (Day 1) and at EOT/EDisc Visit for all study participants. In study participants who experience severe and/or serious headaches or 
suspected aseptic meningitis, samples should also be taken 4 hours after the onset of the event, or otherwise as soon as possible within 72 hours after the onset of the event. 
t Seizure data should be recorded in the seizure diary starting from the day of consent. 
u MRI should be collected per local guidelines during the Screening Period or at the Baseline Visit.A MRI performed within 3 months of the Screening Period may also be acceptable as per the 
investigators judgement. Additional MRI may be performed at any timepoint in the study as deemed necessary by the investigator/local radiologist. 
v The assessments of RBANS and CGI-S should be performed as close as possible prior to the Baseline Visit. 
w  The assessment of mRS at Screening should be performed as close as possible to consent. 
x Visit 17 and Visit 18 were removed in Protocol Amendment 4,; however, the Visit schedule was not renumbered. 
y  Visit 4 was removed in Protocol Amendmet 5; however, the Visit schedule was not renumbered. 
 
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1.3.1 
Additional study assessments 
In addition to those detailed in Table 1-1, the assessments in Table 1-2 may be required in case 
of adverse events of special monitoring (AESM) (severe and/or serious headache, or suspected 
aseptic meningitis, see Section 8.3.7). Note that additional vital sign measurements and/or 
additional investigations may be taken at the discretion of the investigator based on the timing of 
the assessments. 
Table 1-2: 
Additional study assessments 
Assessment 
When applicable 
For study participants who experience severe, and/or serious headache or for study participants 
with a suspected aseptic meningitis: 
Headache or 
Suspected 
aseptic 
meningitis 
follow-up 
questionnaire 
Headache follow-up questionnaire which sites will receive after reporting AESM of 
severe and/or serious headache should be completed promptly and returned to the 
Sponsor via the SAE reporting process. 
Suspected aseptic meningitis follow-up questionnaire which sites will receive after 
reporting AESM of suspected aseptic meningitis should be completed promptly and 
returned to the Sponsor via the SAE reporting process. 
Full neurological 
examination 
Assessments required for all study participants are detailed in the Schedule of 
Activities (Table 1-1). 
In study participants who report severe and/or serious headache or features suggestive 
of suspected aseptic meningitis at the clinic visit, a full neurological examination 
(including fundoscopy) should be performed (see Section 10.13). In study participants 
who report a severe and/or serious headache or features suggestive of aseptic 
meningitis while at home, a visit to the site for the full neurological examination 
(Section 8.2.2) should be arranged for as soon as is practically possible. 
Blood analysis 
Blood sample collection for exploratory analysis 
Other 
In study participants who report severe and/or serious headache, other diagnostic 
procedures including but not limited to CT scan, MRI (gadolinium-enhanced 
preferred) and/or LP for CSF collection are to be performed if indicated at the 
discretion of the investigator. 
For study participants who experience aseptic meningitis: 
LP 
In study participants who report signs and/or symptoms of meningitis which require a 
LP, results of the CSF analysis should be recorded in the eCRF and preliminary data 
should be included on the SAE form used for reporting the event as an AESM within 
24 hours (i.e. preliminary data reported on the first reporting may not have CSF 
results yet but the reporting should occur as soon as there is a suspected diagnosis. 
Full results should be communicated in subsequent exchanges with UCB). 
Additional 
analysis 
Results of all investigations should be recorded in the eCRF and preliminary data 
should be included on the SAE form used for reporting the event as an AESM. 
Please include details on all investigations results including but not limited to blood or 
CSF cultures and analysis/ PCR test (including list of microorganisms tested) / MRI 
scans +/- gadolinium. 
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Table 1-2: 
Additional study assessments 
Assessment 
When applicable 
AE=adverse event; AESM=adverse event of special monitoring; CSF=cerebrospinal fluid; CT=computed 
tomography; eCRF=electronic case report form; LP=lumbar puncture; MRI=magnetic resonance imaging; 
PCR=polymerase chain reaction; SAE=serious adverse event 
The frequency of the collection of samples for exploratory biomarker sample collection after 
severe and/or serious headache or suspected aseptic meningitis are described in Table 1-1. 
2 
INTRODUCTION 
Rozanolixizumab is a humanized IgG4 monoclonal antibody that is being developed as an 
inhibitor of the activity of the FcRn for IgG. By blocking the activity of FcRn, rozanolixizumab 
accelerates the catabolism of IgG antibodies, including IgG pathogenic autoantibodies. The aim 
is to reduce the concentration of pathogenic IgG in patients with autoimmune diseases mediated 
by the action of IgG autoantibodies. 
The FcRn recycles IgG and albumin and transports it bidirectionally across epithelial barriers. 
Recent studies have shown that FcRn rescues both IgG and albumin from intracellular lysosomal 
degradation by recycling it from the sorting endosome to the cell surface (Roopenian and 
Akilesh, 2007). Neonatal Fc receptor may also mediate transcytosis of IgG to facilitate its 
distribution within tissues. Rozanolixizumab has been specifically designed to block IgG binding 
to FcRn without blocking the binding and recycling of albumin. 
Rozanolixizumab binds with high affinity to FcRn at both neutral and acidic pH. 
Immunoglobulin G that is constitutively taken up by pinocytosis into cells fails to bind to FcRn, 
even at the acidic pH found in the endosome. It is therefore not recycled and is trafficked to the 
lysosomes for degradation. 
Production of pathogenic IgG autoantibodies is the major pathophysiology leading to a number 
of autoimmune diseases, which include myasthenia gravis (MG), pemphigus vulgaris, immune 
thrombocytopenia (ITP), Goodpasture’s syndrome, neuromyelitis optica, Guillain-Barré 
Syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and AIE. 
As individual disease entities, IgG autoantibody-mediated conditions are relatively rare. 
Treatment of these disorders remains a difficult clinical problem, requiring in many of these 
conditions the long-term use of corticosteroids alone or combined with other immunomodulatory 
therapy. These therapeutic approaches are not effective in all patients and conditions, and have 
broad immunosuppressive effects causing considerable toxicity and treatment-related morbidity. 
Treatments aimed at reducing the quantity of circulating IgG autoantibodies, including 
plasmapheresis, immunoadsorption, or high dose intravenous immunoglobulin (IVIg), are being 
used for primary and secondary therapy of autoimmune diseases. The therapeutic approach of 
these treatments is thought in part to be based on lowering levels of pathogenic autoantibodies, 
which represents rational and effective treatment modalities of autoimmune diseases. 
Therefore, the removal of IgG antibodies by FcRn blockade may provide an effective therapeutic 
option for IgG autoantibody-mediated autoimmune disorders. 
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More detailed information regarding the nonclinical and clinical development programs for 
rozanolixizumab, including all completed and ongoing studies, can be found in the latest version 
of the Investigator’s Brochure (IB). 
2.1 
Study rationale 
Autoimmune encephalitis comprises a group of related immune system-mediated conditions 
whereby the individual's immune cells erroneously target antigens in healthy cells in the central 
nervous system (CNS), including brain cells, resulting in localized swelling and inflammation 
(Kelley et al, 2017; Genetic and Rare Diseases Information Center, 2017).  
Symptoms of AIE may be neurologic and/or psychiatric. Examples of neurologic symptoms 
include impaired memory; problems with balance, speech or vision; and seizures. Examples of 
psychiatric symptoms include psychosis, aggression, panic attacks, euphoria, fear and 
compulsive behaviors (Lancaster, 2016). The classical presentation of encephalitis consists of a 
subacute (days to a few weeks) progressive decrease in the level of consciousness, often with 
fluctuations and altered cognition. Memory, especially retention of new information, may be 
impaired early in the clinical course. Patients may progress to coma.  
The primary symptoms of LGI1 AIE include cognitive impairment (recent memory loss or 
spatial disorders), seizures (including faciobrachial dystonic seizures [FBDS], other focal 
seizures, and tonic-clonic seizures), hyponatremia, and sleep disorders. Faciobrachial dystonic 
seizures are the pathognomonic sign of LGI1 AIE, and describe a distinctive adult onset, 
frequent, brief dystonic seizure semiology that predominantly affects the arm and ipsilateral face 
(Irani et al, 2011; van Sonderen et al, 2016). Leucine-rich glioma inactivated 1 autoantibodies 
are detected in serum and occasionally in CSF (van Sonderen et al, 2016). In addition, brain 
MRIs may indicate abnormal signals in the temporal lobe, hippocampus, or basal ganglia 
(Lancaster, 2016).  
Leucine-rich glioma inactivated 1 AIE defines a clinical disease with a homogeneous patient 
population that may be responsive to immunotherapy, making it an appropriate target for 
treatment with rozanolixizumab. Leucine-rich glioma inactivated 1 AIE has an estimated 
prevalence of 0.7/100,000 person-years (Dubey et al, 2018), which translates to approximately 
2320 patients in the US. Characteristic clinical presentation of patients with LGI1 AIE includes: 
• Predominantly male (66%); typically adults in their later adult years (60+ years old) (Vogrig 
et al, 2019; Hermetter et al, 2018); rarely observed in children or adolescents. 
• Faciobrachial dystonic seizures as the pathognomonic sign (Irani et al, 2011). This seizure 
type is unique to LGI1 AIE. Patients may also experience other types of focal seizures as 
well as secondarily generalized seizures.  
• Cognitive symptoms including memory loss and confusion, hallucinations, rapid eye 
movement sleep disturbance, and psychiatric disturbance. 
• Muscular symptoms which may include neuromyotonia, causing spontaneous muscular 
activity or twitching. 
• Hyponatremia is common. 
• Brain MRI showing hyperintensities in the mesial temporal lobe (Vogrig et al, 2019). 
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• Rarely associated with a tumor (thymoma <5%; Geis et al, 2019). 
• Frequently associated with specific human leukocyte antigen haplotypes as with other IgG4-
mediated diseases (Vogrig et al, 2019). 
• Anti-LGI1 autoantibodies are detected in serum but often undetected in CSF (van Sonderen 
et al, 2016). 
The array of disease features causes significant clinical burden for the patient, in particular, 
seizures and cognitive impairment. The majority of patients with LGI1 AIE are expected to 
develop seizures (~90% of patients), and all will experience at least some cognitive dysfunction 
over the course of their disease (van Sonderen et al, 2016). Patients with LGI1 AIE may 
experience various types of seizures, including FBDS, which may occur up to 100 times a day 
(median 40/day) with a very short duration of <15 seconds per episode (van Sonderen et al, 
2016). Faciobrachial dystonic seizures are often the presenting clinical feature, with a later onset 
of cognitive impairment (Thompson et al, 2018). Seizures with bilateral tonic-clonic evolution 
usually appear in later stages of the disease at a time when cognitive impairment is also present 
(Vogrig et al, 2019). 
Although LGI1 AIE has a clinical presentation that is distinct from other AIE, diagnosis is 
challenging due to initial similarity in presentation to other types of epilepsy, which can result in 
delayed diagnosis, a subsequent delay in appropriate treatment (de Bruijn et al, 2019) and poorer 
outcome. 
There are currently no approved therapies for the treatment of AIE overall. Current acute and 
chronic treatment paradigms are variable, mainly based on expert opinions, a select number of 
case studies and retrospective reviews, with no approved treatment options. Controlled studies 
are needed to guide treatment decisions in the management of LGI1 AIE, and for more specific 
immunotherapies, to reduce the side effect profile of current chronic treatment options that 
address seizures as well as cognitive and psychiatric symptoms. 
By blocking the activity of FcRn, rozanolixizumab accelerates the catabolism of antibodies and 
reduces the concentration of IgG, thus offering an alternative to existing treatments. This 
Phase 2, randomized, placebo-controlled study will evaluate the efficacy, safety, and PK of 
rozanolixizumab in adult study participants with LGI1 AIE. 
2.2 
Background 
Rozanolixizumab has been administered to human study participants in several clinical studies 
(see the updated IB for listing of completed and ongoing studies). 
Overall, data from completed studies suggest that repeated administrations of rozanolixizumab at 
a dose approximating 7mg/kg and 10mg/kg sc is generally well tolerated, with an acceptable 
safety profile. Treatment-emergent AEs were most frequently reported in the system organ class 
of Nervous system disorders. In study participants with generalized myasthenia gravis (gMG) 
receiving repeated cyclic treatment with rozanolixizumab, the most common TEAEs were 
headache, diarrhoea, pyrexia, nausea, and arthralgia. Dose-dependent, statistically significant 
reductions in levels of total IgG and dose-dependent reductions in levels of IgG subclasses 
(IgG 1 to 4) were observed after rozanolixizumab was administered by iv or sc routes. In study 
participants with gMG, clinically relevant improvements in day-to-day functioning were 
observed following treatment with rozanolixizumab compared with placebo. 
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Further details may be found in the IB. 
2.3 
Benefit/Risk Assessment 
As individual disease entities, IgG autoantibody-mediated conditions are relatively rare. 
Treatment of these disorders remains a difficult clinical problem, requiring in many of these 
conditions the long-term use of corticosteroids alone or combined with cytotoxic agents. These 
therapeutic approaches are not effective in all patients and conditions, and have broad 
immunosuppressive effects causing considerable toxicity and treatment-related morbidity. 
Treatment of patients with LGI1 AIE is comprised of immunotherapy and symptomatic therapy 
including antiseizure medications. Immunotherapeutic agents are classically divided into first-
line (acute phase) and second-line therapies (maintenance phase). First-line therapies include 
high-dose IVMP, IVIg, immunoadsorption, and plasma exchange (PEX). Second-line agents 
such as rituximab, cyclophosphamide, mycophenolate, azathioprine, bortezomib, or tocilizumab 
are used in refractory cases, during relapses or as a maintenance therapy to prevent relapses. 
However, only 1 small prospective study has evaluated the efficacy of immunotherapy (IVIg) in 
LGI1 AIE (Dubey et al, 2020). Current immunotherapy recommendations are based on case 
series and clinical experience. 
Rozanolixizumab represents an innovative, sc anti-FcRn monoclonal antibody that may provide 
a novel and specific therapeutic approach for the treatment of patients with LGI1 AIE. While not 
previously evaluated in LGI1 AIE, data show that rozanolixizumab markedly lowers serum IgG 
and IgG autoantibody levels in patients with gMG. 
In MG0003, a Phase 3 study evaluating efficacy and safety of sc rozanolixizumab in adult 
patients with gMG the 
 clinical efficacy of rozanolixizumab was demonstrated by 
improvements vs placebo in all efficacy endpoints tested in the study. There were clinically 
meaningful and statistically significant reductions from Baseline in the primary endpoint, 
MG-activities of daily living (ADL) score, at Day 43 for both rozanolixizumab dose groups 
versus placebo. 
The identified adverse drug reactions associated with sc administration of rozanolixizumab are 
headaches, diarrhoea, pyrexia, nausea, upper respiratory tract infections, arthralgia, rash, 
injections site reactions, vomiting, myalgia and herpes simplex infections. Headache is the most 
commonly reported ADR, these were mostly mild to moderate and easily managed with 
over-the-counter medications. Important potential risks are serious hypersensitivity reactions and 
serious infections. Other safety topics of interest include effects on vaccination response, effects 
on the kidney, reductions in albumin and plasma proteins, drug-induced aseptic meningitis and 
decreased platelet counts. These risks can be mitigated by careful monitoring, exclusion of 
at-risk study participants, and appropriate protocol withdrawal and stopping criteria. 
Additionally, protocol guidance for management of hypogammaglobulinemia/infection, and 
hypersensitivity is provided in Appendix 14 (Section 10.14) and Appendix 15 (Section 10.15), 
respectively, and the management and expedited reporting requirements of the AESMs (severe 
and/or serious headache and suspected aseptic meningitis) to UCB are specified in Appendix 13 
(Section 10.13). 
Restrictions on the use of live vaccines have been defined in exclusion criterion 20. If 
vaccination with non-live vaccines (including COVID-19 vaccines) is considered necessary once 
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a study participant has started therapy with IMP, the degree of protection afforded with a vaccine 
may be compromised while the participant is being treated with IMP. 
Based on its mechanism of action, rozanolixizumab will reduce total IgG levels including 
vaccine specific IgG. However, it is unknown if the immunogenicity of a vaccine will be 
compromised by FcRn inhibition. Given the study population characteristics (eg, status of the 
underlying disease, concomitant immunosuppressive therapies, etc), it is recommended to 
perform individualized benefit-risk assessment for vaccination and specifically vaccination 
against COVID-19 infection. If vaccination is planned, information regarding vaccine should be 
recorded (Section 6.5.1). Vaccination should be scheduled, if at all possible, to allow 
differentiation of safety profiles of IMP and vaccine (eg, a minimum window of 72 hours 
between COVID-19 vaccination and IMP administration). If any adverse events (AEs) were to 
occur, they should be handled as described in Section 6.5.1 with causality assessment provided 
for both IMP and vaccine. Additionally, to further characterize the effect of rozanolixizumab on 
vaccination response, measurement of vaccine titres are being tested in our development 
programs. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of rozanolixizumab may be found in the current version of the IB. 
3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To assess the efficacy of 
rozanolixizumab as measured 
by seizure freedom 
• Seizure freedom (defined by 28 consecutive days of 
no seizures) maintained until the end of the Treatment 
Period (Week 25) 
Secondary 
• To assess the efficacy of 
rozanolixizumab as measured 
by a change in cognitive 
function 
• Change from Baseline in RBANS total scale index 
score at the end of the Treatment Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab on study 
participants’ overall disability 
• Proportion of participants with a favorable outcome in 
the mRS during the Treatment Period, where 
favorable outcome is defined as no worsening for 
participants with a Baseline mRS score of ≤1 or 
improvement of ≥1 point for participants with a 
Baseline mRS score of ≥2 
• To assess the efficacy of 
rozanolixizumab as measured 
by use of rescue medication 
• Use of rescue medication due to an absence or loss of 
clinical benefit during the Treatment Period 
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Objectives 
Endpoints 
• To assess the efficacy of 
rozanolixizumab as measured 
by the onset of seizure 
freedom 
• Time to first occurrence of seizure freedom defined 
by the number of days after randomization to the first 
day of the first 28 consecutive days without seizures 
during the Treatment Period 
• To assess the safety and 
tolerability of 
rozanolixizumab 
• Incidence of TEAEs during the study 
Exploratory 
• To assess the time of onset of 
efficacy of rozanolixizumab 
for the subgroup of study 
participants who achieve the 
primary endpoint as measured 
by the onset of seizure 
freedom 
• Time to achieving seizure freedom (defined by 
28 consecutive days of no seizures) maintained until 
the end of the Treatment Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab as measured 
by seizure control 
• ‘Good’ or ‘Moderate’ seizure control maintained over 
a period of 4 consecutive weeks until the end of the 
Treatment Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab as measured 
by a change in cognitive 
function (domains of RBANS) 
• Change from Baseline in the domain scores of 
RBANS (immediate memory; 
visuospatial/constructional; delayed memory; 
language; and attention) during the Treatment Period 
• To assess the efficacy of 
rozanolixizumab using an 
integrated ranked analysis of 
combined clinical and 
functional outcome measures 
• Ranked outcome derived from the combined 
integrated analysis of clinical and functional 
assessments (including mRS, seizure freedom, and, 
cognitive function) at the end of the Treatment Period 
(Week 25) 
• To assess the safety and 
tolerability of 
rozanolixizumab 
• Change from Baseline in vital signs and laboratory 
results during the study 
• To assess the PD effect of 
rozanolixizumab as measured 
by the total IgG 
concentrations in serum 
• Value and change (absolute and percentage) from 
Baseline in serum total IgG and IgG subclass 
concentrations during the study 
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Objectives 
Endpoints 
• To assess the PD effect of 
rozanolixizumab as measured 
by LGI1 autoantibody levels 
using the flow cytometry 
LGI1 quantitative assay 
• Value and change from Baseline in LGI1 
autoantibody serum levels during the Treatment 
Period 
• Value and change from Baseline in LGI1 
autoantibody CSF levels during the Treatment Period 
(for consenting participants) 
• To evaluate the effects of 
rozanolixizumab on patient-
reported HRQoL 
• Value and change from Baseline in the SF-36-PCS 
score, SF-36-MCS score, and individual domain 
scores during the Treatment Period 
• Value and change from Baseline in the EQ-5D-5L 
during the Treatment Period 
• Value and shift from Baseline in CGI-S during the 
Treatment Period 
• To evaluate the effects of 
rozanolixizumab on HCRU 
• Disease-related hospitalizations (number, duration) 
• To assess the PK 
characteristics of 
rozanolixizumab 
• Plasma concentration of rozanolixizumab during the 
Treatment Period 
• To evaluate the impact of 
concomitant AEDs on 
rozanolixizumab plasma 
levels 
• Plasma concentration of rozanolixizumab during the 
Treatment Period 
• To evaluate the incidence and 
emergence of ADA of 
rozanolixizumab and impact 
on PK and PD 
• ADA status 
• To evaluate the effects of 
rozanolixizumab on the 
concentration of total protein, 
albumin, 
 and 
serum and plasma 
complement levels 
• Values and change from Baseline in total protein and 
albumin, and serum immunoglobulin concentrations 
 during the Treatment Period 
• Values and change from Baseline in serum 
complement levels (
 and plasma 
complement levels (
) in case of infusion 
or hypersensitivity reaction 
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Objectives 
Endpoints 
• To assess exploratory 
biomarkers 
• DNA, RNA, and genetic analysis that may be 
measured to understand the cause and appropriate 
treatment of LGI1 AIE 
• Exploratory biomarkers such as but not limited to B-
cell activating factor and circulating immune 
complexes 
• Proteins and metabolite changes may be measured to 
understand the cause, progression, and appropriate 
treatment of LGI1 AIE 
4 
STUDY DESIGN 
4.1 
Overall design 
AIE001 is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 2-arm, repeat 
dose study to evaluate the efficacy, safety, and PK of rozanolixizumab for the treatment of LGI1 
AIE. The primary endpoint of the study is seizure freedom defined by 28 consecutive days of no 
seizures, maintained until the end of the Treatment Period (Week 25). 
Approximately 68 study participants with LGI1 AIE with onset of disease symptoms between 0 
to 12 months prior to study entry, as assessed by the investigator, will be randomized to receive 
rozanolixizumab 
 or placebo, administered by sc infusion at 
 intervals for 
24 weeks. 
The study participants will be stratified at randomization by: 
• Time from disease symptom onset (≤6 months or >6 months from disease symptom onset) 
• Cognitive function (RBANS score of ≤85 or >85) 
After the initial 5 IMP administrations have been performed at the clinic, the study participant 
may have the opportunity to be treated at home by a visiting healthcare practitioner. 
Although the use of rescue medication is allowable at any time during the study, the use of 
rescue medications should be delayed, if clinically feasible, for at least 4 weeks following the 
initiation of study treatment. Study participants who require rescue medication will discontinue 
blinded treatment, and complete the assessments for the EDisc Visit. Following this, the 
selection of an appropriate rescue medication will be made at the investigator’s discretion, and 
the study participant will enter the SFU Period. Unscheduled study visits are permitted for any 
study participant, including those study participants who have initiated rescue medication. 
An IDMC will be established for the study to monitor the emerging safety data within the 
clinical study on a periodic basis. 
The maximum study duration per study participant is up to 38 weeks. There are 3 study periods:  
• Screening Period: Eligibility will be assessed during the Screening Period of up to 42 days. If 
a study participant becomes seizure free as a result of steroid treatment, the participant may 
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still be randomized in the study, providing the prior occurrence of seizures is well 
documented.  
Participants who have previously received a first line AIE treatment in the 6 months prior to 
randomization (counted from the onset of treatment to randomization date) may be 
considered for enrollment provided that: 
− The participant is considered to have been under treated in the opinion of the investigator 
AND 
− Currently the participant is experiencing a seizure rebound that requires initiation or re-
initiation of high dose corticosteroids (500-1000mg MP equivalent /day) in the opinion of 
the investigator. 
Following screening and completion of the Baseline assessments, treatment will be initiated 
in study participants who are deemed appropriate for initiation or re-initiation of high dose 
corticosteroids (500 to 1000mg MP equivalent/day) based on clinical symptoms and history, 
or who have initiated corticosteroids within 42 days prior to randomization at a dose of 500 
to 1000mg MP equivalent/day. Corticosteroids can be initiated prior to the start of the 
Screening Period, however, the study participant must be randomized within 42 days of 
corticosteroids initiation. If the study participant has initiated a steroid taper, the study 
participant cannot receive oral steroids at a dose lower than 40mg/day when randomized. 
Study participants receiving a steroid dose of 60mg/day, 50mg/day or 40mg/day at the time 
of randomization will have to maintain that dose for 7 days (±2 days), 14 days (±2 days) or 
21 days(±2 days), respectively, before resuming 
 down-titration steps. Each 
subsequent down-titration step will last for 7 days (±2 days; see Section 1.2). For those 
participants that have not initiated a steroid taper, the down-titration of the oral steroid dose 
will begin after at least 3 days on the initial steroid dose, as per investigator. 
• Treatment Period: Participants who have been confirmed eligible will be randomized in a 
1:1 ratio to receive rozanolixizumab 
 or placebo at 
 intervals over a 24-week 
Treatment Period. Initially, study participants will receive rozanolixizumab or placebo in 
addition to iv or oral steroids that will be tapered as described in Section 1.2. 
• Safety Follow-Up Period: Study participants who complete the 24-week Treatment Period or 
prematurely discontinue IMP, as well as study participants who receive rescue medication 
during the 24-week Treatment Period will undergo the EOT Visit/EDisc Visit and enter the 
SFU Period. At 4 weeks after the final dose, study participants will undergo a SFU phone 
call, and at 8 weeks after the final dose, study participants will undergo the EOS Visit. 
Study participants who complete the 24-week Treatment Period and require further treatment 
may have the option to access rozanolixizumab via another clinical study or an access program, 
if available, as per local laws and regulations. Study participants continuing with 
rozanolixizumab must complete an End of Treatment Visit and be transitioned to 
rozanolixizumab provided by those alternative options without undergoing SFU or EOS Visits. 
4.2 
Scientific rationale for study design 
Leucine‐rich glioma inactivated 1 is a protein mainly expressed in the hippocampus and the 
temporal cortex, where it is secreted into the synaptic space. It is part of an inhibitory pathway 
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linking the presynaptic voltage-gated potassium channel complex and the postsynaptic α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (Fukata et al, 2010; Ohkawa et 
al, 2013). Specifically, it is classified as an antineuronal surface antigen or antisynaptic protein-
associated AIE. Kornau et al (2020) have recently demonstrated that LGI1 antibodies alone are 
sufficient to promote neuronal excitability, a basis of seizure generation. Seven of the overall 26 
LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro 
and their mean LGI1 signal on mouse brain sections was weak as compared to the remaining, 
non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the 
intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 
neurons in slice cultures. 
The binding of autoantibodies to LGI1 disrupts pre- and postsynaptic LGI1 signaling, resulting 
in neuronal hyperexcitability (Petit-Pedrol et al, 2018). By blocking the activity of FcRn, 
rozanolixizumab accelerates the catabolism of antibodies and reduces the concentration of 
pathogenic IgG, thus offering an alternative to existing treatments. Treatment with 
rozanolixizumab is expected to result in a decrease in LGI1 autoantibodies and thus to reduce the 
associated pathological processes and ongoing clinical sequelae. 
Current therapeutic approaches for AIE are thought in part to be based on lowering levels of 
pathogenic autoantibodies, which represents targeted, rational, and effective treatment modalities 
of autoimmune diseases. Therefore, removal of the IgG autoantibodies by FcRn blockade may 
provide an effective therapeutic option for IgG autoantibody-mediated autoimmune disorders, in 
this case for the treatment of LGI1 AIE. 
AIE001 is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 2-arm, repeat-
dose study that aims to enroll approximately 68 study participants with LGI1 AIE. To be eligible 
for inclusion in the study, participants must have disease symptoms onset within 12 months of 
Screening, be deemed appropriate for initiation or re-initiation of high dose corticosteroids (500 
to 1000mg MP equivalent/day) based on clinical symptoms and history, or have initiated high 
dose corticosteroids within 42 days of randomization, and be seropositive for LGI1 antibodies. 
Study participants are eligible for inclusion if they are experiencing FBDS (with or without focal 
[partial] seizures) or focal (partial) seizures including focal to bilateral tonic-clonic seizures, or 
have experienced such seizure which subsided following initiation of high dose corticosteroids 
(500 to 1000mg MP equivalent/day). 
As described in Section 2.1, the FBDS type is unique to LGI1 AIE; however, patients with LGI1 
AIE may also experience focal and tonic-clonic seizures, that are not unique to LGI1 AIE. 
Therefore, participants eligible via these seizure types must also meet additional criteria for 
possible AIE, as outlined by Graus et al (2016) in a position paper designed to provide a practical 
clinical approach to diagnosing AIE. Coupled with this, study participants are excluded if they 
have previously been diagnosed with epilepsy, have a new-onset seizure that is unrelated to 
LGI1 AIE, or if there is any known or suspected medical cause for the onset of seizures, other 
than possible AIE. Therefore, although AIE001 permits the entry of study participants with focal 
(partial) including focal to bilateral tonic-clonic seizures in the absence of FBDS, these 
participants must also meet additional criteria designed to reduce the potential risk of enrolling 
study participants who do not have LGI1 AIE. In this way, AIE001 intends to enroll a study 
population that reflects the characteristics of the real-world LGI1 AIE population. 
At randomization, study participants will be stratified by: 
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• Time from disease symptom onset (≤6 months or >6 months from disease symptom onset) 
• Cognitive function (RBANS score of ≤85 or >85) 
The decision to stratify based on disease symptom onset and cognitive function is based on data 
from Thompson et al (2018) who showed in a multivariate regression analysis, that the time to 
the initiation of immunotherapy, and the presence of cognitive impairment significantly affected 
the likelihood of FBDS cessation. Factors such as the time to antiepileptic drug administration, 
age, sex, or the frequency of FBDS were not statistically significant in the model. These findings 
were supportive of Dubey et al (2017) who showed that early initiation of therapy (<6 months 
from symptom onset) was an independent predictor of favorable seizure outcome. Based on these 
observations, study participants will be stratified at randomization according to time since 
disease symptom onset (≤6 months or >6 months) and the presence or absence of cognitive 
impairment. 
The stratification by cognitive impairment will be based on the RBANS index score. The 
RBANS cognitive battery measures performance across a range of cognitive domains (see 
Section 8.1.2). The RBANS index score reflects an aggregate of performance on these domains, 
and is computed with reference to age-based normative data derived from a cognitively normal 
population. In this context, an RBANS index score of 85 reflects a value of 1 standard deviation 
(SD) below the mean of the age relevant normal population (Duff et al, 2008; Randolph et al, 
1998), such that an RBANS index score of ≤85 is indicative of clinically important cognitive 
impairment, while an RBANS index score above 85 can be categorized as cognitively normal. 
Therefore, to address the extent to which cognitive impairment at baseline may influence the 
nature and magnitude of response to treatment in AIE001, study participants will be stratified by 
RBANS score of ≤85 or >85. 
There are currently no approved treatments for any of the AIE conditions. Given this, and the 
need for appropriately controlled studies to investigate the impact of a new treatment on the 
symptoms of LGI1 AIE, AIE001 has been designed with a placebo control. In AIE001, all study 
participants will enter the study having initiated or having been deemed appropriate for initiation 
or re-initiation of the first-line treatment that will be tapered as per the schedule in Section 1.2. In 
this way, the study aims to ascertain if rozanolixizumab offers a benefit beyond steroid therapy. 
The planned treatment duration for AIE001 is 24 weeks. This duration was selected to allow for 
the steady down-titration of oral steroids, and a sufficient interval for rozanolixizumab to exert a 
pharmacodynamic effect on IgG levels and the hypothesized therapeutic effect on the symptoms 
of LGI1 AIE. To ensure that all study participants are receiving appropriate clinical care 
throughout the duration of the study, participants who do not experience a clinical improvement 
(ie, an absence of clinical benefit) within the first 4 weeks of the Treatment Period or experience 
a clinical worsening (ie, a loss of clinical benefit) at any time (Section 7.1.3) or require rescue 
treatment at any time (Section 6.5.3) must be withdrawn. 
4.3 
Justification for dose 
The planned dose of rozanolixizumab for this study is 
 by sc infusion. 
As outlined below, this dose is justified by: 
• Clinical data from the pivotal Phase 3 study (MG0003) showing a meaningful improvement 
at repeated doses of 7mg/kg and 10mg/kg by body weight tiers in gMG. 
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• Pharmacodynamic data showing a desired reduction in IgG levels of 70% from Baseline after 
repeated doses of 7mg/kg and 10mg/kg. 
• Simulations from a population PK-PD analysis showing comparable exposure and IgG 
reduction for a 
 fixed dose and weight-tiered doses approximating 7mg/kg and 
10mg/kg. 
Rozanolixizumab has been studied in two Phase 2 studies in gMG and ITP with body weight 
normalized dosing (mg/kg). Repeated doses up to 10mg/kg and single doses up to 20mg/kg were 
generally well tolerated with an acceptable safety profile in these Phase 2 studies. In study 
participants with gMG, clinically relevant improvements in day-to-day functioning were 
observed following treatment with rozanolixizumab 7mg/kg compared with placebo. In study 
participants with ITP, rozanolixizumab produced clinically meaningful responses across the 
treatment groups (rozanolixizumab 4mg/kg to 20mg/kg at varying administration frequency), in 
all of the response variables defined by platelet counts. 
A Phase 3 study, MG0003, has been completed to evaluate the efficacy and safety of 
rozanolixizumab in study participants with gMG. The dose regimens being evaluated in these 
studies were weight-tiered doses approximating 7mg/kg and 10mg/kg Q1W. 
The proposed 
 fixed dose of rozanolixizumab is selected to achieve a comparable range of 
exposures and IgG reductions as the weight-tiered doses that have been evaluated in the 
completed Phase 3 pivotal study in gMG. 
A population PK-PD model was developed based on observed PK and IgG data from the pivotal 
Phase 3 study (MG0003), two Phase 2 studies (TP0001, MG0002), and two Phase 1 studies 
(UP0018 and UP0060). Rozanolixizumab exposure and IgG response to rozanolixizumab were 
comparable between healthy participants and the gMG and ITP populations. In addition, 
ethnicity was not found to affect PK or IgG response. Therefore, there are no anticipated changes 
in exposure or IgG responses, where the baseline IgG levels are similar, between different 
indicated populations or ethnicities. 
Simulations performed using the population PK-PD model show that the planned dose of 
 
 should: 
• Produce PK variability similar to that with weight-tiered dosing. 
• Achieve rozanolixizumab exposures that are consistent with those obtained with 
weight-tiered doses of 7mg/kg and 10mg/kg Q1W as used in the currently ongoing Phase 3 
studies. 
• Achieve and maintain a desired IgG reduction of 70% from Baseline, irrespective of body 
weight. 
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians and 
patients and to reduce the potential for dosing errors. Thus, a dose regimen of 
 is 
planned for investigation in this study. 
4.3.1 
Justification for IgG target 
Rozanolixizumab administration resulted in a rapid clearance of serum IgG levels in both healthy 
volunteers (UP0018 and UP0060) and patients with gMG (MG0002 and MG0003) or ITP 
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(TP0001). In MG0003, serum IgG levels decreased reaching a mean maximum reduction of 
approximatley 71% for the rozanolixizumab ≈7mg/kg group and 78% for the ≈10mg/kg group. 
The reduction in IgG was mirrored by a reduction in anti-acetylcholine receptor (AChR) 
autoantibodies in patients with gMG and demonstrated a 
 clinically meaningful 
improvement in clinical outcome scales (MG-ADL and QMG) compared with placebo. 
A rozanolixizumab-induced IgG lowering of about 70% from Baseline is similar to that achieved 
with other FcRn antagonists and alternative strategies such as PEX, and falls within the range 
associated with clinical benefit in various autoimmune indications. 
For AIE, indication-specific targets for IgG lowering are not yet established. The current 
assumption is that the desired level of IgG reduction would be similar to those proved to be 
efficacious in gMG. 
4.4 
End of study definition 
A study participant is considered to have completed the study if he/she has completed all phases 
of the study, including the SFU Period. Study participants will have an EOT Visit performed 
1 week after the final dose of IMP or upon discontinuation of the study, followed by a SFU 
phone call 4 weeks after and an EOS Visit 8 weeks after the final dose. 
The end of study is defined as the date of the last visit of the last study participant in the study. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Study participant must be ≥18 to ≤89 years of age, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
2. Study participant must be seropositive for LGI1 antibody measured by LGI1 serum 
autoantibody cell-binding assay. 
3a. Study participant must have ≥2 seizures/week during the Screening Period or have 
experienced such seizures that stopped following high dose corticosteroids (500 to 1000mg MP 
equivalent/day):  
• Either FBDS with or without other focal (partial) seizures including focal to bilateral tonic 
clonic 
• Or focal (partial) seizures including focal to bilateral tonic clonic and fulfil the following 
new-onset AIE criteria: 
a. Subacute onset (rapid progression of less than 3 months) of working memory deficits 
(short-term memory loss), altered mental status (defined as decreased or altered level 
of consciousness, lethargy, or personality change), or psychiatric symptoms. 
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AND 
b. At least one of the following: 
i. 
New focal CNS finding, as per the investigator's assessment 
ii. 
Seizures not explained by a previously known seizure disorder 
iii. 
CSF pleocytosis (white blood cell count of >5 cells/mm3) 
iv. 
MRI features suggestive of encephalitis (Brain MRI hyperintense signal on T2-
weighted fluid-attenuated inversion recovery sequences highly restricted to one or 
both medial temporal lobes [limbic encephalitis], or in multifocal areas involving 
grey matter, white matter, or both compatible with demyelination or 
inflammation). 
AND 
c. Reasonable exclusion of alternative causes 
4a. Study participant has initiated or re-initiated corticosteroids at a dose of 500 to 1000mg MP 
equivalent/day within 42 days prior to randomization. Participants re-initiating corticosteroids 
are eligible only if re-initiation is due to seizure rebound and within the timeframe outlined in 
Section 4.1. 
If the study participant has initiated a steroid taper, the study participant cannot receive an oral 
steroid dose lower than 40mg/day when randomized. 
5. Study participant with onset of disease symptom between 0 to 12 months prior to Screening, 
per investigator’s assessment. 
Weight 
6. Study participant weighs at least 35kg (for males and females) at Screening. 
Sex 
7a. Male or Female 
− A female participant is eligible to participate if she is not pregnant (see Appendix 4 
[(Section 10.4]), not breastfeeding, and at least one of the following conditions applies: 
◦ 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4) 
OR 
◦ 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the treatment period and for at least 90 days after the final dose 
of study treatment. 
Informed consent 
8a. Study participant is capable of giving signed informed consent or has a legal representative to 
consent for him/her as described in Appendix 1 (Section 10.1.3) which includes compliance with 
the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 
Other 
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9a. Study participant has a reliable caregiver who will be available during the whole study 
period, as determined by the investigator. 
10a. 
Removed in Protocol Amendment 4. 
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Study participant has any medical or psychiatric condition that, in the opinion of the 
investigator, could jeopardize or would compromise the study participant’s ability to participate 
in this study. 
2. Study participant has a history of alcohol use disorder or other substance use disorder (as per 
Diagnostic and Statistical Manual of Mental Disorders-5) within the previous 12 months. 
3. Study participant has a known hypersensitivity to any components of the study medication or 
any other anti-FcRn medications. This includes a known history of 
, since 
 is a constituent of the rozanolixizumab formulation. 
4a. Study participant has a confirmed prior diagnosis of epilepsy or new onset seizures that are 
unrelated to LGI1 AIE or has any known or suspected medical cause for the onset of seizures 
other than possible AIE. 
5. Study participant has a known active neoplastic disease or history of neoplastic disease 
within 5 years of study entry (except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the uterine cervix which has been definitively treated with standard of care 
approaches). 
6. Study participant has 12-lead ECG with findings considered clinically significant by the 
investigator. 
7a. Study participant has renal impairment, defined as glomerular filtration rate (GFR) 
<30mL/min/1.73m2 at the Screening Visit. 
8b. Study participant has a clinically important active infection (including unresolved or not 
adequately treated infection) as assessed by investigator, including participants with a serious 
infection within 6 weeks prior to the first dose of IMP. 
9a. Study participant has a history of chronic ongoing infections (eg, Hepatitis B or C, human 
immune deficiency virus [HIV], active tuberculosis [TB]) or who tests positive for HIV, 
Hepatitis B or C at the Screening Visit. 
− Presence of Hepatitis B surface antigen at the Screening Visit. 
− Positive Hepatitis C antibody test result at Screening or within 3 months prior to the IMP 
dose. NOTE: Study participant with a positive Hepatitis C antibody due to prior resolved 
disease can be enrolled only if a confirmatory negative Hepatitis C RNA test is obtained. 
10. Study participant has current unstable liver or biliary disease, per investigator assessment, 
defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal 
or gastric varices, persistent jaundice, or cirrhosis. Note: An exception is stable chronic 
hepatobiliary conditions (including Gilbert’s syndrome, asymptomatic gallstones). 
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11. Study participant has positive TB test at the Screening Visit unless it is determined by a TB 
specialist that the positive result is related to an adequately treated latent TB infection (see 
Section 10.12). 
12. Study participants met any of the following TB exclusion criteria: 
− Known active TB disease 
− History of active TB involving any organ system unless adequately treated according to 
World Health Organization (WHO)/US Center for Disease Control therapeutic guidance 
and proven to be fully recovered upon consult with a TB specialist 
− Latent tuberculosis infection (LTBI) (unless appropriate prophylaxis is initiated at least 
4 weeks prior to IMP dosing and will be continued to completion of prophylaxis). 
Prophylaxis should be in accordance with applicable clinical guidelines and TB specialist 
judgment based on the origin of infection. 
− High risk of exposure to TB infection, as assessed by the investigator  
− Current nontuberculous mycobacterial (NTM) infection or history of NTM infection 
unless proven to be fully recovered. 
For further information relating to definitions of known active TB, past history of TB, LTBI, 
high risk of acquiring TB infection see Section 10.12. 
13. Study participant has a lifetime history of suicide attempt (including an 
 
), or had suicidal ideation with at least some intent to act 
in the past 6 months as indicated by a positive response (Yes) to either Question 4 or Question 5 
of the Columbia Suicide Severity Rating Scale (C-SSRS) at Visit 1. 
14. Removed in Protocol Amendment 4. 
15. Study participant has a current or medical history of 
 deficiency. 
16. Study participant has a history of solid organ transplant or hematopoietic stem cell transplant. 
17. Study participant has undergone a splenectomy. 
18. Study participant has a current or medical history of primary immune deficiency. 
Prior/concomitant therapy 
19. Study participant has been treated with prohibited immunosuppressants, biologics, and other 
therapies within the timeframe specified in Section 6.5.2. 
20a. 
Study participant has received a live vaccination within 4 weeks prior to the Baseline 
Visit; or intends to have a live vaccination during the course of the study or within 8 weeks 
following the final dose of IMP. 
Prior/concurrent clinical study experience 
21. Study participant has been previously randomized in this study (rescreening for screen-failed 
participants is allowed with prior consultation and permission of the medical monitor/study 
physician). 
22. Study participant has previously received rozanolixizumab drug product. 
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23. Study participant has participated in another study of an IMP (and/or an investigational 
device) within the previous 3 months or 5 half-lives prior to Baseline (whichever is longer) or is 
currently participating in another study of an IMP (and/or an investigational device). 
Diagnostic assessments 
24b 
Alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase 
(ALP) are >3x upper limit of normal (ULN). 
− If study participant has >ULN for ALT, AST, or ALP that does not meet the exclusion 
limit at Screening, the tests must be repeated prior to dosing to ensure there was no 
further ongoing clinically relevant increase. In case of a clinically relevant increase as per 
the investigator’s judgement, the study participant must be excluded. 
− Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit (>2xULN) 
may be repeated once for confirmation. This includes rescreening. If any of the repeated 
tests (ALT, AST, or ALP) are >2xULN, the study participant will meet the exclusion 
criterion #24b and the study participant must be excluded.  
− For randomized study participants with a Baseline result >ULN for ALT, AST, ALP, or 
total bilirubin but <1.5xULN, a Baseline diagnosis and/or the cause of any clinically 
meaningful elevation will have to be understood and recorded in the electronic case 
report form (eCRF). 
25. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%). 
26. Removed in Protocol Amendment 5 as already incorporated in exclusion criterion #10. 
27. Removed in Protocol Amendment 2, and incorporated in exclusion criterion #24. 
28. Removed in Protocol Amendment 2, and incorporated in exclusion criterion #24. 
29. Removed in Protocol Amendment 2, and incorporated in exclusion criterion #24. 
30a. Study participant has a total IgG level ≤5.5g/L at the Screening Visit. 
31. Study participant has absolute neutrophil count <1500 cells/mm3 at the Screening Visit. 
32. Study participant has a planned major elective surgical procedure for the duration of their 
participation in the study. 
33. Removed in Protocol Amendment 4. 
5.3 
Lifestyle restrictions 
There are no lifestyle restrictions during the study. The use of medicinal cannabidiols and 
medicinal marijuana (prescribed by a physician) is permitted. The study participant must be on a 
stable dose of cannabidiols and/or medicinal marijuana for 4 weeks prior to Screening Visit and 
remain stable for the duration of the study. 
5.3.1 
Meals and dietary restrictions 
There are no meal or dietary restrictions during the study. 
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5.3.2 
Caffeine, alcohol, and tobacco 
There are no restrictions for caffeine or tobacco during the study. 
Study participants are to avoid excessive alcohol consumption during the study particularly prior 
to the assessment of cognitive function. 
5.3.3 
Activity 
There are no restrictions on activity during the study. 
5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, following discussion with the sponsor’s medical monitor or study physician. 
Rescreened participants should be assigned a new participant number for rescreening and repeat 
all Visit 1 assessments. 
If a study participant has 1 isolated test result outside the specific range which is deemed 
clinically nonsignificant, the abnormal value may be rechecked at the discretion of the 
investigator, following discussion with the sponsor’s medical monitor or study physician. If the 
normalization of the test result occurs within the Screening Period, then no other Screening 
procedures need to be repeated and the study participant may be randomized, provided all other 
eligibility criteria are met. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit at Screening may be 
repeated once for confirmation. Eligibility assessment will be based on the best of the 2 results 
available before initiating randomized treatment. 
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
Treatments administered 
Eligible study participants will be randomized 1:1 to receive rozanolixizumab 
 or placebo 
(0.9% saline) by sc infusion 
 for 24 weeks. The interval between administration of 2 
consecutive doses should be 
 days. A summary of the treatment administered is provided in 
Table 6-1. 
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Table 6-1: 
Study medications administered 
Study treatment 
name 
Rozanolixizumab 
Placebo 
Dose formulation 
Solution for injection 
Solution for injection 
Unit dose 
strength(s) 
A vial of rozanolixizumab at a 
concentration of 140mg/mL, formulated 
with 
 
 
0.9% sodium chloride aqueous 
solution (physiological saline, 
preservative free) 
Dosage level(s) 
 
Not applicable 
Route of 
administration 
Subcutaneous infusion  
Subcutaneous infusion 
Post-dose 
observation 
On dosing days, for the first 2 weeks (Visit 2 and Visit 5), a 4-hour post-dose 
observation will be in place. Assuming the first 2 doses were well tolerated, on 
dosing days in Week 3, 4, and 5 (Visit 6, Visit 7, and Visit 8), a 1-hour post dose 
observation will be in place. Assuming the first 5 doses were well tolerated, on 
subsequent weeks, a 15-minute post-dose observation will be in place. Following 
a missed dose due to temporary IMP discontinuation, a 1-hour observation will 
be in place for the first 2 doses followed by a 15-minute observation per above. 
The minimum post-dose observation time frame may be extended at the 
discretion of the investigator or study nurse at home dosing visits. These 
recommendations are applicable for dosing at site and at home except where 
specified. The investigator is required to complete a check list to confirm that all 
conditions for home dosing have been met (as outlined in Section 8) prior to the 
start of home dosing.  
Use 
Experimental 
Placebo comparator 
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor 
Packaging and 
labeling 
Packaging will be described in the IMP 
Handling Manual. Packaging will be 
47abelled as required per country 
requirement. 
Packaging will be described in the 
IMP Handling Manual. Packaging 
will be 47abelled as required per 
country requirement. 
Current/Former 
name(s) or 
alias(es) 
UCB7665 
Not applicable 
IMP=investigational medicinal product; w/v=weight/volume 
6.2 
Preparation, handling, storage, and accountability requirements 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized site staff 
or healthcare professionals may supply or administer study treatment. All study treatments must 
be stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
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accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
Details on the preparation of study treatment for infusion, rate of infusion, administration, 
appropriate records handling, and blinded and unblinded site personnel roles are provided in the 
IMP Handling Manual. All site personnel and healthcare professionals delegated to handle study 
treatment storage, preparation, and administration must be trained to IMP Handling Manual. 
The investigator or delegate is responsible for study treatment accountability, reconciliation, and 
record maintenance (ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
Further guidance and information for the final disposition of unused study treatment are provided 
in the IMP Handling Manual. 
6.2.1 
Drug accountability 
A Drug Accountability form will be used to record study medication dispensing and return 
information on a by-participant basis and will serve as source documentation during the course 
of the study. Details of any study medication lost, damaged (due to breakage or wastage), not 
used, partially used, disposed of at the study site, or returned to the sponsor or designee must also 
be recorded on the appropriate forms. All supplies and pharmacy documentation must be made 
available throughout the study for UCB (or designee) to review. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee and/or the healthcare professional. 
The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of study medication until returned or destroyed. 
The investigator must ensure that the study medication is used only in accordance with the 
protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired study medication must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB Standard Operating 
Procedures or returned to UCB (or designee). Investigational medicinal product intended for the 
study cannot be used for any other purpose than that described in this protocol. 
6.3 
Measures to minimize bias: randomization and blinding 
An interactive response technology (IRT) will be used for assigning eligible study participants to 
a treatment regimen (as applicable) based on a predetermined production randomization and/or 
packaging schedule provided by UCB (or designee). The randomization schedule will be 
produced by the IRT vendor. The IRT will generate individual assignments for kits of study 
medication, as appropriate, according to the visit schedule. 
To enroll a study participant (Visit 1), the investigator or designee will contact the IRT and 
provide brief details about the participant to be enrolled. Each study participant will receive a 
5-digit number assigned at Screening that serves as the study participant identifier throughout the 
study. The study participant number will be required in all communication between the 
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investigator or designee and the IRT regarding a particular study participant. Study participant 
numbers and kit numbers will be tracked via the IRT. 
To randomize a study participant, the investigator or designee will contact the IRT and provide 
brief details about the study participant to be randomized. The IRT will automatically inform the 
investigator or designee of the study participant’s randomization number. The IRT will allocate 
kit numbers to the study participant based on the participant number during the course of the 
study. The randomization number must be incorporated into the eCRF. 
The randomization will be stratified by: 
• Time from disease symptom onset (≤6 months or >6 months from disease symptom onset) 
• Cognitive function (RBANS score of ≤85 or >85) 
Early initiation of therapy (<6 months from symptom onset) and detection of a plasma membrane 
protein antibody were independent predictors of favorable seizure outcome (p<0.01; Dubey et al, 
2017). 
6.3.1 
Procedures for maintaining and breaking the treatment blind 
6.3.1.1 
Maintenance of study treatment blind 
All study participant treatment details will be allocated and maintained by the IRT system. 
The following individuals will receive the randomization code at the start of the study: 
• Designated bioanalytical staff analyzing PK samples 
• IRT provider 
The IMP for rozanolixizumab and placebo will not be identical in appearance. Therefore, study 
site pharmacists, other suitably qualified site personnel, or healthcare professionals who are 
responsible for preparation of IMP treatments will have access to treatment allocations for 
individual study participants via the IRT. The unblinded pharmacy monitors from the Contract 
Research Organization (CRO) and the Clinical Supply Set-Up Manager/Clinical Supply Planner, 
and the unblinded Clinical Project Manager (or designee) will also have access to the treatment 
allocations and to the drug accountability records, if applicable. Further details are provided in 
the IMP Handling Manual and Site Unblinded Team Management Plan. 
Due to differences in presentation between rozanolixizumab and placebo, special precautions 
will be taken to ensure blinding. Both products have packaging differences (unblinded labels) but 
also physical appearance differences (volumes, color, viscosity). The IMP preparation will be 
performed by unblinded personnel (unblinded qualified site staff or unblinded home healthcare 
practitioner at the participant’s home). Please note that the difference in appearance of the two 
IMPs can be seen in the syringe but not in the tubing. Therefore, only the syringe will be covered 
by blinding stickers (see IMP Handling Manual). 
The IMP administration will be performed by blinded personnel (blinded qualified site staff or 
blinded home healthcare practitioner at the study participant’s home). 
The following individuals may, as necessary, have access to the randomization code as indicated: 
• Sponsor Patient Safety staff as needed for reporting SAEs to regulatory authorities. 
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• Members of the IDMC who participate in unblinded sessions will be given information about 
the IMP allocation for those study participants for whom data are provided at these sessions. 
• The designated unblinded statistician and supporting programmer(s) responsible for the 
preparation of the data outputs for the IDMC review and/or any interim analyses. 
Certain clinical laboratory results have the potential to unblind the investigator, site personnel, 
and study team. These results will not be reported to investigative sites or other blinded 
personnel (see Section 10.2 for a list of these clinical laboratory parameters). A medical monitor 
independent from the sponsor and unblinded to the serum IgG and albumin levels, but blinded to 
actual treatment assignment (an independent unblinded medical monitor) will monitor these 
parameters during the Treatment Period. If temporary treatment discontinuation due to low 
serum IgG levels or low serum albumin levels (as per Section 7.1.4) is required, the independent 
unblinded medical monitor will contact the IRT system to initiate mock infusions with only 
placebo. This procedure will take place irrespective of the randomized IMP. Allocation of mock 
kit numbers will be handled via the IRT. The independent unblinded medical monitor will 
re-initiate the IMP via the IRT system when the serum IgG and/or albumin levels have returned 
to protocol defined thresholds specified in Section 7.1.4. 
Further details of maintenance of the study treatment blind are provided in the IMP Handling 
Manual and Site Unblinded Team Management Plan. 
6.3.1.2 
Breaking the treatment blind in an emergency situation 
In the event of an emergency, it will be possible to determine to which treatment arm the 
participant has been allocated by contacting the IRT. All sites will be provided with details of 
how to contact the system for code breaking at the start of the study. The medical monitor or 
equivalent should be consulted prior to unblinding, whenever possible. 
The clinical project manager and medical monitor will be informed immediately via the IRT 
when a code is broken but will remain blinded to specific treatment information. Any unblinding 
of the study medication performed by the investigator must be recorded in the source documents 
and on the Study Termination eCRF page. 
Inadvertent unblinding has to be listed as a major protocol deviation. 
6.4 
Treatment compliance 
Drug accountability must be recorded on the Drug Accountability form (Section 6.2.1). 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
Investigator should take utmost precaution for the dosage of concomitant medications for study 
participants who might have impaired renal function (GFR 30ml/min/1.73m2 to 
45ml/min/1.73m2) and should refer to the prescribing information for potential dose adjustment. 
Given that study participants will be administered steroids up to Week 12 of the study, it is up to 
the discretion of investigator to initiate prophylaxis for pneumocystis carinii pneumonia if 
deemed appropriate. 
The following concomitant medications are permitted during the study: 
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• Antiepileptic drugs: all study participants should preferably continue to take their Baseline 
AED regimen unchanged over the whole study period. Decreases in daily dose or 
discontinuation of AEDs are permitted, per investigator assessment. However, initiation of 
new AEDs or dose increase of a AED are not allowed. 
• Corticosteroids (only as specified in the protocol) 
• Topical steroids: the use of topical or local is permitted 
• Antipsychotics: the dose should be stable within 1 week of the cognitive assessments 
• Benzodiazepines may be used if at stable daily dosage regimen as concomitant medication. 
However, per needed benzodiazepine treatment that is deemed medically necessary in the 
opinion of the investigator should be administered, and the study participant’s continuation in 
the study must be discussed between the medical monitor and the investigator. 
Administration of COVID-19 vaccines will be recorded in the concomitant medication eCRF 
page. The specific name of the vaccine and the exact date of administration should be recorded, 
as instructed in the completion guideline. See Section 8.3.9 for details. 
6.5.2 
Prohibited prior and concomitant treatments (medications and 
therapies) 
The following concomitant medications are prohibited during the Treatment Period except for 
use as specified or as rescue medication: 
• High dose corticosteroids (500 to 1000mg MP equivalent/day) within 1 year prior to 
randomization, for any indication, is prohibited, except: 
− as permitted per protocol inclusion criteria (see Section 5.1) 
− if used as first line AIE treatment in the 6 months prior to randomization (counted from 
the onset of treatment to randomization date) (see Section 4.1) 
• Prednisolone is prohibited during the Treatment Period if used outside of the protocol-
specified steroid taper. 
All treatments listed in Table 6-2 are prohibited during the Treatment Period, except for use as a 
rescue medication. 
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Table 6-2: 
Prohibited concomitant treatments and treatment-free period for 
exclusionary immunosuppressants, biologics, and other therapies 
prior to Baseline Visit 
Generic name (commercial/trade names) 
Timeframe for prohibition  
Intravenous or sc Ig 
Used within 4 weeks prior to the Baseline Visit 
PEX or plasmapheresis 
Immunoadsorption 
Immunosuppressants: 
Cyclophosphamide 
Any use prior to the Baseline Visit 
Pimecrolimus 
Used within 4 weeks prior to the Baseline Visit 
Vinca alkaloids (vincristine, vinblastine)  
Used within 12 weeks prior to the Baseline 
Visit 
Azathioprine 
Mycophenolate mofetil 
Biologics (mAbs and fusion proteins): 
Eculizumab 
Used within 3 months prior to the Baseline 
Visit 
Abatacept (CTLA 4-Ig) 
Used within 6 months prior to the Baseline 
Visit 
Belimumab 
Golimumab 
Natalizumab 
Ofatumumab 
Veltuzumab 
Satralizumab 
Other biologics 
Rituximab  
Used within 6 months prior to the Baseline 
Visit, or used ≥6 months prior to the Baseline 
Visit with B cells that have not returned to 
normal levels 
Ocrelizumab 
Inebulizumab 
TACI-Ig (Atacicept) 
Used within 10 months prior to the Baseline 
Visit 
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Table 6-2: 
Prohibited concomitant treatments and treatment-free period for 
exclusionary immunosuppressants, biologics, and other therapies 
prior to Baseline Visit 
Generic name (commercial/trade names) 
Timeframe for prohibition  
Others 
Antineoplastic or treatments for neoplastic 
disease (including Anti-PD-1 mAb) 
Used within 3 months prior to the Baseline 
Visit 
Anti-PD-1=anti-program cell death-1; CTLA-4=cytotoxic T-lymphocyte-associated protein 4; Ig=immunoglobulin; 
mAb=monoclonal antibody; PEX=plasma exchange; sc=subcutaneous 
6.5.3 
Rescue medication 
Rescue medication considered most appropriate for the study participant will be selected by the 
investigator. The study site will supply rescue medication that will be obtained locally. The 
effect of rozanolixizumab on the efficacy of IgG biologics and Fc-fusion proteins is not known. 
Although the use of rescue medication is allowable at any time during the study, the use of 
rescue medications should be delayed, if clinically feasible, for at least 4 weeks following the 
initiation of study treatment. Study participants who require rescue medication will discontinue 
blinded treatment, and complete the assessments for the Edisc Visit. Following this, the selection 
of an appropriate rescue medication will be made at the investigator’s discretion, and the study 
participant will enter the SFU Period during which unscheduled visit’ may be performed. Rescue 
medications are permitted during the SFU Period. 
6.6 
Dose modification 
Dose modifications of IMP are not permitted in this study. 
6.7 
Criteria for study hold or dosing stoppage 
The sponsor’s decision for study hold or dosing stoppage will be based on IDMC 
recommendation. 
6.8 
Treatment after the end of the study 
Study participants who complete the 24-week Treatment Period and require further treatment 
may have the option to access rozanolixizumab via another clinical study or an access program, 
if available, as per local laws and regulations. The participant should discuss any alternative 
treatment options (if needed after the study) with their healthcare provider. 
7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
Participants who are permanently discontinued from IMP will undergo an EDisc and SFU Visit. 
In addition to algorithmic stopping criteria, management of AEs is ultimately at the 
investigator’s discretion.  
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7.1.1 
Liver chemistry stopping criteria 
Discontinuation of study treatment for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined Figure 7-1 or if the 
investigator believes that it is in best interest of the participant. 
Figure 7-1: Liver Chemistry Stopping Criteria and Increased Monitoring 
Algorithm 
 
AST= aspartate aminotransferase; ALT=alanine transaminase; INR=international normalized ratio; SAE=serious 
adverse event; ULN=upper limit of normal 
Specific assessments and follow up actions for potential drug-induced liver injury are provided 
in Appendix 6 (Section 10.6). 
7.1.2 
Permanent discontinuation due to other AEs 
Study participants must be permanently discontinued from IMP if any of the following 
safety-related events occur: 
1. Study participant develops an illness that would interfere with his/her continued 
participation. 
2. Study participant has a significant infective episode including but not limited to 
bacteremia/sepsis, infectious meningitis, septic arthritis, osteomyelitis, complicated 
pneumonia, or visceral abscess which may or may not result in hospitalization. This list is not 
intended to be all inclusive, and the investigator is expected to apply their judgement on 
continuing IMP based on the clinical situation (see Appendix 14; Section 10.14). 
 
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
Yes
➢If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Refer to the Liver Safety Required Actions and Follow up Assessments section in 
Appendix 6. 
Report as an SAE if possible Hy’s Law case: AST/ALT ≥3xULN and Bilirubin 
≥2xULN (>35% direct) or INR>1.5, if measured* 
(Note: INR value not applicable to patients on anticoagulants) 
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3. Study participant has an AE of severe or serious hypersensitivity infusion-related reaction 
(see Appendix 15; Section 10.15) or anaphylaxis requiring corticosteroid and/or epinephrine 
therapy (Sampson et al, 2006). 
4. Study participant has a recurrence of aseptic meningitis (Section 10.13). 
5. Study participant who develops active TB, LTBI, or NTM infection during the study, 
regardless of initiation of TB treatment.  
6. Study participant has active suicidal ideation as indicated by a positive response (Yes) to 
either Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The study 
participant should be referred immediately to a mental healthcare professional. 
7. Study participant has new onset or recurrent neoplastic disease (except for superficial basal 
or squamous cell carcinoma of the skin not requiring targeted biological therapy, 
chemotherapy or radiation). 
7.1.3 
Permanent discontinuation due to absence or loss of clinical benefit 
Study participants must be permanently discontinued from IMP if they do not experience a 
clinical improvement within the first 4 weeks of the Treatment Period (ie, an absence of clinical 
benefit) or if they experience clinical worsening (ie, a loss of clinical benefit) at any time as 
defined by any of the following: 
1. mRS assessment 
a. 
Worsening of 1 point compared with Baseline; or 
b. Lack of improvement of a severe score (4 or 5) after 4 weeks 
2. Worsening of cognitive function: A decrease of ≥8 points in the total RBANS score 
compared to Baseline, and per the assessment of the investigator that the study participant 
has worsened 
3. A clinically meaningful recurrence of seizures of a previously experienced type or a new 
seizure type, either of those requiring a change in therapy (per the assessment of the 
investigator) 
4. Lack of seizure improvement (per the assessment of the investigator) 
If study participant permanently discontinues from IMP for any reason, investigators should 
contact the medical monitor, whenever possible, to discuss the withdrawal of a participant in 
advance. Study participants who permanently discontinue the IMP should complete the 
assessments outlined for the EOT/EDisc Visit and enter the 8-week SFU Period. If IMP is 
permanently discontinued, the requirement for, and selection of, rescue therapy will be made by 
the investigator. 
7.1.4 
Temporary discontinuation of IMP 
Study participants must be temporarily discontinued from the IMP if any of the following 
events occur: 
1. Study participant develops an event of hypogammaglobulinemia with a serum total IgG of 
<1g/L irrespective of infection. When the IgG level reaches ≥2g/L, the study participant may 
be allowed to continue treatment with IMP (see Appendix 14; Section 10.14). In view of re-
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initiating the IMP, additional samples will be collected to monitor participants’ IgG levels 
during the period of temporary discontinuation. In order to preserve the blind (see 
Section 6.3.1.1 for details of mock infusions), additional participants will be selected at 
random and requested to provide additional samples. 
2. Study participant develops an event of hypoalbuminemia with serum albumin level <2g/dL. 
When the serum albumin level returns to ≥2.5g/dL, the participant may be allowed to resume 
treatment with IMP. In view of re-initiating the IMP, additional samples will be collected to 
monitor participants’ serum albumin levels during the period of temporary discontinuation. 
In order to preserve the blind (see Section 6.3.1.1 for details of mock infusions), additional 
participants may be selected at random and requested to provide additional samples. 
3. Study participant has a suspected drug-induced aseptic meningitis. The IMP may be restarted 
if clinically appropriate when signs and symptoms have resolved. 
If IMP treatment is resumed, continue the next dose as previously scheduled. No “make up” dose 
is permitted. The participant should subsequently follow the visit schedule as described in the 
protocol and the eCRF should be completed accordingly. 
Study participants may be temporarily discontinued from the IMP if any of the following 
events occur: 
1. Study participant develops a non-serious persisting or recurrent infection with serum total 
IgG level between ≥1 and <2g/L. Upon resolution of infection and the IgG returning to level 
of ≥2g/L, the study participant may be allowed to resume treatment with the IMP (see 
Appendix 14; Section 10.14). 
2. Study participant may be temporarily discontinued from study medication at the discretion of 
the investigator in cases deemed strictly necessary for the participant's medical care. Efforts 
should be made to keep the length of temporary discontinuation to a minimum. 
If IMP treatment is resumed, continue the next dose as previously scheduled. No “make up” dose 
is permitted. The participant should subsequently follow the visit schedule as described in the 
protocol and the eCRF should be completed accordingly. 
7.2 
Participant discontinuation/withdrawal from the study 
Participants are free to withdraw from the study at any time, without prejudice to their continued 
care. 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, persistent non-
manageable noncompliance, or administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See the Schedule of Activities for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
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7.2.1 
Study withdrawal criteria 
Study participants must be withdrawn from the study if any of the following events occur: 
1. Participant withdraws his/her consent. 
2. The sponsor or a regulatory agency requests withdrawal of the participant. 
3. Study participant becomes pregnant during the study, as confirmed by a positive serum 
pregnancy test. 
Study participants may be withdrawn from the study at the discretion of the investigator, if the 
study participant is persistently noncompliant with the study procedures or medications and this 
noncompliance is not manageable in the opinion of the investigator. 
Study participants who choose to withdraw from the study during the Treatment Period should 
complete the assessments outlined for the EOT/EDisc Visit. 
Study participants who are withdrawn from the study during the Treatment Period should 
complete the assessments outlined for the EOT/EDisc Visit and be encouraged to enter the 8-
week SFU Period. 
Investigators should contact the medical monitor, whenever possible, to discuss the withdrawal 
of a study participant in advance. 
7.3 
Lost to follow up 
A participant will be considered lost to follow up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (at least 1 phone call and 1 written message 
to the participant), and document his/her effort (date and summary of the phone call and copy 
of the written message in the source documents), to complete the final evaluation. All results 
of these evaluations and observations, together with a narrative description of the reason(s) 
for removing the participant, must be recorded in the source documents. The eCRF must 
document the primary reason for withdrawal. 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow up documented in the eCRF. 
Study participants who are withdrawn will not be replaced. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.3). 
Study visits should preferably be conducted at the same time of the day throughout the study. 
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Some study-specific investigations may not be conducted according to the study protocol during 
a pandemic or other exceptional circumstance (eg, hurricanes) due to the need to implement 
safety measures and guidance from regulatory authorities. In such a situation, which may be 
accompanied by local or global containment or other measures, sites may need to prohibit access 
to study participants and study-related personnel. Study participants’ visits to the study site may 
be replaced by contingency measures. These measures are primarily established to ensure the 
safety of study participants during the course of the study and to maintain the study participants’ 
treatment schedules, if the investigator considers it appropriate. These measures include, but are 
not limited to, virtual visits or home-nursing visits replacing site visits, eg, telemedicine contacts 
or home-nursing visits when treatment and/or blood sampling is scheduled. The contingency 
measures are described in a contingency plan which will be maintained by UCB for the 
respective study. The contingency measures are shared with the investigator and the respective 
study-related personnel as soon as there are indications that it is necessary to implement any of 
the measures. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3), is essential and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. Screening assessments may be performed on different days 
throughout the Screening Period, if required. The investigator will maintain a Screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
Screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management and obtained 
before signing of the ICF may be utilized for screening or Baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame defined 
in the Schedule of Activities. 
The study participant may have the option to have home-nursing visits as specified in 
Section 1.3. Home-nursing visits will be conducted by up to 2 fully trained healthcare 
professionals (1 unblinded for IMP preparation and 1 blinded for the other assessments) visiting 
the study participant at his/her home or other locations (eg, rehabilitation or day care centers, 
etc). Alternatively, these visits can be conducted at the site as deemed necessary by site 
personnel and/or study participant, or when home-nursing visits are not available. Where dosing 
is performed at home or at other locations, the same safety monitoring schedule will be followed 
as if in the clinic. Healthcare professional(s) will be present during the full duration of the visit. 
Home visits and visits at other locations can be conducted in case the following conditions are 
met: 
• The study participant is willing to be dosed and monitored at home, or at an alternative 
location for up to 4 hours by healthcare professionals. 
• The study participant has shown good acute tolerability to previous administrations of IMP 
(namely they must have had no moderate or severe infusion reactions, or other AEs which 
the investigator considers could increase the risk of home administration). 
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• The study participant does not require specific medical supervision based on their medical 
history/condition. 
• The team delivering the home dose must be trained in the identification and management of 
infusion reactions and hypersensitivity and must have access to immediate treatments (eg, an 
EpiPen). 
• The study participant’s home or alternative location allows rapid access to emergency 
treatment if required (ie, the study participant must not live so remotely that a reasonable 
arrival time of an ambulance could not be predicted). 
• The investigator is contactable to support the healthcare provider if needed. 
• UCB has not requested to limit the possibility to perform home visits or visits at other 
locations (eg, based on IDMC recommendation). 
During the home visit, a qualified site personnel will assess AEs, concomitant medications, 
withdrawal criteria, and the seizure diary by telephone call prior to IMP administration. During 
the SFU phone call, the qualified site personnel will assess AEs, concomitant medications, and 
evaluation of seizure diary by telephone. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 500mL. Additional blood 
samples may be required for repeat or unscheduled samples may be taken for safety reasons or 
for technical issues. 
An Unscheduled Visit or assessment can be conducted at the discretion of the investigator at any 
time (eg, due to an AE) or to follow study participants who experience symptom worsening 
during the SFU Period and opt to receive rescue therapy. Assessments to be performed during an 
Unscheduled Visit are provided in Section 1.3. 
Blood samples for PK, IgG, hematology, biochemistry, and other laboratory testing and 
assessments may be performed as clinically indicated at discretion of the investigator. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
8.1 
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the Schedule of Activities 
(Section 1.3). 
8.1.1 
Assessment of seizures 
The primary objective of the study is to assess the efficacy of rozanolixizumab as measured by 
seizure freedom, where seizure freedom is defined by 28 consecutive days of no seizures, 
maintained until the end of the Treatment Period (Week 25). Seizures will be assessed during the 
treatment and SFU Period and the information will be recorded using a mobile device with a pre-
installed application (app) which contains a seizure diary to be completed. The presence or 
absence of seizures will be recorded, and if seizures were present, the number of seizures and 
type of seizures will be recorded. Study participants or caregivers have up to 72 hours after the 
end of each day to complete the seizure diary in the mobile device app. The date of data entry 
will be captured in the audit trail. If seizure recording is not completed within the allotted time, it 
will no longer be available for completion and will show as blank in the data record. An overdue 
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or missed entry will not impact the availability of the next day’s seizure diary, as each new 
calendar day triggers a new diary for completion. Retrospective edits to seizure diary entries 
recorded in the mobile device application are not allowed after 72 hours. Daily seizure 
documentation is submitted electronically to the investigator. A printout of electronic records 
will be reviewed and discussed with the patient to ensure completeness and accuracy during the 
next scheduled visit. If any changes are identified during this review, they must be documented 
on the paper printout. Data from the printout with updates as needed are entered into the eCRF. 
Printed records are filed as part of the participant’s source documents at site. 
As a result of the discussion, the investigator will assess the seizures according to the 
International League Against Epilepsy codes and record the seizure types and frequency on the 
printout of electronic records and eCRF; he/she will also confirm the presence of AEs (if 
applicable). Printed records will be filed as part of the participant's source documents at site. 
The recording of seizures should begin from Visit 1 (Screening). At Visit 2 (Baseline), the 
printout of the electronic seizure diary from Screening must be reviewed for seizure data to 
confirm that the study participant meets eligibility criteria before randomization. 
The study participant/caregiver should be educated on how to complete the electronic seizure 
diary daily. 
8.1.2 
Assessment of Cognitive Function: Repeatable Battery for the 
Assessment of Neuropsychological Status 
The RBANS was developed for the dual purposes of identifying and characterizing abnormal 
cognitive decline in the older adult. The RBANS consists of 12 subtests that contribute to 5 age-
based domain index scores (immediate memory, visuospatial, language, attention, delayed 
memory) that are aggregated for a total scale index score. All index scores have an age-based 
mean of 100, with a SD of 15. Higher scores reflect better neurocognitive performance (Phillips 
et al, 2015). The total scale index score is the score typically used to reflect global 
neurocognitive status. The entire battery takes less than 30 minutes to administer. The RBANS 
has been found to be useful in a retrospective assessment of cognitive improvement in patients 
with AIE following treatment with methylprednisolone (Kelley and Bratt, 2015). Thus, RBANS 
may be suitable for evaluating the effects of rozanolixizumab on cognitive function in LGI1 AIE. 
The RBANS is administered by the healthcare provider or qualified designee. Training on 
administering the RBANS is mandatory. 
8.1.3 
Assessment of Disability: Modified Rankin Scale 
The mRS is a commonly used scale for measuring the degree of disability or dependence in the 
daily activities of people who have suffered a stroke or other causes of neurological disability 
(Bonita and Beaglehole, 1988; van Swieten et al, 1988; Rankin, 1957). The mRS has been used 
previously to assess the level of functioning in the LGI1 population (de Bruijn et al, 2019). The 
scale included categories from 0 (perfect health) to 6 (death). The mRS is administered by the 
healthcare provider or qualified designee. Training and certification on administering the mRS is 
mandatory. 
8.1.4 
Patient-reported outcomes 
The PRO questionnaires should be completed in a quiet place prior to any discussion regarding 
study-related issues, disease status, or treatment effect with the investigator/site staff, and prior to 
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any procedures. The patient-reported outcome questionnaires will be self-completed by the study 
participant electronically on a tablet during study visits.  
The PROs should be completed in the following order: SF-36 and EQ-5D-5L. The PROs should 
only be checked for completeness. On dosing days, the PROs will be completed prior to dosing. 
8.1.4.1 
36-item Short Form Survey 
The SF-36 Version 2.0 (acute version, 1-week recall) is a 36-item generic HRQoL instrument 
that uses a recall period of 1 week. Items are grouped into 8 domains as follows: physical 
functioning (10 items), role physical (4 items), bodily pain (2 items), general health (5 items), 
vitality (4 items), social functioning (2 items), role emotional (3 items), mental health (5 items), 
and 1 item for perceived stability or change in health (health transition) during the last year. The 
concepts represented by these domains contribute to physical, mental, and social aspects of 
HRQoL. 
In addition to domain scores, the PCS and MCS scores are calculated from the 8 domains 
(excluding the Health Transition item). Component scores appreciate the impact of each domain 
on physical and mental health status (Maruish, 2011). Each of the 8 domain scores and the 
component summary scores range from 0 to 100, with a higher score indicating a better health 
status. The 2 component summary scores and the domain scores are standardized with a mean of 
50 and a SD of 10 in the general US population. 
8.1.4.2 
EuroQol-5D-5L 
The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EuroQol 
visual analogue scale (EQ VAS). The 5-level EQ-5D is designed to improve the instrument’s 
sensitivity and to reduce ceiling effects. 
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The study participant is 
asked to indicate his/her health state by ticking the box next to the most appropriate statement in 
each of the 5 dimensions. This decision results in a 1-digit number that expresses the level 
selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit 
number that describes the study participant’s health state. 
The EQ VAS records the study participant’s self-rated health on a vertical visual analogue scale, 
where the endpoints are labelled "The best health you can imagine" and "The worst health you 
can imagine." The VAS can be used as a quantitative measure of health outcome that reflect the 
study participant’s own judgement. 
8.1.5 
Clinical Global Impression of Severity 
The Clinical Global Impression of Severity (CGI-S) scale is a clinician-rated measure that 
assesses the severity of cognitive impairment of the study participant of clinical signs and 
symptoms of AIE. The CGI-S scale will include 5 response options: none, mild, moderate, 
severe, and very severe. 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3). 
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8.2.1 
Physical examination 
For full and brief physical examinations, investigators should pay special attention to clinical 
signs related to previous serious illnesses, as well as signs and symptoms of infections. 
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
A full physical examination will include, at a minimum, general appearance; ear, nose, and 
throat; eyes, hair, and skin; and assessments of the cardiovascular, respiratory, GI, and 
musculoskeletal systems. Height and weight will be measured and recorded at Visit 1 
(Screening). Body weight will be measured with the study participant wearing light clothing and 
without wearing shoes. 
A full or brief physical examination should include evaluation for medical history and for signs 
and symptoms of latent or active TB and for risk factors for exposure to TB at the following time 
points: Screening, Baseline, W13, W21, EDisc if applicable and EOS (see Section 10.12). 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
8.2.2 
Neurological examination 
In addition to the Screening and EOT/EDisc Visits, a full neurological examination should be 
performed for any study participant who experiences severe and/or serious headache and for 
study participants who experience suspected aseptic meningitis (see Section 10.13). 
A full neurological assessment will include: (1) General appearance, including posture, motor 
activity and meningeal signs and, the following assessments will be performed; (2) Cranial 
nerves examination; (3) Motor system examination, including muscle tone and power and 
sensory system examination – light touch; (4) Reflexes, including deep tendon reflexes; 
(5) Coordination, gait (if possible); and (6) Fundoscopy. 
A brief neurological assessment will include a selected assessment of the following: cognition, 
general, reflexes, muscle strength, and coordination/cerebellar function. 
8.2.3 
Vital signs 
Temperature, pulse rate, and blood pressure will be assessed at the time intervals specified in the 
Schedule of Activities (Section 1.3). 
Blood pressure (systolic and diastolic), and pulse rate measurements should be preceded by at 
least 5 minutes of rest for the study participant in a quiet setting without distractions (eg, 
television, cell phones). All measurements will be assessed in a sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
On dosing days for the first 2 visits (Visit 2 and Visit 5), vital signs will be measured prior to 
IMP administration, at the end of the infusion (+5 minutes), at 2 hours after the end of infusion 
and at 4 hours after the end of infusion (both ±15 minutes). At Visit 6, Visit 7, and Visit 8, vital 
signs will be measured prior to IMP administration, at the end of the infusion (+5 minutes), and 1 
hour after the end of infusion (±15 minutes). From Visit 9, the vital signs will be measured 15 
minutes prior to IMP administration. At nondosing visits, vital signs need only be taken once 
during the visit. 
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8.2.4 
Electrocardiogram 
12-Lead ECGs will be obtained using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and QTc intervals. 
ECG recordings should be taken with the study participant resting in the supine position for at 
least 5 minutes before the recording. 
Findings will be recorded in the eCRF. 
8.2.5 
Magnetic resonance imaging 
Serial structural brain MRIs will be performed during the Screening Period (or at the Baseline 
Visit) and at an EOT or an EDisc Visit. These MRIs will be used to detect eventual emergent 
alterations in brain structure that may be associated with safety readout issues, as well as any 
structural changes that may indicate a treatment effect. A MRI performed within 3 months of the 
Screening Period may also be acceptable as per the investigators judgement. Brain MRIs will be 
performed using an MRI scanner with a field strength of at least 1.5 Tesla in accordance with 
local guidance and practice. At any time during the study, additional brain MRIs may be 
performed in any study participant if deemed as appropriate by the investigator/local radiologist. 
Brain MRIs shall be analyzed by a local radiologist, and clinical assessment of the findings will 
be based on the investigator’s judgement. 
8.2.6 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Section 1.3) for the timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or Baseline or are no longer 
considered clinically significant by the investigator. 
If such values do not return to normal/Baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the Schedule of Activities. 
8.2.7 
Suicidal risk monitoring 
Study participants should be monitored appropriately for suicidal ideation and behavior or any 
other unusual changes in behavior. Consideration should be given to discontinuing IMP in study 
participants who experience signs of suicidal ideation or behavior. 
Families and caregivers of study participants should be instructed to monitor participants for the 
emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and 
behavior, and to report such symptoms immediately to the study investigator. 
Suicidality will be assessed by trained study personnel using the C-SSRS (Oquendo et al, 2003). 
This scale will be used at Screening, Baseline, and all subsequent visits to assess suicidal 
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ideation and behavior that may occur during the study. The C-SSRS will be performed at the 
scheduled timepoints as described in the Schedule of Activities (Section 1.3). 
8.3 
Adverse events and serious adverse events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3) and in Appendix 12 
(Section 10.2) for TB events. Adverse events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
participant to discontinue the study treatment or AIE001 (see Section 7). 
For results disclosure on public registries (eg, ClinicalTrials.gov), TEAEs and 
treatment-emergent SAEs will be published. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF until the EOS Visit at the time 
points specified in the Schedule of Activities (Section 1.3). In order to ensure complete safety 
data collection, all AEs occurring during the study (ie, after the signing of the Informed Consent 
form), including any pretreatment and posttreatment periods required by the protocol, must be 
reported in the eCRF even if no study medication was taken but specific study procedures were 
conducted. This includes all AEs not present prior to the initial visit and all AEs that recurred or 
worsened after the initial visit. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3 (Section 10.3). The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
The investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the investigator is certain that they are in no way associated with the study 
medication), up to 30 days from the end of the study for each participant, and to also inform 
participants of the need to inform the investigator of any SAE within this period. Serious AEs 
that the investigator thinks may be associated with the study medication must be reported to 
UCB regardless of the time between the event and the end of the study. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AESMs (as defined in Section 8.3.7), will be 
followed until resolution, stabilization, the investigator determines that it is no longer clinically 
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significant, the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study treatment and until 90 days after the final 
dose. 
If a pregnancy is reported, the investigator must immediately inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
The participant should be withdrawn from the study as soon as pregnancy is known (by positive 
serum pregnancy test), and the following should be completed: 
The participant should complete the assessments outlined for the EOT/EDisc Visit and 
encouraged to enter the 8-week SFU Period. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Adverse events of special interest 
An adverse event of special interest (AESI) is any AE that a regulatory authority has mandated 
be reported on an expedited basis, regardless of the seriousness, expectedness, or relatedness of 
the AE to the administration of a UCB product/compound. An AESI should be reported within 
24h. Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin (>35% direct bilirubin) in the absence of ≥2xULN ALP, with no alternative explanation 
for the biochemical abnormality must always be reported to UCB as an AESI (ie, without 
waiting for any additional etiologic investigations to have been concluded). Follow-up 
information should be reported if an alternative etiology is identified during investigation and 
monitoring of the participant.  
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All AESIs will follow the SAE recording and reporting procedures as indicated in Appendix 3 
(Section 10.3). 
8.3.7 
Adverse events of special monitoring 
An AESM is a product-specific AE, adverse reaction or safety topic requiring special monitoring 
by one or more regulatory authorities or by UCB. For rozanolixizumab, AESM that require 
immediate reporting (within 24 h regardless of seriousness) to UCB are: 
• Severe and/or serious headache 
• Suspected aseptic meningitis 
Procedures for the management of AESMs are provided in Appendix 13 (Section 10.13). 
Although hypersensitivity reactions including infused-related reactions and anaphylaxis are not 
classified as AESM, these AEs will be monitored by the investigator. If such an event is 
suspected it should be managed according the guidance provided in Section 10.15 
(Appendix 15). Suspected anaphylactic reactions should be diagnosed using Sampson’s Criteria 
(Sampson et al, 2006). 
All AESM will follow the SAE recording and reporting procedures as indicated in Appendix 3 
(Section 10.3). 
8.3.8 
Anticipated serious adverse events 
Serious AEs anticipated to occur in the population studied in this protocol at some frequency that 
is independent of drug exposure are shown in Table 8-1. 
This list does not change the investigator’s obligation to report all SAEs (including Anticipated 
SAEs) as detailed in Section 8.3.1 and Appendix 3 (Section 10.3). 
Table 8-1: 
Anticipated SAEs for LGI1 AIE population 
MedDRA System Organ Class 
MedDRA Preferred Term 
Injury, poisoning, and procedural 
complication 
Fall, fracturea, injurya 
Nervous system disorders 
Cluster seizures, convulsion, incontinencea, memory 
impairment 
Psychiatric disorders 
Abnormal behavior, acute psychosis, anxiety, cognitive 
disorder, confusional state, psychotic behavior, sleep 
disorder and disturbances 
AIE=autoimmune encephalitis; LGI1= leucine-rich glioma inactivated 1; MedDRA=Medical Dictionary for 
Regulatory Activities; SAE=serious adverse event; SOC=system organ class 
a Event is anticipated when occurring in the context of seizure but not classified in MedDRA primary SOC 
8.3.9 
COVID-19 vaccination 
Use of COVID-19 vaccines will be recorded in the concomitant medication eCRF page 
(Section 6.5.1). 
In the AE eCRF page, there is the possibility to assess causality to the IMP and to any 
concomitant medication. If an AE is considered related to COVID-19 vaccine, causality 
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assessment should be entered in the AE eCRF. Note that in this case, the national 
recommendation for reporting AE-related to COVID-19 vaccines should be followed. If an AE is 
the result of an interaction of a COVID-19 vaccine with an IMP in the study, then the causal 
association should be for both IMP and COVID-19 vaccine. In case of a seriousness criteria, the 
SUSAR process will be followed. 
8.4 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that investigators, clinical study participants, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The study physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Patient Safety 
representative in a blinded manner. 
In addition, an IDMC will be responsible for monitoring safety data during the study. A detailed 
description of the IDMC composition, processes, and responsibilities will be provided in a 
separate IDMC charter. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory, or ECG results) for which data will be periodically reviewed 
during the course of the study. 
8.5 
Treatment of overdose 
Any dose increase of 10% or greater from the assigned dose for each administered dose of IMP 
per week should be considered an overdose. Overdose events are only considered AEs or SAEs 
if there are associated clinical signs and symptoms or if the act of taking the excess study 
medication itself is an AE or SAE (eg, suicide attempt). 
UCB does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator or treating physician should: 
1. Contact the medical monitor immediately. 
2. Closely monitor the participant for any AE/SAE or laboratory abnormalities for at least 5 
days. 
3. Obtain a plasma sample for PK analysis and a serum sample for IgG (total and subclasses) 
autoantibodies and within 3 days from the date of the final dose of study treatment if 
requested by the medical monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.6 
Pharmacokinetics and immunogenicity 
Whole blood samples will be collected for measurement of plasma concentrations of 
rozanolixizumab and ADA as specified in the Schedule of Activities (Section 1.3). Blood 
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samples may be collected at additional time points during the study if warranted and agreed upon 
between the investigator and the sponsor. Instructions for the collection and handling of 
biological samples will be provided by the sponsor. The actual date and time (24-hour clock 
time) of each sample will be recorded. 
Samples will be used to evaluate the PK of rozanolixizumab and ADA and may be used for 
establishing assay parameters (eg, ADA cut point setting and PK selectivity assessment). 
Samples collected for analyses of rozanolixizumab concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising before study completion. 
Participant confidentiality will be maintained. At visits during which plasma samples for the 
determination of multiple aspects of rozanolixizumab will be taken, one sample of sufficient 
volume can be used. 
Drug concentration information that may unblind the study will not be reported to study sites or 
blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the sponsor 
and site study files but will not constitute a protocol amendment. The IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
8.7 
Genetics 
Blood samples for potential genetics analyses are part of this study and are described in 
Appendix 5 (Section 10.5). 
8.8 
Pharmacodynamics 
Venous blood samples will be collected at time points specified in the Schedule of Activities 
(Section 1.3) for measurement of: 
• Total serum IgG concentrations 
• Serum IgG subclass concentrations 
• Serum LGI1 autoantibody (total and subclasses) concentrations 
Cerebrospinal fluid will be collected as specified in the Schedule of Activities (Section 1.3) for 
measurement of LGI1 autoantibody (total) concentrations. This sampling is optional for study 
participants and requires informed consent. A decision not to consent does not exclude the study 
participant from the study. Cerebrospinal fluid samples collected between onset of disease and 
Visit 2 are eligible to replace Visit 2 samples. 
For all PD assessments, samples will be collected predose. Instructions pertaining to sample 
collection, processing, storage, labeling, and shipping are provided in the laboratory manual. 
8.9 
Biomarkers 
The investigational LGI1 cell-binding assay is a qualitative assay to determine the presence of 
circulating LGI1 autoantibodies in serum, which is used as part of the inclusion criteria 
(Section 5.1). 
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Leucine-rich glioma inactivated 1 autoantibodies will also be tested with an independent, 
research-use only, quantitative assay (flow cytometry LGI1 assay) to assess the PD effect of 
rozanolixizumab as quantified by changes in LGI1 autoantibody concentrations in serum and 
CSF (for consenting study participants only). Samples for the LGI1 IgG autoantibody 
concentrations in serum will be collected predose at Baseline (Day1) and at various other visits 
as specified in the Schedule of Activities (Section 1.3) for all study participants. The CSF 
sampling (for consenting participants only) will occur at Screening and the EOT/EDisc Visit. 
Other blood samples specified in the Schedule of Activities (Section 1.3) may be tested for 
protein, metabolites, and biomarkers, such as, but not limited, to albumin, α‑ and β‑globulins, B-
cell activating factor, and circulating immune complexes. Blood sampling for other exploratory 
biomarkers will occur at predose at Baseline (Day 1) and at the EOT/EDisc Visit for all study 
participants. These samples will be used to explore the effect of rozanolixizumab on exploratory 
biomarkers and the cause, progression, and appropriate treatment of LGI1 AIE. 
In addition, where local regulations and IRB/IEC allow, blood samples for pharmacogenomics 
and biomarker research are required and will be collected from all study participants as specified 
in the Schedule of Activities (Section 1.3). In study participants who experience severe and/or 
serious headaches or suspected aseptic meningitis, additional blood samples should also be taken 
4 hours after the onset of the event; or otherwise as soon as possible within 72 hours, but prior to 
next dose. These samples may be tested for exploratory biomarkers such as proteins and 
metabolites to evaluate their association with the cause, progression, and appropriate treatment of 
LGI1 AIE. Details on genetic analysis are described in Appendix 5 (Section 10.5). 
If not used immediately, the samples are planned to be stored at -80°C for up to 20 years to allow 
for later analyses. Any future diagnostic test development or exploratory biomarker analysis will 
only ever be related to the exploration of the cause, progression, and appropriate treatment of 
LGI1 AIE. 
Instructions pertaining to sample collection, processing, storage, labelling, and shipping are 
provided in the laboratory manual for this study. Detailed information on sample analyses will be 
provided in a bioanalytical report. 
8.9.1 
Immunology 
Blood samples for immunological testing are required and will be collected from all study 
participants in this study as specified in the Schedule of Activities (Section 1.3) for measurement 
of: 
Samples for serum complement (
 and plasma complement (
) are collected 
predose at Baseline (Day 1) for all study participants. In study participants who experience an 
infusion reaction or hypersensitivity reaction at site, samples should also be taken 2 hours post 
event and 4 hours post event, or otherwise as soon as possible but prior to the next dosing. 
Instructions pertaining to sample collection, processing, storage, labeling, and shipping are 
provided in the laboratory manual for this study. 
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8.10 
Medical resource utilization and health economics 
Medical resource utilization will be collected in the eCRF by the investigator and study-site 
personnel for all participants throughout the study. Protocol-mandated procedures, tests, and 
encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include: 
• Number and duration of disease-related hospitalization (total days or length of stay, including 
duration by wards [eg, intensive care unit]). 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Definition of analysis sets 
The following analysis sets have been defined for this study: 
• The Enrolled Set: All study participants who have signed the informed consent. 
• The Randomized Set (RS): All enrolled study participants who were randomized to treatment 
arms. This is an equivalent to the Intent-to-Treat (ITT) Population. The study participants 
will be analyzed according to the randomized treatment. 
• The Safety Set (SS): All randomized study participants who received at least one dose of 
IMP. Analysis of this set will be according to the treatment the study participants actually 
received and will be used for the demographic and safety analyses. 
• The Full Analysis Set (FAS): All study participants in the RS, who have a Baseline value and 
at least one post-Baseline efficacy endpoint assessment. In the case of treatment error, the 
study participants will be primarily analyzed according to the predominant treatment actually 
received. 
• The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the SS, consisting of those 
study participants who have at least one quantifiable concentration of rozanolixizumab and 
no important protocol deviations affecting the PK variable. Post-Baseline deviations will not 
necessarily lead to total exclusion of a study participant from the PK-PPS but may lead to 
exclusion of specific data. 
• The Pharmacodynamic Per-Protocol Set (PD-PPS) is a subset of the SS, consisting of those 
study participants who had at least one valid post-Baseline measurement of total IgG, or IgG 
subclasses, and no important protocol deviations affecting the PD variable. Post-Baseline 
deviations will not necessarily lead to total exclusion of a study participant from the PD-PPS 
but may lead to exclusion of specific data. 
9.2 
General statistical considerations 
Summary statistics will be provided for all efficacy, safety, and Baseline or demographic 
variables. 
Continuous variable outcomes will be summarized by visit (where applicable) with descriptive 
statistics represented by the number of study participants, arithmetic mean, standard deviation, 
median with 25th and 75th percentiles, minimum, and maximum. For the purpose of the 
statistical analysis or graphical presentations, some of the continuous variable outcomes may be 
log-transformed to accommodate the observed heterogeneity, mitigate influence of the outliers, 
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or fulfill the distributional assumptions required for statistical testing. Categorical variable 
outcomes will be summarized by visit (where applicable) using number of study participants, 
frequency counts, and percentages. 
If not otherwise stated, a Baseline value will be the last available predose value and will be 
clearly defined in the study Statistical Analysis Plan (SAP). All relevant data will be listed by 
treatment group, visit (where applicable) and study participant. 
Unless otherwise mentioned, all the statistical hypotheses will be tested at a two-sided 5% 
significance level. 
All the analyses will be performed using SAS® version 9.3 or later (SAS Institute, NC, USA). 
9.3 
Planned efficacy/outcome analyses 
All planned primary and secondary efficacy analyses will be conducted on the RS and 
additionally only for specified estimands for the primary and secondary endpoints on the FAS as 
part of the sensitivity analysis. The analyses on the FAS will only be carried out if this 
population differs by more than 10% of study participants to the RS/ITT. 
The efficacy analysis, unless otherwise specified, will use all available efficacy data collected 
over the Treatment Period, and account for stratification factors. 
The following sections outline the planned statistical analyses of the primary, secondary, and 
exploratory efficacy endpoints. 
Further details regarding the statistical analysis will be described in the SAP. 
9.3.1 
Primary efficacy analysis 
9.3.1.1 
Seizure freedom 
The primary objective of the study is the assessment of the efficacy of rozanolixizumab as 
measured by seizure freedom. The definition of the primary endpoint together with the 
description of its primary and supportive analyses are provided in Table 9-1. The main 
intercurrent event is permanent IMP discontinuation resulting in withdrawal from the 
randomized Treatment Period, and entering the SFU, or the complete withdrawal from the study 
(see Section 7). This will include by design participants who take any rescue anti-seizure 
medication who will be required to be withdrawn from the randomized treatment. The other 
intercurrent event is a temporary IMP discontinuation. For the analyses on the RS, participants 
who withdraw from the study prior to receiving the IMP or who do not have any post-
randomization assessment will be considered as not having met the primary endpoint. 
For the purpose of deriving the primary efficacy endpoint, any intermittent missing diary seizure 
count recording will be imputed to non-zero in both treatment arms. 
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Table 9-1: 
Estimands for the primary efficacy endpoint 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): Seizure freedom (defined by 28 consecutive days of no 
seizures) maintained until the end of the Treatment Period (Week 25). 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP 
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
Primary 
RS 
1. Treatment policy strategy: 
Temporary 
discontinuation of the 
IMP will not affect the 
assessment of the primary 
endpoint.  
2. Composite strategy: 
Permanent 
discontinuation of the 
IMP will be considered as 
a failure in meeting the 
primary endpoint. 
The association between randomized 
treatment exposure and the primary 
endpoint will be measured by the 
rozanolixizumab versus placebo common 
OR derived from the 2x2 contingency 
tables corresponding to the stratification 
factors (see Section 6.3). The null 
hypothesis, H0: (true) common OR=1, 
indicating no effect between the 
treatment exposure and the primary 
endpoint, will be tested using a CMH 
test. The CMH estimate of the common 
OR will be reported with its 95% CI and 
the CMH test p-value. The assumptions 
of the CMH test will be validated 
(Mantel-Fleiss criterion) and, if 
appropriate, the exact stratified test of 
independence alternative will be 
considered. 
Sensitivity 
FAS 
As described for the primary 
estimand analysis. 
As described above. 
Sensitivity 
RS 
As described for the primary 
estimand analysis. 
Logistic regression model including 
effect for randomized treatment, 
conditional on the stratification factors 
(see Section 6.3), will be used to test the 
primary efficacy hypothesis. The 
resulting rozanolixizumab versus placebo 
common OR estimate with its 95% CI 
and the treatment factor p-value from the 
model will be reported. As a part of the 
analysis, the model will be extended to 
include an additional binary covariate to 
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Table 9-1: 
Estimands for the primary efficacy endpoint 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): Seizure freedom (defined by 28 consecutive days of no 
seizures) maintained until the end of the Treatment Period (Week 25). 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP 
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
indicate if the participant had achieved 
seizure freedom for at least 1 day over 
the Screening Period (effect of the prior 
IVMP treatment). In the case of model 
convergence issues, the appropriate 
alternatives to the maximum likelihood 
estimation will be considered. 
Supplementary RS 
As described for the primary 
estimand analysis. 
The association between randomized 
treatment and seizure freedom at 
Week 25 will be measured by the 
rozanolixizumab and placebo difference 
in the proportion of the study participants 
reaching the primary endpoint, 
controlling for the effect of the 
stratification factors (see Section 6.3). 
The proportion differences for each 
stratum and the CMH-weighted common 
effect estimate will be reported with its 
95% CI. 
AIE=autoimmune encephalitis; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; FAS=Full Analysis 
Set; H0=null hypothesis; IMP=investigational medicinal product; iv=intravenous; IVMP=intravenous 
methylprednisolone; LGI1=leucine-rich glioma inactivated 1; OR=odds ratio; RS=Randomized Set 
9.3.2 
Secondary efficacy analysis 
The secondary study objectives are the assessment of the efficacy of rozanolixizumab as 
measured by a change from Baseline in cognitive function (assessed using the RBANS; 
Section 9.3.2.1), change in overall disability function (assessed using the mRS scores; 
Section 9.3.2.2), use of rescue medication due to an absence or loss of clinical benefit 
(Section 9.3.2.3), and time to first occurrence of seizure freedom (Section 9.3.2.4). 
A fallback hierarchical testing procedure will be implemented to control the overall type I 
familywise error rate at 0.05 over the primary endpoint and the 4 alpha-controlled secondary 
endpoints. In the event that the null hypothesis relating to the primary endpoint is rejected at 2-
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sided 5% significance, then the secondary endpoints will be tested in the following order with the 
corresponding allocations of alpha, implementing the fallback method of multiplicity control: 
1. Change from Baseline in RBANS total scale index score at the end of the Treatment Period 
(Week 25; Alpha=0.046) (Section 9.3.2.1) 
2. Proportion of participants with a favorable outcome in mRS at the end of the Treatment 
Period (Week 25; Alpha=0.002) (Section 9.3.2.2) 
3. Use of rescue medication due to an absence or loss of clinical benefit during the Treatment 
Period (Alpha=0.001) (Section 9.3.2.3) 
4. Time to first occurrence of seizure freedom (Alpha=0.001) (Section 9.3.2.4) 
For each of the listed endpoints, the hypothesis test will only be considered inferential if the 
endpoint meets statistical significance at its individual allocated level, or in accordance with the 
fallback methodology where the preceding endpoints are statistically significant thus allowing 
the alpha allocated to these preceding endpoints to be carried forward to subsequent endpoints. 
This carryforward of the alpha level is automatically halted at the point that an endpoint in the 
defined sequence is not statistically significant at the testing level assigned by the fallback rule. 
Hence, if the sequential tests are successful, the alpha will accumulate for the later endpoints in 
the sequence. Specifically, if the analysis of the RBANS endpoint results in a p-value ≤0.046 
then the mRS endpoint will be tested at an alpha level of 0.048; if the analysis of the mRS 
endpoint results in a p-value ≤0.048, then the use of rescue medication may be tested at an alpha 
level of 0.049, and so on. However, if a test fails in the sequence, the later endpoints may only be 
tested using the specific 0.002 or 0.001 alpha assigned to them (fallback). 
9.3.2.1 
Change in cognitive function: RBANS 
Table 9-2: 
Estimands for the secondary efficacy endpoint: RBANS 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): Change from Baseline in RBANS total scale index score at the end 
of the Treatment Period (Week 25). 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP  
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
Secondary 
RS 
1. Treatment policy strategy: 
Temporary discontinuation 
of the IMP will not affect 
the assessment of the 
endpoint. 
The mean change from Baseline in 
RBANS total scale index score at Week 
25 will be estimated using the MMRM 
approach utilizing information across all 
the available scheduled visit outcomes for 
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Table 9-2: 
Estimands for the secondary efficacy endpoint: RBANS 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): Change from Baseline in RBANS total scale index score at the end 
of the Treatment Period (Week 25). 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP  
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
2. Hypothetical strategy: For 
permanent discontinuation 
the intervention effect will 
be estimated. 
each study participant. The model 
covariate set will include the Baseline 
response, stratification factors (see 
Section 6.3), randomized treatment group 
indicator, visit as a categorical variable, 
and treatment-by-visit interaction term. 
From the model, the LSM for each 
treatment arm, and their differences will 
be estimated and reported with their 95% 
CI for each scheduled visit. The inference 
will be based on the Week 25 visit 
treatment comparison, which will be tested 
for statistical significance. For the 
analysis, the unstructured covariance 
structure will be used in the first instance. 
Other structures will be considered if 
necessary.  
Sensitivity 
FAS 
As described for the secondary 
estimand analysis. 
As described above. 
Sensitivity 
RS 
As described for the secondary 
estimand analysis. 
The mean change from Baseline in 
RBANS total index score at Week 25 will 
be estimated and compared between the 
treatment arms for statistical significance 
utilizing the ANCOVA model including 
the Baseline response, stratification factors 
(see Section 6.3), and randomized 
treatment group as covariates. Any 
missing score readouts at the Week 25 
visit will be imputed with the multiple 
imputation approach assuming other than 
the MAR mechanism.  
AIE=autoimmune encephalitis; ANCOVA=analysis of covariance; CI=confidence interval; FAS=Full Analysis 
Set; IMP=investigational medicinal product; iv=intravenous; LGI1=leucine-rich glioma inactivated 1; 
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Table 9-2: 
Estimands for the secondary efficacy endpoint: RBANS 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): Change from Baseline in RBANS total scale index score at the end 
of the Treatment Period (Week 25). 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP  
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
LSM=least-squares mean; MAR=missing at random; MMRM=mixed model repeated measures; 
RBANS=Repeatable Battery for the Assessment of Neuropsychological Status; RS=Randomized Set 
9.3.2.2 
Change in overall disability: mRS 
The Modified Rankin Scale (mRS) is a 7 point ordinal categorical scale running from perfect 
health (0) to death (6). 
The overall disability of the study participants will be assessed using the mRS score (see 
Section 8.1.3) measured at the visits specified in the Schedule of Activities (see Section 1.3). The 
changes from Baseline in mRS scores will be descriptively summarized at all visits. 
The analysis of mRS will be carried out on the proportion of participants who experience a 
favorable outcome at Week 25, where a favorable outcome will be defined as: 
• No worsening for participants with a Baseline mRS score of ≤1. 
• An improvement of ≥1 point on the mRS scale for participants with a Baseline mRS of 
≥2. 
The proportion of participants will be analyzed as detailed below, where a Cochran-Mantel-
Haenszel test will be used as the primary estimand, and the resultant odds ratio reported. 
Additionally, the difference in the proportions of participants achieving a favorable mRS 
outcome will be reported. 
To provide the most conservative level of potential improvement for all participants in the 
analysis, the Baseline mRS score used in the analysis will be the better (ie, the lower) score from 
either the Screening or Baseline Visit. 
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Table 9-3: 
Estimands for the mRS improvement efficacy endpoint 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): mRS Improvement (defined according to the definition above) 
at the end of the Treatment Period (Week 25). 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP  
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
Secondary 
RS 
1. Treatment policy strategy: 
Temporary 
discontinuation of the 
IMP will not affect the 
assessment of the primary 
endpoint.  
2. Hypothetical strategy: 
Permanent 
discontinuation of the 
IMP; the assessment of 
mRS at the 
discontinuation 
assessment will be used in 
place of the Week 25 
assessment.  
The association between randomized 
treatment exposure and the mRS 
endpoint will be measured by the 
rozanolixizumab versus placebo common 
OR derived from the 2x2 contingency 
tables corresponding to the stratification 
factors (see Section 6.3). The null 
hypothesis, H0: (true) common OR=1, 
will be tested using a CMH test. The 
CMH estimate of the common OR will 
be reported with its 95% CI and the 
CMH test p-value. The assumptions of 
the CMH test will be validated (Mantel-
Fleiss criterion) and, if appropriate, the 
exact stratified test of independence 
alternative will be considered. 
Sensitivity 
RS 
As described for the primary 
estimand analysis. 
Logistic regression model including 
effect for randomized treatment, 
conditional on the stratification factors 
(see Section 6.3), will be used to test the 
primary efficacy hypothesis. The 
resulting rozanolixizumab versus placebo 
common OR estimate with its 95% CI 
and the treatment factor p-value from the 
model will be reported. In the case of 
model convergence issues, the 
appropriate alternatives to the maximum 
likelihood estimation will be considered. 
Supplementary RS 
As described for the primary 
estimand analysis. 
The association between randomized 
treatment and mRS improvement at 
Week 25 will be measured by the 
rozanolixizumab and placebo difference 
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9.3.2.3 
Use of rescue medication due to an absence or loss of clinical 
benefit 
Table 9-4: 
Estimands for the secondary efficacy endpoint: absence or loss of 
clinical benefit - use of rescue medication 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): Use of rescue medication due to an absence or loss of clinical 
benefit during the Treatment Period. 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP  
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event 
handling strategy 
Population-level summary 
(Analysis): 
Secondary 
RS 
1. Treatment policy 
strategy: Temporary 
discontinuation of the 
IMP will not affect the 
assessment of the 
endpoint. 
2. Composite strategy: 
Permanent 
discontinuation of the 
IMP due to a reason 
other than an absence or 
loss of clinical benefit 
will not be considered as 
meeting the endpoint. 
The association between the 
randomized treatment and the use of 
rescue medication during the 
Treatment Period will be measured by 
the rozanolixizumab versus placebo 
common OR and tested for a 
conditional (across the strata effects; 
see Section 6.3) independence using 
the CMH test. The outcomes will be 
summarized and analyzed as described 
in the primary estimand analysis (see 
Section 9.3.1.1).  
Supplementary RS 
As described for the 
secondary estimand analysis. 
The association between the 
randomized treatment and the use of 
rescue medication during the 
Treatment Period will be measured by 
the difference between 
in the proportion of the study participants 
achieving improvement, controlling for 
the effect of the stratification factors (see 
Section 6.3). The proportion differences 
for each stratum and the CMH-weighted 
common effect estimate will be reported 
with its 95% CI. 
AIE=autoimmune encephalitis; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; FAS=Full Analysis 
Set; H0=null hypothesis; IMP=investigational medicinal product; iv=intravenous; LGI1=leucine-rich glioma 
inactivated 1; mRS=Modified Rankin Scale; OR=odds ratio; RS=Randomized Set 
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Table 9-4: 
Estimands for the secondary efficacy endpoint: absence or loss of 
clinical benefit - use of rescue medication 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Study participants with LGI1 AIE as specified in the inclusion and 
exclusion criteria (Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): Use of rescue medication due to an absence or loss of clinical 
benefit during the Treatment Period. 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP  
2. Permanently discontinued from the IMP 
Analysis 
set 
Intercurrent event 
handling strategy 
Population-level summary 
(Analysis): 
rozanolixizumab and placebo arms in 
the proportion of study participants 
reaching the secondary endpoint, 
controlling for the effect of 
stratification factors (see Section 6.3). 
The outcomes will be summarized and 
analyzed as described in the relevant 
primary estimand supplementary 
analysis (see Section 9.3.1.1).  
AIE=autoimmune encephalitis; CMH=Cochran-Mantel-Haenszel; FAS=Full Analysis Set; IMP=investigational 
medicinal product; iv=intravenous; LGI1=leucine-rich glioma inactivated 1; OR=odds ratio; RS=Randomized 
Set. 
 
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9.3.2.4 
Time to first occurrence of seizure freedom 
Table 9-5: 
Estimands for the secondary efficacy endpoint: TTFSF 
Statistical 
category 
Estimand: 
Treatment: Randomized rozanolixizumab or placebo in study participants who are 
concurrently treated with iv or oral steroids. 
Population: Patients with LGI1 AIE as specified in the inclusion and exclusion criteria 
(Section 5.1 and Section 5.2), respectively. 
Endpoint (Variable): TTFSF defined by the number of days after randomization to the 
first day of the first 28 consecutive days without seizures during the Treatment Period. 
Intercurrent events: The study participant: 
1. Temporarily discontinued from the IMP  
2. Permanently discontinued from the IMP  
Analysis 
set 
Intercurrent event handling 
strategy 
Population-level summary (Analysis): 
Secondary 
RS 
1. Treatment policy strategy: 
Temporary discontinuation 
of the IMP will not affect 
the assessment of the 
endpoint. 
2. While on treatment 
strategy: For permanent 
discontinuation of the IMP 
the participant will be 
censored on the final day 
while on the IMP. 
The null hypothesis of no difference 
between the TTFSF hazard functions 
for the randomized treatment arms 
adjusting for the effect of stratification 
factors (see Section 6.3), will be tested 
using a stratified log-rank test with the 
Breslow approach for handling ties. The 
rozanolixizumab versus placebo hazard 
ratio estimate based on the stratified 
log-rank test and its 95% CI will be 
reported together with the stratified log-
rank test p-value. The assumption 
underlying the utilized statistical 
methodologies is that any censoring is 
non-informative, ie, independent from 
the event of interest. The TTFSF will be 
presented graphically by treatment arm 
using a Kaplan-Meier plot, along with 
median TTFSF estimates reported. 
AIE=autoimmune encephalitis; CI=confidence interval; FAS=Full Analysis Set; IMP=investigational medicinal 
product; iv=intravenous; LGI1=leucine-rich glioma inactivated 1; RS=Randomized Set; TTFSF=time to first 
occurrence of seizure freedom 
9.3.3 
Exploratory efficacy analyses 
9.3.3.1 
Time to seizure freedom maintenance (TTSFM) 
The time to seizure freedom maintenance (TTSFM) defined by the number of days after 
randomization to the first day of the 28 consecutive days without seizures, ‘maintained until the 
end of the Treatment Period (Week 25)’. 
This analysis and summaries of the time to seizure freedom maintenance endpoint will be 
performed on the RS utilizing the methodology as described for the TTFSF endpoint (see 
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Section 9.3.2.4). The participants who do not reach the described endpoint criteria will be 
censored at the last follow-up timepoint. 
In addition, as a further exploratory endpoint, this analysis and summaries will be repeated for 
only the subgroup of participants who achieved the seizure freedom endpoint criteria. 
9.3.3.2 
Seizure control 
Seizure frequencies will be recorded on a daily basis across the 24 weeks of randomized therapy 
and during a variable Screening Period, based on the specific categories of seizure count (“0-
None,” “1-5,” “6-10,” “11-20,” and “More than 20”) that are collected in the myUCB 4me 
participant seizure app. 
For each participant, a median category of seizure counts will be calculated for each week that 
the participant is in the randomized treatment period, such that each participant has one average 
median value for that week, along with a minimum and maximum category range. For the 
Screening Period, a Baseline median category will be calculated for each participant, in the same 
way as described for each week of randomized treatment. This will be to utilize the screening 
data collected in the period up to 6 weeks immediately prior to randomisation. All data will then 
be summarized across time for all participants giving the number of participants falling into each 
of the median categories across the 24 weeks by randomized treatment arm. 
Two success criteria will be considered based on seizure control. ‘Good control’ and ‘Moderate 
control’; full details will be provided in the SAP. 
Any participant who does not reach the end of Week 24 will be considered to have failed both 
these success criteria. In the case of 7 missing data points over an entire week, this will be 
imputed from the previous weeks data. 
The proportion of participants who achieve ‘Good control’ and ‘Moderate control’ will be 
summarized and analyzed on the RS. Specifically 2 models will be created to analyze this data, 
one for each of the success control criterion. A logistic regression model adjusting for the effect 
of randomized treatment, Baseline median seizure category level, stratification factors and also 
the use of prior disease modifying treatments, will be used to test for any difference between the 
randomized treatment arms. The resulting rozanolixizumab versus placebo common OR will be 
reported. Additionally, the other estimands as described for the primary endpoint in 
Section 9.3.1.1 will be considered. Full details will be provided in the SAP. 
9.3.3.3 
Duration of seizure-free period 
The duration of the seizure-free period will be measured from the first day the participant reports 
no seizures for at least 28 consecutive days until the last day without seizures during the 
Treatment Period. The endpoint will be descriptively summarized on the RS with respect to the 
randomized treatment arm and stratification factors (see Section 6.3). 
9.3.3.4 
Change in RBANS domain scores 
The changes from Baseline in the domains of RBANS (immediate memory, 
visuospatial/constructional, delayed memory, language, and attention) will be descriptively 
summarized on the RS with respect to randomized treatment and stratification factors (see 
Section 6.3). The changes in RBANS memory-related domains will be analyzed on the RS as 
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described for the secondary estimand for the change from Baseline in cognitive function 
endpoint (see Section 9.3.2.1). 
9.3.3.5 
Ranked outcome from the integrated score 
The integrated ranked outcome scale comprises three equally weighted key components of LGI1 
AIE: mRS, seizure freedom, and cognitive function. The mRS has been used previously to assess 
the level of functioning in the LGI1 population (de Bruijn et al, 2019) and seizure freedom is 
considered a key factor corresponding to epileptic events (Irani et al, 2011). The assessment of 
seizure freedom component does not require individual seizure counting, minimizing the effect 
of potential inaccuracies in seizure counting. The cognitive function component will utilize the 
RBANS assessment (Dubey et al, 2020). 
The overall summary score for each participant is the unweighted sum of the individual 
comparison scores across all three endpoint components (O’Brien, 1984), which provides a 
comprehensive output with equal contribution from each of the selected clinical domains. In the 
following step, each study participant is ranked from 1 to N based on the overall summary score, 
with the rank of 1 corresponding to the lowest summary output. The individual rank outcomes 
will be summarized within the treatment arms and the observed differences will be compared 
between arms providing a basis for the treatment efficacy assessment. 
Detailed description and discussion regarding the scoring rules corresponding to each of the 
combined endpoint elements and associated statistical methods will be fully described in the 
SAP. 
9.3.3.6 
Values and changes in participant and clinician-reported HRQoL 
assessments 
The study participant-reported health-related quality of life assessments, represented by SF-36, 
EQ-5D-5L and CGI-S scores (see Section 8.1.4), will be collected at the visits specified in the 
Schedule of Activities (see Section 1.3). The changes from Baseline in SF-36 scores will be 
descriptively summarized at each visit. All scoring of the SF-36 will be conducted and weighted 
according to the recommendations and guidelines of the authors of the SF-36 instrument and as 
detailed in the latest version of the test manual. Item scores will be re-coded according to the 
guidelines such that higher scores correspond to better health status. The full derivation of this 
scoring will be described in detail in the SAP. The analysis of the SF-36 endpoint will adhere to 
the guidelines. 
For the semi-quantitative EQ-5D-5L index and categorical CGI-S score, outcomes will be 
summarized across the visits. 
Decisions with respect to the outcome of this study will utilize the operating characteristics as 
described for the primary endpoint but will also consider the strength of evidence of treatment 
effect provided by the secondary endpoints as well as consideration to the safety data observed. 
9.3.4 
Withdrawals from the study 
The proportion of the study participants who withdraw or are withdrawn from the study by the 
end of the Treatment Period (Week 25) will be reported for both treatment groups. 
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9.4 
Planned safety and other analyses 
9.4.1 
Safety analyses 
All safety analyses will be listed and summarized for the SS. 
The frequency and severity of all TEAEs will be presented for each treatment group separately 
by System Organ Class, high level term, and preferred term (Medical Dictionary for Regulatory 
Activities). The data will be displayed as number of study participants experiencing the TEAE, 
percentage of study participants, and number of TEAEs. A TEAE is defined as any event that 
was not present prior to the first administration of IMP or any unresolved event already present 
before the first administration of IMP that worsens in intensity following exposure to treatment 
up to the end of the Treatment Period (Week 25) and including the 8-week SFU. 
Laboratory evaluations and vital signs as well as ECG data will be analyzed over time. Possibly 
clinically significant treatment-emergent abnormalities will be listed and summarized by visit for 
each treatment group. 
9.4.2 
PK and immunogenicity analyses 
9.4.2.1 
Rozanolixizumab 
Plasma concentration data of rozanolixizumab will be summarized by treatment group, actual 
dose received, and time point using the number of available observations, mean, median, SD, 
minimum, maximum, geometric mean (and associated 95% confidence intervals), and geometric 
coefficient of variation (assuming log-normally distributed data). Values below the lower limit of 
quantification (LLOQ) will be reported with a clear sign indicating that they were below the 
LLOQ. Descriptive statistics of concentrations will be calculated if at least two-thirds of the 
individual data points are quantifiable (≥LLOQ). Individual and mean concentrations of 
rozanolixizumab will also be displayed graphically. 
Plasma concentration data of rozanolixizumab may be subjected to population pharmacokinetic 
analysis to derive population estimates of PK parameters and test the effect of various covariates 
such as anti-drug antibodies, age, weight, sex. Details of the analysis will be described in a 
separate Data Analysis Plan (DAP). This analysis may be performed by combining the data from 
the current study with data from other rozanolixizumab studies if deemed appropriate. The 
results of the population PK analysis will not be reported in the clinical study report (CSR) but in 
a separate modelling report. 
9.4.2.2 
Immunogenicity analysis 
A tiered ADA approach will be used for the study. Samples will first be evaluated in the 
screening assay using a false positivity rate of 5% (reported as negative screen or positive 
screen), followed by analysis of screened positive samples in the confirmatory assay (which is a 
drug depletion assay) to confirm the true positivity of the samples (reported as negative 
immunodepletion or positive immunodepletion). Samples that are confirmed as positive will be 
evaluated in a titration assay to quantify the ADA level and will be reported as titer (reciprocal 
dilution factor including minimum required dilution). For ADA positive immunodepletion 
samples (or subset of), further characterization for neutralizing ADA potential in vitro will be 
performed. Results will be presented in a listing and as summary tables with full details provided 
in the SAP. 
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9.4.2.3 
Pharmacodynamic analyses 
For all PD variables, descriptive statistics for the value, change from Baseline, and/or percentage 
change from Baseline will be tabulated by treatment group, actual dose received, and time point. 
The PD variables will include serum total IgG, IgG subclass concentrations, serum LGI1 levels, 
and LGI1 levels in CSF. 
Population PD or population PK/PD analyses may be conducted for the PD variables of interest. 
Details of such PD or PK/PD analyses will be described in a separate DAP. The results of the 
analyses will not be reported in the CSR, but in a separate report. 
9.4.2.4 
Immunological analyses 
All immunologic variables including serum concentrations of immunoglobulins 
 
) serum (
) and plasma (
) complement levels, will be summarized by 
treatment group and visit using descriptive statistics. 
9.5 
Handling of protocol deviations 
Important protocol deviations are identified as part of the data cleaning process in the Data 
Cleaning Plan (DCP). Ongoing data cleaning meetings will be held throughout the duration of 
the study. Objectives of these meetings include to review and update (if necessary) the important 
protocol deviations in the DCP. Furthermore, overall trends in protocol deviations will be 
discussed at the Data Evaluation Meeting. Through this ongoing data cleaning and evaluation 
process, all decisions regarding important protocol deviations are made on an ongoing basis. 
9.6 
Handling of dropouts or missing data 
All imputation of missing or partial dates for safety assessments, as well as the handling of 
missing efficacy data (where applicable), will be detailed in the SAP. Data handling conventions 
for data from study participants affected by COVID-19 will also be detailed fully in the SAP. 
9.7 
Planned interim analysis and data monitoring 
There are no plans for an interim analysis. 
9.8 
Determination of sample size 
The study sample size of 60 participants is considered sufficient to provide acceptable study 
operating characteristics for the primary efficacy endpoint (Section 9.3.1.1). To account for an 
assumed 10% dropouts within each treatment arm and to enable an equal study participant 
allocation between treatment arms, 68 study participants will be randomly assigned to study 
treatment arms. 
Given that there are no randomized published studies in the LGI1 patient population, there is 
uncertainty with respect to the expected proportion of participants who may achieve seizure 
freedom by 24 weeks in the control arm. While the targeted desirable treatment difference is 
40%, a difference of 30% would be considered both clinically relevant and important in this 
disease area, given the lack of approved treatments and the length of prior corticosteroid 
treatment that is permissible in the study, along with potential prior disease specific treatment. 
The study operating characteristics, presented in Table 9-6, were derived based on the assumed 
seizure freedom proportions in the study treatment arms observed at the end of Treatment Period 
(Week 25). Based on Thompson et al (2018), after 30 and 90 days 51% and 88% of LGI1 
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patients, respectively, experienced cessation of FBDS once treated with immunotherapy. These 
rates were consistent with de Bruijn et al (2019) median time to the FBDS freedom of 28 days 
once treated with immunotherapy. 
For the purposes of the dual criteria framework as presented in Table 9-6, the proportions at the 
end of the Treatment Period (Week 25) were assumed not to be lower than 70% in the 
rozanolixizumab treatment arm and 40% in the placebo arm. The treatment effect evaluation, 
based solely on statistical significance testing, was complemented with an assessment of its 
clinical relevance following the dual criteria framework as presented by Fisch et al (2015). 
Assuming 50% seizure-free proportions in the control arm, the sample size of 60 study 
participants will be able to detect a resulting 40% proportion difference with approximately 85% 
and a resulting 30% difference with approximately 55 to 65%. For a target difference (TD) of 
40% in the proportions between the treatment groups, the probability that both significance and 
relevance criteria are met, given a true difference of 40%, is at least 45% with only 9.5% of 
studies where none of the key criteria are met. If the TD achieved is 30%, the probability that 
both key criteria are met is at least 76%. 
If the difference in proportions increases to 50%, because of a larger (90%) seizure-free 
proportion in the rozanolixizumab arm, the power to detect that effect is at least 95% with the 
sample size of 60. For this design, the probability that both the criteria are met is 79% and 44.5% 
for TD of 40% and 50%, respectively, with less than 1% probability that none of the criteria are 
fulfilled. 
Decisions with respect to the outcome of this study will utilize the operating characteristics as 
described for the primary endpoint but will also importantly consider the strength of evidence of 
treatment effect provided by the secondary endpoints, according to the prescribed criteria for 
alpha spending, as outlined in Section 9.3.2, as well as consideration to the safety data observed. 
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Table 9-6: 
Study operating characteristics 
Sample 
size 
PBO arm 
SF 
proportion 
(%) at the 
end of 
Treatment 
Period 
R arm SF 
proportion 
(%) at the 
end of 
Treatment 
Period 
Power 
CMHa 
(%) 
Power 
logisticb 
(%) 
Target 
R-PBO SF 
proportion 
difference 
(%) 
Probabilityc (%) 
Scenario 
A 
Scenario 
B 
Scenario 
C 
60 
40 
70 
54.6 
63.2 
30 
45.7 
20.6 
33.8 
40 
17.3 
49.1 
33.6 
50 
3.7 
62.8 
33.5 
60 
40 
80 
84.5 
86.0 
30 
76.3 
14.1 
9.6 
40 
45.2 
45.3 
9.5 
50 
16.1 
74.7 
9.2 
60 
40 
90 
98.3 
95.4 
30 
95.6 
3.8 
0.6 
40 
79.1 
20.0 
0.9 
50 
44.5 
54.8 
0.7 
CMH= Cochran-Mantel-Haenszel; PBO=placebo; R=rozanolixizumab; SF=seizure freedom 
a Power to detect a statistical difference at a 2-sided 5% significance level based on the CMH test with continuity 
correction (Wittes and Wallenstein, 1987).  
b Power to detect a statistical difference at a 2-sided 5% significance level from a standard logistic regression 
model adjusting for treatment group (Demidenko, 2007). 
c Derived from the Fisch et al (2015) decision framework based on dual criteria: Significance – high confidence 
(0.975) that the effect of the investigational drug, relative to placebo, is greater than zero; Relevance - moderate 
confidence (0.5) that the drug effect, relative to placebo, is larger than the target difference. Possible scenarios: A 
– both criteria hold as an evidence of sufficiently high effect; B – inconclusive as only one criterion holds, 
suggesting a marginal effect (Significance only) or too much variability to make a clear decision (Relevance 
only); C – neither of the criteria holds. The probability of each scenario calculated from S=10,000 simulated 
study outcomes for a given sample size and seizure freedom proportions combination.  
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
International Council on Harmonisation (ICH)-Good Clinical Practice (GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
The investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the investigator/UCB will forward copies of the protocol, Informed 
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Consent form, Investigator’s Brochure, investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other participant-related documents to be used for the study 
to the IRB/IEC for its review and approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to participants or others, and any protocol deviations, to 
eliminate immediate hazards to participants. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the participants. 
For minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of participant risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as specified by 
the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the investigator and/or CRO agreements, as applicable. 
10.1.3 
Informed consent process 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant (or legal representative, if applicable and where 
local regulations allow) in both oral and written form by the investigator (or designee). Each 
participant (or legal representative, if applicable and where local regulations allow) and caregiver 
will have the opportunity to discuss the study and its alternatives with the investigator. 
Prior to participation in the study, the Informed Consent form should be signed and personally 
dated by the participant (or legal representative, if applicable and where local regulations allow), 
and by the person who conducted the informed consent discussion (investigator or designee). 
The participant or his/her legal representative must receive a copy of the signed and dated 
Informed Consent form. As part of the consent process, each participant must consent to direct 
access to his/her medical records for study-related monitoring, auditing, IRB/IEC review, and 
regulatory inspection. 
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If the Informed Consent form is amended during the study, the investigator (or the sponsor, if 
applicable) must follow all applicable regulatory requirements pertaining to the approval of the 
amended Informed Consent form by the IRB/IEC and use of the amended form. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
The participant (or legal representative, if applicable and where local regulations allow) may 
withdraw his/her consent to participate in the study at any time. A participant is considered as 
enrolled in the study when he/she has signed the Informed Consent form. An eCRF must not be 
started, nor may any study specific procedure be performed for a given participant, without 
having obtained his/her written consent to participate in the study. 
10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the participant number 
assigned at Screening. 
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
participant’s primary medical records that directly concerns this study (including, but not limited 
to, laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a participant’s study participation, and autopsy reports for deaths 
occurring during the study). 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Committees structure 
An IDMC will review the safety and tolerability data in this study in order to make 
recommendations for the sponsor to decide on whether to proceed with the study. 
An IDMC will be set up in line with the Food and Drug Administration regulatory requirements 
and European Medicines Agency Guideline on iDMCs (EMEA/CHMP/EWP/5872/03 Corr, 
adopted 27/05/2005). The IDMC will consist of external experts who are independent from UCB 
and the clinical operations CRO, and have no conflict of interest related to the conduct or the 
outcomes of the study. The voting members of the IDMC will include, at minimum, a 
biostatistician and 2 neurologists. 
10.1.6 
Data quality assurance 
All participant data relating to the study will be recorded on printed or electronic eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, legible, contemporaneous, original, and 
attributable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. 
All essential documents must be retained by the investigator for the minimum retention period 
mandatory under the applicable local laws and regulations. The investigator will contact UCB for 
authorization prior to the destruction of any study records or in the event of accidental loss or 
destruction of any study records. The investigator will also notify UCB should he/she relocate or 
move the study-related files to a location other than that specified in the sponsor’s trial master 
file. 
Quality tolerance limits will be established for the study using parameters related to patient 
safety reporting and reliability of study results. The parameters will be monitored throughout the 
study to identify systematic issues. Parameters used, parameter values, important deviations from 
the quality tolerance limits, and actions taken will be summarized in the clinical study report. 
The investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. 
The investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
10.1.7 
Apps 
Study participants will be given a smart phone with the myUCB 4me app to enter information 
about seizures experienced between scheduled visits to the site. 
The data recorded in the myUCB 4me app are not intended to be used to influence the treatment 
decisions of study participants during the conduct of this study. Rather, the site investigator will 
get access to the electronic data (e-diary), and all records should be printed and filed with the 
source documentation. The site investigator will use the information recorded to discuss with the 
participant and/or caregiver to report seizure related information in the eCRF. 
To ensure the confidence in the reliability, quality, and integrity of the data, several security 
measures have been put in place. The iPhone itself is protected by a Personal Identification 
Number that is known only to the participant in AIE001. Furthermore, the myUCB site portal 
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also allows for qualified and trained site personnel to personalize the configuration for each 
participant. The access to the personalized configuration within the myUCB site portal is 
password protected, and the password is only known to the site personnel. 
The participant and/or caregiver responds to the questions and acts on the requested activities in 
the myUCB 4me app. All data collected as part of these activities will be stored locally in the 
myUCB 4me app and are synchronized with the myUCB site portal when the iPhone is online 
and connected to a viable network. All data are reviewable for the investigator in real-time, 
provided the device has been synchronized. The data collected are fully encrypted within the app 
and its transmission to UCB Systems. All data in the myUCB 4me app will be erased upon 
configuration for a new participant. All data collected will be available to the sites in a human 
readable way, via the myUCB site portal and a printable Patient Data Report. 
10.1.8 
Source documents 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). Photocopies and/or printouts of eCRFs are not considered 
acceptable source documents. 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
questionnaires, or video, for example. Source documents should be kept in a secure, limited 
access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the investigator and become a permanent part of the participant’s source documents. The 
investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.9 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
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• Discontinuation of further study medication development 
10.1.10 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
10.2 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in the table below will be performed by the central laboratory.  
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study treatment administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
treatment decision or response evaluation, the results must be entered into the eCRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
• Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded, unless a safety alert 
requires a clinical review of the study participant. 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistrya 
Blood urea 
nitrogen 
(BUN) 
Potassium 
Aspartate aminotransferase 
(AST)/ serum glutamic-
oxaloacetic transaminase 
(SGOT) 
Total and 
direct bilirubin 
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Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Creatinine 
Sodium 
Alanine aminotransferase 
(ALT)/ serum glutamic-
pyruvic transaminase (SGPT) 
Total proteinb 
Albuminb 
Glucose 
(non-fasting) 
Calcium 
Alkaline phosphatase 
Lactate 
dehydrogenase 
(LDH) 
C-reactive 
protein 
(CRP) 
Low-density lipoprotein (LDL) 
High-density lipoprotein (HDL) 
Total cholesterol 
Triglycerides 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
• 
Follicle-stimulating hormone (FSH) and estradiol (as needed in women of 
non-childbearing potential only) 
• 
Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 
• 
Serum human chorionic gonadotropin pregnancy test (as needed for women of 
childbearing potential) 
• 
Serology testing (for Hepatitis A, Hepatitis B surface antigen, Hepatitis C virus 
antibody, and human immunodeficiency virus [HIV]) 
Other Tests 
The following tests are performed locally: 
− 
IGRA TB test 
− 
Dipstick urinalysis (including any microscopy where required) 
− 
Urine pregnancy dipstick testc 
IGRA=interferon-gamma release assay; TB=tuberculosis. 
The results of each test must be entered into the CRF. 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 10.6 (Appendix 6). All events of ALT ≥3 × upper limit of normal 
(ULN) and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and international normalized ratio 
(INR) >1.5, if INR measured, may indicate severe liver injury (possible Hy’s Law) and must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis). 
b The results of these assessments will not be reported to investigative sites or other blinded personnel until the 
study has been unblinded, unless a safety alert requires a clinical review of the study participant. 
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
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Other protocol-required laboratory assessments 
Laboratory 
Assessments 
Parameters 
Other laboratory 
assessments 
• 
LGI1 detection 
• 
Blood sampling for PK of rozanolixizumaba 
• 
Blood sampling for DNA and RNA analysisb 
• 
Serum complement (
), and plasma complement (
)b 
• 
Total IgGa 
• 
IgG subclassesa 
• 
LGI1 IgG (total and subclasses) serum quantificationa 
• 
 
 
• 
Anti-drug antibodiesa 
• 
Optional CSF sample collectiona 
• 
Blood sampling for exploratory biomarker analysisb 
AED=antiepileptic drug; 
 
 COVID-19= coronavirus 2019; CSF=cerebrospinal fluid;  
DNA=deoxyribonucleic acid; Ig=immunoglobulin; LGI1=leucine-rich glioma inactivated 1; NF-L=neurofilament 
light chain; PK=pharmacokinetic(s); RNA=ribonucleic acid. 
a The results of these assessments will not be reported to investigative sites or other blinded personnel until the 
study has been unblinded, unless a safety alert prompts a clinical review of the study participant. 
b The results of these assessments will not be reported to investigative sites. 
10.3 
Appendix 3: Adverse Events – Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Assessment and management of TB and TB risk factor as well as safety reporting requirements 
are provided in Section 10.12 (Appendix 12). 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study medication, whether or not considered related 
to the study medication. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study medication. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, not related to progression of underlying 
disease). 
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• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study medication administration even though 
it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
medication or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study 
participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical events: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
• 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to UCB in lieu of completion of the UCB AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to UCB. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE 
may be either serious or not serious, depending on whether these criteria are also met). 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
should be used as a supportive standardization instrument to evaluate AEs and SAEs but the final 
intensity grading by the investigator must be mild, moderate, or severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study medication and 
each occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study medication 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to UCB. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to UCB. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
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Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by UCB to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other healthcare professionals. 
• 
An AE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the participant is lost to follow up. 
This follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
• 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide UCB with a copy of any post-mortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to UCB within 24 hours of receipt of 
the information. 
Reporting of SAEs 
SAE Reporting to UCB via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to UCB will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
UCB by telephone. 
• 
Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT 
REPORTING. 
 
SAE Reporting to UCB via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to UCB; see SERIOUS ADVERSE EVENT REPORTING. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT 
REPORTING. 
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10.4 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
− A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
− Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
    Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 
Highly Effective Contraceptive Methodsa 
Highly Effective Contraceptive Methods That Are User Dependentb 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation 
• 
Oral 
• 
Intravaginal 
• 
Transdermal  
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Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Methods That Are User Independent 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study medication. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
NOTES: 
a) In case of newly started contraception pills/IUDs, PI should consider the correct timing of 
starting/applying such methods in relation to the menstrual cycle and the manufacturing instruction as 
when these newly started methods would become effective. 
b) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants participating 
in clinical studies. 
Pregnancy testing 
• WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test. 
• Additional pregnancy testing should be performed as specified in the Schedule of Activities 
(Section 1.3) during the treatment period and at the EOT visit, corresponding to protocol-
defined time frame in Appendix 4 after the final dose of study medication and as required 
locally. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• Pregnancy testing, with a sensitivity of ≥25mIU/mL will be performed. A serum and urine 
pregnancy test will be completed at Screening and Baseline, respectively. 
Male participants with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This applies 
only to male participants who receive study medication. If the study participant is later found 
to be on placebo, then pregnancy data collection can stop. 
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• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 1 working day of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the sponsor. Generally, the follow-
up will be at least 12 months after the delivery date. Any termination of the pregnancy will 
be reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female Participants who become pregnant 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
• The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the sponsor within 1 working day of learning of a participant’s 
pregnancy. The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, the follow-up will be at least 
12 months after the delivery date. Any termination of pregnancy will be reported, regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any post-study 
pregnancy related SAE considered reasonably related to the study medication by the 
investigator will be reported to the sponsor as described in Section 8.3.5. While the 
investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
10.5 
Appendix 5: Genetics 
Genetics analyses may evaluate genetic features and epigenetic changes associated with the 
cause, progression, and appropriate treatment of LGI1 AIE. 
Use and Analysis of DNA 
• Genetic variation may impact a participant’s response to study medication, susceptibility to, 
and severity and progression of disease. Variable response to study medication may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from participants in the AIE001 study. 
• Genetics samples will be used for research related to cause, progression, and appropriate 
treatment of LGI1 AIE. They may also be used to develop tests/assays including diagnostic 
tests related to rozanolixizumab and LGI1 AIE. Genetic research may consist of the analysis 
of one or more candidate genes or the analysis of genetic markers throughout the genome. 
Deoxyribonucleic acid samples will be analyzed for genetic and epigenetic changes that may 
promote understanding of the cause, progression, and appropriate treatment of LGI1 AIE. 
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• The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to the study medication to understand study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary. 
• The sponsor will store the blood or isolated DNA samples in a secure storage space with 
adequate measures to protect confidentiality. 
The samples will be retained while research on study medication continues but no longer than 
20 years or other period as per local requirements. 
10.6 
Appendix 6: Liver Safety – Suggested Actions and Follow-up 
Assessments 
Participants with potential drug-induced liver injury must be assessed to determine if study 
medication must be discontinued. In addition, all concomitant medications and herbal 
supplements that are not medically necessary should also be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete the final evaluation. 
Study participants with potential drug-induced liver injury should not be withdrawn from the 
study until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for study medication discontinuation and/or participant 
withdrawal (if applicable), must be recorded in the source documents. The eCRF must document 
the primary reason for discontinuation of study medication. 
A specific monitoring plan must be agreed between the study physician and the investigator for 
study participants who have ALT >3 ULN. The monitoring plan should include any necessary 
follow-up assessments (until resolution of the abnormal lab values). Liver chemistry stopping 
criteria and criteria for increased monitoring are designed to assure study participant safety and 
to evaluate liver event etiology. They are presented in the tables below. 
Phase 2 Liver Chemistry Stopping Criteria and Follow-Up Assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute 
ALT ≥5xULN 
ALT Increase 
ALT ≥3xULN persists for ≥4 weeks 
Bilirubina,b  
ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) 
INRb 
ALT ≥3xULN and international normalized ratio (INR) >1.5, if INR measured 
Cannot Monitor 
ALT ≥3xULN and cannot be monitored weekly for 4 weeks 
Symptomaticc 
ALT ≥3xULN associated with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity 
Suggested Actions and Follow-up Assessments  
Actions 
Follow-Up Assessments 
• 
Immediately discontinue study medication.  
• 
Report the event to UCB within 24 hours. 
• 
Viral hepatitis serologyd 
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Liver Chemistry Stopping Criteria 
• 
Complete the liver event case report form (CRF), and 
complete a serious adverse event (SAE) data collection 
tool if the event also met the criteria for an SAE. b 
• 
Perform liver chemistry follow-up assessments.  
• 
Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to baseline 
(see MONITORING). 
• 
Do not restart/rechallenge participant with study 
medication. 
• 
Permanently discontinue study medication and continue 
participant in the study for any protocol specified 
follow up assessments. 
• 
Consider the need for a toxicology screening 
 
 
MONITORING: 
If ALT ≥3xULN AND bilirubin ≥2xULN or INR >1.5:  
• 
Repeat liver chemistry tests (include ALT, aspartate 
transaminase [AST], alkaline phosphatase, bilirubin) 
and perform liver event follow-up assessments within 
24 hours. 
• 
Monitor participant twice weekly until liver chemistry 
test abnormalities resolve, stabilize, or return to 
baseline. 
• 
A specialist or hepatology consultation is 
recommended. 
If ALT ≥3xULN AND bilirubin <2xULN and INR ≤1.5:  
• 
Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
chemistry follow-up assessments within 24 to 72 
hours. 
• 
Monitor participants weekly until liver chemistry 
abnormalities resolve, stabilize, or return to baseline. 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
• 
Obtain blood sample for pharmacokinetic 
(PK) analysis as soon as feasible after the 
most recent dosee.  
• 
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH) 
• 
Fractionate bilirubin, if total bilirubin 
≥ 2xULN 
• 
Obtain complete blood count with differential 
to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury (eg, fatigue, 
nausea, vomiting, right upper quadrant pain), 
or hypersensitivity, on the adverse event 
(AE) report form 
• 
Record use of concomitant medications 
(including acetaminophen, herbal remedies, 
and other over-the-counter medications) on 
the concomitant medications CRF. 
• 
Record alcohol use on the liver event alcohol 
intake CRF 
• 
Exclude pregnancy 
If ALT ≥3xULN AND bilirubin ≥2xULN or 
INR >1.5: 
• 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total 
immunoglobulin G (IgG) or gamma 
globulins. 
• 
Serum acetaminophen adduct assay for 
assessing the potential acetaminophen 
contribution to liver injury  
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver disease; 
complete liver 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study medication if ALT ≥3xULN and bilirubin ≥2xULN. Additionally, if 
serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin 
on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 
b All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR >1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not 
apply to participants receiving anticoagulants. 
c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia). 
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d Includes:Hepatitis A 
 antibody; HbsAg and HbcAb; hepatitis C RNA; cytomegalovirus 
 antibody; Epstein-Barr viral capsid antigen 
 antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E 
 antibody. 
e PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. 
Record the date/time of the PK blood sample draw and the date/time of the final dose of study medication prior to 
the blood sample draw on the CRF. If the date or time of the final dose is unclear, provide the participant’s best 
approximation. If the date/time of the final dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the IMP Handling Manual. 
 
Liver Chemistry Increased Monitoring Criteria with Continued Study medication 
Liver Chemistry Increased Monitoring Criterion and Follow-Up 
Criterion 
Actions 
ALT ≥3xULN and <5xULN and 
bilirubin <2xULN, without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks 
• 
Notify the UCB medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 
• 
Participant can continue study medication 
• 
Participant must return weekly for repeat liver 
chemistry tests (ALT, AST, alkaline phosphatase, 
bilirubin) until the abnormalities resolve, stabilize or 
return to baseline. 
• 
If at any time, the participant meets liver chemistry 
stopping criteria, proceed as described in 
Section 7.1.1. 
• 
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistry tests resolve, stabilize, or return 
to baseline. 
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10.7 
Appendix 7: Medical Device AEs, Adverse Device Effects, SAEs 
and Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Not applicable. 
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10.8 
Appendix 8: Rapid Alert Procedures 
Not applicable. 
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10.9 
Appendix 9: Country-specific Requirements 
Not applicable. 
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10.10 
Appendix 10: Abbreviations and Trademarks 
AChR 
acetylcholine receptor 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AED 
antiepileptic drug 
AESI 
adverse event of special interest 
AESM 
adverse event of special monitoring 
AIE 
autoimmune encephalitis 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
App 
application 
AST 
aspartate aminotransferase 
CASE 
Clinical Assessment Scale in Autoimmune Encephalitis 
CGI-S 
Global Impression of Disease Severity 
CIDP 
chronic inflammatory demyelinating polyradiculoneuropathy 
CNS 
central nervous system 
COVID-19 
coronavirus 2019 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAP 
Data Analysis Plan 
DCP 
Data Cleaning Plan 
DIAM 
drug-induced aseptic meningitis 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDisc 
early discontinuation 
EOS 
end of study 
EOT 
end of treatment 
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EQ-5D-5L 
EuroQol-5D-5L 
EQ VAS 
EuroQol visual analogue scale 
FAS 
Full Analysis Set 
FBDS 
faciobrachial dystonic seizure(s) 
FcRn 
neonatal Fc receptor 
FSH 
follicle stimulating hormone 
GI 
gastrointestinal 
gMG 
generalized myasthenia gravis 
HCRU 
healthcare resource utilization 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH-GCP 
International Council for Harmonisation Good Clinical Practice 
IDMC 
independent data monitoring committee 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IGRA 
interferon-gamma release assay 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITP 
immune thrombocytopenia 
ITT 
Intent to treat 
iv 
intravenous 
IVIg 
intravenous immunoglobulin 
IVMP 
intravenous methylprednisolone 
LGI1 
leucine-rich glioma inactivated 1 
LLOQ 
lower limit of quantification 
LTBI 
latent tuberculosis infection 
MCS 
Mental Component Summary 
MedDRA® 
Medical Dictionary for Regulatory Activities® 
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MG 
myasthenia gravis 
MG-ADL 
Myasthenia Gravis Activities of Daily Living 
MP 
methylprednisolone 
MRI 
magnetic resonance imaging 
mRS 
Modified Rankin Scale 
NTM 
nontuberculosis mycobacteria 
PCS 
Physical Component Summary 
PD 
pharmacodynamic(s) 
PD-PPS 
Pharmacodynamic Per-Protocol Set 
PEX 
plasma exchange 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Disease Severity 
PK 
pharmacokinetic(s) 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PLEX 
plasma exchange 
PRO 
patient-reported outcome 
Q1W 
once a week 
QTcF 
QT interval corrected using Fridericia’s formula 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
RNA 
ribonucleic acid 
RS 
Randomized Set 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous 
SD 
standard deviation 
SF-36 
36-item Short Form Survey 
SFU 
safety follow up 
SS 
Safety Set 
SUSAR 
suspected unexpected serious adverse reaction(s) 
TB 
tuberculosis  
TD 
target difference 
TEAE 
treatment-emergent adverse event 
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TTFSF 
time to first occurrence of seizure freedom 
TTSFM 
time to seizure freedom maintenance 
ULN 
upper limit of normal 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
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10.11 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
Amendment 5 (date: 09 Feb 2023) 
Overall Rationale for the Amendment 
In the past 3 years (since the initial protocol), there is an emerging understanding about the 
experiences of patients with LGI1 AIE, changes in medical management of such patients, and 
more widespread use of the clinical outcome assessments supporting efficacy endpoints selected 
for this study. Therefore, changes to the protocol have been made to update the secondary 
endpoints and associated statistical methods and better align the protocol with the current 
treatment practices and understanding of the disease. 
Minor grammatical, editorial, and formatting changes have also been made for clarification 
purposes only. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema 
1.3 Schedule of activities 
4.1 Overall design 
Duration of Screening Period changed 
from upto 14 days to upto 42 days. 
To allow participants who 
initiated treatment outside study 
centers to still be considered for 
admission into the study and to 
ensure there is sufficient time for 
all eligibility assessments to be 
performed before dosing. 
1.1 Synopsis 
4.1 Overall design 
Maximum study duration per study 
participant updated from 34 weeks to 
38 weeks. 
Text related to Screening Period was 
updated as follows: 
- 
New text was added to clarify 
eligibility for treatment 
initiation/re-initiation. 
- 
The term IVMP was replaced 
with high dose corticosteroids 
in the text. 
- 
The timeframe for the 
randomization of study 
participants following 
corticosteroids initiation was 
updated from upto 14 days to 
upto 42 days. 
To align with the increase in the 
duration of the Screening Period. 
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Section # and Name 
Description of Change 
Brief Rationale 
- 
Text describing 
corticosteroids initiation and 
steps for down titration was 
added.  
New text describing eligibility of 
participants who have previously 
received a first line AIE treatment was 
added. 
4.2 Scientific rationale for 
study design 
Text regarding eligibility for inclusion 
in the study was updated. 
Clarification and improvement. 
1.1 Synopsis 
3 Objectives and 
endpoints 
9.3.2.2 Change in overall 
disability function (mRS) 
The endpoint relating to the change 
from Baseline in the mRS has been 
moved from exploratory to secondary 
endpoints. The analysis of the mRS 
has been amended from comparing a 
change from Baseline to comparing 
the proportion of participants meeting 
criteria for favorable outcome. 
To offer a basis of comparison 
with other studies in AIE, the 
mRS parameter will be assessed 
as a secondary endpoint. 
The updated analysis is of 
greater clinical relevance. 
Emerging literature suggests that 
over time, the impacts of signs 
and symptoms of AIE, including 
cognitive impairment, lead to 
worsening of functional abilities. 
The expectation is that functional 
ability in the treatment groups 
may not decline/worsen as in the 
placebo arm; the endpoint is 
therefore being revised to 
identify groups with better mRS 
outcomes, similar to endpoints 
evaluated in stroke trials. 
1.1 Synopsis 
3 Objectives and 
endpoints 
The endpoint relating to seizure 
control was updated. 
The analysis for this endpoint 
has been modified to reflect the 
new data type collected in the 
participant daily seizure diary. 
This is now categorical data 
rather than continuous data, 
hence the endpoint and the 
subsequent data analysis has 
been modified to align it with the 
revised format of the data. 
1.1 Synopsis 
3 Objectives and 
endpoints 
1.3 Schedule of activities 
8.1.5 Clinical global 
impression of severity 
The endpoints relating to PGIS and 
PGIC have been removed and 
replaced with CGI-S. 
To reduce the frequency of 
assessments and in turn reduce 
protocol complexities, site and 
patient burden while still 
collecting required data for 
adequate assessment of the 
relevant endpoints. 
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Section # and Name 
Description of Change 
Brief Rationale 
Given that the participants are 
congnitively impaired, CGI-S is 
considered to be more accurate 
and relevant than PGIS. 
1.2 Schema 
1.3 Schedule of activities 
Visit 4 (Day 5) has been removed. 
Procedures have been removed from 
Visits 12, 22 and EOS (RBANS, 
mRS, SF-36 and EQ-5d-5L). 
To reduce the frequency of 
assessments and in turn reduce 
protocol complexities, site and 
patient burden while still 
collecting required data for 
adequate assessment of the 
relevant endpoints. 
1.1 Synopsis 
1.3 Schedule of activities 
3 Objectives and 
endpoints 
8.9.1 Immunology 
9.4.2.3 AED 
The following laboratory assessments 
were removed: PTT, INR, 
 
 and COVID-19 antibodies. 
The assessments of CASE was 
removed. 
Blood sampling for concomitant AED 
assay was removed. 
These measures are deemed not 
mandatory for the safety 
monitoring of the study 
participants and were removed to 
decrease the protocol 
complexities. 
5.1 Inclusion criteria 
Inclusion criterion #4a updated with 
consistent terminology on 
corticosteroids and dose range. 
To provide clarification and for 
consistency with Section 6.5.2. 
5.2 Exclusion criteria 
Exclusion criterion #6 was removed as 
it was covered under exclusion 
criterion #1. 
Exclusion criterion #8a (previously 
#8) has been modified to limit the 
exclusion of a participant due to a 
current active infection, an 
unresolved, or an inadequately treated 
infection. 
Exclusion criteria #11 and #15 have 
been removed. 
Exclusion criterion #20a (previously 
#20) has been modified to exclude 
study participants who have received a 
live vaccination within 4 weeks prior 
to the Baseline Visit instead of 8 
weeks. 
Exclusion criterion #26 was removed 
as it was covered under exclusion 
criterion #10. 
Update based on gained safety 
knowledge on rozanolixizumab, 
to align with current therapeutic 
practices and to remove 
redundancies, as some provisions 
are adequately captured by other 
eligibility points. 
Also, exclusion criterion #11 is 
covered by exclusion criterion 
#12 and Appendix 10.12. 
Exclusion criterion #15 was 
removed to align with the IMP 
mechanism of action as it does 
not interfere with 
 isoforms. 
6.5 Concomitant 
medication(s)/treatment(s) 
Prior medication and duration of those 
medications updated. 
To align with current therapeutic 
practices. 
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Section # and Name 
Description of Change 
Brief Rationale 
The type of permitted prior and 
concomitant medications (BZD, 
AEDs, corticosteroids, PEX, IvIG, 
immunoadsorbtion) has been updated. 
7.1 Discontinuation of 
study medication 
New text was added: “Participants 
who are permanently discontinued 
from IMP will undergo an EDisc Visit 
and SFU Visit.” 
To align across the 
rozanolixizumab program. 
7.1.2 QTc stopping 
criteria 
7.1.4 Temporary 
discontinuation of IMP 
8.11 COVID-19 
vaccination 
The section describing the QTc 
stopping criteria was removed. 
Text related to temporary 
discontinuation in the event of 
COVID-19 was removed. 
This update was based on safety 
knowledge gained from the 
rozanolixizumab program. 
1.3 Schedule of activities 
5.2 Exclusion criterion 12 
sub-bullet 3 
7.1.2 Permanent 
discontinuation due to 
other AEs 
7.2.1 Study withdrawal 
criteria 
8.2.1 Physical 
examination 
8.2.7.Assessment and 
management of 
tuberculosis and 
tuberculosis risk factors 
10.12 Appendix 12: 
Tuberculosis 
Questionnaire 
Text describing diagnosis, assessment 
and management of TB was updated. 
Text related to the TB questionnaire 
was replaced by focused medical 
history. 
The TB questionnaire was removed 
from Section 10.12 Appendix 12. 
The chest x-ray procedure was 
removed. 
Text on the assessment and 
management of TB was moved from 
Section 8.2.7 to Section 10.12 
Appendix 12. In addition, new text on 
safety reporting requirements related 
to TB was added. 
To provide clarification and 
simplified text. 
8.2.3 Vital signs 
The frequency of vital signs measure 
was modified; the current schedule 
includes vital signs measure on the 
days of IMP administration for the 
first 8 weeks and thereafter the 
measures will be aligned with the days 
of the physical examinations. 
This update was based on safety 
knowledge gained from the 
rozanolixizumab program. 
9.3 Planned 
efficacy/outcome analyses Text was updated to indicate that an 
additional adjustment will be made, 
where applicable, in any statistical 
modelling. 
To provide clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.3.2 Secondary efficacy 
analysis 
Text was updated to reflect the 
changes made to the secondary 
endpoints. 
To align with the list of 
secondary endpoints. 
9.3.3 Exploratory efficacy 
analysis 
Section 9.3.3.1 was updated to clarify 
that for the “Time to seizure freedom 
maintenance” endpoint, analysis and 
summaries will be repeated for only 
the subgroup of participants who 
achieved the seizure freedom endpoint 
criteria. 
Section 9.3.3.2 was updated from 
“Seizure reductions” to “Seizure 
control” and the text was updated to 
describe the analysis of the seizure 
control endpoint. Section 9.3.3.3 
“Time to seizure reductions” was 
removed. 
To provide details regarding the 
analysis of the seizure control 
endpoint. 
9.8 Determintation of 
sample size 
Updates were made to the text and 
additional information provided. 
To provide clarification. 
10.1.3 Informed consent 
process 
The wording around the caregiver and 
informed consent was made consistent 
throughout the protocol. 
To clarify the role of the 
caregiver. 
 
Amendment 4 (date: 19 Oct 2022) 
Overall Rationale for the Amendment 
Changes to the protocol have been made to update safety information in line with the revised IB 
dated 06 September 2022. Additional changes have also been made to reduce the study burden 
for patients. 
Minor grammatical, editorial, and formatting changes have also been made for clarification 
purposes only. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
1.3.1 Additional study 
assessments 
2.2 Background 
2.3 Benefit/Risk Assessment 
7.1.3 Permanent discontinuation 
due to other AEs 
Removal of the assessments 
related to the former AESM of 
severe GI disorders and 
opportunistic infections. 
Addition of assessments for the 
new AESM of suspected aseptic 
meningitis. 
The accumulated safety data on 
rozanolixizumab led to an 
update of the adverse events 
requiring special monitoring.  
As of the cut-off date of the IB 
(13 Jul 2022), the following 
SAEs Headache and Meningitis 
Aseptic (PT terms) suggest a 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.5 Temporary discontinuation 
of IMP 
8.2.2 Neurological examination 
8.3.7 Adverse events of special 
monitoring 
8.9 Biomarkers 
10.13 Appendix 13 Management 
of AESM 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Removal of the headache 
questionnaire (formerly 
Appendix 13) and management 
of severe diarrhoea (formerly 
Appendix 15). New 
Appendix 13 detailing the 
management of the AESM 
(severe/serious headache, and 
suspected aseptic meningitis) 
possible causal relationship to 
rozanolixizumab; based on both 
their temporal association with 
IMP infusion (primarily initial 
infusion) and given the events 
have occurred more than once. 
There is a change in the 
headache reporting process such 
that severe and/or serious 
headache will be reported via 
the SAE reporting process. 
1.2 Schema 
1.3 Schedule of activities 
Removal of Visits 17 and 18 
(Week 13), and the removal 
explained in new footnote bb in 
Table 1-1. 
To reduce the study complexity, 
and decrease the burden on 
participants. 
1.1 Synopsis 
3 Objectives and endpoints 
1.3 Schedule of activities 
8.8 Pharmacodynamics 
9.1 Definition of analysis sets 
9.4.2.4 Pharmacodynamic 
analyses 
10.2 Appendix 2: Clinical 
laboratory tests 
Samples for neurofilament light 
chain have been removed from 
the study assessments. 
As the potential scientific value 
of NF-L is limited, and the 
objectives and endpoints were 
amended to reduce study 
complexity. 
1.1 Synopsis 
3 Objectives and endpoints 
1.3 Schedule of activities 
Sampling of DNA and RNA 
analysis to be taken only at 
Baseline, sampling of 
 
 to be taken only at 
Screening, and sampling for 
serum and plasma complements 
to be taken only at Baseline and 
in the event of infusion or 
hypersensitivity reaction. 
Changes have been made to the 
objectives and endpoints, and 
other sections of the protocol to 
reflect these changes in 
sampling strategy. 
To reduce the study complexity, 
and decrease the burden on 
participants. 
1.1 Synopsis 
3 Objectives and endpoints 
The effect of rozanolixizumab 
on α- and β-globulins removed 
from the exploratory objectives 
and endpoints. 
Correction. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3 Objectives and endpoints 
8.2.5 Magnetic resonance 
imaging 
The effect of rozanolixizumab 
on whole brain and hippocampal 
volume removed as an 
exploratory endpoint. Further, 
based on the investigator’s 
judgement MRI performed 
within 3 months of the 
Screening Period may be 
acceptable for the Screening/ 
Baseline assessment. MRI may 
also be assessed at any visit, as 
needed. 
To reduce the study complexity 
and to expedite the analysis of a 
safety endpoint by the 
investigator, MRI will be 
assessed locally as part of safety 
assessments. 
1.1 Synopsis 
4.1 Overall design 
Text updated to note that LGI1 
AIE disease onset is at the 
assessment of the investigator. 
Clarification 
1.3 Schedule of activities 
7.1.2 QTc stopping criteria 
8.2.4 Electrocardiogram 
TB signs and symptoms 
questionnaire as well as 12-lead 
ECG assessments have been 
reduced to occur at Screening 
and EOT/EDisc visits, with 
optional assessments at any 
visit. The ECG assessments 
have been updated to be 
assessed locally, with no 
requirement for triplicate ECGs. 
Update in line with accumulated 
safety data on rozanolixizumab 
1.3 Schedule of activities 
Samples to assess the PK of 
rozanolixizumab have been 
removed from Weeks 2, 3, 13 
(Days 87 and 89), and Week 21. 
Footnote m has also been 
updated to align with these 
changes. 
Samples to assess ADA have 
been removed from Weeks 3, 13 
(Day 87), and 21. 
Updated to reduce the sampling 
burden on participants given the 
fact that the PK of 
rozanolixizumab is better 
defined as a result of data from 
other clinical studies. 
1.3 Schedule of activities 
Samples to assess IgG 
subclasses have been removed 
from Weeks 11, 15, 19, and 22. 
To reduce the participant burden 
associated with this exploratory 
measure. 
1.3 Schedule of activities 
8.9.1 Immunology 
Sampling for serum and plasma 
complements will be collected 
only at Baseline and after an 
injection site reaction or 
hypersensitivity reaction. 
To reduce the participant burden 
associated with this exploratory 
measure. 
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Section # and Name 
Description of Change 
Brief Rationale 
2.2 Background 
Updates to text describing the 
results of completed studies in 
the rozanolixizumab clinical 
development program. Updated 
text to refer to the IB for status 
of ongoing studies. 
Update in line with studies 
status at the time of this 
amendment, and to reference the 
most recent information on 
exposure to rozanolixizumab. 
2.3 Benefit/Risk Assessment 
Revised text on most common 
adverse drug reactions, potential 
risks, and AESM. 
To update the list of most 
common adverse drug reactions, 
potential risks, and adverse 
events of special monitoring. 
4.3 Justification for dose 
4.3.1 Justification for IgG target 
REFERENCES 
Text updated to reflect the latest 
clinical data from completed 
studies. Literature citations 
removed from these sections 
also removed from the 
Reference list 
Updated including recent new 
data from completed Phase 3 
study, MG0003, in gMG. 
5.1 Inclusion criteria 
10.4 Contraceptive guidance and 
collection of pregnancy 
information 
Inclusion criterion #7 (now #7a) 
has been updated to remove the 
requirement for a male 
participant to use contraception 
or refrain from sperm donation. 
To update male contraception 
requirements with current 
guidelines, after completion of 
the required reproductive 
toxicity studies and considering 
that rozanolixizumab has no 
genotoxic potential and 
potential exposure through 
seminal fluid is expected to be 
negligible. 
5.1 Inclusion criteria 
Inclusion criterion #9 (now #9a) 
updated to remove requirement 
for caregiver to provide consent, 
and Inclusion criterion #10a has 
been removed. 
To improve clarity and remove 
redundancy across Inclusion 
criteria #8a and #9a. 
5.2 Exclusion criteria 
Exclusion criterion #14 relating 
to active GI disorders has been 
removed.  
Update in line with accumulated 
safety data on rozanolixizumab 
5.2 Exclusion criteria 
Exclusion criterion #24a 
amended (now #24b) to exclude 
when ALT, AST or ALP are 
>3xULN (rather than >2xULN) 
Update in line with accumulated 
safety data on rozanolixizumab 
5.2 Exclusion criteria 
Exclusion criterion #33 (related 
to prolonged QT interval) has 
been removed. 
This criterion is redundant as 
abnormalities in QT interval 
would be excluded by criterion 
#6 (clinically significant ECG 
findings). 
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Section # and Name 
Description of Change 
Brief Rationale 
5.4 Screen failures 
Text added to the third and 
fourth paragraphs to clarify 
randomization procedures after 
rescreening. 
Clarification 
6.1 Study treatments 
6.3.1.1 Maintenance of study 
treatment blind 
The dose formulation of 
rozanolixizumab has been 
updated from ‘liquid in vial’ to 
‘solution for injection’. The 
description of the amount of 
extractable volume has been 
removed from the description of 
rozanolixizumab. 
To give flexibility in the supply 
of saline, and flexibility to use 
alternative vial fill volumes of 
rozanolixizumab. 
7.1.5 Temporary discontinuation 
of IMP 
Update of the temporary 
discontinuation in relation to 
COVID-19 
Update to adapt the withdrawal 
criteria to the evolution of the 
medical practices and local 
guidelines with regards to 
COVID management 
8 Study assessments and 
procedures 
Removal of text “Protocol 
waivers or exemptions are not 
allowed.” 
Text is already included in 
Section 5 (Study population) 
8 Study assessments and 
procedures 
Text clarified to note that any 
additional blood samples may 
increase the total volume of 
blood collected. 
Clarification. 
8.2.3 Vital signs 
Removed description of the time 
points for vital sign assessments. 
To remove redundancy with the 
Schedule of Activities 
(Section 1.3). 
 
Amendment 3 (date: 14 Jan 2022) 
Overall Rationale for the Amendment 
The overall rationale for the amendment is to address comments and queries from FDA raised 
during the IND review. Minor grammatical, editorial, and formatting changes have also been 
made for clarification purposes only. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.3 Schedule of activities 
3 Objectives and endpoints 
8.9 Biomarkers 
The collection and analysis of 
cytokines has been removed 
from the protocol. 
The endpoint was removed as 
the analysis of cytokines is not 
required in this protocol as 
samples have been collected in 
other rozanolixizumab studies 
and no additional information is 
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Section # and Name 
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Brief Rationale 
8.9.1 Immunology 
9.4.2.5 Immunological analyses 
10.2 Appendix 2 Clinical 
laboratory tests 
10.17 Appendix 17 Management 
of infusion reactions or 
hypersensitivity reactions 
expected from the AIE 
population, and the scientific 
value is limited. 
1.3 Schedule of activities 
7.1.5 Temporary discontinuation 
of IMP 
Text has been added to 
footnote p of Table 1-1 and to 
#1 and #2 of Section 7.1.5 to 
indicate that ad hoc assessments 
of albumin and IgG can be 
performed to monitor the 
recovery of albumin and IgG 
levels, or for random sampling 
of study participants to maintain 
the blind. 
To enhance the rigor of the 
study blind. 
1.3 Schedule of activities 
8.2.3 Vital signs 
In footnote k of Table 1-1 and 
paragraph 3 of Section 8.2.3, 
text has been added to indicate a 
time window for the measuring 
of vital signs. 
To provide a time window for 
which the measurement of vital 
signs can take place. 
1.3 Schedule of activities 
A new footnote z in Table 1-1 
for RBANS, PGIS, SF-36, and 
EQ-5D-5L has been added to 
note that the assessment 
scheduled at Screening should 
be performed as close as 
possible to the Baseline Visit. 
For the PGIS, SF-36, and EQ-
5D-5L assessments, this is to 
capture the potential for 
improvement in these 
assessments resulting from 
IVMP administration between 
Screening and Baseline. 
For RBANS, this is to account 
for any change in cognitive 
status during the screening 
period. 
1.3 Schedule of activities 
9.3.3.6 Change in the overall 
clinical assessment (CASE) 
9.3.3.7 Change in overall 
disability function (mRS) 
The CASE and mRS 
assessments will also be 
performed at the Baseline Visit 
(as well as at Screening). The 
assessment at Screening should 
be performed as close as 
possible to consent. The better 
of the 2 scores will be defined as 
the Baseline and used in the 
secondary analyses. 
To capture the potential for 
change in these assessments as a 
result of IVMP administration 
between Screening and 
Baseline. 
1.3.1 Additional study 
assessments 
Description of the circumstances 
when additional study 
To add clarity to the description. 
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Section # and Name 
Description of Change 
Brief Rationale 
assessments are required was 
updated. 
4.3 Justification for dose 
The dose currently under 
investigation in the Phase 3 ITP 
studies has been updated to 
weight-tiered doses of 10mg/kg 
Q1W. 
Update in the dose being 
investigated in the 
rozanolixizumab studies in ITP. 
5.2 Exclusion criteria 
Exclusion criterion #7 (now 
criterion #7a) has been updated 
to exclude study participants 
with a GFR of 
<30ml/min/1.73m2 (formerly 
<45ml/min/1.73m2). 
To make exclusions based on 
renal clearance consistent with 
FDA guidance. Given the 
accumulated data from the 
rozanolixizumab development 
program indicating an absence 
of a safety signal related to renal 
function, the protocol has been 
updated to exclude study 
participants with a GFR of 
impairment (ie, 
<30ml/min/1.73m2.  
6.5.1 Permitted concomitant 
treatments (medications and 
therapies) 
Section updated to note that at 
the discretion of the 
investigator, study participants 
may initiate prophylaxis for 
pneumocystis carinii pneumonia 
(PCP). 
As study participants will 
receive steroids for up to 12 
weeks, they may be immune 
compromised and at a potential 
increased risk of PCP. Based on 
the investigator's discretion 
prophylaxis medication may be 
administered. 
6.5.1 Permitted concomitant 
treatments (medications and 
therapies) 
Section updated to note that in 
study participants with a GFR 
between 30 and 
45mL/min/1.73m2, the dose of 
concomitant medications should 
be adapted to the study 
participant's renal function. 
To align with changes made to 
criterion #7a in Section 5.2 
(Exclusion criteria). 
6.5.1 Permitted concomitant 
treatments (medications and 
therapies) 
The use of topical or local 
steroids has been added as a 
permitted concomitant 
medication. 
Clarification. 
7.1.3 Permanent discontinuation 
due to other AEs 
Clarified that study participants 
permanently discontinuing from 
IMP must move to the Safety 
Follow-Up Period. 
Correction. 
7.1.3 Permanent discontinuation 
due to other AEs 
Criterion #2 updated: Study 
participant has a serious 
significant infective episode 
requiring hospitalization or iv 
To add precision to the 
permanent discontinuation 
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Section # and Name 
Description of Change 
Brief Rationale 
antibiotic therapy (including but 
not limited to bacteremia/or 
sepsis, bacterial infectious 
meningitis, osteomyelitis or 
septic arthritis, osteomyelitis, 
bacterial complicated 
pneumonia, or visceral abscess) 
which may or may not result 
in hospitalization. This list is 
not intended to be all inclusive 
and the investigator is 
expected to apply their 
judgement on continuing IMP 
based on the clinical situation 
(see Appendix 16; Section 
10.16). 
criteria, and to avoid 
unnecessary withdrawals. 
8.1.1 Assessment of seizures 
Text updated to note that study 
participants or caregivers have 
up to 24h from the end of the 
day to complete the seizure 
diary, after that, the diary will 
no longer be available for 
completion. Retrospective edits 
to seizure records in the app are 
not permitted but changes can 
be identified during the review 
with the investigator and edits 
made to the printed record. 
To provide clarity. 
8.2.7.3 Tuberculosis assessment 
by interferon-gamma release 
assay 
1.3 Schedule of activities 
Text updated to note that the 
IGRA assessment should be 
performed first at the Screening 
Visit. 
Cross reference to 
Section 8.2.7.3 added to 
footnote j of Table 1-1. 
Text also updated to note that 
the IGRA TB screening test 
should be performed at a local 
(rather than central) laboratory, 
and the name of the preferred 
brand of IGRA test has been 
removed. 
There is a risk of indeterminate 
results in the presence of steroid 
use. To reduce this risk, the 
IGRA should be the first 
assessment performed at 
Screening. 
To ensure that the IGRA TB test 
result is available within the 
screening period, the test can be 
performed at a local (rather than 
central) laboratory using the 
available IGRA test at the local 
site. 
9.3.1.1 Seizure freedom 
Text added to note that for 
deriving the primary efficacy 
endpoint, intermittent missing 
diary seizure count data will be 
imputed to non-zero. 
To clarify how intermittent 
missing seizure diary days will 
be handled in the derivation of 
the primary endpoint. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.3.2 Secondary efficacy 
analysis 
Text added to define a 
hierarchical testing procedure 
for the analysis of the secondary 
efficacy endpoints. 
To control analyses of efficacy-
related secondary endpoints for 
type I error. 
9.3.3.2 Seizure reductions 
Text updated to note that 
intermittent missing daily 
seizure counts in a given 
reporting period will be 
(indirectly) imputed with the 
daily average seizure count 
observed in that period. 
For consistency with changes 
made to Section 9.3.1.1 relating 
to imputation of missing seizure 
count data. 
10.6 Appendix 6: Liver Safety – 
Suggested Actions and Follow-
up Assessments 
A correction to state that a 
specific monitoring plan must 
be agreed for study participants 
with an ALT of >3 ULN 
(previously >5 ULN). Removal 
of redundant and contradictory 
text. 
Correction and to improve 
clarity. 
10.9.1 China 
Section has been removed as the 
study will no longer be 
performed in China. 
Correction. 
10.16 Appendix 16: 
Management of Infections and 
Hypogammaglobulinemia 
Text has been added to indicate 
that the unblinded medical 
monitor will review available 
safety information for study 
participants with low IgG levels 
and may query the site for 
supportive information. In 
addition, the unblinded medical 
monitor may request additional 
IgG sampling and/or supportive 
information for any study 
participants at random to 
preserve the blind. 
To enhance the rigor of the 
study blind. 
10.16: Appendix 16: 
Management of Infections and 
Hypogammaglobulinemia 
Paragraph 2 updated to be 
consistent with changes made to 
criterion #2 in Section 7.1.3. 
To add precision to the 
permanent discontinuation 
criteria, and to avoid 
unnecessary withdrawals. 
 
Amendment 2 (date: 07 Sep 2021) 
Overall Rationale for the Amendment 
Changes to the protocol have been made to amend the inclusion critera to ensure greater 
specificity for the target population, the addition of regular monitoring of lipid parameters, and to 
provide clarity on how the treatment blind will be maintained. This amendment also introduces 
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blood sampling for antibody response to COVID-19 vaccination, and provides clarity on the 
management of study participants undergoing COVID-19 vaccination. Requests from regulatory 
authorities or ethics committees have been incorporated, and country-specific revisions added to 
Section 10.9. Minor grammatical, editorial, and formatting changes have also been made for 
clarification purposes only. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion criteria 
Inclusion criterion #3a 
(previously criterion #3) revised 
to specify the presentation of 
additional clinical criteria to 
allow for the inclusion of study 
participants with seizures other 
than FBDS. 
To reduce the potential risk of 
enrolling participants in the 
study who do not have LGI1 
AIE. The revised criterion was 
based on a position paper for a 
practical approach for 
diagnosing AIEs (Graus et al, 
2016). 
5.1 Inclusion criteria 
1.1 Synopsis 
1.2 Schema 
1.3 Schedule of activities 
4.1 Overall design 
Inclusion criterion #4a 
(previously criterion #4) 
updated to permit inclusion of 
“participants who are deemed 
appropriate for initiation of 
IVMP based on clinical 
symptoms and history” and 
removal of “being currently 
considered for treatment with 
IVMP by the investigator.” 
Clarification of wording to 
indicate that the study 
participant would be 
appropriately treated with 
IVMP. 
1.3 Schedule of activities 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Addition of HDL, LDL, total 
cholesterol, and triglycerides to 
the hematology, chemistry, and 
urinalysis assessments with 
samples to be taken at 
Screening, Baseline, Visit 5, 
Visit 8, Visit 12, Visit 16, Visit 
22, Visit 26, and at Unscheduled 
visits, as well as EOT/EDisc 
Visit, and EOS Visit. 
Preliminary, unblinded data for 
another anti-FcRn mAb, IMVT-
1401 showed evidence of 
increases in some lipid 
parameters in patients with 
thyroid eye disease (eyewire, 
2021). Given rozanolixizumab 
acts via a similar mechanistic 
pathway, lipids will be assessed 
in this clinical study. 
1.1 Synopsis 
3 Objectives and endpoints 
1.3 Schedule of activities 
8.9.1 Immunology 
Addition of COVID-19 antibody 
sampling to procedures to be 
undertaken as well as a new 
objective and endpoint.  
To allow for an exploratory 
analysis assessing the effect of 
rozanolixizumab on response to 
COVID-19 vaccination. 
1.1 Synopsis 
3 Objectives and endpoints 
Removal of ‘T1-weighted’ from 
the description of volumetric 
sequence, addition of 3D to 
description of T2 FLAIR scans. 
Clarification of the MRI 
parameters to be assessed. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
8.11 COVID-19 vaccination 
New Section 8.11 and new 
footnote y in Table 1-1 noting 
that there should be a minimum 
of 72 hours between COVID-19 
vaccination and IMP 
administration. The scheduled 
dosing of IMP can be adjusted 
to accommodate COVID-19 
vaccination, provided that the 
interval between 2 consecutive 
doses is at least 5 days. 
A delay between IMP 
administration and COVID-19 
vaccination has been introduced 
to aid in determining the 
relationship between any 
potential AEs due to the vaccine 
or IMP. A 72-hour delay was 
selected as this falls 
approximately half way between 
 IMP administration 
schedule. 
1.3 Schedule of activities 
8.2.7.3 Tuberculosis assessment 
by interferon-gamma release 
assay 
Updated to note the procedures 
that should be followed in the 
event of any positive IGRA or 
2 indeterminate IGRA. 
To clarify the process in the 
event of IGRA test results with 
an indeterminate outcome. 
1.3 Schedule of activities 
6.1 Treatments administered 
8.2.3 Vital signs 
Updates have been made to text 
in footnote l of Table 1-1 and a 
new row inserted into Table 6-1 
of Section 6.1 to add the 
observation period following 
IMP administration, as well as 
text requiring that the 
investigator completes a 
checklist prior to the initiation 
of home dosing. The timings of 
vital sign assessments in 
footnote k and in Section 8.2.3 
have also been updated to match 
the change in post-dose 
observation period. 
This change is to be 
implemented across the 
development program as a result 
of safety monitoring from 
ongoing studies in other patient 
populations indicating that 
observation period can be 
reduced in study participants 
who have shown acceptable 
tolerability following IMP 
administration. The change in 
observation period will also 
reduce the clinic waiting time 
for the study participant. 
Clarification on the requirement 
of investigator approval 
preceding the initiation of home 
dosing added for completeness. 
1.3 Schedule of activities 
8.2.3 Vital signs 
Updates have been made to text 
in footnote k of Table 1-1 and in 
Section 8.2.3 to remove the 
requirement for vital signs to be 
measured at 15 mins after the 
start of the infusion. 
The infusion time is 15 mins. 
The schedule of activities also 
requires a vital sign 
measurement at the end of the 
infusion. This change removes 
duplication and provides clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
8.2.5 Magnetic resonance 
imaging 
The assessment “MRI scan 
including T1,T2 coronal 
images” has been moved from 
the Baseline Visit to the 
Screening Visit, and footnote w 
updated to read: “MRI should be 
collected per imaging guidelines 
during the Screening Period or 
at the Baseline Visit.” 
To ensure that the MRI scan is 
performed as close as possible 
to the start of IVMP treatment. 
1.3.1 Additional study 
assessments 
2.1 Study rationale 
8.3.7 Adverse events of special 
monitoring 
10.14 Appendix 14: 
Management of Headache 
A headache questionnaire will 
be used as an additional study 
assessment in case of moderate, 
severe and/or serious headache. 
It was originally planned only in 
case of severe and/or serious 
headache. 
Extended assessment 
implemented across the 
development program to better 
characterize the events of 
headaches. 
2.1 Study rationale 
Changes to indicate that in 
patients with LGI1 AIE, LGI1 
autoantibodies are detected in 
serum and occasionally CSF and 
updated literature reference. 
For increased precision. 
2.2 Background 
The number of ongoing 
rozanolixizumab clinical studies 
has increased from 6 to 9.  
Update based on current clinical 
information. 
2.3 Benefit/Risk assessment 
Text updated to add a benefit-
risk assessment of vaccinations 
while receiving 
rozanolixizumab. 
To incorporate guidance from 
health authority relating to the 
management of clinical studies 
during COVID-19. 
4.1 Overall design 
8.1.1 Assessment of seizures 
Update to the description of the 
primary endpoint. 
Correction. 
4.1 Overall design 
1.1 Synopsis 
Added a clarification of the 
steroid taper. 
For consistency and 
completeness. 
4.2 Scientific rationale for study 
design 
New paragraph justifying the 
use of a placebo control and 24-
week Treatment Period. 
To incorporate health authority 
feedback. 
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Section # and Name 
Description of Change 
Brief Rationale 
4.2 Scientific rationale for study 
design 
The paragraph justifying the use 
of a placebo control and 24-
week Treatment Period added to 
AIE001 Protocol Amendment 1, 
Addendum A (UK) has been 
reworded to reflect the change 
made to inclusion criterion #4a, 
and to improve clarity and 
precision.  
To improve clarity and 
precision. 
4.2 Scientific rationale for study 
design 
New text describing the 
rationale of updated inclusion 
criteria #3a (formerly #3). 
To provide a justification for the 
selected inclusion criteria. 
5.1 Inclusion criteria 
The text in inclusion criterion 
#8a (formerly criterion #8) has 
been updated to allow a legal 
representative to give informed 
consent on the study participants 
behalf. 
Clarification and for consistency 
with Section 10.1.3. 
5.1 Inclusion criteria 
The text in inclusion criterion 
#10a (formerly criterion #10) 
has been updated to allow the 
investigator to assess the 
capability of a participant 
adhering to the protocol visit 
schedule and medication intake, 
based on the study participant 
alone or with the assistance of a 
caregiver. 
In practice at the time of 
entering the study, the majority 
of study participants are likely 
to require a caregiver to assist 
with adhering to the protocol. 
5.2 Exclusion criteria 
Updated exclusion criterion #4a 
(previously criterion #4) 
excluding participants with new 
onset seizures unrelated to LGI1 
AIE or known or suspected 
medical cause for the onset of 
seizures other than possible 
AIE. 
Coupled with the changes to the 
inclusion criterion #3a, this 
addition is designed to reduce 
the potential risk of enrolling 
study participants who do not 
have LGI1 AIE. 
5.2 Exclusion criteria 
Exclusion criterion #9a 
(formerly criterion #9) has been 
modified to add that the 
presence of HBsAg and HCV 
Ab will be tested at Screening. 
In case of positivity to HCV Ab, 
Hepatitis C RNA testing will be 
performed. 
Regulatory authority request to 
clarify this criterion. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion criteria 
The removal of exclusion 
criteria #27, #28, and #29 and 
incorporation of these criteria as 
sub-bullets to updated criterion 
#24a (previously criterion #24). 
A re-ordering of the liver 
function test-related exclusion 
criteria to provide greater 
clarity.  
5.2 Exclusion criteria 
In exclusion criterion #24a 
(previously criterion #28) the 
following changes have been 
made: “If study participant has 
>ULN for ALT, AST, or ALP 
that does not meet the exclusion 
limit at Screening, the test must 
be repeated prior to dosing to 
ensure there was no further 
ongoing clinically relevant 
increase. In case of a clinically 
relevant increase, inclusion of 
the study participants will have 
to be discussed with the medical 
monitor as per the 
investigators judgement, the 
study participant must be 
excluded.” 
To incorporate health authority 
request to remove the medical 
monitor from making a decision 
pertaining to the participants 
eligibility, and to ensure the 
investigator is responsible for 
determining eligibility. 
5.2 Exclusion criteria 
“Total IgG” added to inclusion 
criterion #30a (previously 
criterion #30). 
For clarity. 
6.3.1.1 Maintenance of study 
treatment blind 
Text has been added to describe 
the measures being taken to 
maintain the treatment blind 
given that rozanolixizumab and 
placebo are not identical in 
appearance.  
To correct an omission 
following health authority 
feedback. 
6.3.1.1 Maintenance of study 
treatment blind 
A new paragraph has been 
added that describes the 
procedures in place for the 
monitoring of clinical laboratory 
results, and in the event that 
IMP is discontinued, the 
initiation of mock infusions, 
while maintaining the blind of 
the investigator, site personnel, 
and the study team.  
Clarification regarding the 
proper maintenance of the study 
blind and the administration of 
mock infusions in the event of 
temporary discontinuation of 
IMP. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5.2 Prohibited prior and 
concomitant treatments 
(medications and therapies) 
Prednisolone is prohibited 
during the Treatment Period if 
used outside of the protocol-
specified steroid taper, and 
prohibited if used prior to 
enrollment and since the onset 
of LGI1 AIE. 
Clarification. 
6.5.3 Rescue medication 
The text has been updated to 
remove the list of specified 
rescue medications, and replace 
with a statement indicating that 
the investigator will select the 
most appropriate rescue 
medication for the study 
participant. 
The choice of rescue medication 
does not need to be specified 
per protocol. It is the 
responsibility of the investigator 
to choose the most appropriate 
treatment. 
7.1 Discontinuation of study 
medication 
Added the following text: “In 
addition to algorithmic stopping 
criteria, management of adverse 
events is ultimately at the 
investigator’s discretion.” 
A program-level change based 
on regulatory authority feedback 
to clarify that the management 
of AEs is at the investigator’s 
discretion and should not be 
determined solely by 
algorithmic stopping rules. 
7.1.3 Permanent discontinuation 
due to other AEs 
Added “Study participant 
develops an illness that would 
interfere with his/her continued 
participation” to the reasons for 
permanent discontinuation from 
IMP. 
For further clarity. 
7.1.4 Permanent discontinuation 
due to absence or loss of clinical 
benefit 
Added the following text to 
criterion #1a: “compared with 
Baseline.” 
Clarification. 
7.1.5 Temporary discontinuation 
of IMP 
For ‘must be temporarily 
discontinued’, criterion #1 
(hypogammaglobulinemia), text 
has been added to allow ad hoc 
assessments to monitor recovery 
in IgG levels. 
For consistency with footnote p 
of Table 1-1 and Appendix 16. 
7.1.5 Temporary discontinuation 
of IMP 
For ‘must be temporarily 
discontinued’, a new temporary 
discontinuation criterion (#2) 
has been added for the 
occurrence of 
hypoalbuminemia, and the 
remaining criteria have been 
renumbered.  
A program-level change based 
on regulatory authority 
feedback. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.5 Temporary discontinuation 
of IMP 
Added that the eCRF should be 
completed to include 
information if the visit was 
impacted by COVID-19 
infection. 
To ensure that data impacted by 
COVID-19 is identifiable.  
7.1.5 Temporary discontinuation 
of IMP 
For ‘may be temporarily 
discontinued’, a new temporary 
discontinuation criterion (#2) 
has been added for events at the 
discretion of the investigator. 
To allow for temporary 
discontinuation at the 
investigators discretion, without 
needing to withdraw the study 
participant. 
7.2 Participant 
discontinuation/withdrawal from 
the study 
7.2.1 Study withdrawal criteria 
In Section 7.2.1, for ‘may be 
withdrawn from the study’, 
changes have been made to 
criterion #1: Study participant is 
persistently noncompliant with 
the study procedures or 
medications and this 
noncompliance is not 
manageable in the opinion of the 
investigator. Updates have been 
made to Section 7.2 for 
consistency. 
To provide clarification. 
8.2.5 Magnetic resonance 
imaging 
Added detail pertaining to what 
the MRIs will be used to detect. 
To provide clarification. 
8.3.9 COVID-19 vaccination 
6.5.1 Permitted concomitant 
treatments (medications and 
therapies) 
Section 8.3.9 added outlining 
the procedure to be followed in 
the event of a study participant 
receiving a COVID-19 
vaccination. The requirement to 
record COVID-19 vaccination 
details in the eCRF were also 
added to Section 6.5.1. 
To incorporate guidance from 
health authority relating to the 
management of clinical studies 
during COVID-19. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.4 Safety signal detection 
New paragraph stating that the 
study physician or medically 
qualified designee/equivalent 
will conduct an ongoing review 
of SAEs and perform ongoing 
SAE reconciliations in 
collaboration with the Patient 
Safety representative in a 
blinded manner. 
To provide additional details on 
the safety signal detection 
methods being employed in the 
study. 
8.6 Pharmacokinetics and 
immunogenicity 
A sentence in the second 
paragraph has been updated: 
Samples collected for analyses 
of rozanolixizumab 
concentration may also be used 
to evaluate safety or efficacy 
aspects related to concerns 
arising during or after the study 
before study completion. 
To provide clarification. 
8.9 Biomarkers 
Updates have been made to 
correct the sampling time points. 
Text has also been updated to 
describe that samples stored for 
later exploratory analyses may 
be used for future diagnostic test 
development related to the 
exploration of the cause, 
progression, and appropriate 
treatment of LGI1 AIE. 
For correction and to clarify that 
samples may be used for 
diagnostic test development. 
9.1 Definition of analysis sets 
The definition of the FAS 
changed to include all study 
participants in the RS, who have 
a Baseline value and at least one 
post-Baseline efficacy endpoint 
assessment. 
For compliance with ICH E9 
guidelines. 
9.3.1.1 Seizure freedom 
Removal of sentence pertaining 
to participants that contract 
COVID-19 during the study.  
This information is included in 
Section 7.1.5. 
9.3.1.1 Seizure freedom 
In Table 9-1, edits made to 
population-level summary for 
primary and sensitivity 
statistical analyses. 
For improved accuracy. 
9.3.3.1 Time to seizure freedom 
Updates have been made to add 
detail to the description of the 
analysis. 
To complement the endpoint 
analysis. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.3.3.2 Seizure reductions 
A definition of how seizure 
frequency will be calculated has 
been added. 
To improve precision. 
9.6 Handling of dropouts or 
missing data 
A sentence was added to explain 
that data handling conventions 
for data affected by COVID-19 
will be detailed fully in the SAP. 
Added to confirm that the 
potential effects of COVID-19 
on the data analysis will be 
addressed. 
9.8 Determination of sample size Updates made to the text and 
Table 9-5 to reflect amendments 
to the power assessment.  
To improve the precision of the 
assessment. 
10.1.3 Informed consent process 
Removal of a repeated sentence 
pertaining to the provision of 
informed consent for CSF 
sampling, and clarification that 
legal representatives can provide 
consent for CSF sampling only 
where local regulations allow. 
Genetic analyses and storage of 
samples do not require a 
separate consent and text has 
been updated. Clarification of 
the role of the legal 
representative during the 
informed consent process. 
To avoid repetition, correct text, 
and improve clarity. Regulatory 
authority request to clarify that 
in some regions, legal 
representatives can not provide 
consent for CSF sampling. 
10.2 Appendix 2: Clinical 
Laboratory Tests 
The table describing protocol-
required safety laboratory 
assessments has been re-
ordered. A new table detailing 
other protocol-required 
laboratory tests has been added. 
A new footnote has been added 
to both tables indicating which 
parameters will not be reviewed 
by the investigator until the 
study has been unblinded. 
For transparency to include all 
laboratory tests in one section of 
the protocol and for clarity to 
highlight which assessment 
results will not be disclosed to 
investigative sites or other 
blinded personnel. 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Updates have been made to the 
table summarizing safety 
laboratory assessments 
clarifying HBsAg and HCV Ab 
For consistency with changes to 
exclusion criterion #9a. 
10.4 Appendix 4: Contraceptive 
Guidance and Collection of 
Pregnancy Information 
In contraception guidance for 
male participants, bullet #2 was 
removed. 
To clarify that the use of a male 
condom alone is acceptable. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.4 Appendix 4: Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Removal of the requirement for 
2 forms of highly effective 
contraception. 
Given the mechanism of action 
of rozanolixizumab, there is no 
scientific rationale to suggest a 
drug-drug interaction between 
rozanolixizumab and hormones. 
10.5 Appendix 5: Genetics 
Text has been updated to 
differentiate between biomarker 
and genetic samples, and to add 
clarity. The following sentence 
has been removed: Additional 
analyses may be conducted if it 
is hypothesized that this may 
help resolve issues with the 
clinical data.  
The use and analysis of 
biomarker samples is described 
in Section 8.9, and has been 
removed from Section 10.5 to 
improve clarity.  
10.14 Appendix 14: 
Management of Headache 
The text in the third paragraph 
has been updated to define 
resolution of the headache as 
‘mild or completely resolved, 
whichever comes first’. 
Previously, the definition also 
included nonserious.  
To take into account the 
extension of the questionnaire to 
study participants who 
experience moderate headaches.  
10.16 Appendix 16: 
Management of Infections and 
Hypogammaglobulinemia 
Text has been added that 
describes the role of the 
independent unblinded medical 
monitor in maintaining the study 
blind and reviewing serum IgG 
levels. A cross-reference has 
been added to Section 6.3.1.1 
for further details of maintaining 
study blind. The following 
sentence has been updated: The 
risks and benefits of the 
treatment should be carefully 
considered prior to reinitiating 
the IMP and the decision should 
be discussed and agreed upon by 
the investigator and the sponsor-
designated unblinded medical 
monitor of the CRO. 
For consistency with additions 
to Section 6.3.1.1 (Maintenance 
of study treatment blind). 
10.9.1 China 
New section (Section 10.9.1) 
describing the elements of the 
protocol that differ for study 
participants and investigators 
based in China. 
Changes made to comply with 
country-specific regulatory 
requirements. 
 
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Amendment 1 (04 Dec 2020) 
Overall Rationale for the Amendment 
Changes to the protocol have been made to change the dose of rozanolixizumab from weight-
tiered doses approximating 7mg/kg to fixed dose of 
 Other corrections to ensure 
consistency across the rozanolixizumab clinical development program have also been made. 
Minor grammatical, editorial, and formatting changes have also been made for clarification 
purposes only. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis  
1.2 Schema 
4.1 Overall design 
4.3 Justification of dose 
4.3.1 Justification for IgG target 
6.1 Treatments administered 
Removal of text relating to the 
administration of 
rozanolixizumab in weight-
range based doses of 
approximately 7mg/kg and 
replaced with rozanolixizumab 
 
Update to the dose justification 
section. 
Inclusion of a new subsection 
(Section 4.3.1) to describe the 
rationale for the IgG target. 
Following availability of PK 
data from Phase 1 study 
UP0060, the need for weight-
tiered dosing for 
rozanolixizumab was 
reassessed. Simulations 
performed using a population 
PK-PD (IgG) model of 
rozanolixizumab show that the 
fixed dose of 
 
produces PK variability similar 
to that with weight-tiered dosing 
and will provide 
rozanolixizumab exposures that 
are consistent with those 
obtained with an approximate 
7mg/kg and 10mg/kg weight-
tiered dose Q1W; and will 
achieve and maintain a desired 
IgG reduction of 70% from 
Baseline, irrespective of body 
weight. A fixed-dose regimen 
will simplify the dosing regimen 
to be more convenient for 
physicians and patients and to 
reduce potential for dosing 
errors. 
1.1 Synopsis 
1.3 Schedule of activities 
4.1 Overall design 
4.4 End of study definition 
8 Study assessments and 
procedures 
The SFU Visit has been 
corrected to SFU phone call. 
Correction to align with the 
Schedule of activities 
(Table 1-1) 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
New footnote l stating that the 
interval between administration 
of 2 consecutive 
rozanolixizumab doses should 
be 7 ±2 days. Update to footnote 
q and the rows Total IgG and 
IgG subclasses assessments to 
clarify that total IgG and IgG 
subclasses only need to be 
assessed at the middle visit 
(Visits 10, 14, 20, and 24). 
To provide further clarification. 
1.3 Schedule of activities 
The row MRI scan, including 
T1, T2 coronal images updated 
to note that unscheduled MRIs 
may be performed. 
For consistency with 
Section 8.2.5 (Magnetic 
resonance imaging). 
8.2.5 Magnetic resonance 
imaging 
Updated to note that brain MRI 
may be performed within 
2 weeks prior to Baseline, and if 
performed prior to the Screening 
Period, may be used as the 
Baseline MRI if performed 
according to Protocol 
specifications. 
For clarity and consistency with 
1.3 Schedule of activities. 
Updated to note that if needed, 
additional MRIs may include 
non-protocol specified 
sequences, and these additional 
MRIs will also be assessed by 
the central reader. 
To allow flexibility in the 
assessment of AEs. 
Throughout 
Removal of 24-week and 
addition of (Week 25) to the 
following sentence: “… end of 
the 24-week Treatment Period 
(Week 25). . .” 
Rewording to clarify that the 
end of the Treatment Period is 
at Week 25. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3 Objectives and endpoints 
Details of the MRI endpoints 
updated to distinguish between 
assessments for volumetric 
changes and additional 
assessments for safety. 
To improve accuracy and 
precision. 
4.2 Scientific rationale for study 
design 
Rationales for the selection of 
time from disease onset and 
cognitive impairment as 
stratification factors have been 
added. 
To provide a background 
clarifying the reason these 
factors were selected. 
5.2 Exclusion criteria 
Exclusion criterion #3 updated 
to specifically exclude any other 
anti-FcRn mediations. 
To improve precision. 
Exclusion criterion #14 updated 
to exclude only those with 
active GI disorders. 
There is no scientific rationale 
for excluding participants who 
have recovered from a GI 
disorder from the study.  
New criterion #16 excluding 
study participants with a history 
of solid organ or hematopoietic 
stem cell transplant. 
To correct an omission. 
Exclusion criterion #20 updated 
to exclude live vaccination 
within 8 weeks of the final dose. 
A correction to ensure that the 
exclusion covers the entirety of 
the SFU Period. 
Exclusion criterion #32 updated 
to state that major elective 
surgery procedures are excluded 
throughout the study duration. 
To exclude only major surgeries 
and to ensure this exclusion 
applies throughout the study 
duration. 
6.5.2 Prohibited prior and 
concomitant treatments 
(medications and therapies) 
Update to the list of prohibited 
immunosuppressants in 
Table 6-2 to include 
azathioprine and 
mycophenolate. 
To improve precision and 
completeness.  
Update to the list of prohibited 
biologics in Table 6-2 to include 
inebulizumab and satralizumab.  
Updated as a result of recent 
biologics license application 
approvals.  
For rituximab, ocrelizumab and 
inebulizumab, the prohibited 
timeframe updated to ensure 
B-cell levels have returned to 
normal before use. 
These mAbs cause near 
complete depletion of B cells. 
Given the mechanism of action 
of rozanolixizumab, allowing 
the recovery of B cells is 
preferable regardless of the 
lapsed time. 
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Section # and Name 
Description of Change 
Brief Rationale 
The timeframe for the 
prohibition of eculizumab 
changed from 6 months prior to 
Baseline to 3 months prior to 
Baseline. 
To align rozanolixizumab 
prohibited prior and 
concomitant treatments across 
the rozanolixizumab 
development program. 
6.5.3 Rescue medication 
Inebulizumab and satralizumab 
added to rescue medications. 
Updated as a result of recent 
biologics license application 
approvals. 
7.1.4 Permanent discontinuation 
due to absence or loss of clinical 
benefit 
Addition of ‘at any time’ to the 
following sentence: Study 
participants must be 
permanently discontinued from 
IMP if . . . or if they experience 
clinical worsening (ie, a loss of 
clinical benefit) at any time as 
defined by any of the following: 
To clarify that in the event of a 
protocol-defined clinical 
worsening, IMP must be 
permanently discontinued. 
7.1.4 Permanent discontinuation 
due to absence or loss of clinical 
benefit 
#2 Updated such that cognitive 
worsening defined by an ≥8-
point worsening in RBANS, 
should be confirmed by 
investigator assessment before 
permanent discontinuation of 
IMP. 
To allow for confirmation that 
any deterioration in score is a 
result of cognitive decline, 
assessed by RBANS, rather than 
an external confounding factors 
(eg, forgetting of glasses)  
7.1.5 Temporary discontinuation 
of IMP 
Text relating to the 
discontinuation of study 
participants with suspected 
COVID-19 infection moved 
from ‘may be temporarily 
discontinued from IMP’ to 
‘must be temporarily 
discontinued from IMP’. Text 
relating to restarting IMP after 
suspected COVID removed 
from ‘may be temporarily 
discontinued’. 
To align rozanolixizumab 
clinical study discontinuation 
criteria across the 
rozanolixizumab development 
program. 
8 Study assessments and 
procedures 
Addition of ‘or when home-
nursing visits are not available’ 
to the following sentence: 
Alternatively, these visits can be 
conducted at the site as deemed 
necessary by site personnel 
and/or study participant, or 
when home-nursing visits are 
not available. 
To clarify that in countries or 
sites where home-nursing visits 
are not available, the visits 
defined as home-nursing visits, 
may take place at the clinical 
site. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.2 Planned efficacy/outcome 
analyses 
Updated to note that only 
specified estimands of the 
primary and secondary 
endpoints will be analyzed on 
the FAS for sensitivity, and that 
the analyses on the FAS will 
only be carried out if this 
population differs by more than 
10% of study participants to the 
RS/ITT. 
Correct an omission of decision 
criterion to carry out analyses 
based on FAS. 
9.3.1.1 Seizure freedom 
Update to the intercurrent event 
definitions. 
Clarification and improvement. 
Updates to the text describing 
the primary statistical analysis, 
and the second sensitivity 
analysis. 
Clarification and improvement 
of the estimand description. 
New supplementary analysis 
added. 
Analysis addressing alternative 
to the primary measure of 
association. 
9.3.2.1 Change in cognitive 
function (RBANS) 
Updates to the text describing 
the secondary statistical analysis 
and the second sensitivity 
analysis. 
Clarification and improvement 
of the estimand description. 
9.3.2.2 Use of rescue medication 
due to an absence or loss of 
clinical benefit 
Text describing the secondary 
statistical analysis updated. 
Added ‘Composite strategy’ 
name for the intercurrent event 
handling strategy 2. 
Clarification and improvement 
of the estimand description. 
Second sensitivity analysis 
changed to supplementary. 
Different measure of association 
used for a more complete 
assessment of the endpoint. 
9.3.2.3 Time to first occurrence 
of seizure freedom 
Text describing the secondary 
statistical analysis updated. 
Clarification and improvement 
of the estimand description. 
Excluded the second sensitivity 
analysis. 
Reduced level of granularity of 
the analysis. 
9.3.3.4 Duration of seizure-free 
period 
Text describing the endpoint 
analysis updated 
To reduce the number of 
summary tables describing an 
exploratory endpoint. 
9.8 Determination of sample size Description updated to note that 
sample size selected enables an 
equal study participant 
allocation between treatment 
arms. 
Clarification of sample size 
rationale. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.5 Committees structure 
Removal of the clinical 
pharmacology expert and 
addition of biostatistician to the 
listed members of the IDMC. 
Correction. 
10.16 Appendix 16: 
Management of infections and 
hypogammaglobulinemia 
Removal of the study participant 
from being involved in a 
discussion about resuming IMP. 
Correction. This is a blinded 
study and this discussion would 
unblind the study participant. 
 
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10.12 
Appendix 12: Assessment and Management of Tuberculosis 
and Tuberculosis Risk Factors 
Tuberculosis is a safety topic of interest. The safety topics of interest are selected based on 
findings from the IMP clinical program to date, potential risks generally associated with biologic 
immunomodulators, or findings from other medicines with a related mechanism of action. 
For rozanolixizumab clinical studies, the safety topic of interest was selected because it is a 
biologic immunomodulator, although its mechanism of action is less likely to be associated with 
increased risk of infection compared with other immunomodulators such as glucocorticoids. 
10.12.1 
TB definitions 
a. Known TB infection whether present or past is defined as: 
• Active TB disease or clinical signs and symptoms strongly suggestive of TB 
(pulmonary or extrapulmonary). 
• History of active TB disease involving any organ system or findings in other organ 
systems consistent with TB, unless adequately treated and proven to be fully recovered 
upon consultation with an appropriate specialist. 
• Any evidence by radiography or other imaging modalities consistent with previously 
active TB disease that is not reported in the study participant’s medical history. 
b. High risk of acquiring TB infection is defined as: 
• HIV infection. 
• Known close exposure (eg, sleeping in the same room) to another person with active TB 
disease within 3 months prior to Screening. 
• Time spent within 3 months prior to Screening in a healthcare delivery setting or 
institution where individuals infected with TB are housed or where the risk of 
transmission of infection is high. 
c. LTBI is defined as an infection by Mycobacterium tuberculosis with: 
• Evidence of prior exposure (ie, a positive IGRA or TB skin test result) AND 
• Chest imaging (or other imaging) negative for TB infection, AND 
• Absence of signs, symptoms (eg, evidence of organ-specific involvement), or physical 
findings suggestive of TB infection. 
d. Tuberculosis (IGRA) test conversion is defined as a positive or indeterminate (and 
confirmed indeterminate on repeat) IGRA result for the current test when previous IGRA test 
results were negative. 
10.12.2 
Screening Period 
IGRA TB testing should be performed at Screening, and it is recommended that it is the first 
study procedure to be performed after signing the ICF. 
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10.12.3 
Physical Examination 
The investigator should consider all potential sites of infection when assessing for TB during the 
physical examination, and other evaluations, and based on the study participant’s medical or 
social history. 
The most common primary focus of TB is the lung. Other sites may include gastrointestinal 
system, bone/joints, lymph glands and meninges etc. However, in immune compromised patients 
and/or patients treated with biologics, especially TNF inhibitors, extra-pulmonary manifestations 
of TB are common compared to a normal population. 
In addition to a physical examination done intermittently throughout the study, study participants 
will be evaluated for medical history and for signs and symptoms of latent or active TB and for 
risk factors for exposure to TB. Interferon gamma release assay testing during the study should 
be performed as clinically indicated. 
10.12.4 
Interferon gamma release assay (IGRA) 
IGRA is a whole-blood testing methodology for diagnosing Mycobacterium tuberculosis 
infection. It has become the gold standard but does not allow differentiating LTBI from active 
tuberculosis disease. 
The choice of a commercially available IGRA test should be made in accordance with current 
clinical practice. 
The result must be recorded in the eCRF. 
10.12.5 
Practical steps 
An IGRA test will be performed at Screening and the test results will be reported as positive, 
negative, or indeterminate. Schematic representation on IGRA testing is presented as follows: 
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Table 10-1: Decision tree for IGRA TB results at Screening or before entering a 
study 
 
IGRA=interferon-gamma release assay; LTBI=latent tuberculosis infection; TB=tuberculosis 
a IGRA retest must be done during the Screening period. 
b Study participants with LTBI may be randomized in the study only after they have completed at least 4 weeks of 
appropriate TB preventive therapy and thereafter, will continue and complete the entire preventive therapy. 
If an IGRA is positive or indeterminate the study participant must be evaluated by an appropriate 
specialist. 
The positive IGRA may represent LTBI or active TB disease. The positive IGRA result may also 
reflect positivity from a prior diagnosed and adequately or inadequately treated past TB 
infection.  
If the IGRA test result is indeterminate, the IGRA previously performed may be repeated once. 
The retest must be done during the Screening Period. If the test is positive or indeterminate on 
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retest, the study participant must not be randomized to IMP without further evaluation by an 
appropriate specialist. 
If upon evaluation by an appropriate specialist, active TB is diagnosed at Screening the study 
participant is not eligible for the study and must not be enrolled. 
If upon evaluation LTBI is diagnosed at Screening, an appropriate TB preventive therapy must 
be initiated and the study participant can be enrolled after successful completion of at least 
4 weeks of TB preventive therapy. 
10.12.6 
IGRA Test Conversion 
All study participants with positive or indeterminate IGRA test results must immediately stop 
IMP administration. In case of a IGRA test conversion, the study participant must be considered 
as having either a suspected new latent or an active TB infection and be promptly referred to an 
appropriate specialist (eg, pulmonologist, infectious disease specialist) for further evaluation. 
Additional assessments (eg, blood tests or IGRA, chest X-rays, or other imaging) should be 
performed where medically relevant and documented. Such conversions should be reported as 
AEs - see Section 10.3. The AE term would need to be updated with final diagnosis once 
available. 
10.12.7 
Latent TB 
In case the evaluation by the appropriate specialist diagnoses a new LTBI, a TB preventive 
therapy in accordance with applicable clinical guidelines should be immediately initiated. The 
investigator must provide full documentation of duration, start and stop dates of TB preventive 
therapy (of at least 4 weeks duration) and discuss with the UCB study physician (or medical 
monitor) in an anonymized manner prior to allowing study participant to receive IMP. The 
investigator must assess that the study participant’s likelihood of completing the full course of 
therapy is high and duly record their opinion in the study participant’s record prior to 
randomizing the study participant. 
Evidence of treatment adherence or compliance should be recorded within the treatment 
timeframe and should be completed in appropriate sections of the eCRF. 
Study participants who prematurely discontinue treatment for LTBI should return for the End of 
Treatment/ EDisc Visit, complete all EDisc assessments, and complete an End of Study Visit. 
LTBI must be reported as an AE. Follow-up reports should be completed as per protocol 
requirement until such time as the LTBI resolves. 
Additional considerations regarding including LTBI study participants in the study 
• Study participants who initiated treatment for LTBI during the Screening Period should 
repeat chemistry laboratory parameters (can also be done at a local laboratory), medical 
history and all physical examinations for signs and symptoms of TB (after completing at least 
4 weeks of treatment for LTBI) prior to randomization in the study and must continue the full 
course of TB preventive treatment. 
Rescreening may occur only after discussion with and approval by the study physician (or 
medical monitor). 
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10.12.8 
Active TB 
Study participants who develop active TB during the study must  be immediately permanently 
discontinued from study medication and a EDisc Visit must be scheduled as soon as possible, but 
no later than the next scheduled visit. The study participant should be encouraged to keep the 
End of Study Visit as specified by the protocol. Treatment for active TB should be started 
immediately. 
10.12.9 
Safety Reporting Requirements 
The reporting requirements for events relating to TB are as follows: 
• IGRA test conversions defined as a positive or indeterminate (and confirmed indeterminate 
on repeat) should be reported as AEs. The AE term would need to be updated with final 
diagnosis once available. 
• LTBI must be reported as an AE. It is usually reported as a non-serious AE unless it meets 
SAE criteria. Follow-up reports should be completed as per protocol requirement until the 
LTBI resolves. 
• Confirmed active TB is always considered an SAE and must be reported per SAE reporting 
instruction. Follow-up reports should be completed as per protocol requirement until TB 
infection resolves. 
Notes: 
− “TB Positive” is an unclear term and the study investigative site will be queried for 
clarification to obtain event diagnosis. 
− Suspected LTBI and suspected active TB are considered working diagnosis that should 
be clarified before final database lock. The study investigative site will be queried for 
final diagnosis. 
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10.13 
Appendix 13: Management of AESM 
Adverse event of special monitoring are defined as product specific adverse events, adverse 
reactions, or safety topics requiring special monitoring by one or more regulatory authorities or 
by UCB.  
For rozanolixizumab, AESMs (defined by UCB) are: 
• Severe and/or serious headache 
• Suspected aseptic meningitis 
Occurrence of AESM require immediate reporting (within 24 hours regardless of seriousness) to 
UCB. Upon reception of AESM by UCB a standard medical follow-up query will be sent to the 
site to gather extensive medical information about the AESM. See Table 1-2 for assessments that 
may be required in case of AESM. 
Suspected Aseptic Meningitis 
Drug induced aseptic meningitis (DIAM) is a diagnosis of exclusion after ruling out infectious 
causes (Jolles et al 2000). A few cases of aseptic meningitis (drug induced) have been reported in 
the rozanolizamab program. Consequently, suspected aseptic meningitis is being managed as an 
adverse event of special monitoring (Section 8.3.7). 
Participants should be monitored for signs and symptoms suggestive of CNS system involvement 
and evaluated immediately if meningitis is suspected. A full neurological workup should be 
strongly considered including, but not limited to imaging eg, computed tomography scan, or 
preferably gadolinium enhanced MRI, a lumbar puncture with CSF analysis inclusive of glucose, 
protein, differential complete blood count, cultures, gram stain, and/or viral polymerase chain 
reactions as appropriate. Whenever possible, CSF should be stored for assessment of 
rozanolixizumab PK, PD, specific antibody titers, or other biomarkers. A concurrent blood 
sample should be collected as per local practice. The ultimate investigative procedures are at the 
discretion of the investigator or the treating physician. For studies where a neurologist is not the 
investigator, a neurological consultation is also recommended to aid in decision making and 
patient management. In addition, blood samples for exploratory safety biomarkers (Table 1-1) 
should be collected for participants with a diagnosis of DIAM preferably within 72 hours after 
onset of symptoms. These investigations will be performed to further understand the potential 
mechanisms of DIAM in the participants. 
All procedures related to the diagnosis, treatment and investigation of meningitis should be 
recorded in the eCRF and preliminary data should be included on the SAE form used for 
reporting the event as an AESM within 24 hours (ie, preliminary data reported on the first 
reporting may not have CSF results yet, but the reporting should occur as soon as there is a 
suspected diagnosis. Full results should be communicated in subsequent exchanges with the 
sponsor). 
Treatment must be temporarily held if a participant has a diagnosis of suspected meningitis of 
any cause until the diagnostic workup is complete. Based on CSF findings, negative cultures, 
absence of other disease causes, and relationship with IMP a diagnosis of potential DIAM can 
be made (potential given that the blinded portions of a study should remain blinded to actual 
treatment assignment). If deemed appropriate by the investigator and agreed upon by the 
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participant and the Sponsor, the study treatment can resume upon the complete resolution of 
symptoms. The benefit and risk of the treatment should be carefully considered prior to 
reinitiating the IMP. If a participant experiences a second episode of similar symptoms 
suggestive of DIAM, then the participant must discontinue the IMP and treatment must be 
permanently discontinued. 
Participants experiencing an event of DIAM should be strongly encouraged to remain in the 
study regardless of IMP discontinuation. This will allow for monitoring and follow-up of the 
participant including a complete neurological exam on subsequent physical examinations. 
Longer term follow-up on any AEs related to DIAM that are ongoing may be warranted until 
resolution. 
Associated symptoms with aseptic meningitis should be managed at the investigator’s discretion. 
Severe headache and/or serious headache 
Based on current available clinical data, headache is the most commonly reported adverse drug 
reaction in study participants treated with rozanolixizumab. Study participants should be well 
informed of this potential adverse drug reaction, and should be instructed on how to manage it. 
Determination of the severity of headache will be consistent with Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. Severe headache is defined as severe pain limiting 
self-care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, and taking medications. 
In the event of a headache, the investigators should take the medical history of previous 
headaches, concomitant medication, and co-morbidities (eg, asthma) in consideration. If the 
severe and/or serious headache is initially reported at a home visit or during a telephone call, the 
study participant should be evaluated by a healthcare professional as soon as possible for further 
investigations. Study participants should be monitored for signs and symptoms suggestive of 
CNS involvement and evaluated immediately for other causes (eg, meningitis, intracranial 
bleeding) are suspected (see Section 1.3.1). In addition, samples for exploratory safety 
biomarkers should be collected for study participants experiencing severe or serious headache 
when possible. These investigations will be performed to further understand the mechanism of 
headaches in the study participants. 
If deemed appropriate by the investigator and agreed upon by the study participant and the 
sponsor, the study treatment can resume upon the resolution of the severe headache event. The 
benefit and risk of the treatment should be carefully considered prior to reinitiating the IMP. 
However, if a treatment-related severe headache reoccurs, the treatment must be permanently 
discontinued. 
Headaches will be treated as clinically indicated according to national guidelines. It is 
recommended that the study participants have an analgesic available in case of headache with the 
instruction for frequency and dosage provided by a healthcare professional. The analgesic can be 
started at the early onset of headache. Study participants experiencing any treatment-related 
headache will be followed until resolution of the event. 
Prophylactic treatment of headaches may be permitted for study participants who have 
experienced previous episodes of treatment-related moderate or severe headache after discussion 
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with the medical monitor. The benefit risk of continuing treatment with IMP and chronic 
prophylactic with analgesics must be carefully evaluated by the investigator. 
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10.14 
Appendix 14: Management of Infections and 
Hypogammaglobulinemia 
Study participants who have signs or symptoms of any infection should be monitored closely and 
managed according to local guidelines. This may include tests for specific organisms if clinically 
indicated. 
Study participants MUST discontinue IMP, perform the EOT/EDisc Visit, AND move into 
the SFU Period if the following event occurs: Study participant has a significant infective 
episode including but not limited to bacteremia/sepsis, infectious meningitis, septic arthritis, 
osteomyelitis, complicated pneumonia, or visceral abscess which may or may not result in 
hospitalization. This list is not intended to be all inclusive, and the investigator is expected to 
apply their judgement on continuing IMP based on the clinical situation (Section 7.1.2). 
To maintain the study integrity, IgG level will remain blinded to the study sites and the study 
team (see Section 6.3.1.1 for further details on the maintenance of the study blind). During this 
time, serum IgG level will be monitored by an independent unblinded medical monitor external 
to UCB. As part of the overall safety surveillance, the unblinded medical monitor will review 
available safety information for study participants with low IgG levels and may query the site for 
supportive information. In addition, to preserve the blind, the unblinded medical monitor may 
request additional IgG sampling and/or supportive information for any study participants at 
random. 
The IMP may be temporarily discontinued as requested by the independent unblinded medical 
monitor in case of low serum IgG levels as described in Section 7.1.4. Mock infusions will be 
administered to maintain the blind in case of low IgG levels. 
Treatment may be temporarily discontinued for the study participant who develops a non-serious 
persisting or recurrent infection with a serum total IgG level between ≥1g/L and <2g/L. Upon 
resolution of infection and the IgG returning to the level of ≥2g/L, the study participant may be 
allowed to resume treatment with the IMP. Ad hoc assessments can be performed to monitor 
recovery of IgG levels. 
Treatment must be temporarily discontinued for the study participant who develops an event of 
hypogammaglobulinemia with a serum total IgG of <1g/L irrespective of infection. When the 
IgG level reaches ≥2g/L, the study participant may be allowed to continue treatment with IMP. 
The risks and benefits of the treatment should be carefully considered prior to reinitiating the 
IMP. 
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10.15 
Appendix 15: Management of Infusion Reactions or 
Hypersensitivity Reactions 
Study participants must be closely monitored for reactions during and after the study drug 
administration period. Standard precautions must be taken for the study participants with regards 
to potential infusion-related reactions. Suggested management guidelines for infusion-related 
reactions or anaphylaxis at the study site are provided in Table 10-2. Definitions of severity of 
the relevant events should be consistent with CTCAE version 5.0. Nurses administering the IMP 
at home should follow their own management guidelines, which should be reviewed and 
endorsed by the investigator prior to first home administration. 
Table 10-2: Suggested management guidelines at site for infusion reactions or 
anaphylaxis 
Type of reaction 
Suggested action 
Acute – Mild 
Grade 1 
Monitor vital signs every 10 min. 
If the reaction worsens to Grade 2, follow the instruction below.  
Acute – Moderate 
Grade 2 
Interrupt/hold infusion temporarily to further assess and initiate 
treatment if necessary.  
Consider the use of iv fluid and antihistamine iv/im. 
Consider administering acetaminophen or NSAIDs. 
Monitor vital signs initially every 5 min. 
If the reaction improves and upon further assessment it is clear that the 
event is not an anaphylaxis, restart the infusion cautiously. Continue to 
monitor vital signs every 5 minutes. 
If reaction recurs or worsens to Grade 3, discontinue infusion. 
Acute – Severe 
Grade 3 or 
anaphylaxis 
Discontinue IMP infusion permanently. 
Alert crash team. 
Maintain airway; ensure oxygen is available. 
Administer: 
− Antihistamine iv/im, corticosteroids iv, epinephrine im, and iv 
fluids as appropriate. 
− Monitor vital signs every 2 min. 
− Hospitalize, if condition not improving or worsens.  
− Monitor participant until symptoms resolve. 
CTCAE=Common Terminology Criteria for Adverse Events; im=intramuscular; IMP=investigational medicinal 
product; iv=intravenous(ly); NSAID=nonsteroidal anti-inflammatory drug 
Note: Management criteria were adapted from the CTCAE v5.0 (National Cancer Institute, 2017). 
Suspected anaphylactic reactions should be diagnosed using Sampson’s Criteria (Sampson et al, 
2006). The infusion must be discontinued immediately and emergency resuscitation measures 
implemented. 
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In study participants experiencing an infusion-related reaction or anaphylaxis, blood samples will 
be collected as soon as possible, while the event is ongoing, to investigate the nature of the 
reaction as per Schedule of Activities (Section 1.3). 
Samples for serum complement (
) and plasma complement (
) should be 
collected as specified in the Schedule of Activities (Section 1.3). Additional tests such as 
 
levels, tryptase may be performed when there is a suspicion of Type I or III hypersensitivity 
reaction. The results of all monitoring, including laboratory testing, should be made available to 
the study site and sponsor. 
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SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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Approval Signatures
Name:
AIE001-protocol-amendment-6-18jul2023
Version:
1. 0
Document Number:
CLIN-000230482
Title:
AIE001-Protocol-Amendment-6
Approved Date:
20 Jul 2023
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 19-Jul-2023 08:07:20 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 19-Jul-2023 14:27:46 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 20-Jul-2023 20:05:30 GMT+0000
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SAP_001.pdf: 
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Statistical Analysis Plan 
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AIE001 
 
 
 
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STATISTICAL ANALYSIS PLAN 
AMENDMENT 1 
Study: AIE001 
Product: Rozanolixizumab 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
MULTICENTER, PHASE 2 STUDY TO EVALUATE THE 
EFFICACY, SAFETY, AND PHARMACOKINETICS OF 
ROZANOLIXIZUMAB IN ADULT STUDY PARTICIPANTS WITH 
LEUCINE-RICH GLIOMA INACTIVATED 1 AUTOIMMUNE 
ENCEPHALITIS 
SHORT TITLE 
A PHASE 2 STUDY EVALUATING THE EFFICACY AND 
SAFETY OF ROZANOLIXIZUMAB IN PARTICIPANTS WITH 
LEUCINE-RICH GLIOMA INACTIVATED 1 AUTOIMMUNE 
ENCEPHALITIS 
Sponsor Name: UCB Biopharma SRL 
Legal Registered Address: Allée de la Recherche 60, 1070 Brussels, BELGIUM 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
Eudra CT Number 
2019-004778-25 
IND Number 
157206 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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TABLE OF CONTENTS 
VERSION HISTORY ................................................................................................................5 
LIST OF ABBREVIATIONS ....................................................................................................6 
1 
INTRODUCTION ............................................................................................................10 
1.1 
Objectives and Endpoints .............................................................................................10 
1.2 
Study Design ................................................................................................................13 
2 
STATISTICAL HYPOTHESES ......................................................................................16 
3 
SAMPLE SIZE DETERMINATION ...............................................................................16 
4 
POPULATIONS FOR ANALYSIS .................................................................................18 
4.1 
Enrolled Set ..................................................................................................................18 
4.2 
Randomized Set ............................................................................................................18 
4.3 
Safety Set ......................................................................................................................19 
4.4 
Pharmacodynamic/Pharmacokinetic Per-Protocol Set .................................................19 
4.5 
Pharmacokinetic Per-Protocol Set ................................................................................19 
5 
STATISTICAL ANALYSES ...........................................................................................19 
5.1 
General Considerations ................................................................................................19 
5.1.1 
General study level definitions .............................................................................20 
5.1.1.1 
Analysis Time Points .................................................................................20 
5.1.1.2 
Protocol Deviations ....................................................................................22 
5.1.1.3 
Treatment assignment and treatment groups .............................................22 
5.1.1.4 
Center pooling strategy ..............................................................................23 
5.1.1.5 
Coding dictionaries ....................................................................................23 
5.1.1.6 
Multicenter studies .....................................................................................23 
5.1.1.7 
Multiple comparisons/multiplicity .............................................................23 
5.1.1.8 
Adjustments for covariates ........................................................................23 
5.1.2 
Rescue medication................................................................................................23 
5.1.3 
Missing Data Strategies for efficacy analyses......................................................23 
5.2 
Participant Dispositions ................................................................................................24 
5.3 
Primary Endpoint Analysis ..........................................................................................24 
5.3.1 
Definition of endpoint ..........................................................................................24 
5.3.2 
Main analytical approach .....................................................................................25 
5.4 
Secondary Endpoints Analyses ....................................................................................26 
5.4.1 
Change in cognitive function (RBANS) ..............................................................26 
5.4.2 
Change in overall disability: mRS .......................................................................26 
5.4.3 
Use of rescue medication due to an absence or loss of clinical benefits ..............27 
5.4.4 
Time to first occurrence of seizure freedom (TTFSF) .........................................27 
5.5 
Exploratory Endpoints Analyses ..................................................................................27 
5.5.1 
Seizure control......................................................................................................27 
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5.5.2 
Duration of seizure-free period ............................................................................28 
5.5.3 
Change in RBANS domains .................................................................................28 
5.5.4 
Short Form 36-item (SF-36) .................................................................................28 
5.5.5 
Euro-Quality of Life 5-Dimensions, 5 Levels (EQ-5D-5L) .................................28 
5.5.6 
A by-participant listing  will be produced using the RS to summarize answers 
provided to each of the 5 dimensions of the EQ-5D descriptive system at each 
scheduled visit for each participant by treatment group.Clinical Global 
Impression of Severity (CGI-S) ...........................................................................28 
5.6 
Safety Analyses ............................................................................................................28 
5.6.1 
Extent of Exposure ...............................................................................................29 
5.6.2 
Adverse Events .....................................................................................................29 
5.6.2.1 
Data considerations ....................................................................................29 
5.6.2.2 
Adverse events summaries .........................................................................30 
5.6.3 
Additional Safety Assessments ............................................................................31 
5.6.3.1 
Clinical laboratory evaluations ..................................................................31 
5.6.3.2 
Potential drug-induced liver injury (pDILI) ..............................................33 
5.6.3.3 
Vital Signs ..................................................................................................34 
5.6.3.4 
12-Lead Electrocardiograms (ECG) ..........................................................34 
5.6.3.5 
Physical examination .................................................................................34 
5.6.3.6 
Neurological examination ..........................................................................34 
5.6.3.7 
Childbearing potential ................................................................................34 
5.6.3.8 
Assessment and management of Tuberculosis (TB) ..................................34 
5.6.3.9 
Headache questionnaire .............................................................................34 
5.6.3.10 
Suicidal risk monitoring .............................................................................35 
5.7 
Other Analyses .............................................................................................................35 
5.7.1 
Other endpoints and/or parameters ......................................................................35 
5.7.1.1 
Pharmacokinetics .......................................................................................35 
5.7.1.2 
Pharmacodynamics ....................................................................................36 
5.7.1.3 
ADA will not be performed or evaluated in this study. Immunology .......37 
5.7.1.4 
Healthcare resource utilization ..................................................................37 
5.8 
Interim Analyses ...........................................................................................................38 
5.9 
Data Monitoring Committee (DMC) ............................................................................38 
6 
SUPPORTING DOCUMENTATION .............................................................................38 
6.1 
Non-key analysis specifications ...................................................................................38 
6.1.1 
Baseline characteristics and demographics ..........................................................38 
6.1.1.1 
Demographics ............................................................................................38 
6.1.1.2 
Baseline disease characteristics .................................................................39 
6.1.2 
Protocol deviations ...............................................................................................39 
6.1.3 
Medical history .....................................................................................................39 
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6.1.4 
Prior/concomitant/follow-up medications ............................................................40 
6.1.4.1 
Categories of prior and concomitant medications .....................................40 
6.1.4.2 
Assignment of Treatment and/or SFU Period ............................................40 
6.1.5 
Rescue medications ..............................................................................................41 
6.1.6 
Antiepileptic Drug (AED) ....................................................................................41 
6.1.7 
Data derivation rules ............................................................................................41 
6.1.7.1 
Handling of dropouts or missing data ........................................................41 
6.1.7.2 
Handling of repeated and unscheduled measurements ..............................43 
6.1.8 
Treatment Compliance .........................................................................................43 
6.1.9 
AEs of Special Interest .........................................................................................43 
6.2 
Appendix 1: RBANS ....................................................................................................43 
6.3 
Appendix 2: mRS .........................................................................................................44 
6.4 
Appendix 3: Classification of the SF-36v2 questionnaire ............................................44 
6.5 
Appendix 4: Markedly abnormal criteria for Rozanolixizumab program ....................52 
6.6 
Appendix 6: Genetics ...................................................................................................54 
6.7 
Appendix 7: Changes to Protocol-Planned Analyses ...................................................55 
6.8 
Appendix 8: Amendment(s) to the Statistical Analysis Plan .......................................55 
6.8.1 
Amendment 1 .......................................................................................................55 
7 
REFERENCES .................................................................................................................59 
 
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Statistical Analysis Plan 
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VERSION HISTORY 
SAP Version 
Approval Date 
Change 
Rationale 
1 
19 Oct 2021 
Not Applicable 
Original version 
Amendment 1 
18 Mar 2024 
See Section 6.8.1 for 
details 
To implement 
changes in Protocol 
Amendments 
 
 
 
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Statistical Analysis Plan 
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AIE001 
 
 
 
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LIST OF ABBREVIATIONS 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
AED 
Antiepileptic Drug 
AESI 
Adverse Event of Special Interest 
AESM 
Adverse Event of Special Monitoring 
AIE 
Autoimmune Encephalitis 
ALP 
Alkaline Phosphatase 
ALQ 
Above the Limit of Quantification 
ALT 
Alanine Aminotransferase 
ANCOVA 
AR(1) 
Analysis of Covariance 
First Order Autoregressive   
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
BP 
Bodily Pain 
BUN 
Blood Urea Nitrogen 
CGI-S 
Clinical Global Impressions of Severity 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus 2019 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DILI 
DMC 
Drug-Induced Liver Injury 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
EDisc 
Early Discontinuation 
eGFR 
Estimated Glomerular Filtration Rate 
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EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D-5L 
Euro-Quality of Life 5-Dimensions, 5 Levels 
ES 
Enrolled Set 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FWER 
Family-Wise Type-I Error Rate 
GEE 
Generalized Estimating Equations 
geoCV 
Geometric Coefficient of Variation 
geoMean 
Geometric Mean 
GGT 
Gamma Glutamyl transferase 
GH 
General Health 
HCRU 
Healthcare Resource Utilization 
HD 
Health Domain 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICE 
Intercurrent Event 
ICH 
International Council for Harmonisation  
IDMC 
Independent Data Monitoring Committee 
Ig 
Immunoglobulin 
IgG 
Immunoglobulin G 
IGRA 
Interferon Gamma Release Assay 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IPD 
Important Protocol Deviation 
ITT 
Intent-to-treat 
IVMP 
Intravenous Methylprednisolone 
IWRS 
Interactive Web Response System 
J2R 
Jump to Reference 
LDH 
Lactate Dehydrogenase 
LGI1 
Leucine-Rich Glioma Inactivated 1 
LLOQ 
Lower Limit of Quantification 
LLT 
Lower Level Term 
LSMD 
Least Squares Mean Difference 
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MA 
Markedly Abnormal 
MAR 
Missing at Random 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mental Health 
MI 
Multiple Imputation 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not at Random 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
MSE 
Minimum Symptom Expression 
MSR 
Minimum Significant Ratio 
n 
Number of Participants 
NAb 
Neutralizing Antibody 
OR 
Odds Ratio 
PCS 
Physical Component Summary 
PD 
Pharmacodynamic 
pDILI 
Potential Drug Induced Liver Injury 
PF 
Physical Functioning 
PiDMC 
Program independent Data Monitoring Committee 
PK 
Pharmacokinetic 
PLS 
Population-Level Summary 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
RBANS 
Repeatable Battery for The Assessment of Neuropsychological Status 
RBC 
Red Blood Cell Count 
RE 
Role Emotional 
RLZ 
Rozanolixizumab 
RNA 
Ribonucleic Acid 
RP 
Role Physical 
RS 
Randomized Set 
SAP 
Statistical Analysis Plan 
sc 
Subcutaneous 
SD 
Standard Deviation 
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SDR 
Safety Data Reviews 
SF 
Social Functioning 
SF-36 
36-Item Short Form Survey 
SFU 
Safety-Follow Up 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SS 
Safety Set 
TB 
Tuberculosis 
TD 
Target Difference 
TEAE 
Treatment-Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
TTSFM 
Time to Seizure Freedom Maintenance 
VAS 
Visual Analogue Scale 
VT 
Vitality 
WBC 
White Blood Cell 
WHODD 
World Health Organization Drug Dictionary 
 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the statistical analyses of study AIE001, including Program independent Data 
Monitoring Committee (PiDMC) and final analyses. It also defines the summary tables, figures, 
and listings (TFLs) to be included in the final Clinical Study Report (CSR) according to the 
protocol. 
This SAP is based upon, and assumes familiarity with, the following document: 
•  
• Protocol Amendment 6: 18 July 2023 and all previous protocol versions. 
. Changes to the analysis from the protocol are documented in Section 6.7. The content of this 
SAP is compatible with the International Council for Harmonisation (ICH)/Food and Drug 
Administration (FDA) E9 Guidance documents. 
Note that although protocol amendment was approved in both the USA and Canada no 
participants were randomized to the study under this amendment. 
1.1 
Objectives and Endpoints 
The study objectives and endpoints attributes are listed in Table 1‒1 below.  
Table 1‒1: 
Objective and Endpoints 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
• To assess the efficacy of 
rozanolixizumab as measured 
by seizure freedom 
• Seizure freedom (defined by 28 consecutive days of 
no seizures) maintained until the end of the 
Treatment Period (Week 25) 
Secondary 
• To assess the efficacy of 
rozanolixizumab as measured 
by a change in cognitive 
function 
• Change from Baseline in Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS) 
total scale index score at the end of the Treatment 
Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab on study 
participants’ overall disability 
• Proportion of participants with a favorable outcome 
in the Modified Rankin Scale (mRS) during the 
Treatment Period, where favorable outcome is 
defined as no worsening for participants with a 
Baseline mRS score of ≤1 or improvement of 
≥1 point for participants with a Baseline mRS score 
of ≥2 
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Objectives 
Endpoints 
• To assess the efficacy of 
rozanolixizumab as measured 
by use of rescue medication 
• Use of rescue medication due to an absence or loss of 
clinical benefit during the Treatment Period 
• To assess the efficacy of 
rozanolixizumab as measured 
by the onset of seizure 
freedom 
• Time to first occurrence of seizure freedom (TTFSF) 
defined by the number of days after randomization to 
the first day of the first 28 consecutive days without 
seizures during the Treatment Period 
• To assess the safety and 
tolerability of 
rozanolixizumab 
• Incidence of treatment-emergent adverse events 
(TEAEs) during the study 
Exploratory 
• To assess the time of onset of 
efficacy of rozanolixizumab 
for the subgroup of study 
participants who achieve the 
primary endpoint as measured 
by the onset of seizure 
freedom 
• Time to achieving seizure freedom (defined by 
28 consecutive days of no seizures) maintained until 
the end of the Treatment Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab as measured 
by seizure control 
• ‘Good’ or ‘Moderate’ seizure control maintained 
over a period of 4 consecutive weeks until the end of 
the Treatment Period (Week 25) 
• To assess the efficacy of 
rozanolixizumab as measured 
by a change in cognitive 
function (domains of 
RBANS) 
• Change from Baseline in the domain scores of 
RBANS (immediate memory; 
visuospatial/constructional; delayed memory; 
language; and attention) during the Treatment Period 
• To assess the efficacy of 
rozanolixizumab using an 
integrated ranked analysis of 
combined clinical and 
functional outcome measures 
• Ranked outcome derived from the combined 
integrated analysis of clinical and functional 
assessments (including mRS, seizure freedom, and, 
cognitive function) at the end of the Treatment 
Period (Week 25) 
• To assess the safety and 
tolerability of 
rozanolixizumab 
• Change from Baseline in vital signs and laboratory 
results during the study 
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Objectives 
Endpoints 
• To assess the 
pharmacodynamic (PD) effect 
of rozanolixizumab as 
measured by the total IgG 
concentrations in serum 
• Value and change (absolute and percentage) from 
Baseline in serum total IgG and IgG subclass 
concentrations during the study 
• To assess the PD effect of 
rozanolixizumab as measured 
by LGI1 autoantibody levels 
using the flow cytometry 
LGI1 quantitative assay 
• Value and change from Baseline in LGI1 
autoantibody serum levels during the Treatment 
Period 
• Value and change from Baseline in LGI1 
autoantibody cerebrospinal fluid (CSF) levels during 
the Treatment Period (for consenting participants) 
• To evaluate the effects of 
rozanolixizumab on patient-
reported health-related quality 
of life (HRQoL) 
• Value and change from Baseline in the 36-item 
Short Form Survey (SF-36) Physical Component 
Summary (PCS) score, Mental Component 
Summary (MCS) score, and individual domain 
scores during the Treatment Period 
• Value and change from Baseline in the EuroQol-5D-
5L (EQ-5D-5L) during the Treatment Period 
• Value and shift from Baseline in Clinical Global 
Impression of Severity (CGI-S) during the 
Treatment Period 
• To evaluate the effects of 
rozanolixizumab on 
healthcare resource 
utilization (HCRU) 
• Disease-related hospitalizations (number, duration) 
• To assess the pharmacokinetic 
(PK) characteristics of 
rozanolixizumab 
• Plasma concentration of rozanolixizumab during the 
Treatment Period 
• To evaluate the impact of 
concomitant antiepileptic 
drugs (AEDs) on 
rozanolixizumab plasma 
levels  
• Plasma concentration of rozanolixizumab during the 
Treatment Period 
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Objectives 
Endpoints 
• To evaluate the incidence and 
emergence of antidrug 
antibody (ADA) of 
rozanolixizumab and impact 
on PK and PD 
• ADA status 
• To evaluate the effects of 
rozanolixizumab on the 
concentration of total protein, 
albumin, 
, and 
serum and plasma 
complement levels 
• Values and change from Baseline in total protein, 
albumin, and serum immunoglobulin concentrations 
(
) during the Treatment 
Period  
• Values and change from Baseline in serum 
complement levels 
 and plasma 
complement levels (
) in case of infusion 
or hypersensitivity reaction 
• To assess exploratory 
biomarkers 
• Deoxyribonucleic acid (DNA), ribonucleic acid 
(RNA), and genetic analysis that may be measured to 
understand the cause and appropriate treatment of 
LGI1 AIE 
• Exploratory biomarkers such as but not limited to 
 
 
• Proteins and metabolite changes may be measured to 
understand the cause, progression, and appropriate 
treatment of LGI1 AIE 
 
 
1.2 
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 2-arm, repeat dose 
study to evaluate the efficacy, safety, and PK of rozanolixizumab for the treatment of LGI1 
AIE. 
Approximately 68 adult study participants with LGI1 AIE with onset of disease symptoms 
between 0 to 12 months prior to study entry, as assessed by the investigator, will be randomized 
to receive rozanolixizumab 
 or placebo, administered by subcutaneous (sc) infusion at 
 intervals for 24 weeks. A Treatment Period of 24 weeks has been selected to ensure a 
sufficient time period to evaluate a difference between rozanolixizumab and placebo in key 
symptoms of the disease. The primary objective of the study is to assess the efficacy of 
rozanolixizumab as measured by seizure freedom.  
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Down titration of steroids will begin after at least 3 days on the initial high dose corticosteroids 
(based on the decision of the investigator). 
The study participants will be stratified at randomization by: 
• Time from disease symptom onset (≤6 months or >6 months from the disease symptom 
onset) 
• Cognitive function (RBANS score of ≤85 or >85)  
After the initial 5 investigational medicinal product (IMP) administrations have been performed 
at the clinic, the study participant may have the opportunity to be treated at home by a visiting 
healthcare practitioner.  
Although the use of rescue medication is allowed at any time during the study, the use of rescue 
medications should be delayed, if clinically feasible, for at least 4 weeks following the initiation 
of study treatment. Study participants who require use of rescue medication will discontinue 
blinded treatment and complete the assessments for the Early Discontinuation Visit. Following 
this, the selection of an appropriate rescue medication will be made at the investigators 
discretion, and the study participant will enter the Safety Follow-Up (SFU) Period. Unscheduled 
study visits are permitted for any study participant including those study participants who have 
initiated rescue medication. 
An Independent Data Monitoring Committee (IDMC) will be established for the study to 
monitor the emerging safety data within the clinical study on a periodic basis. 
Number of Participants 
Sixty-eight participants will be randomly assigned to the study. 
Treatment Groups and Duration 
The maximum study duration per study participant is 38 weeks. There are 3 study periods:  
• Screening Period: Eligibility will be assessed during the Screening Period of up to 42 days. 
If a study participant becomes seizure free as a result of steroid treatment, the participant 
may still be randomized in the study, providing the prior occurrence of seizures is well 
documented.  
Following screening and completion of the Baseline assessments, treatment will be initiated 
in study participants who are deemed appropriate for initiation or re-initiation of high dose 
corticosteroids (500 to 1000mg methylprednisolone [MP] equivalent /day) based on clinical 
symptoms and history, or who have initiated corticosteroids within 42 days prior to 
randomization at a dose of 500 to 1000mg MP equivalent/day. Corticosteroids can be 
initiated prior to the start of the Screening Period, however, the study participant must be 
randomized within 42 days of corticosteroids initiation. If the study participant has initiated 
a steroid taper, the study participant cannot receive oral steroids at a dose lower than 
40mg/day when randomized. Study participants receiving a steroid dose of 60mg/day, 
50mg/day or 40mg/day at the time of randomization, will have to maintain that dose for 7 
days (±2 days), 14 days (±2 days) or 21 days (±2 days), respectively, before resuming 
 down-titration steps. Each subsequent down-titration step will last for 7 days (±2 
days; see Figure 1‒1). For those participants that have not initiated a steroid taper, the 
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down-titration of the oral steroid dose will begin after at least 3 days on the initial high dose 
corticosteroids, as per investigator’ discretion. 
• Treatment Period: Participants who have been confirmed eligible will be randomized in a 
1:1 ratio to receive rozanolixizumab 
 or placebo at 
 intervals over a 24-week 
Treatment Period. Initially, study participants will receive rozanolixizumab or placebo in 
addition to intravenous (iv) or oral steroids that will be tapered as described in protocol 
Section 1.2. 
• Safety Follow-Up Period: Study participants who complete the 24-week Treatment Period 
or prematurely discontinue IMP, as well as study participants who receive rescue 
medication during the 24-week Treatment Period will undergo the End of Treatment (EOT) 
Visit/Early Discontinuation Visit and enter the SFU Period. At 4 weeks after the final dose, 
study participants will undergo a SFU phone call, and at 8 weeks after the final dose, study 
participants will undergo the End of Study (EOS) Visit.  
A schematic of the study design is provided in Figure 1‒1. 
Figure 1‒1: Study schematic 
EDisc=early discontinuation; EOT=end of treatment; EOS=end of study; MP=methylprednisolone; SFU=safety 
follow-up; W=Week 
Note: Rozanolixizumab or placebo will be initiated in study participants who are deemed appropriate for initiation 
or re-initiation of corticosteroids based on clinical symptoms and history, or have initiated corticosteroids within 42 
days prior to randomization at a dose of 500 to 1000mg MP equivalent/day. Study participants will be administered 
rozanolixizumab or placebo in addition to iv or oral steroids that will be tapered. The dotted line indicates the 
period in which each down-titration step may occur. 
Note: Visit 17 and Visit 18 were removed in Protocol Amendment 4 and Visit 4 was removed in Protocol 
Amendment 5; however, the Visits were not renumbered. 
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2 
STATISTICAL HYPOTHESES 
The null hypothesis (H0) for the primary endpoint is: 
There is no association between randomized treatment (Rozanolixizumab) exposure and 
reaching the primary endpoint (seizure freedom (defined by 28 consecutive days of no seizures) 
maintained until the end of the Treatment Period (Week 25)) conditional on the stratification 
factors (time from the disease onset and RBANS score, see Section 5.1.1.8) as measured by 
rozanolixizumab versus placebo odds ratio (OR): H0: OR = 1. 
 
Due to the low number of participants recruited into this study due to the study being terminated 
prematurely, no statistical testing will be carried on the primary endpoint. 
 
3 
SAMPLE SIZE DETERMINATION 
The study sample size of 60 participants is considered sufficient to provide acceptable study 
operating characteristics for the primary efficacy endpoint (Section 1.1). To account for an 
assumed 10% dropouts within each treatment arm and to enable an equal study participant 
allocation between treatment arms, 68 study participants will be randomly assigned to study 
treatment arms in a 1:1 ratio.  
It should be noted that due to feasibility issues with recruitment, which was suspended as of 29 
November 2023,  the study has a limited sample size of 12 participants, which does not provide 
adequate statistical power to address the efficacy objectives defined for this study. 
Given that there are limited randomized published studies in the LGI1 AIE patient population, 
there is uncertainty with respect to the expected proportion of participants who may achieve 
seizure freedom by 24 weeks in the control arm. While the targeted desirable treatment 
difference is 40%, a difference of 30% would be considered both clinically relevant and 
important in this disease area, given the lack of approved treatments and the length of prior 
corticosteroid treatment that is permissible in the study, along with potential prior disease 
specific treatment. 
The study operating characteristics presented in Table 3‒1, were derived based on the expected 
seizure freedom proportions in the randomized study treatment arms that may be observed at the 
end of Treatment Period (Week 25). Based on Thompson et al  (Thompson, 2018), after 30 and 
90 days 51% and 88% of LGI1 AIE patients, respectively, experienced cessation of 
Faciobrachial Dystonic Seizures (FBDS) once treated with immunotherapy. These rates were 
consistent with  (de Bruijn MAAM, 2019) median time to the FBDS freedom of 28 days once 
treated with immunotherapy.  
For the purposes of the dual criteria framework as presented in Table 3‒1, the proportions of 
seizure freedom at the end of the Treatment Period (Week 25) are assumed not to be lower than 
70% in the rozanolixizumab treatment arm and 40% in the placebo arm. The treatment effect 
evaluation based solely on statistical significance testing, is complemented with an assessment 
of its clinical relevance following the dual criteria framework as presented by (Fisch, 2015).  
Assuming 50% seizure-free proportions in the control arm, the sample size of 60 study 
participants will be able to detect a resulting 40% proportion difference with approximately 
85% and a resulting 30% difference with approximately 55 to 65%. For a target difference (TD) 
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of 40% in the proportions between the treatment groups, the probability that both significance 
and relevance criteria are met, given a true difference of 40%, is at least 45% with only 9.5% of 
studies where none of the key criteria are met. If the TD achieved is 30%, the probability that 
both key criteria are met is at least 76%. 
If the difference in proportions increases to 50%, because of a larger (90%) seizure-free 
proportion in the rozanolixizumab arm, the power to detect that effect is at least 95% with the 
sample size of 60. For this design, the probability that both the criteria are met is 79% and 
44.5% for TD of 40% and 50%, respectively, with less than 1% probability that none of the 
criteria are fulfilled. 
Decisions with respect to the outcome of this study will utilize the operating characteristics as 
described for the primary endpoint but will also importantly consider the strength of evidence of 
treatment effect provided by the secondary endpoints, according to the prescribed criteria for 
alpha spending, as outlined in protocol Section 9.3.2, as well as consideration to the safety data 
observed. 
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Table 3‒1: 
Study Operating Characteristics 
Sample 
size 
PBO arm 
SF 
proportio
n (%) at 
the end of 
Treatmen
t Period 
RLZ arm 
SF 
proportion 
(%) at the 
end of 
Treatment 
Period 
Power 
CMHa 
(%) 
Power 
logisticb 
(%) 
Target 
RLZ-PBO 
SF 
proportion 
difference 
(%) 
Probabilityc (%) 
Scenario 
A 
Scenari
o B 
Scenari
o C 
 
60 
40 
70 
54.6 
63.2 
30 
45.7 
20.6 
33.8 
40 
17.3 
49.1 
33.6 
50 
3.7 
62.8 
33.5 
60 
40 
80 
84.5 
86.0 
30 
76.3 
14.1 
9.6 
40 
45.2 
45.3 
9.5 
50 
16.1 
74.7 
9.2 
60 
40 
90 
98.3 
95.4 
30 
95.6 
3.8 
0.6 
40 
79.1 
20.0 
0.9 
50 
44.5 
54.8 
0.7 
CMH= Cochran-Mantel-Haenszel; PBO=placebo; RLZ=rozanolixizumab; SF=seizure freedom 
a Power to detect a statistical difference at a 2-sided 5% significance level based on the CMH test with continuity 
correction (Wittes, 1987). The calculations were made using the R package samplesizeCMH ver. 0.0.0. 
b Power to detect a statistical difference at a 2-sided 5% significance level from a standard logistic regression model 
adjusting for treatment group (Demidenko, 2007). The calculations were made using the R package WebPower ver. 
0.6. 
c Derived from the Fisch et al (Fisch, 2015) decision framework based on dual criteria: Significance – high confidence 
(0.975) that the effect of the investigational drug, relative to placebo, is greater than zero; Relevance – moderate 
confidence (0.5) that the drug effect, relative to placebo, is larger than the target difference. Possible scenarios:  
o 
A – both criteria hold as an evidence of sufficiently high effect 
o 
B – inconclusive as only one criterion holds, suggesting a marginal effect (Significance only) or too much 
variability to make a clear decision (Relevance only)  
o 
C- neither of the criteria holds.  
The probability of each scenario calculated from S=10,000 simulated study outcomes for a given sample size and 
seizure freedom proportions combination. 
4 
POPULATIONS FOR ANALYSIS 
4.1 
Enrolled Set 
The Enrolled Set (ES): All study participants who have signed the informed consent. 
4.2 
Randomized Set 
The Randomized Set (RS): All enrolled study participants who were randomized to blinded 
IMP (Investigational Medicinal Product). This is an equivalent to the Intent-to-Treat (ITT) 
Population. The study participants will be analyzed according to the randomized treatment. 
 
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4.3 
Safety Set  
Safety Set (SS): All randomized study participants who received at least one dose of IMP. 
Analysis of this set will be according to the treatment the study participants actually received 
and will be used for the demographic and safety analyses. 
4.4 
Pharmacodynamic/Pharmacokinetic Per-Protocol Set 
The Pharmacodynamic Per-Protocol Set (PD-PPS) is a subset of the SS, consisting of those 
study participants who had at least one valid post-Baseline measurement of total IgG, or IgG 
subclasses, and no important protocol deviations (as defined in Section 5.1.1.2) affecting the PD 
variable. 
Post-Baseline deviations will not necessarily lead to total exclusion of a study participant from 
the PD-PPS but may lead to exclusion of specific data 
4.5 
Pharmacokinetic Per-Protocol Set 
The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the SS, consisting of those study 
participants who have at least one quantifiable concentration of rozanolixizumab and no 
important protocol deviations affecting the PK variable. Post-Baseline deviations will not 
necessarily lead to total exclusion of a study participant from the PK-PPS but may lead to 
exclusion of specific data. 
5 
STATISTICAL ANALYSES 
The RS will be used for all summaries unless it is specified otherwise. For safety summaries, 
RS will be used as this is the same as the SS.  
It should be noted that participants were all randomized under different versions of the protocol 
up until Protocol Amendment 5.   The result of this is that there will be different assessments 
(eg. Health outcomes and PK/PD) available for the 12 participants.   Some assessments may 
have very limited data. 
5.1 
General Considerations 
 Generation of tables, figures, participant data listings, and statistical output will be performed 
using SAS® Version 9.4 or higher. All tables and listings will use Courier New font size 9. 
Descriptive statistics will be displayed to provide an overview of the study results. For 
continuous variables, descriptive statistics will include number of participants with available 
measurements (n), mean, standard deviation (SD), median, minimum, and maximum. 
For categorical variables, the number and percentage of participants in each category will be 
presented. Unless otherwise noted, the denominator for percentages will be based on the 
number of participants included in the respective analysis set. Participants with missing data can 
generally be accounted for using the following approaches: 
• For summaries of demographics and Baseline characteristics: summarize percentages based 
on all participants in the analysis set and include a “Missing” category (corresponding to 
participants with missing data for the variable being summarized) as the last row in the list 
of categories being summarized.  
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• For summaries of efficacy and safety variables, unless otherwise specified: summarize 
percentages based only on those participants with observed data for the variable being 
summarized. As the denominator may be different from the number of participants in the 
analysis set being considered, the denominator should be displayed in the table. The general 
format for displaying this will be “n/Nsub (%).” 
Unless otherwise noted, all percentages will be displayed to one decimal place. No percentage 
will be displayed for zero counts, and no decimal will be presented when the percentage is 
100%.  
All summaries of PK variables will be based on the observed values. No imputation will be 
used. 
Decimal places for descriptive statistics will always apply the following rules: 
• “n” will be an integer; 
• Mean (arithmetic, geometric), SD, and median will use one additional decimal place 
compared to the original data; 
• geometric CV [%] will be presented with one decimal place; 
• Minimum and maximum will have the same number of decimal places as the original value. 
If no participants have data at a given time point, for example, then only n=0 will be presented. 
However, if 0<n<3, present the n, minimum and maximum only. If n=3, n, mean, median, 
minimum and maximum will be presented only. The other descriptive statistics will be left 
blank.  
Derived variables in general will display the mean, SD and median to 1 more decimal place 
than the variables used in the derivation. If the number of decimal places reported in the raw 
data is varied, then use either the maximum raw number of reported decimal places or 3, 
whichever is the lowest, as a guide for the descriptive statistics. 
5.1.1 
General study level definitions 
5.1.1.1 
Analysis Time Points 
All data will be analyzed based on the visits identified per the Schedule of Activities in the 
protocol. 
Mapping to visit windows will not be applied.  For Early Withdrawal visits refer to 
Section 5.1.1.1.4. 
 
5.1.1.1.1 
Relative day 
Relative day for an event will be derived with the date of the first SC infusion of IMP as 
reference. 
Relative days for an event of measurement occurring before the date of first SC infusion will be 
prefixed with '-' and are calculated as follows: 
 
Relative Day = [(Event Date – Date of First Infusion)] 
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Relative days for an event or measurement occurring on or after the date of first SC infusion are 
calculated as follows: 
 
Relative Day = [(Event Date - Date of First Infusion) + 1] 
For events or measurements occurring after the date of the last SC infusion, relative day will be 
prefixed with ‘+’ in the data listings and are calculated as follows: 
 
Relative Day = + [(Event Date – Date of Last Infusion)] 
There is no relative Day 0. Relative day is not calculated for partial dates in cases where relative 
day is shown in a participant data listing. In such cases, relative day should be presented as ‘- -’ 
in the participant data listings. 
5.1.1.1.2 
End date of the Treatment Period 
The end date of the Treatment Period will be either the date of EOT visit (Week 25) for 
participants completing the Treatment Period, or the date of the early discontinuation (EDisc) 
visit for participants who discontinued during the Treatment Period. If a subject does not have 
an EOT/EDisc visit, then either the date of the last scheduled or unscheduled visit during the 
Treatment Period or the date of last known dose of IMP during the Treatment Period, whichever 
is later, will define the end date of the Treatment Period. 
5.1.1.1.3 
Study periods 
The maximum study duration per study participant is 38 weeks. There are 3 study periods:  
• Screening Period: up to 42 days; 
• Treatment Period: 24 weeks;  
• Safety Follow-Up Period: 8 weeks. 
The following definitions for starting and entering the study periods will be applied: 
• Screening Period starts at the time of the informed consent date and ends the day before the 
first dose administration of IMP (i.e. generally the day before Day 1 visit date). 
• Treatment Period starts on the day of first dose administration of IMP (Day 1) and ends at 
EOT visit or at EDisc visit for participants withdrawn from the study before Week 24 visit. 
Participants who are withdrawn from the study during the Treatment Period should 
complete the assessments outlined for the EOT/EDisc visit and enter the SFU Period.  
• Safety Follow-Up Period starts with one day after Treatment Period and ends at the final 
assessments at the EOS visit. Participants who have a completed status in the study 
termination CRF are considered to have completed the Treatment and SFU Period (i.e. 
entire study).  
Notes: 
• The end of the study is defined as the date of the last visit of the last participant in the study. 
• Patients should be dosed within 2 days of being randomized.  
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5.1.1.1.4 
Mapping of assessments performed at Early Discontinuation Visit 
Assessments performed at EDisc Visit will be assigned to the next scheduled site visit 
(following the last scheduled visit that the participant completed prior to EDisc Visit) where 
each assessment is evaluated as per protocol. This approach means that there is a chance that 
EDisc Visit will be mapped to different visits according to the schedule of assessments. 
5.1.1.1.5 
Definition of Baseline values 
Baseline will be derived in the screening period prior to randomization for efficacy assessments 
including RBANS, seizure counts, and on the date of randomization for PK/PD markers prior to 
the first dose of IMP. If there are multiple assessments, then the last one available prior to the 
randomization date will be used. Scheduled or unscheduled measurements can be used as the 
Baseline value. If a Baseline measurement is not available, but an unscheduled measurement 
occurs after the planned baseline measurement time point but before randomization, then the 
unscheduled measurement will be used. 
For Modified Rankin Scale (mRS), the Baseline score will be the better (i.e., the lower) score 
from either the Screening or Baseline visit. 
For safety assessments, a Baseline value will be the last available predose value if not otherwise 
stated.  
5.1.1.1.6 
Calculation of Baseline Category of Seizure Count  
The median category of seizure count will be calculated for each week of the screening period 
up to 6 weeks prior to randomization, and the average median value will be used as the Baseline 
category of seizure count. 
5.1.1.2 
Protocol Deviations 
Important protocol deviations (IPDs) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or on the primary efficacy, key safety, or PK/PD 
outcomes (if applicable) for an individual study participant. The criteria for identifying 
important protocol deviations will be defined within the appropriate protocol-specific 
document. Important protocol deviations will be reviewed as part of the ongoing data cleaning 
process and data evaluation. All IPDs will be identified and documented prior to unblinding. 
5.1.1.3 
Treatment assignment and treatment groups 
If after unblinding it is determined that study participants at any time receive incorrect treatment 
from their randomized assignment, then for safety and PK/PD analyses these study participants 
will be reallocated to the appropriate treatment group. For example, if study participants 
randomized to placebo received rozanolixizumab, then for the safety and PK/PD analyses, these 
study participants will be reallocated to rozanolixizumab. Study participants randomized to 
rozanolixizumab will only be reallocated to the placebo treatment group if they never received 
rozanolixizumab.  
Efficacy and safety data will be summarized by randomized treatment group as shown below:  
• Placebo 
• Rozanolixizumab 
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5.1.1.4 
Center pooling strategy 
It is planned to recruit participants in North America, Europe, Australia, and Asia in this study. 
The data from all sites will be pooled for analyses.  
5.1.1.5 
Coding dictionaries 
Adverse events (AEs) and medical histories will be coded using version 24.1 or later of the 
Medical Dictionary for Regulatory Activities (MedDRA®).  
Medications will be coded according to B3 version Mar 2021 or later of the World Health 
Organization Drug Dictionary (WHODD). 
5.1.1.6 
Multicenter studies 
Individual center results will not be displayed. 
5.1.1.7 
Multiple comparisons/multiplicity 
A fallback hierarchical testing procedure was planned to be implemented to control the overall 
type I familywise error rate at 0.05 over the primary endpoint and the 4 defined secondary 
endpoints. See details in Section Error! Reference source not found..   This however will no 
longer be implemented due to early study termination and the limited number of study 
participants. 
5.1.1.8 
Adjustments for covariates 
The efficacy analyses was planned to be adjusted for the following stratification factors (as 
randomized). This adjustment or any summaries that were planned by these factors, will no 
longer be possible due to the limited number of participants 
• Time from disease onset (≤6 months or >6 months from the disease onset), 
• Cognitive function (RBANS score of ≤85 or >85 at the Screening). 
5.1.2 
Rescue medication 
Rescue medication considered most appropriate for the study participant will be selected by the 
investigator. The study site will supply rescue medication that will be obtained locally.  
Study participants who require rescue medication will discontinue IMP and complete the 
assessments for the Early Discontinuation Visit.  
5.1.3 
Missing Data Strategies for efficacy analyses 
Table 5‒1: 
Missing data strategies for the analysis of efficacy endpoints 
Efficacy endpoint 
Statistical analysis 
category 
Statistical 
Analysis Methods 
Imputation Method 
Primary 
Primary 
OR 
Any missing daily seizure 
count in a given reporting 
period will be (indirectly) 
imputed with the daily 
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average seizure count 
observed in that period 
OR: odds ratio 
5.2 
Participant Dispositions 
The following summary outputs will be presented. 
• Reasons for screen failures (as collected on the Study Termination Screen Failure CRF 
page) will be summarized using the ES.  
• Disposition of study participants screened will be summarized using the ES for overall, 
by region and by site. In this summary, the site number, principal investigator name, first 
participant in date, last participant out date, will be captured by randomized treatment and 
by each analysis set (RS, SS, FAS). 
• Disposition of Analysis Sets will be summarized by treatment group and overall for each 
analysis set (RS, SS) using the RS. 
• Disposition and Discontinuation Reasons will be tabulated using the RS, and will contain 
the number and percentage of study participants by treatment group and overall who: 
◦ 
Started Treatment Period / SFU Period 
◦ 
Ongoing Treatment Period / SFU Period 
◦ 
Completed Treatment Period / Study 
◦ 
Discontinued Treatment Period / Study 
Primary Reason for discontinuation (reason for treatment discontinuation as collected in the 
Study Medication Discontinuation CRF and primary reason for premature study termination 
as collected in the Study Termination Complete/Dropout CRF). 
• Discontinuation due to AEs will be summarized by treatment group and overall for the 
following types of AEs using the RS: 
− AE, serious fatal, 
− AE, non-fatal, 
− Other (AE, non-serious fatal). 
Listings of study participant disposition, study discontinuation and study participants who did 
not meet study eligibility criteria will be provided.   The impact of COVID data will be listed. 
5.3 
Primary Endpoint Analysis 
5.3.1 
Definition of endpoint 
Participants who reported no seizures for 28 consecutive days and maintained the seizure count 
as zero until the end of Treatment Period will be treated as meeting the primary endpoint.  
For the purpose of deriving the primary efficacy endpoint, any intermittent missing diary  
 
 
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seizure count recording will not be imputed but considered as non-zero for the purposes of the 
primary endpoint.  
A by-participant listing of daily seizure count will be provided, including seizure freedom, time 
to first occurrence of seizure freedom, time to seizure freedom, and duration of seizure freedom.  
. 
5.3.2 
Main analytical approach 
Participants meeting the primary endpoint will be defined using the strategies indicated below: 
Estimand attributes: 
1. Treatment conditions:  
− Rozanolixizumab: Subcutaneous infusion, 
  
− Placebo: Subcutaneous infusion, 0.9% sodium chloride aqueous solution (physiological, 
saline, preservative free). 
2. Population of interest: Study participants with LGI1 AIE who comply with the inclusion and 
exclusion criteria (Protocol Section 5.1 and Section 5.2). 
3. Endpoint: Seizure freedom (defined by 28 consecutive days of no seizures) maintained until 
the end of the Treatment Period (Week 25). 
4. Intercurrent events (ICE) / Intercurrent Event Strategy (ICES) and missing data strategies: 
o ICE1: Temporary discontinuation from the IMP 
o ICE2: Permanent discontinuation from the IMP 
 The strategies to handle ICEs are summarized below: 
Table 5‒2: 
Intercurrent events (ICE) / Intercurrent Event Strategy (ICES) and 
missing data strategies for the analysis of the primary endpoint 
ICE 
ICE Strategy 
Missing Data Strategy 
ICE1 
Treatment Policy: The occurrence of 
intercurrent event ICE1 doesn’t affect the 
assessment of primary endpoint. All seizure 
counts collected during the treatment period will 
be included in the assessment of primary 
endpoint. 
See Section 5.1.3 for 
details. 
 
ICE2 
 
Composite strategy: Permanent discontinuation 
of the IMP will be considered as non achieving 
seizure freedom (non-responder). 
5. Population-level summary: 
On the RS, odds ratio will be calculated to investigate the association between the treatment and 
chance to reach primary endpoint.  
The ICEs will be handled per Table 5‒2.  
The data will be summarized in 2 × 2 contingency table:  
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Table 5‒3: 
2 × 2 contingency table 
 
Rozanolixizumab 
Placebo 
Row Total 
Seizure Freedom 
A 
B 
A + B 
No Seizure Freedom 
C 
D 
C + D 
Column Total 
A + C 
B + D 
N 
Note: A, B, C and D are the number of participants in the cells of the 2 × 2 table. N represents the total number of 
participants. 
Hypothesis testing 
Due to the low number of participants randomized to treatment there will be no hypothesis 
testing for the efficacy endpoints.   
Treatment effect estimation 
The OR estimate with its 95% CI will be reported in a summary table using the RS.  
The estimate of OR will be computed as (see Table 5‒3) 
𝑂𝑅
̂ = 𝐴𝐷
𝐵𝐶  
and reported to assess the strength and direction of the association with its 95% CI. Resulting 
OR>1 indicates a clinical benefit from the RLZ, and the magnitude from 1 shows its strength.  
In the case where none of the Placebo subjects reaches the primary endpoint, the calculation of 
the odds ratio estimate is not feasible as it requires division by zero (B = 0). In this situation, the 
OR is not estimable and the median unbiased estimator of the odds ratio (lower end of the 1-
sided 50% CI) and 1-sided exact 95% CI will be reported. 
5.4 
Secondary Endpoints Analyses 
All secondary efficacy endpoints will be summarized only and not tested for statistical 
significance due to the low number of participants recruited due to the study being terminated 
early.   
5.4.1 
Change in cognitive function (RBANS) 
RBANS 5 domain index scores and total scale index score will be captured and calculated at the 
Screening visit, then post-Baseline visits 8, 16, 26, early treatment discontinuation visit and end 
of study visit according to the RBANS US v2.0 (13Nov2019) (see Section 6.2). The last 
available results of RBANS scores prior to first dose will be served as Baseline. 
The observed Baseline and post-Baseline RBANS total scale index score at each scheduled visit 
where RBANS is collected will be summarized using descriptive statistics by randomized 
treatment group, together with the changes from Baseline. A by-participant listing of RBANS 
scores will be provided. 
5.4.2 
Change in overall disability: mRS 
The mRS score will be captured according to the mRS manual (see Section 6.3). 
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The observed Baseline and post-Baseline mRS scores at each scheduled visit will be 
descriptively summarized on the RS by treatment group, together with the change from 
Baseline. 
A by-participant listing of mRS category/score will be provided. 
5.4.3 
Use of rescue medication due to an absence or loss of clinical 
benefits 
Use of rescue medications with associated reasons will be recorded as part of the assessment of 
prior and concomitant medications during the study. Participants with use of any rescue 
medications during Treatment Period due to an absence or loss of clinical benefit will be 
considered as meeting this endpoint. 
A by-participant listing of use of rescue medication, PT of rescue medications and associated 
reasons will be provided. 
5.4.4 
Time to first occurrence of seizure freedom (TTFSF) 
TTFSF will be summarized as a continuous variable by treatment group on the RS. A by-
participant listing of time to first occurrence of seizure freedom will be provided. 
5.5 
Exploratory Endpoints Analyses 
5.5.1 
Seizure control 
Seizure frequencies will be recorded on a daily basis across the 24 weeks of randomized therapy 
and during a variable Screening Period, based on the following categories: 
1. 0 seizures 
2. 1-5 seizures 
3. 6-10 seizures 
4. 11-20 seizures 
5. >20 seizures 
For each participant, a median category of seizure count categories will be calculated for each 
week that the participant is in the randomized treatment period, such that each participant has 
one average median category for that week, along with a minimum and maximum category 
range. In case of missing seizure count category, calculated median category will be rounded up 
to fit into the 5 categories. For example, if the calculated median is 2.5, then this value will be 
rounded up to 3 as the final median. 
For the Screening Period, a Baseline median category will be calculated for each participant, in 
the same way as described for each week of randomized treatment. This will be to utilize the 
screening data collected in the period up to 6 weeks immediately prior to randomization. 
The frequency counts and percentages of participants falling into each of the median categories 
across the 24 weeks will be summarized by treatment group using RS. 
In the case of 7 missing data points over an entire week, this will be imputed from the previous 
weeks data. For 1 week of data, the median will not be calculated if more than 5 missing values.  
.  
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5.5.2 
Duration of seizure-free period 
The duration of the seizure-free period will be measured from the first day the participant 
reports no seizures of at least 28 consecutive days until the last day reported without seizures 
during the Treatment Period. Missing daily seizure counts will be treated as non-zero reports, 
without any value assigned.   This statistic will be provided for each participant. 
The endpoint will be included on the listing related to participants seizures; listed on the RS and 
by  randomized treatment arm. 
5.5.3 
Change in RBANS domains 
The individual RBANS domain index scores (immediate memory, visuospatial/constructional, 
delayed memory, language, and attention) will be calculated per RBANS US v2.0 (13Nov2019) 
(see Section 6.2). 
The observed Baseline and post-Baseline individual RBANS domain index scores at each 
scheduled visit will be descriptively summarized on the RS by treatment group, together with 
the change from Baseline.   All scores will be listed for each participant; produced by 
randomized treatment arm. 
5.5.4 
Short Form 36-item (SF-36) 
By-participant listings of the SF-36 V2 questionnaire responses only, SF-36 V2 will be 
provided by treatment group. Domains and component scores will not be calculated.  
5.5.5 
Euro-Quality of Life 5-Dimensions, 5 Levels (EQ-5D-5L) 
The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual 
analogue scale (VAS). 
A by-participant listing  will be produced using the RS to summarize answers provided to each 
of the 5 dimensions of the EQ-5D descriptive system at each scheduled visit for each participant 
by treatment group. 
5.5.6 
Clinical Global Impression of Severity (CGI-S) 
The CGI-S is a clinician reported outcome that requires the clinician to assess how much the 
patient's illness has improved or worsened relative to a baseline state at the beginning of the 
intervention. 
A frequency table will be produced using the RS to summarize answers provided to the CGI-S 
(“none,” “mild,” “moderate,” “severe", “very severe”) at each scheduled visit by treatment 
group 
A by-participant listing of CGI-S will be provided. 
If any other data is available on PGI-S, PGI-C for any participants this will be listed. 
5.6 
Safety Analyses 
All safety analyses will be presented using the RS unless RS and SS are different and then SS 
will be used. Listings will be presented by treatment group, participant, and stratification factors 
(time from the disease onset and RBANS score, see Section 5.1.1.8); tabulations will be 
presented by treatment group  .  Unless otherwise specified, safety analyses will be presented by 
safety treatment group as defined in Section 4.3.  
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5.6.1 
Extent of Exposure 
The following summaries will be generated using descriptive statistics based on the SS: 
a) Study IMP duration (day) calculated as follow: 
Study IMP duration (day) = Date of last dose – Date of first dose + 1 
If data cut-off is applied and date of last dose > date of cut off, date of last dose will be 
replaced by the cut-off date in the above formula. 
b) Cumulative study IMP Duration using > 0 weeks, ≥ 4 weeks, ≥ 8 weeks, ≥ 12 weeks, ≥ 
16 weeks, ≥ 20 weeks, and 24 weeks; 
c) Number of Infusions Received as continuous and using the following categorical values: 
1-4, 5-8, 9-12, 13-16, 17-20, and 21-24;  
All drug administration details will be listed. 
5.6.2 
Adverse Events 
5.6.2.1 
Data considerations 
Adverse events will be recorded from the time of informed consent until study completion. All 
AEs will be coded (see Section 5.1.1.5). 
In addition, AEs will be classified according to the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5 or later for severity. For any AEs where it is not possible to provide 
a CTCAE grading, the events will be assessed using a standard intensity classification (mild, 
moderate and severe). For the purpose of the tabulations all CTCAE severity classifications will 
be mapped to a mild/moderate/severe grade as described below: 
Grade: Intensity 
• Grade 1 - Mild 
• Grade 2 - Moderate 
• Grade 3, 4, 5- Severe  
These will be tabulated together with the AEs that were not classified according to CTCAE 
criteria i.e., all Grade 1 AEs as per CTCAE criteria will be included in the ‘mild’ category 
together with those AEs classified as mild as per the ‘standard’ intensity classification. In the 
case a mapped standard intensity classification per above rule is different from the standard 
intensity classification on CRF, the worst case will be used as the standard intensity 
classification (i.e., an AE with Grade 1 and moderate as intensity classification will be classified 
into moderate). 
Any AE that occurred during the study will be defined as “any AE”.  
A TEAE is defined as an AE starting on or after the time of first administration of IMP or any 
unresolved event already present before the first administration of IMP that worsens in intensity 
following exposure to treatment up to the end of the Treatment Period and including the 8-week 
(56 days) SFU. Adverse events starting before the date of the first administration of IMP or after 
SFU will not be considered TEAEs. Such events will be listed only. 
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Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent 
unless evidence exists that does not allow the AE to be treatment-emergent. Handling of 
missing dates for classification of AEs as TEAEs is described in Section 6.1.7.1.2. 
The following rules will be used to assign a TEAE to a study period: 
• Treatment Period: a TEAE will be assigned to the Treatment Period for the tabulations if 
the start date of the event is on or after the date of the first administration of IMP on Day 1, 
up to 7 days following the final dose of IMP;  
• SFU Period: a TEAE will be assigned to the SFU Period for the tabulations if the start date 
of the event is greater than 7 days after the date of the final dose of IMP until 8 weeks 
following the final dose; events starting later than 8 weeks (56 days) following the final 
dose of IMP are not considered TEAEs. 
In the case of early withdrawal in the Treatment Period, a TEAE will be assigned to the 
Treatment Period based on the last received IMP plus 168 hours (7 days). Subsequent TEAEs 
(up to 8 weeks (56 days) post-last dose) will be assigned to the SFU Period. 
A TEAE will be counted as a TEAE related to IMP if the response to the question “Relationship 
to Study Medication” is “Related”. Severe TEAEs are those with CTCAE Grade 3 or above, or 
those without a CTCAE grading classified as ‘severe’ by the Investigator. 
AEs will be presented as “number of participants (percentage of participants) [number of 
events]”.  In this style of output, “[number of events]” will include all cases of an AE including 
repeat occurrences in individual participants, while “number of participants” will count each 
participant only once. 
5.6.2.2 
Adverse events summaries 
The number and percentage of participants who experience AEs will be summarized by 
treatment group. The following outputs will be created: 
• Incidence of TEAEs (defined as the number and percentage of participants with at least one 
TEAE (incidence proportion) – Overview. The following categories will be included by 
treatment arm: 
− Any TEAEs 
− Serious TEAEs  
− Participant discontinuation due to TEAEs (defined as TEAEs with “Did the Adverse 
Event Lead to Dropout ticked” as “Yes”) 
− Permanent withdrawal of IMP due to TEAEs (defined as TEAEs with an action taken 
with study medication of “drug permanently withdrawn”) 
− Temporary withdrawal of IMP due to TEAEs (defined as TEAEs with an action taken 
with study medication of “drug temporarily interrupted”) 
− Treatment-related TEAEs  
− Severe TEAEs  
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All Deaths (AEs leading to death). Note: Above TEAEs will be summarized to capture the 
overall and by MedDRA Primary SOC (PSOC), Higher level term (HLT) and PT. 
Additionally, the frequency of TEAEs will be summarized by MedDRA PSOC and PT. 
• The number, percentage of participants and frequency of the following TEAEs will be 
summarized by SOC, HLT and PT for:  
− Incidence of any TEAEs  
− Incidence of Serious TEAEs 
− Incidence of Permanent withdrawal of IMP due to TEAEs  
− Incidence of Any TEAEs by Maximum Intensity (mild, moderate and severe)Incidence 
of Any TEAEs by Relationship 
− Incidence of Any TEAEs by Event Outcome 
− Incidence of any TEAE’s per 100 Patient years. 
AESIs are the cases of potential Hy’s Law (see Section 6.1.9). 
AESMs or AESIs will be identified based on the assessment by the Investigator as recorded in 
the CRF. An AE will be counted as an AESMs or AESIs if there is a ‘yes’ response to the 
question “Adverse Event of Special Interest or Event of Special Monitoring?” and not 
otherwise. These flags will be included in the listings. 
When applicable, adverse event summaries will be ordered by alphabetical SOC, alphabetical 
HLT within SOC and decreasing frequency of PT in the rozanolixizumab total column for 
tables.  
Listings of all AEs, permanent withdrawal of IMP due to AEs, participant discontinuation from 
study due to AEs, and AEs leading to death will be presented by treatment group. 
5.6.3 
Additional Safety Assessments  
5.6.3.1 
Clinical laboratory evaluations 
The following Table 5‒ lists safety laboratory assessments that are collected throughout the 
study: 
Table 5‒9: 
Clinical Laboratory Parameters 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Indices: 
Mean corpuscular 
volume (MCV) 
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red Blood Cell (RBC) 
Count 
Hemoglobin 
Hematocrit 
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Laboratory 
Assessments 
Parameters 
Clinical Chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST) / Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and 
direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
 (ALT) / Serum Glutamic-
Pyruvic Transaminase 
(SGPT) 
Total Protein 
 
Glucose (non-
fasting) 
Calcium 
Alkaline phosphatase 
Albumin 
Lactate 
dehydrogenase 
(LDH) 
C-reactive 
protein 
(CRP) 
Low-density lipoprotein 
(LDL) 
High-density lipoprotein 
(HDL) 
Total cholesterol 
Triglycerides 
 
Routine Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
• Follicle-stimulating hormone (FSH) and estradiol (as needed in women of 
non-childbearing potential only) 
• Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) 
• Serum (at Screening) or urine (all other visits) human chorionic 
gonadotropin pregnancy test (as needed for women of childbearing 
potential)a 
• Serology testing (for Hepatitis A, Hepatitis B, Hepatitis C, and HIV) 
Note: The tests detailed in the table will be performed by the central laboratory. Local laboratory results are only 
required in the event that the central laboratory results are not available in time for either study treatment 
administration and/or response evaluation. 
a  IGRA, TB and Dipstick uri-analysis and urine pregnancy dipstick tests will be performed locally.  
Chemistry, hematology and quantitative urinalysis (observed value, absolute change from 
Baseline) will be listed in standard unit  by treatment group at each scheduled visit. 
All  lab data will be used for the listings.  
 
Measurements BLQ will be imputed with half of the lower limit of quantification LLOQ for the 
purpose of calculating change from Baseline. Measurements ALQ will be imputed to the upper 
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quantification limit for the purpose of any quantitative individual participant data.  These rules 
will be applied to all safety laboratory data including clinical chemistry and urinalysis. 
All central and local laboratory test results will be listed using the SS, including Baseline, 
scheduled and unscheduled visits with results in standard unit. Values outside the reference 
range for the continuous variables and any MA values will be flagged in the listings. The 
reference ranges will also be reported in the listings. Additional lab test, including pregnancy 
testing, will be listed separately.  
5.6.3.2 
Potential drug-induced liver injury (pDILI) 
The number and percentage of participants who meet one or more of the following pDILI 
criteria will be summarized by treatment group at any visit (including unscheduled visit): 
• Participants with at least one post-Baseline liver laboratory assessment 
• Incidence of potential hepatotoxicity with symptoms potentially associated with hepatitis or 
hypersensitivity 
• Incidence of potential hepatotoxicity with no symptoms potentially associated with hepatitis 
or hypersensitivity 
• Laboratory criteria for pDILI: 
− (AST or ALT ≥ 3 x ULN) and TBL ≥ 1.5 x ULN 
− (AST or ALT ≥ 3 x ULN) and TBL ≥ 2 x ULN 
− (AST or ALT ≥ 3 x ULN) and TBL ≥ 2 x ULN and ALP < 2 x ULN (Hy’s Law) 
In order to meet the above criteria, a study participant must experience the elevation in bilirubin 
and ALT or AST (and the absence of the ALP elevation) at the same visit. For example, a study 
participant who experiences a ≥2xULN elevation of bilirubin at one visit and a ≥3xULN 
elevation in ALT (or AST) at a subsequent visit has not fulfilled the Hy’s law criteria. If 
participant meets part of one criterion but at least one parameter is unknown, then he/she should 
not be considered for meeting the criterion. 
Additional analyses for liver function tests (LFTs) will be performed to assess the potential for 
liver toxicities in accordance with the United States Food and Drug Administration guidelines. 
Per guidelines, the following criteria will be used to define levels of LFT elevation: 
• Aspartate aminotransferase (AST): >3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x 
ULN 
• Alanine aminotransferase (ALT): >3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x 
ULN 
• AST or ALT: >3 x ULN, >5 x ULN, >8 x ULN, >10 x ULN, >20 x ULN 
• Total bilirubin (TBL): >1.5 x ULN, >2 x ULN 
• Alkaline phosphatase (ALP) >1.5 x ULN 
The number and percentage of study participants who meet one or more of the above LFT 
elevation criteria will be summarized by treatment group at any visit (including unscheduled 
visit). 
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A listing will also be provided for study participants who meet at least one of the above criteria. 
All results obtained at that visit for the specified parameters will be displayed. 
5.6.3.3 
Vital Signs 
A by-participant listing of all vital sign measurements and change from Baseline will be 
presented by treatment group and timepoint. The listing will include a flag for values identified 
as MA outlined in Section 6.5. 
Repeated and unscheduled measurements will be handled as described in Section 6.1.7.2. 
5.6.3.4 
12-Lead Electrocardiograms (ECG) 
The following 12-Lead ECG variables will be listed if the data is available.  (NB.  These 
assessments were removed from protocol amendment 4). 
− Heart rate 
− PR interval 
− RR interval 
− QRS duration 
− QT interval 
− QT corrected for heart rate using Fridericia’s formula (QTcF = QT/RR1/3) 
A listing of electrocardiogram data will be presented, including repeated and unscheduled 
measurements. Electrocardiogram findings for the individual triplicate measurements will be 
listed separately. 
5.6.3.5 
Physical examination 
Data from the Physical Examination are provided in subject data listings presented by treatment 
group, subject and visit, displaying all data collected for all subjects. No summaries will be 
provided. Findings that are considered clinically significant will be reported as AEs. 
5.6.3.6 
Neurological examination 
Data from the Neurological Examination are provided in subject data listings presented by 
treatment group, subject, and visit, displaying all data collected for all subjects. No summaries 
will be provided. Findings that are considered clinically significant will be reported as AEs. 
5.6.3.7 
Childbearing potential 
Childbearing potential will be collected at Screening. A by participant listing will be provided 
using the RS. 
5.6.3.8 
Assessment and management of Tuberculosis (TB) 
Results of the interferon gamma release assay (IGRA) TB test, chest X-ray and TB signs and 
symptoms questionnaire for TB will be listed. 
5.6.3.9 
Headache questionnaire 
The results of the headache questionnaire will be listed for each participant. 
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5.6.3.10 
Suicidal risk monitoring 
Suicidal ideation is defined as an event in any of the following 5 categories: 
Suicidal behavior is defined as an event in any of the following 5 categories: 
Suicidal behavior or ideation is defined as an event in any of the above 10 categories. 
Self-injurious behavior without suicidal intent is corresponding to the response to 
 
 in questionnaire. 
A by-participant listing of the C-SSRS questionnaire data will be provided by treatment group if 
this data is reported by any participant in the study 
5.7 
Other Analyses 
5.7.1 
Other endpoints and/or parameters  
All analyses described in Section 5.7.1.1 will be performed on the RS, and all other analyses 
will be performed on Safety set. 
5.7.1.1 
Pharmacokinetics 
5.7.1.1.1 
Rozanolixizumab 
All analyses described in this section will be based on the RS. 
Individual plasma concentrations of rozanolixizumab will be summarized by scheduled 
sampling day for the RS on an individual participant basis due to the low participant numbers. 
• Scatter dot plot of individual rozanolixizumab postdose plasma concentrations categorized 
by Day (Days 3, 5, 164, 166) with all days in the same plot. 
The following rules will apply for PK data listings and summaries: 
• Values below the LLOQ will be reported as below the limit of quantification (BLQ) 
• Descriptive statistics of concentrations will be calculated if at most 1/3 of the individual data 
points at a timepoint are missing or are not quantifiable (<LLOQ). Values that are BLQ will 
be replaced by the numerical value of the LLOQ/2 in this instance. If more than 1/3 of the 
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individual data points at a timepoint are missing or are not quantifiable, then only n, 
minimum, median and maximum will be presented. The other descriptive statistics will be 
left blank.  
• If n<3, then only the n, minimum and maximum will be presented. If no study participants 
have data at a given timepoint, then only n=0 will be presented. 
• The 95% CI lower and 95% CI upper should be left blank if the SD (or equivalently, the 
geoCV) is 0 
• The geoCV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data 
geoCV(%) = √exp(SD2) −1 × 100. 
Individual concentrations of rozanolixizumab will be listed for the RS and will include the 
actual sampling time in days relative to the previous dose and the IgG observed at the same 
visit, for the same visit, IgG and IgG subclasses by achievement of primary endpoint of seizure 
freedom (yes/no).  
5.7.1.2 
Pharmacodynamics 
All analyses described in this section will be based on the RS.    
5.7.1.2.1 
Total serum Immunoglobulin G (IgG) and IgG subclasses 
Total serum IgG concentrations will be summarized by treatment group and time point for 
observed values, change from Baseline, and percentage change from Baseline.  
The maximum absolute and percentage decrease from Baseline in total serum IgG and IgG 
subclasses will be summarized for each treatment. In the event that a decrease from Baseline is 
not observed in a given participant, the maximum decrease will be reported as the smallest 
increase from Baseline.  
The following plots will be generated: 
• Geometric mean change from Baseline values in total serum IgG, IgG subclasses over time 
by treatment group, with all PD endpoints and treatment groups overlaid on the same plot.  
• Spaghetti plots for absolute IgG over time stratified by treatment group. 
• Serum concentrations of total IgG and IgG subclasses will be listed together with 
concentrations of rozanolixizumab,  LGI1 serum and CSF levels by achievement of primary 
endpoint of seizure freedom (yes/no), as specified in Section 5.7.1.1. 
5.7.1.2.2 
Serum concentrations of 
 will be listed 
together with concentrations of rozanolixizumab,  LGI1 serum and 
CSF levels by achievement of primary endpoint of seizure freedom 
(yes/no), Leucine-Rich Glioma Inactivated 1 (LGI1) autoantibody 
levels 
LGI1 autoantibody serum levels will be summarized at scheduled visit for observed values, 
absolute and percentage changes from Baseline. Same summary will be repeated for LGI1 
autoantibody CSF levels for consenting participants. Individual participant will be plotted 
representing percentage change from Baseline in LGI1 autoantibody serum levels, total IgG, 
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IgG1 and IgG4 with all endpoints in the same plot and indication of dosing time points and flag 
if dosing was missed. The sub-title of the graph will include achievement of primary endpoint 
of seizure freedom (yes/no).  
LGI1 autoantibody serum levels and CSF levels will be listed, together with total IgG, IgG 
subclasses as described in Section 5.7.1.2.1. 
It should be noted that these summaries and plots will not be produced for the CSR as the data 
will not be available. 
5.7.1.3 
ADA will not be performed or evaluated in this study. Immunology 
All analyses described in this section will be based on the SS. 
Serum complements levels and plasma complement levels Serum 
 and plasma (
 
) complement variables will be listed by visit and time point including changes from 
Baseline. Descriptive summaries will be presented for both absolute values and changes from 
Baseline for all participants, and separately for participants who experience an infusion reaction 
or hypersensitivity reaction at site. The selection criteria of infusion reaction or hypersensitivity 
reaction are described in Section Error! Reference source not found.. 
Measurements BLQ will be imputed with half of the LLOQ for the purpose of calculating 
change from Baseline. Measurements above the limit of quantification (ALQ), if applicable, 
will be imputed to the upper limit of quantification. 
5.7.1.4 
Healthcare resource utilization 
The following data, if it is available, will be listed  by treatment group on the RS. a: 
• Number of participants with hospitalization/ ER visit 
• Total number of hospitalization/ ER visit 
• Reason of hospitalization/ ER visit 
• Number of participants discharged from hospitalization/ ER visit 
• Total number of days in hospitalization/ ER visit, calculated as follow: 
Note: / 
• Total number of days in hospitalization/ ER visit = Discharge date – hospitalization/ER visit 
date +1. If a participant does not have discharge date, last available visit date will be used. 
• Only hospitalization started after first IMP and before last visit will be considered in the 
summary. 
• In case of missing or incomplete discharge date, the following imputation rules will be 
applied: 
− Hospital start date of next hospital stay – 1 as end date of this hospital stay; 
− Death date in case subject died and previous case does not apply; 
− Last visit date if previous cases do not apply. 
A listing will be provided for the hospitalization/ ER visit. 
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5.8 
Interim Analyses 
There is no interim analysis planned for this study. 
5.9 
Data Monitoring Committee (DMC) 
There is no individual DMC set up for this study. Instead, an overarching Rozanolixizumab 
program independent DMC (PiDMC) will oversee the safety of this study by reviewing safety 
data at periodic data reviews in collaboration with other Rozanolixizumab studies. The timing 
and data required for the overarching PiDMC will be described in overarching 
Rozanolixizumab PiDMC charter. 
6 
SUPPORTING DOCUMENTATION 
6.1 
Non-key analysis specifications 
6.1.1 
Baseline characteristics and demographics 
Unless otherwise specified, all summaries will be based on the RS. 
6.1.1.1 
Demographics 
Demographic variables will be summarized using descriptive statistics by treatment group and 
overall on the RS for categories mentioned below.  
Categories for continuous variables (including n, mean, SD, Median, Min and Max): 
• Age at the time of first study entry (years), 
Note: Missing age (captured on Demographics CRF) will be calculated as year of informed 
consent signed – year of birth 
• Weight (kg), 
• Height (cm), 
• BMI (kg/m2) calculated as: 𝐵𝑀𝐼= 
Weight (kg)
(Height (m))2; 
Categorical variables (using frequency counts and percentages): 
• Age (18 -<65, 65 - <85, ≥85 years), 
• Age (≤18, 19 -<65, ≥65 years), 
• BMI (<30, ≥30 kg/m2), 
• Weight (35kg-<50 kg, 50-<70kg, 70-<100kg, ≥100kg), 
• Gender (Male, Female), 
• Race (American Indian or Alaska native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Other/Mixed), 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino), 
• Region (North America, South America, Europe, Australia, Asia [excluding Japan], Japan 
and Africa), 
• Country. 
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• Alcohol Use 
A by-participant listing of demographics will be provided.  
Childbearing potential will also be listed for the RS separately. 
6.1.1.2 
Baseline disease characteristics 
The following variables will be summarized using descriptive statistics on the RS by treatment 
group and overall. All baseline characteristics will be provided in by-participant listings using 
the RS. 
Continuous variables (including n, mean, SD, Median, Min and Max): 
• Baseline RBANS score 
• Baseline total IgG value 
• Baseline LGI1 level 
Categorical variables (using frequency counts and percentages): 
• Baseline median category of seizure count over the Screening Period (1: 0 seizures, 2: 1-5 
seizures, 3: 6-10 seizures, 4: 11-20 seizures, 5: >20 seizures) 
• Time from disease onset (≤6 or >6 months) 
• Cognitive function (RBANS score of ≤85 or >85) 
• Baseline AIE medication 
• Baseline mRS score 
Notes: 
• Historical seizures will be listed only: 
− Number of seizures (Week of any seizure experienced during the past 2 weeks prior to 
screening visit (week -2 or week -1)) 
− Seizure description experienced during the past 2 weeks prior to screening visit 
• Time from disease onset and cognitive function (RBANS score) will be based on the values 
recorded in the eCRF.  This should be the same as the data entered into the interactive web 
response system (IWRS) at randomization, if for any reason eCRF values are missing then 
IWRS will be used. 
• Baseline AIE medication will be collected in Prior and Concomitant Medication CRF where 
indication is AIE and presented by Preferred Terms. 
6.1.2 
Protocol deviations 
A by-participant listing of important protocol deviations will be provided using the RS. 
6.1.3 
Medical history 
Previous and ongoing medical history will be listed using the RS. Besides, procedure history 
will be provided in a separate by-participant listing using the RS. 
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6.1.4 
Prior/concomitant/follow-up medications 
Participants taking Past, Prior, Baseline, Concomitant or Concomitant Only medications will be 
listed  using the RS by Anatomical Therapeutic Chemical (ATC) class, presenting as 
Anatomical Main Group (ATC Level 1), Pharmacological Subgroup (ATC level 3), PT, 
treatment group and overall. The number and percentage of participants taking rescue 
medications identified on CRF will be summarized using the RS. 
Medications classified as past, prior, baseline, concomitant or concomitant only will be listed 
using the RS. A by-participant listing of concomitant procedures will also be listed using the 
RS. Originally reported dates will be used for listings. 
6.1.4.1 
Categories of prior and concomitant medications 
Definitions:  
• Past Medications: defined as any medications that started and stopped before the first 
administration of IMP.  
• Prior Medications: defined as any medications that started before the first administration of 
IMP. 
• Baseline Medications: defined as any medications that started prior to dosing and 
continued after (classified as prior and concomitant medications). 
• Concomitant Medications: defined as any medications that have been taken at least once 
after the first administration of IMP during the Treatment and/or SFU Period.  
• Concomitant Only Medications:  defined as any medication that started after the first 
administration of IMP and continues during the Treatment and/or SFU Period. 
Table 6‒1 below summarizes concomitant medication classification with details around 
medication start and finish. 
Table 6‒1: 
Prior and Concomitant Medications Classification 
Medication Started 
Medication finished 
Classification 
Before 1st Dose IMP 
Before 1st Dose IMP 
Past 
Before 1st Dose IMP 
Any time 
Prior 
Before 1st Dose IMP 
After 1st Dose IMP 
Baseline (= prior and 
concomitant) 
Any time 
After 1st Dose IMP 
Concomitant 
After 1st Dose IMP 
After 1st Dose IMP 
Concomitant Only 
6.1.4.2 
Assignment of Treatment and/or SFU Period 
The following rules will be used to assign a Prior, Baseline, Concomitant or Concomitant Only 
to following two study periods: 
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• Treatment Period: a medication will be assigned to the Treatment Period if the start date of 
the medication is on or after the date of the first administration of IMP on Day 1, up to 7 
days following the final dose of IMP. This includes medications that started prior to the 
Treatment Period and those that continued into the SFU Period.  
• SFU Period: a medication will be assigned to the SFU Period if it has been taken at least 
once from the day after Treatment Period to the EOS visit. This includes medications that 
started prior to the SFU Period.  
6.1.5 
Rescue medications 
Rescue medication considered most appropriate for the study participant will be selected by the 
investigator. The study site will supply rescue medication that will be obtained locally. The 
effect of rozanolixizumab on the efficacy of IgG biologics and Fc-fusion proteins is not known. 
6.1.6 
Antiepileptic Drug (AED) 
The number and percentage of subjects receiving AEDs (determined by medical review) over 
the course of the study will be summarized using the RS. Data will be presented at 6-week 
intervals (i.e., at Week 6, 12, 18 24 etc.). 
6.1.7 
Data derivation rules 
6.1.7.1 
Handling of dropouts or missing data 
6.1.7.1.1 
Efficacy data 
Seizure freedom, time to seizure freedom,  will be derived based on the weekly reported seizure 
frequency categories  captured on Seizure Count CRF. Imputation methods to handle the 
missing data (including missing data due to intercurrent events)  
In the case of all other endpoints (RBANS and mRS), the observed case method will be applied.    
This is also the case for any  ordinal endpoints (EQ-5D-5L, CGI-S). No imputation of data will 
be applied.   
6.1.7.1.2 
Dates and times 
Partially or completely missing dates may be imputed for the following reasons: 
• Classification of AEs as TEAEs; 
• Classification of medications as past, prior, or concomitant medications;  
• Durations of AEs. 
• Imputed dates will not be shown in listings.  All dates will be displayed as reported in the 
database. 
The following rules will be applied for partially or completely missing start dates: 
• If year, month and day are all missing then assign the date of first dose of IMP. If an 
imputed start date is after the specified end date, then assign January 01 of the year of the 
end date, or the date of screening if this is later (if the latter imputation results in an end date 
that is earlier than the start date, then use January 01). 
• If month and day are missing, and year is: 
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− the same as the year of the first dose of IMP then assign the month-day of first dose of 
IMP. If the imputed start date is after the specified end date, then assign January 01, or 
the month-day of screening date if this is later (if the latter imputation results in an end 
date that is earlier than the start date, then assign January 01); 
− not the same as the year of the first dose of IMP then assign January 01. 
• If only day is missing, and month-year is: 
− the same as the month-year of the first dose of IMP then assign the day of first dose of 
IMP. If the imputed start date is after the specified end date, then assign first day of the 
month, or the day of screening date if this is later (if the latter imputation results in an 
end date that is earlier than the start date, then assign first day of the month); 
− not the same as the month-year of the first dose of IMP then assign the first day of the 
month. 
The following rules will be applied for partially or completely missing stop dates: 
• If only the month and year are specified, then use the last day of the month. If an imputed 
stop dates is after last contact date, then assign last contact date as the stop date; 
• If only the year is specified, then use December 31 of the known year. If an imputed stop 
dates is after last contact date, then assign last contact date as the stop date; 
• If the stop date is completely unknown, then use discharge date or data cut-off date. 
Discharge date refers to the date of the end of study visit for completed participants or the 
date of discontinuation for participants that were withdrawn. For any AEs with known start 
date after the date of discontinuation, the date of last contact will be used as the discharge 
date. For participants still ongoing in the study at the time of the data cut-off, and for whom 
no discharge date is available, the date of the data cut-off will be used instead of the 
discharge date. 
Any medication with a start date on the first dosing date and time unknown, will be assumed to 
be concomitant. 
Imputed AE dates will be used for the calculation of duration of AEs as described in Table 6‒2.  
Table 6‒2: 
Calculation Rules for Duration of AEs 
Data 
availability 
Onset 
date 
Outcome 
date 
Calculation rules 
Complete data 
D1 
D2 
Duration = D2 – D1 + 1  d 
Start date 
partially or 
completely 
missing 
-- 
D2 
Duration ≤ D2 – D0 + 1 d 
Notes: D0 is imputed start date per above rules.  
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Data 
availability 
Onset 
date 
Outcome 
date 
Calculation rules 
End date 
partially or 
completely 
missing 
D1 
-- 
For ongoing AE: 
Duration ≥ D3 – D1 d 
For resolved AE: 
Duration ≤ D3 – D1 d 
Notes: D3 is imputed end date per above rules.  
Start and end 
date partially or 
completely 
missing 
-- 
-- 
For ongoing AE: 
Duration ≥ D3 – D0 d 
For resolved AE: 
Duration ≤ D3 – D0 d 
Notes: D0 is imputed start date and D3 is imputed end 
date per above rules. 
6.1.7.2 
Handling of repeated and unscheduled measurements 
All repeated and unscheduled measurements will be presented in the listings, where applicable. 
The following general rules will apply to all repeated and unscheduled measurements: 
• For repeated or unscheduled measurements obtained prior to the first dose of IMP the latest 
non-missing value (scheduled or unscheduled) will be used in the calculation of descriptive 
statistics (ie, Screening and/or Baseline); 
• For repeated or unscheduled measurements obtained at the designated Baseline visit and 
prior to the first dose of IMP, the latest non-missing value (scheduled or unscheduled) will 
be defined as the Baseline;  
• For repeated or unscheduled measurements obtained at any time point after the first dose of 
IMP, the scheduled values (if non-missing) will always be used in the calculation of changes 
from Baseline and for the descriptive statistics (ie, in summaries by time point). If repeated 
scheduled values are obtained at any time point, the latest non-missing will be used. 
See Section 5.6.3.1 for the rules applied to repeated lab results. 
See Section 5.6.3.4 for the rules applied to ECG triplicate measurements. 
6.1.8 
Treatment Compliance 
Not applicable. The number of infusions will be recorded as detailed in Section 5.6.1. 
6.1.9 
AEs of Special Interest 
Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total bilirubin 
(>35% direct bilirubin) in the absence of ≥2xULN ALP, with no alternative explanation for the 
biochemical abnormality must always be reported to UCB as an AESI (ie, without waiting for 
any additional etiologic investigations to have been concluded). 
6.2 
Appendix 1: RBANS 
To be added. 
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6.3 
Appendix 2: mRS 
The mRS is a commonly used scale for measuring the degree of disability or dependence in the 
daily activities of people who have suffered a stroke or other causes of neurological disability. 
The scale runs from 0 (perfect health) to 6 (death). 
 Modified Rankin Scale 
 
6.4 
Appendix 3: Classification of the SF-36v2 questionnaire 
 
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Table 6‒3: 
SF-36v2® Health Survey Acute, United States 
 
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6.5 
Appendix 4: Markedly abnormal criteria for Rozanolixizumab 
program 
The following criteria will be applied in the determination of marked abnormalities for 
laboratory assessment values. They are based on Version 5 of the Common Terminology 
Criteria for Adverse Events (CTCAE) grade 3 or higher criteria unless otherwise noted. If both 
high and low criteria are shown for a parameter, the criteria should be summarized separately in 
tabular or graphical data summaries.   
Table 6‒4: 
Hematology 
Parameter 
Unit 
(conventional) 
Unit 
(standard) 
Marked Abnormality 
Criteria 
Hemoglobin  
g/dL 
 
g/L 
<8.0 g/dL; <80 g/L  
WBC (Leukocytes)1 
109/L 
109/L  
Low: <2.0 x 109/L  
High:  >30 x 109/L  
Lymphocytes 
Absolute 
109/L 
109/L  
Low:  <0.5 x 109/L  
High: >20 x 109/L 
Neutrophils Absolute  
109/L 
109/L  
 <1.0 x 109/L   
Platelets 
109/L 
109/L  
<50.0 x 109/L  
1WBC (Leukocytes) markedly abnormal high criterion is not based on Version 5 CTCAE Grade 3 or higher 
criteria. Due to the mechanism of action of RLZ, the safety alert is related to infection risk which would be 
identified by a lower cut-point than the standard which is related to acute leukemias. A markedly abnormal high 
cut-point >30 x 109/L is applied to flag leukocytosis (George 2012). 
Table 6‒5: 
Chemistry 
Parameter 
Unit 
(conventional) 
Unit 
(standard) 
Marked Abnormality Criteria 
AST (SGOT) 
U/L 
U/L 
>5.0 x ULN  
ALT (SGPT) 
U/L 
U/L 
>5.0 x ULN  
ALP (Alkaline 
Phosphatase) 
U/L 
U/L 
>5.0 x ULN  
GGT (Gamma 
Glutamyl 
Transferase) 
U/L 
U/L 
>5.0 x ULN  
Bilirubin (Total) 
mg/dL 
umol/L 
>3.0 x ULN if Baseline value is normal; 
>3.0 x Baseline value if Baseline is 
abnormal  
Albumin 
g/dL 
g/L 
<2 g/dL; <20 g/L  
Creatinine 
mg/dL 
umol/L 
>3.0 x ULN 
Estimate 
glomerular 
filtrate rate 
(eGFR)1 
mL/min/1.73 m2 
mL/min/1.73 
m2 
eGFR <29 mL/min/1.73 m2 
C reactive protein 
(CRP)2 
mg/L 
mg/L 
>10 mg/L 
Calcium 
mg/dL 
mmol/L 
Low: Corrected serum calcium3 of <7.0 
mg/dL; <1.75 mmol/L 
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High: Corrected serum calcium3 of >12.5 
mg/dL; >3.1 mmol/L 
Immunoglobulin 
G4  
(g/L) 
(g/L) 
≤1 g/L 
Potassium 
mmol/L 
mmol/L 
Low: <2.5 mmol/L 
High: >6.0 mmol/L 
Sodium 
mmol/L 
mmol/L 
Low: <125 mmol/L  
High: >155 mmol/L 
Glucose5 
mg/dL 
mmol/L 
Low: <40 mg/dL; <2.2 mmol/L  
High: > 250 mg/dL; >13.9 mmol/L 
Total Cholesterol 
mg/dL 
mmol/L 
>400 mg/dl; >10.34 mmol/L  
Triglycerides 
mg/dL 
mmol/L 
>500 mg/dl; >5.7 mmol/L 
Abbreviations: ALT= alanine aminotransferase; AST = aspartate aminotransferase; dL = deciliter; GGT: 
gamma-glutamyl transferase; L = liter; mg = milligram; mmol = millimoles; μg = microgram; U = unit; ULN = 
upper limit of normal 
Note: Marked abnormality criteria are defined by Grade 3 or higher events according to the Common 
Terminology for Adverse Events (CTCAE), Version 5.0, November 17, 2017 unless otherwise noted.  
1eGFR is calculated by eGFR = 141 * min(Scr/κ,1)α * max(Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female];  where 
Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for 
males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. For derivation 
from values in standard units (umol/L) the κ values are 61.88 for females and 79.56 for males. 
2Includes CRP and High Sensitivity (HS) CRP. Reference for marked abnormality criteria: Nehring, 
S.M.; Goyal, A.; Patel, B.C. (2020). StatPearls Publishing, web link: 
https://www.ncbi.nlm.nih.gov/books/NBK441843/. 
3corrected calcium will be calculated using the formular: corrected calcium (mmol/L) =0.02 * (40 – albumin 
(g/L)) + calcium(mmol/L); (40 because Normal albumin level is typically assumed to be equal to 40 g/L). 
4Immunoglobulin G criterion based on immunodeficiency literature and noted in RLZ study protocols. 
5Glucose high criterion defined by Grade 3 and higher events according to CTCAE, Version 4.03, June 14, 
2010. 
Table 6‒6: 
Vital Signs 
Parameter 
Abnormality Criteria 
Pulse Rate (beats/minute) 
 
<50 and a decrease from Baseline of ≥15 
>120 and an increase from Baseline of ≥15 
Systolic Blood Pressure (mmHg) 
≤ 90 and a decrease from Baseline of ≥20 
≥ 180 and an increase from Baseline of ≥20 
Diastolic Blood Pressure (mmHg) 
<50 and a decrease from Baseline of ≥15 
>105 and an increase from Baseline of ≥15 
Temperature 
>101 0F (38.3 0C) 
Body Weight 
≥ 10% decrease from Baseline 
≥ 10% increase from Baseline 
Table 6‒7: 
Electrocardiogram 
Parameter 
Abnormality Criteria 
QT interval (ms) 
 
>500ms 
≥60ms increase from Baseline 
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Parameter 
Abnormality Criteria 
QTc(F) (ms) 
>500ms 
≥60ms increase from Baseline 
PR interval (ms) 
Treatment-emergent value >200ms 
QRS interval (ms) 
Treatment-emergent value >100ms 
Heart rate (bpm) 
<50bpm 
>120bpm 
Abbreviations: bpm = beats per minute; ms = milliseconds; QTc(F) = Fridericia corrected QT interval;  
Note: Treatment-emergent is defined as meeting the criteria at any post-Baseline visit after the first infusion of 
study medication and within 56-days of the last infusion and not meeting the same criteria during Baseline 
6.6 
Appendix 6: Genetics 
Biomarker analyses may evaluate genetic features and epigenetic changes associated with the 
cause, progression, and appropriate treatment of LGI1 AIE.  
Use and Analysis of DNA 
• Genetic variation may impact a participant’s response to study medication, susceptibility to, 
and severity and progression of disease. Variable response to study medication may be due 
to genetic determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
• Deoxyribonucleic acid samples and exploratory biomarker samples will be used for research 
related to cause, progression, and appropriate treatment of LGI1 AIE. They may also be 
used to develop tests/assays including diagnostic tests related to rozanolixizumab and LGI1 
AIE. Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome. 
• Deoxyribonucleic acid samples will be analyzed for genetic and epigenetic changes that 
may promote understanding of the cause, progression, and appropriate treatment of LGI1 
AIE. Additional analyses may be conducted if it is hypothesized that this may help resolve 
issues with the clinical data.  
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to the study medication to understand study disease or related 
conditions.  
• The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary.  
• The sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality.  
The samples will be retained while research on study medication continues but no longer than 
20 years or other period as per local requirements. 
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6.7 
Appendix 7: Changes to Protocol-Planned Analyses 
Not applicable. 
6.8 
Appendix 8: Amendment(s) to the Statistical Analysis Plan  
6.8.1 
Amendment 1 
Rationale for the amendment 
This amendment is to apply following changes: 
• Changes caused by Protocol Amendment 3, 4 and 5 
• Incorporate the changes in the objectives relating to PK/PD in Protocol Amendment 6  
• Reduce the scope of the analyses and data reporting planned for this study due to the fact 
that recruitment was terminated early, meaning that only a total of 12 participants were 
randomized to the study.  This meant that it was not possible to carry out the extensive 
statistical analyses that had been planned. 
• Minor cosmetic updates 
• Incorporate the changes in the objectives relating to PK/PD in Protocol Amendment 6  
• Reduce the scope of the analyses and data reporting planned for this study due to the fact 
that recruitment was terminated early, meaning that only a total of 12 participants were 
randomized to the study.  This meant that it was not possible to carry out the extensive 
statistical analyses that had been planned. 
Section # and Name 
Description of Change 
Brief Rationale 
1 INTRODUCTION 
Removed PiDMC Charter 
Not relevant 
1.1 Objectives and Endpoints 
Removed Cytokines; Updated 
endpoint definition for the 
effect of rozanolixizumab on 
whole brain and hippocampal 
volume; Removed NF-L, α- and 
β- globulins, and MRI from 
Exploratory Endpoints; Moved 
mRS from Exploratory to 
Secondary Endpoints; Seizure 
reduction was replaced by 
seizure control as Exploratory 
Endpoint; CASE, ECG, AED 
plasma concentration,
 
 and COVID-19 antibody 
were removed from Exploratory 
Endpoint; PGI-S and PGI-C 
were replaced by CGI-S. 
To be consistent with 
Amendment 3, Amendment 4 
and Amendment 5 
1.2 Study Design 
Text update and study 
schematic update 
To be consistent with Protocol 
Amendment 3 and Protocol 
Amendment 5 
3 Sample Size Determination 
Text update 
To be consistent with Protocol 
Amendment 5 
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Section # and Name 
Description of Change 
Brief Rationale 
5 STATISTICAL ANALYSES 
Removed COVID-19 related 
ICEs 
The COVID-19 impact will be 
covered in exploratory analysis 
and protocol deviations. 
5.1.1.1.5 Definition of Baseline 
values 
Updated the definitions of mRS 
Baseline and removed CASE, 
added Baseline definition for 
safety assessments 
To be consistent with Protocol 
Amendment 3 and Protocol 
Amendment 5 
5.1.1.1.6 Calculation of 
Baseline Category of Seizure 
Count  
Specified the calculation of 
Baseline median category of 
seizure count  
To be consistent with Protocol 
Amendment 5 
5.1.1.7 Multiple 
comparisons/multiplicity 
Added hierarchical testing 
To be consistent with Protocol 
Amendment 5 
5.1.2 Rescue medication 
Removed irrelevant text 
For clarity 
5.1.3 Missing Data Strategies 
for efficacy analyses 
Added imputation method for 
intermittent missing daily 
seizure counts; Added analyses 
for secondary endpoint mRS 
and sensitivity analysis for time 
to event secondary #4 analysis; 
Added sensitivity analysis for 
Primary and Secondary 
Endpoint #1  
For missing data imputation; To 
account for the informative 
censoring resulting from study 
participant withdrawals from 
the randomized treatment group 
5.2 Participant Dispositions 
Removed analysis by COVID-
19 periods 
Not relevant 
5.3.1 Definition of endpoint 
Text update 
For clarity 
5.3.2 Main Analytical Approach Hypothesis Testing removed for 
primary endpoint 
Not meaningful for small 
sample size 
5.3.3.2 Sensitivity analysis #2 
Removed the extended analysis 
with prior seizure freedom 
information 
Data not collected 
5.3.3.3 Sensitivity analysis #3 
Added sensitivity analysis to 
account for existence of a prior 
undertreated AIE event 
To understand the impact of 
existence of a prior undertreated 
AIE event 
5.4.1 Change in cognitive 
function (RBANS) 
Updated total score to total 
scale 
To adjust for demographic 
factors 
5.4.1.2.3 Sensitivity analysis #3 
Added sensitivity analysis to 
account for existence of a prior 
undertreated AIE event 
To understand the impact of 
existence of a prior undertreated 
AIE event 
5.4.2 Change in overall 
disability: mRS 
Added secondary analysis for 
mRS 
To be consistent with Protocol 
Amendment 5 
5.4.3 Use of rescue medication 
due to an absence or loss of 
clinical benefit 
Removed Sensitivity Analysis 
for the use of rescue medication 
To be consistent with Protocol 
Amendment 4 
5.4.4 Time to first occurrence of 
seizure freedom (TTFSF) 
Removed Sensitivity Analysis 
based on FAS 
To be consistent with Protocol 
Amendment 4 
5.4.4.2 Sensitivity analysis  
Added a sensitivity analysis for 
time to first occurrence of 
seizure freedom 
To account for the informative 
censoring resulting from study 
participant withdrawals from 
the randomized treatment group 
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Statistical Analysis Plan 
Rozanolixizumab 
AIE001 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
5.4.5 Hierarchical testing 
Added hierarchical testing 
To control the overall type I 
familywise error rate 
5.5 Exploratory Endpoints 
Analyses 
Removed analysis for NF-L, 
MRI, seizure reductions, 
Clinical Assessment Scale in 
Autoimmune Encephalitis and 
mRS; Added the analysis of 
seizure control; analysis for 
PGI-S and PGI-C were replaced 
by analysis for CGI-S 
To be consistent with Protocol 
Amendment 4 and Protocol 
Amendment 5 
5.5 Exploratory Endpoints 
Time to seizure freedom 
maintenance, and ranked 
outcome from integrated score 
removed 
Not meaningful for small 
sample size 
5.5 Exploratory Endpoints 
For SF-36 and EQ-5D-5L, only 
item responses listed, 
summaries not calculated 
Summaries not meaningful for 
small sample size 
5.5.2 Seizure reductions 
Added imputation method for 
intermittent missing daily 
seizure counts 
For missing data imputation 
5.6.1  Extent of Exposure 
Number of infusions received 
excluding mock infusions not 
summarized 
Only listing excluding mock 
infusions is needed. 
5.6.2.2 Adverse Events 
summaries 
Most adverse events summaries 
have been removed  
Summaries not needed for small 
sample size, all adverse events 
have been listed. 
5.6.2.2 Adverse events 
summaries 
Removed incidence of non-
serious TEAEs above reporting 
threshold of 5% of participants 
by relationship; Updated AESM 
definition 
The summary was already 
covered by other analyses; To 
be consistent with 
Rozanolixizumab program SAP 
5.6.3.1 Clinical laboratory 
evaluations  
Removed most laboratory 
summaries  
Summaries not meaningful for 
small sample size; listings being 
retained. 
5.6.3.2 Potential drug-induced 
liver injury (pDILI) 
Updated laboratory criteria for 
pDILI 
To be consistent with 
Rozanolixizumab program SAP 
5.6.3.3 Vital signs  
Removed most vital signs 
summaries  
Summaries not meaningful for 
small sample size; listings being 
retained. 
5.6.3.4 12-Lead 
Electrocardiograms (ECG) 
The summary analysis for ECG 
were removed and only listing 
will be provided 
To be consistent with Protocol 
Amendment 5 
5.6.3.8 MRI 
MRI listings removed 
No meaningful data collected in 
study 
5.6.3.10 Headache 
questionnaire 
Summary of headache 
questionnaire was removed 
Listing of headache is enough to 
present the data 
5.7 Other Analyses 
Analysis for plasma 
concentration of AEDs was 
removed 
Plasma concentration will not 
be collected according to PA5 
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Statistical Analysis Plan 
Rozanolixizumab 
AIE001 
 
 
 
Confidential 
Page 58 of 60 
Section # and Name 
Description of Change 
Brief Rationale 
5.7.1.1  Pharmacokinetics 
All figures removed 
Not meaningful for small 
sample size 
5.7.1.3 ADA 
Entire section remove 
ADA and NAb samples not 
analyzed 
5.7.1.4 Immunology 
Removed analysis for cytokines 
and serum immunoglobulin 
concentration 
To be consistent with Protocol 
Amendment 3 and Protocol 
Amendment 5 
6.1 Non-key analysis 
specifications 
AED was separated from 
prior/concomitant medication 
summaries 
For better presentation of data 
6.1.1.1 Demographics 
Removed demographic by 
COVID-19 periods analysis 
Not relevant 
6.1.1.2 Baseline disease 
characteristics 
Removed CASE and weekly 
seizure frequency; Added 
median category of seizure 
count; Removed table for 
historical seizures 
To be consistent with Protocol 
Amendment 5 
6.1.2 Protocol deviations 
Removed protocol deviation 
summary by COVID-19 periods 
analysis 
Not relevant 
6.1.2 Protocol Deviations 
Summary removed 
Not meaningful for small 
sample size, listing retained 
6.1.3 Medical History 
Summary removed 
Not meaningful for small 
sample size, listing retained 
6.1.6.1.2 Dates and times 
Updated the calculation rules 
for duration of AEs 
To be consistent with other 
studies within Rozanolixizumab 
program 
6 Supporting Documentation 
Removed appendix for CASE 
To be consistent with Protocol 
Amendment 5 
6.5 Appendix 4: Markedly 
abnormal criteria for 
Rozanolixizumab program 
Updated eGFR formula by 
removing race correcting factor 
To be consistent with current 
scientific consensus 
6.6 Appendix 5: AEs of focus 
for Rozanolixizumab program 
Removed Section 
Not Needed 
 
 
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Statistical Analysis Plan 
Rozanolixizumab 
AIE001 
 
 
 
Confidential 
Page 59 of 60 
7 
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Statistical Analysis Plan 
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AIE001 
 
 
 
Confidential 
Page 60 of 60 
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Approval Signatures
Name:
aie001-sap-amend-1
Version:
1. 0
Document Number:
CLIN-000185663
Title:
AIE001 - Statistical Analysis Plan Amendment 1
Approved Date:
29 Apr 2024
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 29-Apr-2024 16:38:10 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 29-Apr-2024 17:25:47 GMT+0000
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This document cannot be used to support any marketing authorization 
application and any extensions or variations thereof.