Clinical trial NCT05254613
Conditions: Healthy
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2019-11-12; Completion date: 2021-01-22
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the effects of single ascending doses (SAD) and multiple ascending doses (MAD) of ALXN1830 administered subcutaneously (SC) to healthy adult participants.

Detailed description:
This Phase 1 study will consist of 3 SAD (Cohorts 1 to 3) and 4 MAD (Cohorts 4 to 7) cohorts. Participants will be randomly assigned in a 6:2 ratio to each of the 7 cohorts to receive either single or multiple doses of ALXN1830 (n = 6 per cohort) or single or multiple doses of placebo (n = 2 per cohort).

Arms: arm 1: Participants will receive a single SC dose of ALXN1830 or placebo (750 mg). arm 2: Participants will receive a single SC dose of ALXN1830 or placebo (1500 mg). arm 3: Participants will receive a single SC dose of ALXN1830 or placebo (2250 mg). arm 4: Participants will receive multiple SC doses of ALXN1830 or placebo (300 mg twice weekly; 8 doses total). arm 5: Participants will receive multiple SC doses of ALXN1830 or placebo (750 mg once weekly; 12 doses total). arm 6: Participants will receive multiple SC doses of ALXN1830 or placebo (1500 mg once weekly; 4 doses total). arm 7: Participants will receive multiple SC doses of ALXN1830 or placebo (2250 mg once weekly; 4 doses total).
Interventions: intervention 1: ALXN1830 intervention 2: Placebo
Intervention descriptions: intervention 1: ALXN1830 will be administered as SC infusion(s). intervention 2: Placebo will be administered as SC infusion(s).

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
NCT #: NCT05254613


ALXN1830-HV-105 Amendment 2 
24 January 2020 
MENT 
I have read the ALXN1830-HV-105 study protocol and agree to conduct the study in accordance 
with this protocol, all applicable government regulations, the principles of the ICH E6 
Guidelines for Good Clinical Practice, and the principles of the World Medical Association 
Declaration of Helsinki. I also agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  
____________________________________ 
Printed Name of Investigator 
_______________________ 
Signature of Investigator 
_______________ 
Date 
 
 
 
 
 
 
 
Page 2 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 
24-Jan-2020
Amendment 1 
28-Oct-2019
Original Protocol 
23-Sep-2019 
Amendment 2 (24 January 2020) 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout the 
document 
Editorial and minor grammatical 
changes  
To enhance clarity 
Section 1.1 
Synopsis 
Progression to the next 
dosing cohort will be gated by review 
of initial dosing data by a Safety 
Review Committee (SRC) consisting 
of the Investigator, Safety Monitor, 
Medical Monitor, Study Statistician, 
To summarize in the synopsis how progression to 
the next dosing cohort is gated, in alignment with 
criteria presented in Table 11 
Section 1.1 
Synopsis 
Section 4.1 
Overall Design 
Changed duration of Screening period 
from 28 to 42 days and overall study 
duration from 169 days to 183 days 
accordingly 
To allocate a sufficient amount of time for 
vaccination during screening, if required (ie, at 
least 28 days prior to Day 1) 
Section 1.3 
Schedule of 
Activities
Increased start of Screening window 
from D -28 to D -42  
To allocate a sufficient amount of time for 
vaccination during screening, if required (ie, at 
least 28 days prior to Day 1)
Section 1.3 
Schedule of 
Activities
Removed ±1-day window for visits 
that occur at the CRU 
Participants are admitted to the CRU for the 
corresponding activities, therefore a window of 
time (±1-day) is not relevant
Section 1.3 
Schedule of 
Activities 
immunity to Haemophilus influenzae / 
Tetanus toxoid / Streptococcus 
To align with changes to the vaccination 
requirements in Section 5.1 Inclusion Criteria 
Section 1.3 
Schedule of 
Activities
Moved time point for pregnancy test 
for Cohorts 1,2 and 3 from Day 5 to 
Day 4
Correction and alignment with other cohorts 
Section 1.3 
Schedule of 
Activities 
timepoints 
for sample to 
be taken
To specify time points for samples to be taken for 
assessment of Pneumovax 23 titers 
Section 1.3 
Schedule of 
Activities
A full physical examination is to be performed 
only at screening, and symptom-driven thereafter 
Section 1.3 
Schedule of 
Activities 
Day 1
Holter assessment. 
Cardiac health as assessed by Holter monitor does 
not need to be repeated at Screening if a result is 
available within the previous 3-months. 
Page 3 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 
Schedule of 
Activities 
vaccinated as described in Section 
6.5.3. 
To enhance utility and readability of the protocol 
by directing the reader to additional detail 
Section 1.3 
Schedule of 
Activities 
Updated footnote superscripts as 
appropriate. 
For accuracy as a result of footnotes that were 
added and / or deleted, described above 
Section 2.2 
Background 
Shortened summary of ALXN1830 
background. 
To enhance readability by focusing the body of the 
protocol on procedural elements and consolidating 
detailed justifications and rationale in the 
appendix. 
Section 2.3 
Benefit / risk 
Assessment 
Added cross reference to Section 4.2 
To refer the reader to a discussion of theoretical 
risks associated with the reduction of IgG 
Section 4.1 
Overall Design 
Added geographic location of the 
single study site (United Kingdom) 
For completeness 
Section 4.1 
Overall Design 
Added cross reference to Table 11 
To enhance utility and readability of the protocol 
by directing the reader to additional detail. 
Section 4.2 
Scientific 
Rationale for 
Study Design 
Shortened summary of scientific 
rationale for study design by moving 
detailed rationale to Section 10.7 
To enhance readability by focusing the body of the 
protocol on procedural elements and consolidating 
detailed justifications and rationale in the appendix 
Section 4.2 
Scientific 
Rationale for 
Study Design 
Revised rationale for the 
implementation of certain inclusion 
criteria that were designed to 
minimize the potential risk of 
infection in the healthy participants 
due the theoretical concerns 
associated with reducing total IgG
Alignment with changes to vaccination 
requirements (see Section 5.1 and Section 6.5.3) 
Section 4.4 End of 
Study Definition 
Deleted the phrase 
This study does not consist of pre-defined phases. 
A participant is considered to have completed the 
study if he/she has completed the last scheduled 
visit shown in the Schedule of Activities (SoA).
Section 5.1 
Inclusion Criteria
Updated numbering of inclusion 
criteria (1-10)
Correction 
Section 5.1 
Inclusion Criteria 
Added footnote to Inclusion Criterion 
#5 as follows: 
IgM levels are expected to be above 
the upper level of normal per local 
laboratory reference range if the 
participant has recently received 
Pneumovax 23 vaccination. 
Therefore, participants are eligible if 
they have been vaccinated with 
Pneumovax 23 per vaccination 
criteria described in Section 6.5.3 and 
the IgM level corresponds with the 
post-vaccination normal limits, per 
include participants with a healthy immune system 
prior to dosing with ALXN1830. In this trial 
subjects need to have been vaccinated against 
pneumococcal infection. A rise IgM level post 
vaccination is a sign of a healthy immune system 
and can therefore 
vaccinated). 
Page 4 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.1 
Inclusion Criteria 
Revised Inclusion Criteria #6 to 
remove requirement for evidence of 
current vaccination against tetanus 
toxoid, Hib, and MMR 
To limit potential vaccinations to those 
recommended for immunosuppression in the Green 
with underlying medical 
Section 5.1 
Inclusion Criteria 
Revised Inclusion Criteria #7 to 
administration during the influenza 
To enhance clarity as all participants must be 
vaccinated against seasonal influenza for the 
current season 
Section 5.2 
Exclusion Criteria 
Revised Exclusion Criterion #5 to 
include tension headache disorder as 
follows: 
Participants with the history of 
frequent and/or chronic headaches, 
including migraine disorder, cluster 
headache disorder, and tension 
headache disorder. 
To specify types of chronic headache disorders, 
including tension headache 
Section 5.2 
Exclusion Criteria 
Added Exclusion Criterion #11: 
For consistency with Section 8.3.5 which states 
that pregnant or breastfeeding females are 
excluded from the study 
Section 5.2 
Exclusion Criteria 
Moved text from Exclusion Criterion 
#24 regarding exclusion of 
individuals with children who are 
first-year college/university students 
to a separate exclusion criterion (#25) 
To enhance clarity 
Section 5.2 
Exclusion Criteria 
Added new Exclusion Criterion (#26) 
to exclude first-year 
college/university students
First-year college/university students are 
considered to have a high risk of acquiring 
sinopulmonary infections
Section 5.4 Screen 
Failures 
Revised language regarding re-testing 
to specify that any study-related 
testing performed at Screening may 
be repeated within the screening visit 
window per the Investigato
discretion for the purpose of further 
determining eligibility 
To enhance clarity 
Section 6.5.1 
Premedication and 
Hydration
Replaced ranitidine with famotidine 
Due to voluntary recall of ranitidine 
Section 6.5.1 
Premedication and 
Hydration
Changed units for recommended 
amounts of water from ounces to 
liters
For consistency 
Section 6.5.1 
Premedication and 
Hydration 
Added a cross reference to the 
detailed justification for 
recommended hydration in section 
10.7.2
To enhance utility and readability of the protocol 
by directing the reader to additional detail 
Section 6.5.2 
Supportive / 
Symptomatic Care
Moved justification for premedication 
and hydration to the Appendix 
(Section 10.7.2)
To enhance readability by focusing the body of the 
protocol on procedural elements and consolidating 
detailed justifications and rationale in the appendix
Page 5 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.5.3 
Vaccinations 
To remove requirement for evidence 
of current vaccination against tetanus 
toxoid, Hib, and MMR 
To align with changes to Inclusion Criteria 
(Section 5.1) 
Section 6.5.3 
Vaccinations 
Added requirements for taking blood 
samples for assessment of Pneumovax 
titers 
To enhance clarity 
Section 6.5.4 
Antibiotics 
Prophylaxis 
New sub-heading for information 
regarding prophylactic use of 
antibiotics. Revised recommendations 
for when to start antibiotics  
To enhance clarity 
Section 7.2.1 
Immunoglobulin 
Stopping Rules 
Added specific vaccination titers to be 
assessed (Pneumovax 23) 
To enhance clarity 
Section 8.2.1 
Physical 
Examinations 
description of when to perform a full 
physical examination 
A full examination is only required at Screening, 
and symptom directed thereafter 
Section 8.2.3 
Oxygen 
Saturation 
Added 
information regarding the brand of 
device used to measure oxygen 
saturation 
For alignment with the Schedule of Assessments 
and updated information 
Section 8.2.4.3 
24-hour Holter
ECG
-
To enhance clarity 
Section 8.2.4.4 
Real Time 
Display (ECG 
Telemetry)
To enhance clarity 
Section 8.2.7 
Vaccination
Information replaced with a cross-
reference to Section 6.5.3
To reduce redundancy and enhance readability 
Section 8.3.6 
Infusion-Related 
Reaction 
Deleted section 
To reduce redundancy and enhance readability. 
Information regarding definition and management 
of IRRs is presented in Section 8.3.6.1 and Section 
10.4
Section 8.3.7 
Injection/Infusion-
associated 
Reactions
Deleted section 
To reduce redundancy and enhance readability.  
Information regarding definition and management 
of IRRs is presented in Section 8.3.6.1 and Section 
10.4
Section 8.4 
Treatment 
Overdose 
Added further information for the 
definition and recommended action in 
the case of an overdose of 
ALXN1830
To enhance clarity 
Section 8.8 
Biomarkers
To enhance clarity 
Section 9.3 
Populations for 
Analyses
To enhance clarity 
Section 9.4.2 
Other Analyses
Added text to specify analysis sets 
used for PK and PD analyses
To enhance clarity 
Page 6 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.1.3 
Informed Consent 
Process 
Changed statement to require re-
screened participants to sign a new 
ICF 
Correction 
Section 10.2 
Appendix 2: 
Clinical 
Laboratory Tests 
Added laboratory assessments for 
signs of infection and Pneumovax 23 
titers to Table 14 
For alignment with the Schedule of Activities 
Section 10.2 
Appendix 2: 
Clinical 
Laboratory Tests 
Revised language regarding 
laboratory results that may unblind 
the study site to include review of 
results that could unblind the study by 
dedicated unblinded staff at the 
investigative site 
To further ensure participant safety 
Section 10.3.6 
Reporting of 
Serious Adverse 
Events 
Deleted information regarding 
reporting of SAEs via an electronic 
data collection tool 
An EDC is not being used for SAE reporting in 
this study 
Section 10.4 
Appendix 4: 
Infusion Related 
Reactions  
Definitions of 
Severity Levels 
and Management 
Algorithm 
To enhance clarity 
Section 10.6 
Appendix 6 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Female participants of childbearing potential, if 
heterosexually active, must use only highly 
effective contraception as defined in the protocol 
Section 10.7 
Appendix 7: 
Justification for 
Protective 
Measures 
Secti
Detailed rationale/justification for protective 
measures, including mitigation of the potential risk 
of infection due to IgG lowering, and hydration 
recommendations due to the risk of infusion-
induced headaches was moved from within the 
body of the protocol to the appendix for improved 
clarity/readability
Page 7 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
MENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................13 
1.
PROTOCOL SUMMARY ..........................................................................................14 
1.1. 
Synopsis ......................................................................................................................14 
1.2. 
Schema ........................................................................................................................17 
1.3. 
Schedule of Activities .................................................................................................17 
2.
INTRODUCTION ......................................................................................................31 
2.1. 
Study Rationale ...........................................................................................................32 
2.2. 
Background .................................................................................................................33 
2.3. 
Benefit/Risk Assessment ............................................................................................33 
2.3.1. 
Risk Assessment .........................................................................................................34 
2.3.2. 
Benefit Assessment .....................................................................................................34 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................34 
3.
OBJECTIVES AND ENDPOINTS ............................................................................36 
4.
STUDY DESIGN .......................................................................................................37 
4.1. 
Overall Design ............................................................................................................37 
4.2. 
Scientific Rationale for Study Design ........................................................................40 
4.3. 
Justification for Dose ..................................................................................................41 
4.4. 
End of Study Definition ..............................................................................................43 
5.
STUDY POPULATION .............................................................................................44 
5.1. 
Inclusion Criteria ........................................................................................................44 
5.2. 
Exclusion Criteria .......................................................................................................45 
5.3. 
Lifestyle Considerations .............................................................................................47 
5.4. 
Screen Failures ............................................................................................................48 
6.
STUDY DRUG ...........................................................................................................49 
6.1. 
Study Drug Administered ...........................................................................................49 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................49 
Page 8 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................50 
6.4. 
Study Drug Compliance .............................................................................................50 
6.5. 
Concomitant Therapy .................................................................................................51 
6.5.1. 
Premedication and Hydration .....................................................................................51 
6.5.2. 
Supportive/Symptomatic Care ....................................................................................51 
6.5.3. 
Vaccinations ...............................................................................................................52 
6.5.4. 
Antibiotics Prophylaxis ..............................................................................................52 
6.5.5. 
Disallowed Medication ...............................................................................................52 
6.6. 
Dose Modification ......................................................................................................53 
6.7. 
Drug After the End of the Study .................................................................................53 
7.
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ..................................................................54 
7.1. 
Discontinuation of Study Drug ...................................................................................54 
7.2. 
Stopping Criteria .........................................................................................................54 
7.2.1. 
Immunoglobulin Stopping Rules ................................................................................54 
7.2.2. 
Safety Stopping Rules (Individual, Cohort and Study Level Stopping Rules) ...........54 
7.3. 
Participant Discontinuation/Withdrawal from the Study ...........................................55 
7.4. 
Lost to Follow-up .......................................................................................................55 
7.5. 
Criteria for Study Termination ...................................................................................56 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................57 
8.1. 
Efficacy Assessments .................................................................................................57 
8.2. 
Safety Assessments .....................................................................................................57 
8.2.1. 
Physical Examinations ................................................................................................57 
8.2.2. 
Vital Signs ..................................................................................................................57 
8.2.3. 
Oxygen Saturation ......................................................................................................57 
8.2.4. 
Electrocardiograms .....................................................................................................58 
8.2.4.1. 
Recording of 12-Lead ECGs ......................................................................................58 
8.2.4.2. 
Safety Review of 12-lead ECGs .................................................................................58 
8.2.4.3. 
24-hour Holter ECG ...................................................................................................58 
8.2.4.4. 
Real time display (ECG telemetry) .............................................................................58 
8.2.5. 
Clinical Safety Laboratory Assessments ....................................................................59 
8.2.6. 
Virus Serology ............................................................................................................59 
8.2.7. 
Vaccination .................................................................................................................59 
Page 9 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
8.2.8. 
Drug and Alcohol Screen ............................................................................................59 
8.2.9. 
Pregnancy Testing ......................................................................................................59 
8.2.10. 
Injection or Infusion Site Evaluation ..........................................................................60 
8.3. 
Adverse Events and Serious Adverse Events .............................................................60 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................60 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................60 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................60 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................60 
8.3.5. 
Pregnancy ...................................................................................................................61 
8.3.5.1. 
Exposure During Pregnancy and Lactation ................................................................61 
8.3.6. 
Adverse Events of Special Interest .............................................................................62 
8.3.6.1. 
Infusion-Related Reaction ..........................................................................................62 
8.3.6.2. 
Non-acute Hypersensitivity Reaction .........................................................................62 
8.4. 
Treatment of Overdose ...............................................................................................62 
8.5. 
Pharmacokinetics ........................................................................................................63 
8.6. 
Pharmacodynamics .....................................................................................................63 
8.7. 
Genetics ......................................................................................................................63 
8.8. 
Biomarkers ..................................................................................................................63 
8.9. 
Immunogenicity Assessments ....................................................................................64 
8.10. 
Medical Resource Utilization and Health Economics ................................................64 
9.
STATISTICAL CONSIDERATIONS .......................................................................65 
9.1. 
Statistical Hypotheses .................................................................................................65 
9.2. 
Sample Size Determination ........................................................................................65 
9.3. 
Populations for Analyses ............................................................................................65 
9.4. 
Statistical Analyses .....................................................................................................65 
9.4.1. 
Safety Analyses ..........................................................................................................65 
9.4.2. 
Other Analyses ............................................................................................................66 
9.5. 
Interim Analyses .........................................................................................................66 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................67 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................67 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................67 
Page 10 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.1.2. 
Financial Disclosure ...................................................................................................67 
10.1.3. 
Informed Consent Process ..........................................................................................68 
10.1.4. 
Data Protection ...........................................................................................................68 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................68 
10.1.6. 
Data Quality Assurance ..............................................................................................69 
10.1.7. 
Source Documents ......................................................................................................69 
10.1.8. 
Study and Site Start and Closure ................................................................................69 
10.1.9. 
Publication Policy .......................................................................................................70 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................71 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................73 
10.3.1. 
Adverse Event Definition ...........................................................................................73 
10.3.2. 
Adverse Reaction Definition ......................................................................................73 
10.3.3. 
Serious Adverse Event Definition ..............................................................................73 
10.3.4. 
Suspected Unexpected Adverse Reaction Definition .................................................74 
10.3.5. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............74 
10.3.6. 
Reporting of Serious Adverse Events .........................................................................75 
10.4. 
Appendix 4: Infusion Related Reactions  Definitions of Severity Levels and 
Management Algorithm ..............................................................................................77 
10.5. 
Appendix 5: United Kingdom Resuscitation Council Anaphylaxis Algorithm .........79 
10.6. 
Appendix 6 Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................80 
10.7. 
Appendix 7: Justification for Protective Measures .....................................................83 
10.7.1. 
IgG Lowering and the Potential Risk of Infection......................................................83 
10.7.1.1. 
IgG Level Stopping Rule ............................................................................................84 
10.7.1.2. 
Evidence of Immunity/Vaccination ............................................................................85 
10.7.2. 
Hydration ....................................................................................................................85 
10.8. 
Appendix 8: Abbreviations .........................................................................................86 
11.
REFERENCES ...........................................................................................................88 
Page 11 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
LIST OF TABLES 
Table 1: 
Dose and Dose Regimen of ALXN1830 in Healthy Participants ...............................16 
Table 2: 
Schedule of Activities (Single Ascending Dose Cohorts 1, 2 and 3) .........................18 
Table 3: 
Schedule of Activities (Multiple Ascending Dose Cohort 4) .....................................20 
Table 4: 
Schedule of Activities (Multiple Ascending Dose Cohort 5; Screening 
Through Day 36) .........................................................................................................22 
Table 5: 
Schedule of Activities (Multiple Ascending Dose Cohort 5; Day 43 Through 
Day 141) .....................................................................................................................24 
Table 6: 
Schedule of Activities (Multiple Ascending Dose Cohort 6 and optional 
Cohort 7) .....................................................................................................................26 
Table 7: 
Schedule of Activities during Clinical Research Unit confinement for Single 
Ascending Dose / Multiple Ascending Dose Day 1 ...................................................18 
Table 8: 
Schedule of Activities during Clinical Research Unit confinement for 
Multiple Ascending Dose ...........................................................................................30 
Table 9: 
Risk Assessment for ALXN1830 ...............................................................................34 
Table 10: ALXN1830-HV-105 Dosing Cohorts .........................................................................38 
Table 11: Minimum Data Requirements for Dose Escalation ....................................................39 
Table 12: Predicted ALXN1830 Exposure, Safety Margin, and Immunoglobulin G 
Reduction after Subcutaneous Administration ...........................................................42 
Table 13: Lifestyle Considerations for Participants in Study ALXN1830-HV-105 ...................47 
Table 14: Recommended Premedication ....................................................................................51 
Table 15: Populations for Analyses ............................................................................................65 
Table 16: Protocol--Required Safety Laboratory Assessments ..................................................72 
Page 12 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
LIST OF FIGURES 
Figure 1: 
Study Schematic Diagram ..........................................................................................17 
Page 13 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple 
Ascending Dose Study of Subcutaneous ALXN1830 in Healthy Participants 
Short Title: Safety and Pharmacokinetic Study of Subcutaneous ALXN1830 in Healthy Adult 
Participants 
Rationale: ALXN1830, an anti-neonatal crystallizable fragment receptor (FcRn) monoclonal 
antibody (mAb), has the potential to reduce the level of pathogenic immunoglobulin G (IgG) 
involved in certain autoimmune disorders. The purpose of this Phase 1 study in healthy adult 
participants is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics 
(PD), and immunogenicity of single ascending doses (SAD) and multiple ascending doses 
(MAD) of ALXN1830 administered subcutaneously (SC). Data from this study are anticipated to 
help design future studies in patients with IgG-mediated diseases.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
To assess the safety and 
tolerability of single and 
multiple doses of ALXN1830 
SC 
Safety assessed by the incidence and relatedness of TEAEs, 
SAEs, AESIs, physical examination, vital sign 
measurements, clinical laboratory and ECG results 
Secondary 
To assess the PK of single and 
multiple doses of ALXN1830 
SC 
To explore the PD effects of 
single and multiple doses of 
ALXN1830 SC 
To assess the immunogenicity 
of ALXN1830 SC
ALXN1830 PK profiles and PK parameters 
Change in IgG levels  
Measurement of ADA levels and NAbs 
Abbreviations: ADA = antidrug antibody; AESI = adverse events of special interest; ECG = electrocardiogram; 
IgG = immunoglobulin G; IV = intravenous; NAb = neutralizing antibody; PD = pharmacodynamics; 
PK = pharmacokinetics; SAE = serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse 
event. 
Overall Design: 
This is a Phase 1 study in up to 56 healthy adult participants (42 on active treatment, 14 on 
placebo [PBO]) conducted at a single site. Eight participants will be randomly assigned in a 6:2 
ratio to each of 7 cohorts to receive either single or multiple doses of ALXN1830 SC (n = 6 per 
cohort) or single or multiple doses of PBO (n = 2 per cohort). 
Of these 7 cohorts, 1 cohort is optional; a dose to be determined (based on the safety of the 
predetermined doses) in the MAD. Initially, the first 4 participants randomized to each cohort 
will be dosed, 3 participants with ALXN1830 and 1 participant with PBO. The dosing will be 
staggered, with an interval of at least 3 days for the SAD cohorts and at least 7 days for the MAD 
cohorts, before dosing the rest of the participants in the cohort. The shorter interval of staggered 
Page 14 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
dosing for the SAD cohorts compared to the MAD cohorts is considered appropriate as the 
expected PK exposure of the ALXN 1830 SC doses will be a fraction of that of the IV dose 
demonstrated to be safe and well tolerated in previous IV studies. The reduction of IgG after a 
single SC dose will be well within the observed IgG reduction observed in previous IV studies; 
and in general, there will be low risk of immunogenicity and infusion related reactions after a 
single dose. See Section 4.3 for details regarding expected PK exposures and IgG reduction. All 
participants will be observed during the infusion and for 2 hours following the end of infusion 
for safety and participants will be encouraged to report any discomfort immediately, especially 
within 24 hours post dosing. At no time will more than 4 participants per cohort be dosed on a 
given day.  
Progression to the next dosing cohort will be gated by review of initial dosing data by a Safety 
Review Committee (SRC) consisting of the Investigator, Safety Monitor, Medical Monitor, 
sultation 
with the SRC, additional participants may be enrolled as replacement participants if a participant 
discontinues within 3 weeks of the last dose for reasons other than drug-related adverse events. 
Number of Participants: 
A maximum of 56 participants will be randomly assigned to study drug such that approximately 
8 evaluable participants per cohort complete the study. The number of participants was chosen 
based on feasibility and was considered adequate to meet the study objectives.  
Study Drug Groups and Duration:  
Participants will be randomly assigned in a 6:2 ratio to each of 7 cohorts (Table 1) to receive 
either single or multiple doses of ALXN1830 SC (n = 6 per cohort) or single or multiple doses of 
PBO (n = 2 per cohort). The planned study duration is approximately 183 days: up to 42 days for 
screening and approximately 141 days for dosing and follow-up. 
Page 15 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Table 1: 
Dose and Dose Regimen of ALXN1830 in Healthy Participants 
Cohort (n) 
Regimen/Route of Administration 
Study Drug (N) 
1 
Single dose SC 
Placebo (n = 2) or 
ALXN1830 750 mg (n = 6) 
2 
Single dose SC 
Placebo (n=2) or 
ALXN1830 1500 mg (n = 6) 
3 
Single dose SC 
Placebo (n=2) or 
ALXN1830 2250 mg (n = 6) 
4 
Multiple dose (8 doses biw) SC 
Placebo (n=2) or 
ALXN1830 300 mg (n = 6) 
5 
Multiple dose (12 doses qw) SC 
Placebo (n=2) or 
ALXN1830 750 mg (n = 6) 
6 
Multiple dose (4 doses qw) SC 
Placebo (n=2) or 
ALXN1830 1500 mg (n = 6) 
7a 
Multiple dose (4 doses or 12 doses qw) 
SC 
Placebo (n=2) or 
ALXN1830 2250mgb(n = 6) 
a Optional 
b If Cohort 6 is terminated early due to safety or IgG stopping rules, then Cohort 7 may be dosed at a < 1500 mg 
lower weekly dose for 4 doses. If Cohort 6 does not reach the expected IgG reduction, and no safety or IgG 
stopping rules are met, then Cohort 7 may be dosed at higher dose > 1500 mg (but not to exceed 2250 mg) weekly 
for 4 doses). 
Abbreviations: biw = twice weekly; qw = weekly; SC = subcutaneous. 
Page 16 of 89 
Alexion Confidential 
l


ALXN1830-HV-105 Amendment 2 
24 January 2020 
1.2. 
Schema 
Figure 1: 
Study Schematic Diagram 
Abbreviations: D = day; MAD = multiple ascending dose; max = maximum; PBO = placebo; qw = weekly; 
SAD = single ascending dose; SC = subcutaneous; SRC = Safety Review Committee; wk = week. 
1.3. 
Schedule of Activities 
The schedule of activities (SoA) for the SAD, MAD Cohort 4, MAD Cohort 5, and MAD 
Cohort 6 (and the optional MAD Cohort 7) are shown in Table 2, Table 3, Table 4, Table 5, and 
Table 6, respectively. The schedules of activities during CRU confinement for all SAD and 
MAD cohorts are shown in Table 7 and Table 8.  
Page 17 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 2:  
Schedule of Activities (Single Ascending Dose Cohorts 1, 2 and 3) 
Assessments 
Screening 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 10 
D 12 
D 15 
D 22 
D 29 
D 36 
D 43 
D 50 
D 57 
D 64/ET 
Status (OP or 
CRU) 
D -42 to  
D -2 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Window (days) 
ADM 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X 
X 
Serum pregnancy 
test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol breath test 
X 
X 
Urine drug screen 
X 
X 
Hepatitis B and C 
screen 
X 
Evidence of 
vaccinationg 
X 
X 
Sample for 
Pneumovax 23 
titerg
X 
Xc,d 
Xc,d 
HIV (types 1 and 
2) screen 
X 
Medical history 
and demographics 
X 
X 
Physical 
examinationa,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight and 
BMI 
X 
Randomization 
X 
Study drug 
administration 
(ALXN1830 or 
PBO) 
X 
PK blood 
samplingb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling 
- IgA, IgM, IgG b,c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling 
- IgG subtypes 1-
4b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling 
 CICb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicityd 
X 
X 
X 
X 
X 
Biochemistryc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 18 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 2:  
Schedule of Activities (Single Ascending Dose Cohorts 1, 2 and 3) (Continued) 
Assessments 
Screening 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 10 
D 12 
D 15 
D 22 
D 29 
D 36 
D 43 
D 50 
D 57 
D 64/ET 
Status (OP or 
CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Window (days) 
D -42 to  
D -2 
ADM 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Hematologyc
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory 
biomarker 
sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisc
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen 
saturationg 
X 
12-lead ECG 
(triplicate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac 
Holter/telemetrye 
X 
X 
Injection/infusion 
site evaluation 
X 
X 
X 
Adverse events 
X 
Review potential 
safety risk of 
ALXN1830 
X 
Concomitant 
medications 
X 
a Full PE at screening and symptom directed PE thereafter. 
b Refer to Table 7 and Table 8 for timing. 
c Could be done on the day prior to dosing. 
d Predose. 
e Holter at Screening (or up to 3 months prior to Day1); telemetry at 1-hour predose until 24 hours after start of infusion. 
f Oxygen saturation measurement on dosing days should be done with vital signs. 
g Participants must be vaccinated as described in Section 6.5.3.   
Abbreviations: ADM = admission; BMI = body mass index; CIC = circulating immune complexes; CRU = Clinical Research Unit; D = day; 
ECG = electrocardiogram; ET = early termination; HIV = human immunodeficiency virus; Ig = immunoglobulin; NA = not applicable; OP = outpatient; 
PD = pharmacodynamic(s); PE = physical examination; PK = pharmacokinetic(s).
Page 19 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 3: 
Schedule of Activities (Multiple Ascending Dose Cohort 4) 
Assessments 
Screeni
ng 
D -
1 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 
11 
D 
15 
D 
18 
D 
22 
D 
25 
D 
32 
D 
39 
D 
46 
D 
53 
D 
60 
D 
67 
D 
74 
D 
81 
D 88/ 
ET 
Status (OP or 
CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Window (days) 
D -42 
to 
D -2 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Informed consent 
X 
Inclusion/ 
exclusion criteria 
X 
X 
Serum pregnancy 
test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Alcohol breath 
test 
X 
X 
Urine drug screen 
X 
X 
Hepatitis B and C 
screen 
X 
Evidence of 
vaccinationh
X 
X 
Sample for 
Pneumovax 23 
titerh
X 
Xc,d
Xc,d 
X 
HIV (types 1 and 
2) screen 
X 
Medical history 
and demographics 
X 
X 
Physical 
examinationa,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Height, weight 
and BMI 
X 
Randomization 
X 
Study drug 
administration 
X 
X 
Xg 
X 
X 
X 
X 
X 
PK blood 
samplingb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
PD blood 
sampling - IgA, 
IgG, IgMb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
PD blood 
sampling - IgG 
subtypes 1-4b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Page 20 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 3: 
Schedule of Activities (Multiple Ascending Dose Cohort 4) (Continued) 
Assessments 
Scree
ning 
D -
1 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 
11 
D 
15 
D 
18 
D 
22 
D 
25 
D 
32 
D 
39 
D 
46 
D 
53 
D 
60 
D 
67 
D 
74 
D 
81 
D 
88/
ET
Status (OP or 
CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Window (days) 
D -42 
to 
D -2 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
PD blood sampling 
 CICb,c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicityd 
X 
X 
X 
X 
X 
X 
Biochemistryc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory 
biomarker sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen saturationf 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
(triplicate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac 
Holter/telemetrye 
X 
X 
X 
X 
X 
X 
Injection/infusion 
site evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
Review potential 
safety risk of 
ALXN1830  
X 
Concomitant 
medications 
X 
a Full PE at screening and symptom directed PE thereafter. 
b Refer to Table 7 and Table 8 for timing. 
c Could be done on the day prior to dosing. 
d Predose. 
e Holter at Screening (or up to 3 months prior to Day 1); telemetry at 1-hour predose until 24 hours after start of infusion. 
f Oxygen saturation measurement on dosing days should be done with vital signs. 
g Discharge after all 24-hour procedures are completed. 
h Participants must be vaccinated as described in Section 6.5.3.  Abbreviations: BMI = body mass index; CIC = circulating immune complexes; CRU = Clinical 
Research Unit; D = day; ECG = electrocardiogram; ET = early termination; HIV = human immunodeficiency virus; Ig = immunoglobulin; NA = not 
applicable; OP = outpatient; PD = pharmacodynamic(s); PE = physical examination; PK = pharmacokinetic(s). 
Page 21 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 4: 
Schedule of Activities (Multiple Ascending Dose Cohort 5; Screening Through Day 36) 
Assessments 
Screening 
D -1 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 11 
D 15 
D 18 
D 22 
D 25 
D 29 
D 36 
Status (OP or CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
CRU 
OP 
CRU 
OP 
CRU 
CRU 
Window (days) 
D -42 to 
D -2 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
NA 
±1 
NA 
±1 
NA 
NA 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X 
X 
Serum pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol breath test 
X 
X 
Urine drug screen 
X 
X 
X 
X 
Hepatitis B and C 
screen 
X 
Evidence of 
vaccinationg 
X 
X 
Sample for Pneumovax 
23 titerg 
X 
Xc,d 
Xc,d 
HIV (types 1 and 2) 
screen 
X 
Medical history and 
demographics 
X 
Physical examinationa,c 
X 
X 
X 
X 
X 
X 
X 
Height, weight and BMI 
X 
Randomization 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
PK blood samplingb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling - 
IgA, IgG, IgMb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling - 
IgG subtypes 1-4b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling 
CICb,c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicityd 
X 
X 
X 
Biochemistryc  
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyc 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationc 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarker 
sample 
X 
X 
X 
X 
X 
X 
X 
Urinalysisc 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen saturationf 
X 
X 
X 
X 
X 
X 
12-lead ECG (triplicate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 22 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 4: 
Schedule of Activities (Multiple Ascending Dose Cohort 5; Screening Through Day 36) (Continued) 
Assessments 
Screening 
D -1 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 11 
D 15 
D 18 
D 22 
D 25 
D 29 
D 36 
Status (OP or CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
CRU 
OP 
CRU 
OP 
CRU 
CRU 
Window (days) 
D -42 to 
D -2 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
NA 
±1 
NA 
±1 
NA 
NA 
Cardiac 
Holter/telemetrye 
 X 
X 
X 
X 
X 
X 
Injection/infusion site 
evaluation 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
Review potential safety 
risk of ALXN1830  
X 
Concomitant 
medications 
X 
a Full PE at screening and symptom directed PE thereafter. 
b Refer to Table 7 and Table 8 for timing. 
c Could be done on the day prior to dosing. 
d Predose. 
e Holter at Screening (or up to 3 months prior to Day 1); telemetry at 1-hour predose until 24 hours after start of infusion. 
f Oxygen saturation measurement on dosing days should be done with vital signs. 
g Participants must be vaccinated as described in Section 6.5.3. 
Abbreviations: BMI = body mass index; CIC = circulating immune complexes; CRU = Clinical Research Unit; D = day; ECG = electrocardiogram; 
HIV = human immunodeficiency virus; Ig = immunoglobulin; NA = not applicable; OP = outpatient; PD = pharmacodynamic(s); PE = physical examination; 
PK = pharmacokinetic(s).
Page 23 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 5: 
Schedule of Activities (Multiple Ascending Dose Cohort 5; Day 43 Through Day 141) 
Assessments 
D 43 
D 50 
D 57 
D 64 
D 71 
D 78 
D 85 
D 92 
D 99 
D 106 
D 113 
D 120 
D 127 
D 134 
D 
141/ET 
Status (OP or CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Window (days) 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Serum pregnancy test 
X 
X 
X 
X 
X 
X 
Alcohol breath test 
Urine drug screen 
X 
X 
X 
X 
X 
X 
Evidence of 
vaccinationh 
Sample for 
Pneumovax 23 titerh 
X 
Physical 
examinationa,b 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
PK blood samplingb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling - 
IgA, IgG, IgMb,c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling - 
IgG subtypes 1-4b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood sampling 
CICb,c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicityd 
X 
X 
X 
X 
X 
X 
Biochemistryc
X 
X 
X 
X 
X 
X 
Hematologyc
X 
X 
X 
X 
X 
X 
Coagulationc 
X 
X 
X 
X 
X 
X 
Exploratory 
biomarker sample 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen saturationf 
X 
X 
X 
X 
X 
X 
12-lead ECG 
(triplicate) 
Cardiac Holter / 
telemetrye
Injection/infusion site 
evaluation 
Adverse events 
X 
Review potential 
safety risk of 
ALXN1830 
X 
Page 24 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 5: 
Schedule of Activities (Multiple Ascending Dose Cohort 5; Day 43 Through Day 141) (Continued) 
Assessments 
D 43 
D 50 
D 57 
D 64 
D 71 
D 78 
D 85 
D 92 
D 99 
D 106 
D 113 
D 120 
D 127 
D 134 
D 
141/ET 
Status (OP or CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Window (days) 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Concomitant 
medications 
X 
a Full PE at screening and symptom directed PE thereafter. 
b Refer to Table 7 and Table 8 for timing. 
c Could be done on the day prior to dosing.  
d Predose. 
e Holter at Screening (or up to 3 months prior to Day 1); telemetry at 1-hour predose until 24 hours after start of infusion. 
f Oxygen saturation measurement on dosing days should be done with vital signs. 
g Participants must be vaccinated as described in Section 6.5.3. 
Abbreviations: BMI = body mass index; CIC = circulating immune complexes; CRU = Clinical Research Unit; D = day; ECG = electrocardiogram; ET = early 
termination; HIV = human immunodeficiency virus; Ig = immunoglobulin; NA = not applicable; OP = outpatient; PD = pharmacodynamic(s); PE = physical 
examination; PK = pharmacokinetic(s).
Page 25 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 6: 
Schedule of Activities (Multiple Ascending Dose Cohort 6 and optional Cohort 7) 
Assessments 
Screeni
ng 
D -
1 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 
11 
D 
15 
D 
18 
D 
22 
D 
25 
D 
29 
D 
32 
D 
39 
D 
46 
D 
53 
D 
60 
D 
67 
D 
74 
D 
81 
D 
88/
ET
Status (OP or 
CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
CRU 
OP 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP
Window 
(days) 
D -42 
to 
D -2 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
NA 
±1 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Informed 
consent 
X 
Inclusion/excl
usion criteria 
X 
X 
Serum 
pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol breath 
test 
X 
X 
Urine drug 
screen 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B 
and C screen 
X 
Evidence of 
vaccinationg 
X 
X 
Sample for 
Pneumovax 23 
titerg 
X 
X 
X 
X 
HIV (types 1 
and 2) screen 
X 
Medical 
history and 
demographics 
X 
X 
Physical 
examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
and BMI 
X 
Page 26 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 6: 
Schedule of Activities (Multiple Ascending Dose Cohort 6 and optional Cohort 7) (Continued) 
Assessments 
Scree
ning 
D -
1 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 
11 
D 
15 
D 
18 
D 
22 
D 
25 
D 
29 
D 
32 
D 
39 
D 
46 
D 
53 
D 
60 
D 
67 
D 
74 
D 
81 
D 
88/
ET 
Status (OP or 
CRU) 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
OP 
CRU 
OP 
CRU 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Window (days) 
D -42 
to 
D -2 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
NA 
±1 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Randomization 
X 
Study drug 
administration 
X 
X 
X 
X 
PK blood 
samplingb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood 
sampling - IgA, 
IgG, IgMb,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood 
sampling - IgG 
subtypes 1-4b,c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood 
sampling 
CICb,c
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogen-
icityd 
X 
X 
X 
X 
X 
X 
Biochemistryc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory 
biomarker 
sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen 
saturationf  
X 
X 
X 
X 
12-lead ECG 
(triplicate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac Holter / 
telemetrye 
 X 
X 
X 
X 
X 
X 
Page 27 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 6: 
Schedule of Activities (Multiple Ascending Dose Cohort 6 and optional Cohort 7) (Continued) 
Assessments 
Screeni
ng 
D -1 
D 1 
D 2 
D 3 
D 4 
D 5 
D 6 
D 7 
D 8 
D 
11 
D 
15 
D 
18 
D 
22 
D 
25 
D 
29 
D 
32 
D 
39 
D 
46 
D 
53 
D 
60 
D 
67 
D 
74 
D 
81 
D 
88
/E
T 
Status (OP or 
CRU) 
CR
U 
CR
U 
CR
U 
CR
U 
CR
U 
CR
U 
CR
U 
CR
U 
CR
U 
OP 
CR
U 
OP 
CR
U 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
O
P 
Window 
(days) 
D -42 
to 
D -2 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
±1 
NA 
±1 
NA 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Injection/infus
ion site 
evaluation 
X 
X 
X 
X 
X 
X 
Adverse 
events 
X 
Review 
potential 
safety risk of 
ALXN1830  
X 
Concomitant 
medications 
X 
a Full PE at screening and symptom directed PE thereafter 
b Refer to Table 7 and Table 8 for timing 
c Could be done on the day prior to dosing  
d Predose. 
e Holter at Screening (or up to 3 months prior to Day 1); telemetry at 1-hour predose until 24 hours after start of infusion 
f Oxygen saturation measurement on dosing days should be done with vital signs. 
g Participants must be vaccinated as described in Section 6.5.3.Abbreviations: BMI = body mass index; CIC = circulating immune complexes; CRU = Clinical 
Research Unit; D = day; ECG = electrocardiogram; ET = early termination; HIV = human immunodeficiency virus; Ig = immunoglobulin; NA = not 
applicable; OP = outpatient; PD = pharmacodynamic(s); PE = physical examination; PK = pharmacokinetic(s).
Page 28 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 7: 
Schedule of Activities during Clinical Research Unit confinement for Single Ascending Dose / Multiple 
Ascending Dose  
Study Day 
Time (h)a 
Injection/Infusio
n Site Evaluation 
PKa/PD 
Sampling 
[IgA, IgG, IgM, 
IgG Subtypes 1-
4, CIC] 
 
Vital Signs 
Hematology, 
Chemistry, 
Urinalysis, and 
Coagulation 
ECG 
D1 
Predoseb 
X 
X 
X 
EOI 
X 
X 
X 
0.5 
X 
X 
X 
X 
2 
X 
X 
X 
X 
4 
X 
X 
X 
X 
8 
X 
X 
X 
X 
12 
X 
X 
X 
D2 
24 
X 
X 
X 
X 
X 
D3 
48 
X 
X 
X 
D4b 
72 
X 
X 
X 
X 
D5 
96 
X 
X 
X 
D6 
120 
X 
X 
X 
D7 
144 
X 
X 
X 
D8c
168 
X 
X 
X 
X 
a All samples collected from Start of Infusion unless otherwise specified.  
b Not applicable for Cohort 4. 
c Activities may be done on the admission day prior to dosing. PK and PD samples must always be taken together. 
Abbreviations: CIC = circulating immune complex; D = day; ECG = electrocardiogram; EOI = end of infusion; h = hour; Ig = immunoglobulin; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s). 
Page 29 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2
24 January 2020
Table 8: 
Schedule of Activities during Clinical Research Unit confinement for Multiple Ascending Dose 
Study Day 
Time (h)a 
Injection/Infusio
n Site 
Evaluation 
PKa/PD Sampling 
[IgA, IgG, IgM, 
IgG Subtypes 1-4, 
CIC] 
 
Vital Signs 
Hematology, 
Chemistry, 
Urinalysis, and 
Coagulation 
ECG 
Cohort 4: 
D4/D8/D11/D15/D18
/D22/D25 
Cohort 5: D8/D15/ 
D22/ 
D29/D36/D43/D50/D
57/D64/D71/D78 
Cohort 6 (and 
optional Cohort 7): 
D8//D15/D22 
Predoseb
X 
X 
X 
X 
EOI 
X 
X 
X 
0.5 
X 
X 
X 
X 
2 
X 
X 
X 
X 
4 
X 
X 
X 
X 
8 
X 
X 
X 
X 
12 
X 
X 
X 
Day after dosing - 
discharge after blood 
sampling 
24 
X 
X 
X 
X 
a Samples collected from start of infusion unless otherwise noted. 
b Activities may be done on the admission day prior to dosing. PK and PD samples must always be taken together.
Abbreviations: CIC = circulating immune complex; CRU = Clinical Research Unit; D = day; ECG = electrocardiogram; EOI = end of infusion; h = hour; 
Ig   immunoglobulin; PD = pharmacodynamic(s); PK = pharmacokinetic(s). 
Page 30 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
2.
INTRODUCTION
ALXN1830 is a humanized, affinity-matured IgG4 kappa monoclonal antibody (mAb) that binds 
to the neonatal crystallizable fragment receptor (FcRn) and blocks FcRn-mediated recycling of 
immunoglobulin G (IgG) and IgG immune complexes (ICs), thereby lowering total IgG 
(including pathogenic autoantibodies) and ICs in circulation.  
Immunoglobulin G can indirectly cause disease activity through the formation of ICs, which 
induce the production of inflammatory cytokines or promote antigen presentation and the 
pathogenic activity of T cells, which also provide help to B cells resulting in the production of 
additional pathogenic IgG antibodies (Blumberg et al, 2005). The FcRn contributes to such 
immunopathology by both maintaining the levels of pathogenic IgG antibodies and orchestrating 
the inflammatory activities of IgG-ICs (Baker et al, 2009; Pyzik et al, 2015; Roopenian, 2007). 
There has been increasing recognition that FcRn blockade is a desirable, unique, reversible, and 
potentially effective means to treat a large number of autoimmune diseases in humans. This has 
led to the development of mAbs that specifically target the IgG, but not albumin binding site on 
FcRn. This approach was originally supported by preclinical studies in experimental autoimmune 
myasthenia gravis (MG) in rats, wherein such FcRn blockade can impede both passive MG 
induced by administration of an anti-acetylcholine receptor antibody, or in active MG in rats that 
were immunized against the acetylcholine receptor (Liu et al, 2007). More recently, it has been 
directly demonstrated that fully human mAbs that block the IgG binding site on FcRn led to 
similar decreases in endogenous IgG levels in nonhuman primates without affecting serum 
albumin levels (Mezo et al, 2008; Nixon et al, 2015). Such studies support the approach of mAb 
therapy directed at disrupting IgG binding to FcRn as a potential means to treat IgG-mediated 
diseases. 
ALXN1830 is an mAb that specifically blocks the FcRn-IgG interaction and is intended for the 
treatment of IgG-mediated autoimmune diseases. In order to identify optimal targets for 
anti-FcRn therapy, Alexion has focused initially on autoimmune disorders with an accepted 
pathologic role for autoantibodies in which drugs such as intravenous immunoglobulin (IVIG) 
and/or plasmapheresis have been demonstrated to have a clinically meaningful benefit. While 
current treatments for certain autoimmune disorders, including chronic steroids, 
immunosuppressants, IVIG, plasmapheresis, and anti-CD20 mAbs (such as rituximab) can be 
effective, they are associated with significant adverse effects, and delayed or non-durable 
responses. 
Due to the significant adverse effects of long-term use of high-dose corticosteroids and chronic 
immunosuppressants particularly in an elderly population, there remains a clear unmet medical 
need for the treatment of IgG-mediated diseases. Administration of ALXN1830, leading to a 
significant decrease in total IgG, pathogenic IgG autoantibodies and the circulating immune 
complexes (CICs) of which these IgG are constituents, should lead to a decrease in the clinical 
manifestations of diseases of this type. Moreover, the ability of ALXN1830 to reduce CICs and 
the innate and adaptive immune responses triggered by CICs may result in sustained disease 
modification. 
In the Phase 1 first-in-human study, Study SYNT-101, ALXN1830 was administered as single 
ascending intravenous (IV) doses in healthy adult participants at doses up to 30 mg/kg and 
Page 31 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
demonstrated a good safety profile. The purpose of this Phase 1 study in healthy adult 
participants is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics 
(PD), and immunogenicity of single ascending doses and multiple ascending doses of 
ALXN1830 administered subcutaneously. 
Data from this study are anticipated to help design future studies in patients with IgG-mediated 
diseases.  
2.1. 
Study Rationale 
ALXN1830 is a humanized, affinity-matured IgG4 kappa mAb that binds to the FcRn and blocks 
FcRn-mediated recycling of IgG and IgG ICs, thereby lowering total IgG (including pathogenic 
autoantibodies) and ICs in circulation. While current treatments for certain autoimmune 
disorders, including chronic steroids, immunosuppressants, IVIG, plasmapheresis, and anti-
CD20 mAbs (such as rituximab) may be effective, they are associated with significant adverse 
effects, and delayed or non-durable responses. 
ALXN1830 has been studied in 4 clinical studies to date, each using the IV route of 
administration. It was initially tested in a single ascending dose (SAD) study in healthy 
participants, Study SYNT-101. The highest dose tested in the SAD study, 30 mg/kg, was well 
tolerated. ALXN1830 was then studied in 2 Phase 1b/2a studies in autoimmune patients: Study 
SYNT001-102 in warm autoimmune hemolytic anemia (WAIHA) patients, and Study 
SYNT001-103 in pemphigus patients. In both studies, the participants received 5 qw doses of 
10 mg/kg, a dose and regimen which was well tolerated.   
While these studies were ongoing, a multiple ascending dose (MAD) study in healthy 
participants, Study SYNT001-104, was initiated to investigate the safety, tolerability, PK, PD, 
and immunogenicity of ALXN1830. The dose level of the first cohort in the MAD study was 
20 mg/kg, with 3 doses given once weekly (3 × qw) followed by 3 doses given every 2 weeks 
(3 × q2w). A second cohort was initiated using a dose level of 30 mg/kg, but the study was 
paused after 4 participants in Cohort 2 each received only a single dose.  
All of the active clinical studies (SYNT001-102, SYNT001-103, and SYNT001-104) were 
paused at this time for a Good Manufacturing Practice (GMP) investigation of the study drug 
batches, due to the observation of acute infusion-related reactions (IRRs) in the 20 mg/kg cohort 
of Study SYNT001-104. Although there was no conclusive clinical or safety link between the 
findings of the GMP investigation and the IRRs, and the drug product lots used had met all of the 
approved release specifications, the investigation did identify potential impurities in the drug 
product that could have possibly confounded the safety profile. Alexion has implemented 
changes to the manufacturing process for future batches to enhance the control and detection of 
impurities.  
The purpose of this Phase 1 study in healthy adult participants is to evaluate the safety, 
tolerability, PK, PD, and immunogenicity of single ascending doses and multiple ascending 
doses of ALXN1830 administered subcutaneously. Data from this study are anticipated to help 
design future studies in participants with IgG-mediated diseases. 
Healthy participants are the appropriate population for this study because it will enable PK and 
PD assessments without the potential confounding effects due to other disease activities, 
comorbidities, or medications. This study has been designed to minimize risks to participants 
Page 32 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
with strict inclusion/exclusion criteria, as well as a robust safety monitoring and a risk mitigation 
plan. 
2.2. 
Background 
A detailed description of the chemistry, pharmacology, efficacy, safety, and toxicology data 
available for ALXN1830 is provided in the 
Nonclinical studies have assessed both the potential toxicity and primary PD effects associated 
with ALXN1830 antagonism of IgG binding to FcRn and IgG recycling mediated by FcRn. The 
administration of ALXN1830 to cynomolgus monkeys by qw IV infusion at doses from 
5 to 100 mg/kg for 2 to 27 weeks was well tolerated, with the exception of immunogenicity 
related effects of this humanized monoclonal antibody in monkeys, and produced 
dose-dependent, IgG isotype-selective and reversible reductions in circulating immunoglobulin 
(Ig) levels.  
ALXN1830 has been evaluated in four clinical studies: SYNT-101 (healthy participants, single 
dose study), SYNT001-102 (WAIHA patients, 5 × 10 mg/kg qw), SYNT001-103 (pemphigus 
patients, 5 × 10 mg/kg qw), and SYNT001-104 (healthy participants, 3 × 20 mg/kg qw, then 
3 × 20 mg/kg q2w). In all the clinical studies, ALXN1830 was shown to increase the catabolism 
of IgG, as manifested by decreased total IgG in serum. ALXN1830 also decreased the level of 
circulating IgG-IC. This predicts that ALXN1830 will also accelerate degradation of endogenous 
circulating IgG autoantibodies and IgG-IC specifically involved in the pathogenesis of 
autoimmunity. 
2.3. 
Benefit/Risk Assessment 
This is a healthy participant study, and there is no direct benefit to study participants. However, 
the PK/PD data together with safety profiles without being confounded by underlying disease or 
concomitants medications, may benefit our future human studies in general. Detailed risk 
assessment is listed in the following table, as well as in the IB. In addition, a discussion of 
theoretical risks associated with the reduction of IgG is provided in Section 10.7. 
Page 33 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
2.3.1. 
Risk Assessment 
Table 9: 
Risk Assessment for ALXN1830 
Identified and Potential Risk 
of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation 
Strategy 
Study Drug (s) ALXN1830 
Important Potential Risk: 
Immunogenicity 
Treatment with any therapeutic protein may induce 
an immune response. Occasionally, this immune 
response is clinically meaningful. The 
consequences of an immune reaction to a 
therapeutic protein range from transient 
appearance of antibodies, without any clinical 
consequence, to severe, life-threatening 
conditions. Potential clinical consequences also 
may include severe hypersensitivity-type 
reactions, decrease in efficacy and induction of 
autoimmunity, including antibodies to the 
endogenous form of the protein. 
A total of 6 IRRs have been reported in clinical 
studies, along with high incidence of ADA (+) 
have been observed 
See Section 10.4 for 
IRR management 
stopping rules; 
staggered dosing; See 
Section 7.2 for details 
related to stopping 
rules 
Abbreviations: ADA = antidrug antibody; IRR = infusion-related reaction. 
2.3.2. 
Benefit Assessment 
As this is a study in healthy participants, only societal benefit is expected. Initial testing in 
healthy participants is warranted, as trials in patients, especially those with rare autoimmune 
diseases, may take years to accrue and complete. Healthy participant trials however may be 
completed more rapidly and without the multiple confounding variables of the underlying 
disease and concomitant medications. Also, for studies in healthy participants, the study duration 
is limited to the protocol-defined dosing regimen. Therefore, the total exposure is considerably 
less than what is likely to be required for patients who may require chronic dosing. Most adverse 
events (AEs) reported in previous trials with ALXN1830 were nonserious and resolved with 
discontinuation of investigational therapy. While the potential of serious AEs or unexpected AEs 
exists, this healthy participant trial will provide meaningful scientific information which will 
continue to play an important role in future development of this drug. 
2.3.3. 
Overall Benefit: Risk Conclusion 
ALXN1830 was well tolerated at 10 mg/kg x 5 doses in autoimmune patients. However, at 
multiple doses of 20 mg/kg in healthy participants, the development of potentially immune 
mediated IRRs that resulted in immediate and permanent discontinuation of study drug, together 
with 100% incidence rate of headache, suggested that close safety monitoring and 
implementation of risk mitigation measures are warranted for future studies in the clinical 
development program. Of note, these IRRs were mild and moderate in severity and all resolved 
after cessation of the study drug, without treatment. Similarly, all AEs of headache were mild to 
moderate and were resolved. 
The proposed safety measures in this trial include vaccination/confirmation of vaccination; 
staggered dosing; stopping rules; close participant monitoring through 60 days after the last dose; 
Page 34 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
close safety and PD monitoring with an unblinded medical monitor; prophylaxis for IRRs and 
headache as needed; avoidance of participants with a high risk of infections; prophylactic 
infection management when warranted in the healthy participants after iatrogenic 
immunosuppression; rescue measures such as IVIG replacement in an extremely unlikely event 
of profoundly low IgG; as well as use of an SRC for safety monitoring and dose selections. 
Considering the measures taken to minimize risk to participants in this study, the risks associated 
with ALXN1830 are justified by the anticipated benefits that may be afforded to patients with 
autoimmune disease. 
Page 35 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
3.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of single 
and multiple doses of ALXN1830 SC 
Safety assessed by the incidence and 
relatedness of TEAEs, SAEs, AESIs, physical 
examination, vital sign measurements, clinical 
laboratory and ECG results 
Secondary 
To assess the PK of single and multiple doses 
of ALXN1830 SC 
To explore the PD effects of single and 
multiple doses of ALXN1830 SC 
To assess the immunogenicity of ALXN1830 
SC 
ALXN1830 PK profiles and PK parameters 
Change in IgG levels  
Measurement of ADA levels and NAbs 
Abbreviations: ADA = antidrug antibody; AESIs = adverse events of special interest; ECG = electrocardiogram; 
IgG = immunoglobulin G; NAb = neutralizing antibody; PD = pharmacodynamics; PK = pharmacokinetics; 
SAE = serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse event. 
Page 36 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
4.
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 1 study in up to 56 healthy adult participants (42 on active treatment, 14 on 
placebo [PBO]) conducted at a single site in the United Kingdom. Eight participants will be 
randomly assigned in a 6:2 ratio to each of 7 cohorts to receive either single or multiple doses of 
ALXN1830 SC (n = 6 per cohort) or single or multiple doses of PBO (n = 2 per cohort; 
Table 10). Of these 7 cohorts, 1 cohort is optional; a dose to be determined (based on the safety 
of the predetermined doses) in the MAD. Initially, the first 4 participants randomized to each 
cohort will be dosed with 3 participants on active treatment and 1 participant on PBO. Initially, 
the first 4 participants randomized to each cohort will be dosed with 3 participants on 
ALXN1830 and 1 participant on PBO. The dosing will be staggered, with an interval of at least 
3 days for the SAD cohorts and at least 7 days for the MAD cohorts, before dosing the rest of the 
participants in the cohort. The shorter interval of staggered dosing for the SAD cohorts compared 
to the MAD cohorts is considered appropriate as the expected PK exposure of the ALXN 1830 
SC doses will be a fraction of that of the IV dose demonstrated to be safe and well tolerated in 
previous IV studies. The reduction of IgG after a single SC dose will be well within the observed 
IgG reduction observed in previous IV studies; and in general, there will be low risk of 
immunogenicity and infusion related reactions after a single dose. See Section 4.3 for details 
regarding expected PK exposures and IgG reduction. All participants will be observed during the 
drug administration and for 2 hours after dosing for safety and participants will be encouraged to 
report any discomfort immediately, especially within 24 hours post dosing. At no time will more 
than 4 participants per cohort be dosed on a given day. 
An SRC, consisting of the Investigator, safety monitor, medical monitor, study statistician, and 
clinical pharmacologist, will evaluate the study data at prespecified time points for participant 
safety and make recommendations on dose escalation, dose modification, or termination of the 
study (see SRC charter for description of membership, schedule of meetings, data required for 
each safety review, and requirements for documenting meeting discussions and outcome). 
Relevant safety data from any other studies ongoing with ALXN1830 will be made available to 
the SRC. 
 with the SRC, additional participants 
may be enrolled as replacement participants if a participant discontinues within 3 weeks of the 
last dose for reasons other than drug-related AEs. 
The timing and dependencies of the dosing cohorts are described in Table 11. 
Page 37 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Table 10: 
ALXN1830-HV-105 Dosing Cohorts 
Cohort (n) 
Regimen/Route of Administration 
Study Drug (N) 
1 
Single dose SC 
Placebo (n = 2) or 
ALXN1830 750 mg (n = 6) 
2 
Single dose SC 
Placebo (n = 2) or 
ALXN1830 1500 mg (n = 6) 
3 
Single dose SC 
Placebo (n = 2) or 
ALXN1830 2250 mg (n = 6) 
4 
Multiple dose (8 doses biw) SC 
Placebo (n = 2) or 
ALXN1830 300 mg (n = 6) 
5 
Multiple dose (12 doses qw) SC 
Placebo (n = 2) or 
ALXN1830 750 mg (n = 6) 
6 
Multiple dose (4 doses qw) SC 
Placebo (n = 2) or 
ALXN1830 1500 mg (n = 6) 
7a 
Multiple dose (4 or 12 doses qw) SC 
Placebo (n = 2) or 
ALXN1830 2250mgb (n = 6) 
a Optional. 
b If Cohort 6 is terminated early due to safety or IgG stopping rules, then Cohort 7 may be dosed at a < 1500 mg 
lower weekly dose for 4 doses. If Cohort 6 does not reach the expected IgG reduction, and no safety or IgG 
stopping rules are met, then Cohort 7 may be dosed at higher dose > 1500 mg (but not to exceed 2250 mg) weekly 
for 4 doses).  
Abbreviations: biw = twice weekly; qw = weekly; SC = subcutaneous. 
Page 38 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Table 11: 
Minimum Data Requirements for Dose Escalation 
Decision-
making time 
point: 
Dosing 
regime 
Person or 
body 
making 
the 
decision: 
Minimum data to be looked 
at (in accordance with the 
CSP): 
Method of documentation 
of decision and/or 
communication to Alexion 
(if applicable): 
Continuation 
from any sub-
cohort to the 
next sub-
cohort, within 
any cohort 
As per 
relevant 
cohort 
PI 
A minimum of 3 days (SAD) / 7 
days (MAD) post-dose safety 
and tolerability data from the 
first sub-cohort. 
The Investigator will document 
the decision in an email to 
Alexion. The email does not 
unless there is disagreement 
Cohort 1 
750 mg, 
single dose 
SC 
N/A 
N/A 
N/A 
Cohort 2 
1500 mg, 
single dose 
SC 
SRC 
Review all available safety data 
and IgA, IgG and IgM data 
through Day 15 from Cohort 1, 
from a minimum of six 
participants. 
The SRC will document the 
decision on the 
escalation/progression approval 
form. 
Cohort 3 
2250 mg, 
single dose 
SC 
SRC 
Review of all available safety 
data, IgA, IgG and IgM data and 
PK data through Day 15 for 
Cohort 2, from a minimum of 
six participants. 
The SRC will document the 
decision on the 
escalation/progression approval 
form. 
Cohort 4 
300 mg, 
8 doses 
SC, 
twice 
weekly
SRC 
Review all available safety data 
and IgA, IgG and IgM data 
through Day 15 from Cohort 1, 
from a minimum of six 
participants.
The SRC will document the 
decision on the 
escalation/progression approval 
form. 
Cohort 5 
750 mg, 
12 doses 
SC, 
once 
weekly
SRC 
Review all available safety data 
and IgA, IgG and IgM data 
through Day 15 from Cohort 1, 
from a minimum of six 
participants.
The SRC will document the 
decision on the 
escalation/progression approval 
form. 
Cohort 6 
1500 mg, 
4 doses 
SC, 
once 
weekly 
SRC 
Review all available safety data, 
IgA, IgG and IgM data and PK 
data through Day 25 of Cohort 4 
and Day 22 from Cohort 5 
(whichever occurs later), from a 
minimum of six participants.
The SRC will document the 
decision on the 
escalation/progression approval 
form. 
Cohort 7 
2250 mg, 
4 doses 
SC, 
once 
weekly
SRC 
Review all available safety data 
and IgA, IgG and IgM data 
through Day 22 from Cohort 6, 
from a minimum of six 
participants.
The SRC will document the 
decision on the 
escalation/progression approval 
form. 
Abbreviations: CSP = Clinical Study Protocol; IG = immunoglobulin; MAD = multiple ascending dose; N/A = not 
applicable; PI = Principal Investigator; PK = pharmacokinetics; SAD = single ascending dose; SC = subcutaneous; 
SRC = Safety Review Committee 
The planned study duration is approximately 183 days: up to 42 days for screening and 
approximately 141 days for dosing and follow up. 
Page 39 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
4.2. 
Scientific Rationale for Study Design 
ALXN1830 has been studied in four clinical studies, each using the IV route of administration. 
Refer to Section 2.2 for background on clinical studies conducted with ALXN1830 to date.  
This randomized, double-blind, PBO-controlled, SAD/MAD design was chosen for initial 
assessment of the safety, tolerability, PK/PD, and immunogenicity of ALXN1830 administered 
SC. 
Healthy participants are the appropriate population for this study, enabling the effects of 
ALXN1830 without the potential confounding effects of other disease activities, comorbidities, 
or medications.  
A staggered dosing paradigm is being used for participant protection. A PBO control is 
implemented in each cohort. Due to the difficulty of providing a matching PBO, participants 
randomized to PBO will receive an equivalent volume of saline at the same infusion rate as the 
active treatment.  
ALXN1830 is an anti-FcRn mAb that blocks recycling of IgG antibodies, reducing the total IgG 
in circulation, including potentially pathogenic IgG autoantibodies associated with multiple 
autoimmune diseases. Thus, reduction in IgG level is used to measure the anti-FcRn PD activity 
of ALXN1830.  
A comprehensive approach to minimize the potential risk of infection in the healthy participants 
due the theoretical concerns associated with reducing total IgG (discussed in greater detail in 
Section 10.7). The following criteria will be observed as part of the inclusion criteria 
(Section 5.1), monitoring, and specified response to certain signs, symptoms or laboratory 
results:  
Inclusion criteria of heathy participants with: 
 1,000 mg/dL (above the upper limit of normal 
[ULN]) 
No history of acute and chronic infections; ie, enrolled healthy participants will be 
immunocompetent 
Absence of any immunologic deficiencies; eg, IgM, IgA within normal limits 
Pneumococcus and seasonal influenza vaccination (see Section 6.5.3 and 
Section 10.7). 
To ensure a timely and adequate intervention if needed, IgG levels will be 
continuously and closely monitored during this study 
Stopping rules (Section 7.2) for individuals and cohorts will be based on reduction of 
 300 
 300 mg/dL is provided in 
Section 10.7). 
Dosing will be permanently stopped in any individual if the IgG level is reduced 
 300 mg/dL 
 300 mg/dL, 
dosing in that cohort will stop and no further dose escalation will occur. 
Page 40 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Although unlikely to occur, in the unexpected instance of an IgG reduction falling 
into the severe category (ie, less than 100 mg/dL) or if there is any suggestion, signs 
or symptoms of infection, prophylactic antibiotics and/or IVIG will be considered as 
detailed in the protocol (Section 6.5). 
4.3. 
Justification for Dose 
Single and multiple IV doses of ALXN1830 have been administered in healthy participants, and 
in patients with WAIHA and pemphigus vulgaris (PV). In healthy participants, single IV doses 
were given at 1, 3, 10 and 30 mg/kg (Studies SYNT-101 and SYNT001-104), and multiple IV 
doses were given at 20 mg/kg qw for 3 doses and then q2w for 3 doses (Study SYNT001-104). 
In WAIHA (Study SYNT001-102) and PV (Study SYNT001-103) patients, IV doses of 
10 mg/kg qw for 5 doses were given.  
A physiologically based PK/PD model for IV dosing was established and was fitted to the IV 
PK/PD data from healthy participants. Due to the lack of SC data in human, SC PK/PD model is 
not yet available. However, the following has been observed: 
1. The bioavailability (F) of ALXN1830 after SC administration is likely low:
a.
Based on the preliminary results from the 5-week SC monkey toxicity
(Study 2455-024), the bioavailability (F) after a single dose of 30 mg/kg SC in
monkeys is around 21.5%.
b. For healthy participants, SC bioavailability of another anti-FcRn mAb was around
11%.
2. The maximum reduction of IgG for ALXN1830 is likely similar between IV and SC at
the same mg/kg dose:
a.
At 100 mg/kg IV or SC in the 5-week Good Laboratory Practice (GLP) toxicology
studies (Studies 2455-002 and 2455-024), the maximum IgG reduction was 68% after
IV and 69% after SC.
b. Similar IgG reduction was observed at the same mg/kg dose in a clinical trial in
healthy participants with another anti-FcRn mAb.
Based on these observations, ALXN1830 exposure, safety margin and IgG reduction after SC 
administration was predicted (see Table 12).  The following assumptions have been used: 
1. ALXN1830 bioavailability after SC administration is 20%.
2. ALXN1830 clearance (CL) and body weight have the following relationship:
CL = (Median CL) × (body weight/median body weight)0.75
Page 41 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Table 12: 
Predicted ALXN1830 Exposure, Safety Margin, and Immunoglobulin G 
Reduction after Subcutaneous Administration 
Cohort
Dose 
(mg) 
Body 
Weight
(kg) a 
Weekly 
Dose in 
mg/kg a,b
F 
AUC of SC 
Dosing 
 a,c
Margin 
Based on 
NOAEL of 
Monkey 
Toxicology 
Studies a,d 
Margin 
Based on 5-
week 
Monkey 
SC 
Toxicology 
Studya,e 
Margin 
Based on 
27-week 
Monkey IV 
Toxicology 
Study a,f 
Expected 
Maximum 
IgG 
Reduction 
(%) g 
1 
750 
75 
(50-90) 
10 
(8.3-15) 
0.2
675 
(589-983) 
10 
(6.7-12) 
10 
(7-11) 
52 
(35-59) 
-30
2 
1500 
75 
(50-90) 
20 
(16.7-
30) 
0.2
1451 
(1265-2664) 
5 
(3.3-6) 
4 
(2-5) 
24 
(13-28) 
-45
3 
2250 
75 
(50-90) 
30 
(25-45) 
0.2
2948 
(2571-3996) 
3.3 
(2.2-4) 
2.2 
(1.6-2.5) 
12 
(9-14) 
-48
4 
300 twice 
weekly x 
4 
75 
(50-90) 
8 
(6.7-12) 
0.2
540 
(471-732) 
13 
(8-15) 
12 
(9-14) 
64 
(48-74) 
-53
5 
750 qw x 
12 
75 
(50-90) 
10 
(8.3-15) 
0.2
675 
(589-983) 
10 
(7-12) 
10 
(7-11) 
52 
(35-59) 
-68
6 
1500 qw 
x 4 
75 
(50-90) 
20 
(16.7-
30) 
0.2
1451 
(1265-2664) 
5 
(3-6) 
4 
(2-5) 
24 
(13-28) 
-69
7 
2250 qw 
x 4 
75 
(50-90) 
30 
(25-45) 
0.2
2948 
(2571-3996) 
3 
(2-4) 
2.2 
(1.6-2.5) 
12 
(9-14) 
-72
a Values are median (min, max). 
b Weekly dose in mg/kg = (dose in mg) / (body weight in kg). 
c AUCSC = AUCIV * F. Median AUCIV at 10 mg/kg = 2.89 mL/h/kg with a median body weight of 82.7 kg (SYNT-101); Median 
AUCIV at 20 mg/kg = 215 mL/h with a median body weight of 79 kg (SYNT001-104); Median AUCIV at 30 mg/kg = 2.03 
mL/h/kg with a median body weight of 75.8 kg (SYNT-101). Where median AUCIV is not available at certain dose levels (e.g. 
15 mg/kg), doses (mg/kg) are round up to obtain a conservative estimate. Median AUCIV for 45 mg/kg is set to equal to 
median AUCIV at 30 mg/kg (2.03 mL/h/kg). 
d Safety margin = (Monkey NOAEL in mg/kg) / (Human dose in mg/kg). Monkey NOAEL for weekly dosing is 100 mg/kg 
(Studies 2455-024 and 2455-016). 
e Safety margin = (Monkey AUC0-120h at NOAEL) / (Predicted human AUCSC). Day 29 AUC0-120h 
mg/kg weekly SC (Study 2455-024). 
f Safety margin = (Monkey AUC0-Tlast at NOAEL) / (Predicted human AUCSC). Day 92 AUC0-Tlast 
mg/kg weekly IV (Study 2455-016). 
g IgG reduction is based on predicted IgG reduction at equivalent IV dose in mg/kg. IgG reduction at median body weight is 
presented.  
Abbreviations: AUC = area under the concentration-time curve; AUC0-120h = area under the concentration-time curve from time 
0 (dosing) to 120 hours post-dose; AUC0-Tlast = Area under the serum concentration versus time curve from time 0 to the last 
quantifiable concentration; F = bioavailability; IV = intravenous; q2w = once every two weeks; qw = weekly; 
SC = subcutaneous.
Study ALXN1830-HV-105 will include 3 SAD cohorts and up to 4 MAD cohorts in healthy 
adult participants (Figure 1). The starting dose of the SAD portion of the SC study will be 
750 mg, equivalent to 10 mg/kg in a 75 kg participant, or 15 mg/kg in a 50 kg participant. 
Previously, 30 mg/kg has been shown to be well tolerated when administered as a single dose by 
IV infusion in healthy participants (Study SYNT-101 and Study SYNT001-104). Compared to 
the no observed adverse effect level (NOAEL) in the GLP IV (100 mg/kg/week IV, Study 
2455-002 and Study 2455-016) or SC (100 mg/kg/week SC, Study 2455-024) toxicology studies 
in monkeys, the SC starting dose of 750 mg will have a safety margin of approximately 6.7-fold 
(for a 50-kg participant) or 10-fold (for a 75-kg participant). Assuming a human bioavailability 
of 20% the expected AUC at 750 mg SC will have a safety margin of 7-fold (for a 50-kg 
Page 42 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
participant) or 10-fold (for a 75-kg participant) based on the NOAEL exposure from the 5-week 
SC monkey toxicity study, and 35-fold (for a 50-kg participant) or 52-fold (for a 75-kg 
participant) based on the NOAEL exposure from the 27-week IV monkey toxicity study. More 
importantly, a 30 mg/kg IV single dose has been tested in healthy participants and this starting 
dose of 750 mg SC is expected to be roughly 1/10 to 1/15 of the exposure at 30 mg/kg IV, based 
on the low bioavailability observed in monkey for ALXN1830 and in healthy participants from 
other anti-FcRn compounds . Based on these observations, the expected maximum IgG reduction 
at 750 mg SC would be around -30% from baseline. 
In the SAD portion, the SC dose will be escalated 2-fold from 750 mg (Cohort 1) to 1500 mg 
(Cohort 2), and then 1.5-fold to 2250 mg (Cohort 3). SRC review of safety, tolerability and IgG 
data will be conducted before each dose escalation. Staggered dosing and pre-specified stopping 
rules based on safety and IgG reduction will be implemented in all cohorts. 
As shown in Table 12 the first two MAD cohorts will be administered 300 mg SC biw for 
4 weeks (Cohort 4) and 750 mg SC qw for 12 weeks (Cohort 5). On a mg/kg basis, the 300 mg 
SC biw dose represents at least a 9 to 48-fold safety margin, and the 750 mg SC qw dose 
represents at least a 7 to 35-fold safety margin when compared to the NOAEL exposures of the 
5-week SC and 27-week IV monkey GLP studies. Both MAD cohorts will start after SRC review
of the first SAD cohort (single dose of 750 mg SC). While most of the MAD cohorts have
treatment duration of 4 weeks, Cohort 5 (750 mg SC weekly for 12 weeks) is of an extended
duration to enable the evaluation of immunogenicity after long term administration of
ALXN1830.
The SC multiple doses will be escalated 2.5-fold from 300 mg twice weekly and 750 mg weekly 
to 1500 mg once weekly (Cohort 5 and 6, respectively) after SRC review. At this dose level, the 
expected maximum IgG reduction is expected to be around 69%, which is similar to that 
observed with 20 mg/kg IV in Study SYNT001-104 (after the three weekly loading doses).  
An optional fourth MAD cohort (Cohort 7) may be enrolled under the following scenarios: 
3. If Cohort 6 is terminated early due to safety or IgG stopping rules, then Cohort 7 may be
dosed at a < 1500 mg weekly dose for 4 doses.
4. If Cohort 6 does not reach the expected IgG reduction, and no safety or IgG stopping
rules are met, then Cohort 7 may be dosed at > 1500 mg (but not more than 2250 mg)
weekly for 4 doses.
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed the last 
scheduled visit shown in the Schedule of Activities (SoA) (Section 1.3). 
The end of the study is defined as the date of the last participant follow-up visit in the study, as 
specified in the SoA. 
Page 43 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
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 
Male and female participants are eligible to be included in the study only if all of the following 
criteria apply: 
Age 
1. Participants must be between the ages of 18 and 65 years, inclusive, at the time of signing
the informed consent.
Type of Participant 
2. Participants who are healthy as determined by medical evaluation including medical
history, physical examination, laboratory tests, and cardiac monitoring.
3. Participant agrees to not donate blood for 4 months after completion of their last study
visit.
4. Baseline IgG concentrations  1000 mg/dL at Screening.
5. Baseline IgA and IgM1 within normal levels at Screening.
6. Participants must have had vaccination against pneumococcus (Pneumovax 23
[PPSV23]) at least 28 days, and maximally 4 years prior to Day 1.
7. Participants must have had seasonal influenza vaccination for the current season at least
28 days prior to Day 1.
Weight 
8. Body weight within 50 to 90 kg, inclusive, and body mass index (BMI) within the range
of 18 to 24.9 kg/m2, inclusive.
1   IgM levels are expected to be above the upper level of normal per local laboratory reference range if the 
participant has recently received Pneumovax 23 vaccination. Therefore, participants are eligible if they have been 
recently vaccinated with Pneumovax 23 per vaccination criteria described in Section 6.5.3 and the IgM level 
corresponds with the post-
Page 44 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Contraception 
9. Female participants of childbearing potential and male participants with female partners
of childbearing potential must be willing to follow protocol-specified contraception
guidance during the study and for up to 3 months after last dose of study drug.
Informed Consent 
10. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and the protocol.
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal,
endocrinological, hematological, or neurological disorders capable of significantly
altering the absorption, metabolism, or elimination of drugs; constituting a risk when
taking the study intervention; or interfering with the interpretation of data.
2. Abnormal blood pressure (BP) as determined by the Investigator (resting BP should be
between 120/80 mmHg and 90/60 mmHg) at Screening.
3. Participants who have any clinically significant history of allergy or hypersensitivity.
4. History of unexplained, recurrent infection, or infection requiring treatment with systemic
antibiotics within 90 days prior to dosing on Day 1.
5. Participants with the history of frequent and/or chronic headaches, including migraine
disorder, cluster headache disorder, and tension headache disorder.
6. Lymphoma, leukemia, or any malignancy active within the past 5 years except for locally
curable cancers that have been completely removed such as superficial basal cell or
squamous epithelial carcinomas of the skin.
7. Alanine transaminase (ALT) > 1.5 × ULN at Screening and Day -1.
8. Bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is
fractionated and direct bilirubin < 35%) at Screening and Day -1.
9. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with
the exception of Gilbert's syndrome or asymptomatic gallstones).
10. Corrected QT (QTc) > 450 msec for male participants or > 470 msec for female
participants.
NOTE: The QTc is the QT interval corrected for heart rate accordi
formula (QTcF). It is either machine-read or manually over-read.
11. Female participants who are pregnant or breastfeeding.
Page 45 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Prior/Concomitant Therapy 
12. Past or intended use of over-the-counter or prescription medication including herbal
medications within 14 days (or longer in case of a specific herbal medication) prior to
dosing.
13. Known exposure to therapeutic proteins, such as mAbs, including marketed drugs prior
to dosing.
14. Participants who have prior exposure to ALXN1830.
15. Any vaccination within 2 weeks of screening other than those required for this study.
Any live virus vaccination within 6 months of screening.
Prior/Concurrent Clinical Study Experience 
16. Exposure to more than 4 new (small molecule) investigational compounds within
12 months prior to dosing.
17. Current enrollment or past participation within the last 90 days before signing of consent
in this or any other interventional clinical study.
Diagnostic Assessments 
18. Presence of hepatitis B surface antigen (HBsAg) at Screening.
19. Positive hepatitis C antibody test result at Screening.
20. Positive pre-study drug/alcohol screen at Screening.
21. Positive human immunodeficiency virus (HIV) antibody test at Screening.
Other Exclusions 
22. History of illicit drug abuse, history of significant alcohol abuse within 1 year prior to the
screening visit, or clinical evidence of substance and/or alcohol dependence within the
2 years before screening. Alcohol abuse is defined as regular weekly intake of more than
14 units (for both males and females) (NHS, 2018).
23. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing
products in any form (eg, gum, patch, electronic cigarettes) within 3 months prior to the
planned first day of dosing.
24. Individuals who are intimate with or who are in prolonged contact with (defined as living
under the same roof or providing personal care to) people younger than 3 years of age or
older than 65 years of age, or who are either immunocompromised or have one of the
following underlying medical conditions: anatomic or functional asplenia (including
sickle cell disease); primary antibody deficiencies; or HIV.
25. Individuals with children attending daycare and/or with children who are first-year
college/university students.
26. First-year college/university students.
27. Individuals who are one of the following:
Page 46 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Professionals (eg, healthcare workers) exposed to environments of greater risk for 
infectious disease. 
Research, industrial and clinical laboratory personnel who are routinely exposed 
to infectious agents (bacterial or viral).  
28. Has a tattoo or body piercing which might interfere with injection site examination
throughout the duration of the study.
5.3. 
Lifestyle Considerations 
Table 13: 
Lifestyle Considerations for Participants in Study ALXN1830-HV-105 
Items participants must not 
consume or do: 
When participants must stop: 
When participants can re-
start: 
Tobacco in any form (eg, smoking 
or chewing) or other nicotine-
containing products in any form 
(eg, gum, patch, electronic 
cigarettes).  
From three months prior to the 
planned first day of dosing. 
After study completion/last visit. 
Meals/snacks/water 
Whenever participants are confined 
in the ward, only the drinks and 
meals provided by the trial 
personnel will be allowed. 
Standard meals will be provided at 
the standard unit times as stated in 
the study plan, and meals should be 
completed each time. 
Standard meals will be given at 
regular intervals throughout the in-
house stay. 
Any other substances known to be 
potent inhibitors or inducers of 
CYP P450s. This includes food or 
drink products containing 
cranberry, pomegranate, star fruit, 
grapefruit, pomelos, exotic citrus 
fruits or Seville oranges (including 
marmalade and juices made from 
these fruits).
Within three weeks before the 
planned first study drug 
administration. 
After study completion/last visit. 
Caffeine-containing or Xanthine-
containing products.  
48 hours before the planned first 
study drug administration and each 
out-patient/ follow-up visit.
After study completion/last visit. 
Energy drinks or drinks containing 
taurine, glucuronolactone (eg Red 
Bull). 
48 hours before the planned first 
study drug administration and each 
out-patient/ follow-up visit.
After study completion/last visit. 
Alcohol. 
48 hours before the planned first 
study drug administration and each 
out-patient/ follow-up visit. 
After study completion/last visit. 
Strenuous physical activity. 
48 hours before screening, 
admission and 
out-patient/follow-up visit. 
After study completion/last visit. 
[Participants should not start new 
physical training activities during 
the study until study completion 
(last visit)]
Page 47 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Table 13: 
Lifestyle Considerations for Participants in Study ALXN1830-HV-105 
(Continued) 
Items participants must not 
consume or do: 
When participants must stop: 
When participants can re-
start: 
Any prescription medication. For 
details, including exceptions see 
Section 6.5. 
14 days before the planned first 
study drug administration. 
After study completion/last visit. 
Please refer to Section 6.5. 
N.B: If participants have a medical
need to take any medication or have
any medications prescribed to them
by a doctor, they should follow the
medical advice but inform the
Investigator as soon as possible
afterwards. Participants should be
informed not to stop taking any
medication that has been prescribed
by their GP or other doctor.
Any over-the-counter medication. 
For details, including exceptions 
see Section 6.5. 
14 days before the planned first 
study drug administration. 
After study completion/last visit.
Any herbal remedy or dietary 
supplement containing St John's 
Wort. 
Three weeks before the planned 
first study drug administration. 
After study completion/last visit. 
Blood and plasma donation. 
Sixteen weeks before the planned 
first study drug administration. 
Three months after study 
completion/last visit. 
Contraception: Participants must 
comply with the appropriate 
contraceptive requirements as 
stated in Section 10.6.
Start times for contraceptives vary 
according to method used - see 
applicable contraceptive method in 
in Section 10.6.
Until the end of systemic exposure 
(for this study, this is until the 
follow-up visit). 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study drug. 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 (CONSORT) publishing requirements (Schulz et al, 2010) and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details (eg, failed eligibility criteria), and any serious adverse event (SAE) 
occurring during the screening period.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned the same participant number as for the 
initial screening. 
Any study-related testing performed at Screening may be repeated within the screening visit 
Page 48 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
6.
STUDY DRUG
Study drug is defined as any investigational intervention(s), marketed product(s), PBO, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study Drug Administered 
The study drug formulation and doses to be administered in this study are presented in Table 10 
and study drug dose preparation is presented below. 
Drug Name 
ALXN1830   
Placebo 
Type  
Biologic  
Diluent 
Dose 
Formulation 
Sterile liquid 
Sterile liquid 
Unit Dose 
Strength(s) 
ALXN1830 is formulated at 150 mg/mL, 
and supplied as a 1500 mg/10mL vial 
Placebo 
Dosage Level(s) 
Refer to Table 10 
Not applicable 
Route of 
Administration 
SC injection or infusion 
SC push for 300 mg (2 ml) and SC 
infusion for 750 mg and above 
SC injection or infusion 
SC push for cohort of 300 mg (2 ml) 
ALXN1830 and SC infusion for cohorts of 750 
mg ALXN1830 and above 
Use 
Investigational Product 
Placebo 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Provided by Alexion 
Provided by trial site 
Packaging and 
Labeling 
Study Drug will be provided in a 10mL 
Vial. Each vial will be labeled as required 
per country requirement
Study Drug will be provided in country-
specific commercially available form   
Abbreviations: IMP = investigational medicinal product; SC = subcutaneous 
6.2. 
Preparation/Handling/Storage/Accountability 
Details regarding preparation, handling, storage, accountability, and administration of the study 
drug are discussed below. Additional guidance is provided in the pharmacy manual. 
1. The Investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study drug received and any discrepancies are reported and
resolved before use of the study drug.
2. Only participants enrolled in the study may receive study drug and only authorized site staff
may supply or administer study drug. All study drug must be stored in a secure,
environmentally controlled, and monitored (manual or automated) area in accordance with
the labeled storage conditions with access limited to the Investigator and authorized site staff.
3. The
record maintenance (ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study drugs are provided
in the Pharmacy Manual.
Page 49 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a double-blind study. Eligible participants who meet all inclusion and no exclusion 
criteria will be assigned unique numbers for enrollment and randomization. 
On Day 1 participants will be assigned a unique number (randomization number) in ascending 
7 
cohorts of the study, according to the randomization schedule generated prior to the study by the 
Statistics Department at Alexion (or designee).  
Participants will be randomly assigned in a 6:2 ratio to receive ALXN1830 or PBO. The 
of the study. In order to maintain this blind, site's pharmacy staff will be responsible for the 
reconstitution and dispensation of all study drug. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study drug records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
In the event of an emergency, an envelope for each participant containing his/her study drug 
assignment will be available in the pharmacy at the clinical study site. Unblinding should only be 
considered for the safety of the participant. If unblinding is deemed necessary by the 
envelope available from the pharmacy staff. The Investigator must note the date, time, and 
reason for unblinding. The Investigator should inform the Medical Monitor that the participant 
was unblinded; however, the Investigator should not reveal to the Medical Monitor the 
 blind will be maintained for persons responsible for the 
ongoing conduct of the study (such as the management, monitors, Investigator, etc) and those 
responsible for data analysis and interpretation of results at the conclusion of the study, such as 
biometrics personnel. Unblinded information will only be accessible to those who need to be 
involved in the safety reporting to health authorities, independent ethics committees (IECs), or 
persons performing ongoing safety evaluations during the study. The Investigator will receive 
only blinded information unless unblinded information is judged necessary for safety reasons. 
6.4. 
Study Drug Compliance 
Participants will receive study drug directly from the Investigator or designee, under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents and recorded in the electronic case report form (eCRF). The dose of study 
drug and study participant identification will be confirmed at the time of dosing by a member of 
the study site staff other than the person administering the study drug. 
Page 50 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with: 
Reason for use 
Dates of administration including start and end dates 
Dosage information including dose and frequency 
Concomitant treatment that is medically indicated for any AEs the participant experiences during 
the study is permitted. 
If concomitant medication is needed during the study, this medication must be recorded on the 
eCRF, stating its generic name, time of administration, dose, route and duration, as well as the 
reason for administration. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Premedication and Hydration 
Premedication is recommended as shown in the table below. 
Table 14:  
Recommended Premedication 
Medication 
Dose 
Route 
When given 
Max dosing 
Paracetamol
1 g
Oral
30 minutes prior to each dose
Single dose
Chlorpheniramine
4 mg
Oral
30 minutes prior to each dose
Single dose
Famotidine 
20 mg 
Oral 
30 - 60 min before meal on 
dosing day 
Single dose 
In addition, it is recommended that study participants drink approximately 2 L (women)/2.5 L 
(men) of water every day during the 3 days preceding and following an infusion treatment 
(further information on hydration prior to dosing is provided in Section 10.7.2). 
6.5.2. 
Supportive/Symptomatic Care 
The use of supportive therapy/symptomatic treatment is allowable at any time during the study to 
treat AEs. The date and time of administration of supportive therapy / symptomatic treatment as 
well as the name and dosage regimen of any medication must be recorded. Details are provided 
in the study manual. 
Supportive/symptomatic care such as H1 and H2 blockers, eg, diphenhydramine and famotidine 
is recommended for any manifesting allergic reactions and associated gastrointestinal symptoms, 
ondansetron for persistent nausea, bronchodilators for potential dyspnea, eg, salbutamol or 
pirbuterol, analgesics/antipyretics for headache, pyrexia and myalgia, eg, acetaminophen, fluids 
of normal saline in case of hypotension. 
Page 51 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
6.5.3. 
Vaccinations 
To mitigate the risk of sinopulmonary infections associated with anti-FcRN targeted IgG 
reduction therapy, all participants in this study must have been adequately vaccinated against the 
following: 
1. Pneumococcus
2. Seasonal influenza vaccine (if being dosed
Satisfactory documentation must be provided for the stated vaccinations. The following (and 
 based on recommendations from Chapter 
7 of t
sation of Individuals with Underlying 
(Public Health England, 2016). 
1. Pneumococcus:
a.
Has received: pneumococcal polysaccharide vaccine, Pneumovax 23 (PPSV23),
at least 28 days, and maximally 4 years prior to dosing of ALXN1830 on Day 1.
i. One dose must have been given.
2. Seasonal influenza vaccine:
a.
Has received: quadrivalent influenza vaccine for the current season, at least 28
days prior to dosing of ALXN1830 on Day 1. This must be most recent and up-to-
date formulation available.
i. One dose must have been given.
Vaccination titers 
Blood samples for assessment of vaccination titers (both prevaccination and postvaccination) 
will be taken at various time points. Titers will have no consequence on eligibility. 
6.5.4. 
Antibiotics Prophylaxis 
3. Prophylactic antibiotic treatment may be utilized as a temporary measure, oral
azithromycin 250 mg once daily under following conditions:
a.
When to consider starting*: when IgG level is equal to or falls below 300 mg/dL.
b. When to stop: 
 600mg/dL and no further doses of ALXN1830 are 
to be given. 
c.
At the discretion of the investigator, if they observe a prodromal state or any clinical
sign or symptom of infection, which warrants antibiotic treatment.
*Once started, azithromycin will be given every day, until IgG level is > 600mg/dL and
no further doses of study drug are to be given.
6.5.5. 
Disallowed Medication 
During the study, participants are not allowed to use any kind of prescribed medication, 
including mAbs other than the study drug, any investigational drug or device, and vaccinations 
within 2 weeks of screening (other than those to be administered as part of this study; refer to 
Section 5.1) and for the duration of the study. 
Page 52 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
The use of over-the-counter medication is not allowed from 14 days prior to the first 
administration of study drug until the end of study (EOS) with the exception of the medications 
described above. 
6.6. 
Dose Modification  
Decisions to continue or modify dosing will be made by the Investigator and/or SRC after 
reviewing of the blinded data. The SRC may also make recommendations regarding safety 
issues, study conduct, or study suspension.  
6.7. 
Drug After the End of the Study 
This is a healthy participant study and no follow-up study drug administration is planned. 
Page 53 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
7.
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Drug
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study drug. Unless a participant fully withdraws their consent, they will 
continue their enrollment without study drug administration but will be required to complete a 
follow up visit for safety purposes. See the SoA (Section 1.3) for data to be collected at the time 
of discontinuation of study drug and follow-up and for any further evaluations that need to be 
completed. 
7.2. 
Stopping Criteria 
7.2.1. 
Immunoglobulin Stopping Rules 
 300 mg/dL as an individual stopping 
rule for the healthy participant study. More specifically, if any predose measurements show a 
 300 mg/dL, the individual stopping rule will be met. Repeat testing to 
confirm the consistency of the result is permitted, and the procedure to maintain blinding under 
these circumstances will be described in the study operations manual (SOM). Healthy 
participants can rebound to their baseline IgG level when the drug is discontinued because they 
are not immunocompromised, as evidenced by existing anti-FcRn studies. Additionally, risk 
mitigation strategies such as antibiotics or immunoglobulin (Ig) replacement therapy are 
implemented if participants have lab evidence of infection and/or are clinically symptomatic. 
 300 mg/dL, dosing in that 
cohort/dose level will stop and no further dose escalation will occur. 
In addition, any individual for whom IgA, IgM, or Pneumovax 23 vaccine titers fall below the 
normal limits (according to the reference ranges of the laboratory) will be discontinued from 
further dosing. 
7.2.2. 
Safety Stopping Rules (Individual, Cohort and Study Level Stopping Rules) 
Individual Level: 
Study drug will be discontinued immediately (if applicable) and permanently if any of 
the following occurs: 
 Grade 3) AR. 
Development of an IRR: 
a.
That has not fully resolved after symptomatic treatment / supportive care;
b.
Manifesting as dyspnea on moderate exertion, which is associated with
any other constitutional symptoms.
c.
With evidence of hemodynamic instability (isolated hypotension not
requiring intervention is however permitted) that responds to 1 L of fluids,
infused rapidly.
Page 54 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
If a moderate Grade 2 AR is observed, study drug administration may be continued, 
consultation with Alexion. 
Cohort and Study Level:  
A cohort and other cohort with a dose at an equal or higher level will be stopped or 
not initiated if any of the following occurs: 
 2 participants on study drug in the cohort experience a moderate (Grade 2) AR 
that does not improve by 14 days after treatment 
 2 participants on study drug in the cohort experience an IRR as described earlier 
(see individual level) 
Study will be discontinued (all dosing [lower, equal or higher doses]) and 
continuation of the cohort or study will require a substantial amendment, if any of the 
following occurs: 
Two participants on study drug in any cohort experience a severe (Grade 3) AR 
One participant on study drug in any cohort experiences a serious AR 
7.3. 
Participant Discontinuation/Withdrawal from the Study 
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, 
compliance, or administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3). See SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
The participant will be permanently discontinued both from the study drug and from 
the study at that time. 
If the participant withdraws consent for disclosure of future information, Alexion 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. 
7.4. 
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 
Page 55 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
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 (where possible, three 
telephone call
mailing address or local equivalent methods). These contact attempts should be 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole is handled as part of Section 10.1.8. 
7.5. 
Criteria for Study Termination 
The Investigator, competent authority, or Sponsor may terminate the study for reasonable cause. 
Conditions that warrant termination of the study include, but are not limited to, the following: 
Discovery of an unexpected, serious, or unacceptable risk to participants enrolled in 
the study. 
Decision on the part of Alexion to suspend or discontinue testing, evaluation, or 
development of the study drug. 
Failure of the Investigator to comply with the approved protocol, pertinent guidelines, 
and/or regulations. 
Submission of knowingly false information from the Investigator to Alexion and/or 
regulatory authorities. 
Page 56 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with Alexion immediately upon
occurrence or awareness to determine if the participant should continue or
discontinue study drug.
Adherence to the study design requirements, including those specified in the SoA, is
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. 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.
8.1. 
Efficacy Assessments
No efficacy assessments will be obtained during this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations 
A full physical examination will be performed at Screening. A symptom-driven physical 
examination will be performed at the EOS visit and may be performed at other times, at the 
Each examination will include the following assessments: general appearance; skin; head, ears, 
eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous 
system; and musculoskeletal system. 
Height (screening only) and weight will also be measured and recorded at Screening. Body mass 
index will be calculated and recorded at Screening. 
8.2.2. 
Vital Signs 
Vital sign measurements will be taken after the participant has been resting in the supine or semi 
recumbent position for at least 5 minutes and will include temperature (°C; tympanic or oral), 
respiratory rate, oxygen saturation (Section 8.2.3), supine BP, and pulse. Orthostatic (standing) 
BP will only be measured at Screening. The timing of vital sign measurements is described in the 
SoA (Section 1.3
discretion. Confirmed, clinically significant vital sign measurements will be recorded as AEs. 
8.2.3. 
Oxygen Saturation 
Functional oxygen saturation (SpO2), which is measured along with vital signs (Section 8.2.2), is 
the ratio of oxygenated hemoglobin capable of transporting oxygen. The measurement is 
performed using automated monitors. 
Page 57 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
8.2.4. 
Electrocardiograms 
8.2.4.1. 
Recording of 12-Lead ECGs 
A triplicate 12-lead electrocardiogram (ECG) will be obtained using a GE Marquette MAC1200® 
/MAC1200ST® recorder connected via a fixed network connection to the MUSE® Cardiology 
Information System (hereinafter referred to as MUSE) after the participant has been resting for at 
least 10 minutes. The 12-lead ECGs will be conducted before PK/PD/biomarker blood sampling 
if these 2 events occur at the same time. The timing of 12-lead ECGs is described in the SoA 
(Section 1.3).  
The 12-lead ECGs recorded during screening will be stored electronically on the MUSE® 
information system. Only ECGs recorded electronically will be valid ECGs for any purpose 
form (CRF) for medical safety reviews. 
Each 12-lead ECG recorder will be set up to the required technical specifications and containing 
the information required to identify the records. Each ECG recording will be clearly identified 
(Participant ID, visit date, and the actual times of ECG recordings).  
The 12-lead ECG recordings will be made after the participants have been resting in a supine 
position for at least 10 minutes. The participants will avoid postural changes during the ECG 
recordings and clinical staff will ensure that participants are awake during the ECG recording. 
At each time point, the 12-lead ECG will be recorded in triplicate, to reduce variance and 
improve the precision of measurement. The triplicates will be performed at approximately 
1-minute intervals. Each ECG recording (trace) will last 10 seconds. Repeat ECGs will be
performed until at least three 10-second ECG records per scheduled timepoint meet the quality
criteria set out in the SOM and the applicable Standard Operating Procedure to enable reading
and analyzing at least 5 complexes per derivation.
8.2.4.2. 
Safety Review of 12-lead ECGs  
All recorded 12-lead ECGs will be reviewed by the Investigator, or qualified designee, and the 
review findings will be documented in the CRF. If a participant shows an abnormal ECG, 
additional safety recordings (including the use of 5- or 12-lead Holter equipment) may be made 
and the abnormality be followed to resolution, if required. 
8.2.4.3. 
24-hour Holter ECG 
Holter recording will be performed at Screening, or up to 3 months prior to Day 1, as described 
in the SoA (Section 1.3). Each electronic Holter ECG file will be downloaded onto the GE 
Gatemed Holter Analysis system. 
8.2.4.4. 
Real time display (ECG telemetry) 
A 12-lead real time ECG will be recorded as described in the SoA (Section 1.3). 
Electrocardiogram (ECG) telemetry will be monitored by the investigator or qualified member of 
clinical staff. The system will be managed according to local working practices. The ECG 
telemetry reports will be archived with study documents. 
Page 58 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
8.2.5. 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoA (see 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 
CRF. The laboratory reports must be filed with the source documents.  
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 5 half-lives after the last dose of study drug should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or Medical Monitor. 
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 Alexion 
notified. 
All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA. 
If laboratory values from non-protocol specified laboratory assessments 
management or are considered clinically significant by the Investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF. 
8.2.6. 
Virus Serology 
Blood samples collected at Screening will be analyzed for HIV-1, HIV-2, HBsAg, hepatitis B 
core antibody, and hepatitis C virus antibody titers. 
8.2.7. 
Vaccination  
Participants will be adequately vaccinated as described in Section 6.5.3.  
8.2.8. 
Drug and Alcohol Screen 
A urine sample for drug screen will be analyzed for the substances listed in Section 10.2. Timing 
of urine drug and alcohol breath tests is specified in the SoA (Section 1.3). 
8.2.9. 
Pregnancy Testing 
Pregnancy testing will be performed for all female participants of childbearing potential at the 
time points specified in the SoA (Section 1.3). 
If a pregnancy is reported, the Investigator should inform Alexion within 24 hours of learning of 
the pregnancy and should follow the procedures outlined in Section 8.3.5. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
Page 59 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
8.2.10. 
Injection or Infusion Site Evaluation 
Injection/infusion site evaluations will be performed at the time points specified in the SoA 
(Section 1.3
 1 cm in size) will not be listed as 
an AE unless they persist for more than 24 hours. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE and specific reporting requirements are located in Section 10.3. 
The Investigator and any qualified 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 drug or study procedures, or that caused 
the participant to discontinue the study (See Section 7). 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Section 1.3).  
All SAEs will be recorded and reported to Alexion or designee within 24 hours of awareness, as 
indicated in Section 10.3. The Investigator will submit any updated SAE data to Alexion within 
24 hours of it being available. Investigators are not obligated to actively seek AEs or SAEs after 
conclusion of the study participation. However, if the Investigator learns of any SAE, including a 
death, at any time after a participant has exited the study, and he/she considers the event to be 
reasonably related to the study drug, the Investigator must promptly notify Alexion. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
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 Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.4). Further information on follow-up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to Alexion of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the 
safety of a study drug under clinical investigation are met. 
Page 60 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Alexion has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
Alexion will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRB)/IEC, and 
Investigators. 
Alexion must prepare Investigator safety reports for suspected unexpected serious 
adverse reactions (SUSARs) according to local regulatory requirements and Sponsor 
policy and forward to investigators as necessary. 
An Investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from Alexion must 
review and then file it along with the IB and must notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
No studies of ALXN1830 have been conducted in pregnant women. Pregnant or breastfeeding 
females are excluded from the clinical study. Participants enrolled in the study, and a spouse or 
partner, will use a highly effective or acceptable method of contraception (Section 10.6). 
8.3.5.1. 
Exposure During Pregnancy and Lactation 
Pregnancy data will be collected during this study for all participants. For all Alexion products, 
both in development or post-approval, exposure during pregnancy must be recorded and 
followed. Exposure during pregnancy, also called exposure in utero, can be the result of either 
maternal exposure or transmission of drug product via semen following paternal exposure. 
If a female par
or is found to be pregnant while being treated or exposed to study drug, the Investigator must 
r designee via 
the same method as SAE reporting. Female participants who become pregnant will be 
discontinued from dosing but will continue to be followed for safety where feasible. Male 
participants may continue in the study if an accidental pregnancy of their female partner occurs 
despite adequate contraception. 
The female participant should be followed until the outcome of the pregnancy is known 
(spontaneous miscarriage, elective termination, normal birth or congenital abnormality), even if 
the participant discontinues study drug or discontinues from the study. When the outcome of the 
pregnancy becomes known, the form should be updated and returned to Alexion or designee. If 
additional follow-up is required, the Investigator will be requested to provide the information. 
Pregnancy in and of itself is not regarded as an AE, unless there is a suspicion that 
investigational product may have interfered with the effectiveness of a contraceptive medication. 
However, complications of pregnancy and abnormal outcomes of pregnancy are AEs, and many 
may meet criteria for an SAE. Complications of pregnancy and abnormal outcomes of 
pregnancy, such as ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal 
death, or congenital anomaly, would meet the criteria of an SAE and therefore should be 
reported as an SAE. 
Page 61 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Elective abortions without complications should not be handled as an AE. Exposure of an infant 
and 
to be reported to Alexion or designee. 
8.3.6. 
Adverse Events of Special Interest 
Any nonserious AE of special interest (AESI) is required to be reported by Investigator to 
Al
 24 hours after learning of the AESI). The AESI will be documented in 
safety database and a narrative will be required for each event. 
The AESIs for ALXN1830 include the following: 
Any IRRs equal to or higher than Grade 3; or any IRR that may jeopardize the 
participant and requires immediate intervention to prevent it from leading to severe 
outcomes.  
Potential cases of any delayed hypersensitivity reactions, equal to or higher than 
Grade 2. 
8.3.6.1. 
Infusion-Related Reaction 
Infusion-related reactions to mAbs include both immune mediated and non-immune mediated 
reactions. Symptoms of IRRs may include flushing, alterations in heart rate and BP, dyspnea, 
bronchospasm, back pain, fever, urticaria, edema, nausea, and all types of rashes. Anaphylaxis is 
recognized as a severe, life-threatening, generalized, or systemic reaction. IRRs usually develop 
during drug infusion, or within hours of infusion, although may be delayed for up to 24 hours. 
Most IRRs are mild to moderate in severity.  
Refer to Section 10.4 for guidance on management of IRRs. 
8.3.6.2. 
Non-acute Hypersensitivity Reaction 
Non-acute hypersensitivity (ie, serum sickness) and immune responses secondary to IC 
formation typically have a subacute presentation (FDA, 2014). Clinical signs may include 
delayed onset of fever, rash, arthralgia, myalgia, hematuria, proteinuria, serositis, etc., in the face 
of an ongoing antibody response to the study drug (Hunley et al, 2004). Assessment of AE 
causality will likely require evaluation of CICs and complement activation. 
8.4. 
Treatment of Overdose 
An overdose is defined as a significant variation above the recommended/scheduled dosage for a 
product. The dosing for this study will be conducted in a controlled clinical setting and an 
overdose is not anticipated. However, in the event of an accident, for this study, an overdose of 
ALXN1830 is considered any dose of ALXN1830 greater than 2250 mg. 
In the event of an overdose, the Investigator should: 
Immediately contact the Medical Monitor. 
Monitor the participant for any AE/SAE and laboratory abnormalities until IgG levels 
have returned to normal. 
Page 62 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Follow-up until ALXN1830 can no longer be detected systemically or IgG levels 
have returned to Baseline. 
Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
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. 
8.5. 
Pharmacokinetics 
Whole blood samples will be collected for measurement of serum concentrations of 
ALXN1830 as specified in the SoA. The timing of sampling may be altered during 
the course of the study based on newly available data (eg, to obtain data closer to the 
time of peak plasma concentrations) to ensure appropriate monitoring.  
Instructions for the collection and handling of biological samples will be provided by 
Alexion. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
Samples will be used to evaluate the PK of ALXN1830. Each serum sample will be 
divided into 2 aliquots (1 each for [primary and a back-up]). Samples collected for 
analyses of study drug (serum) concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study. 
Genetic analyses will not be performed on these serum samples. Participant 
confidentiality will be maintained. At visits during which whole blood samples for 
the determination of PK/PD of ALXN1830 will be taken, one sample of sufficient 
volume can be used. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.6. 
Pharmacodynamics 
Venous blood samples will be collected for measurement of IgA, IgM, IgG, and IgG subtypes 
(1-4), and CIC at timepoints described in the SoA (Section 1.3). Blood will be separated into 
2 aliquots for Igs; 1 each for Ig and subclass testing. A separate sample will be collected for CIC. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Whole blood for assessment of exploratory biomarkers will be collected as per the SoA 
(Section 1.3). Residual PK/PD samples may also be used for exploratory analyses. 
In the event of an IRR, it is recommended to collect a blood sample for assessment of tryptase, 
histamine, C-reactive protein, complement, and cytokines as soon as the IRR is observed (prior 
to administering any IRR medication), and 2 hours, 24 hours and 7 days (prior to the next dose of 
study drug) after onset of the IRR. 
Page 63 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
8.9. 
Immunogenicity Assessments 
Serum samples will be screened for antibodies binding to ALXN1830 and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to ALXN1830 and/or further characterize the immunogenicity of ALXN1830. 
In the event of an IRR, a sample for PK/PD and antidrug antibodies (ADAs) may be collected if 
there is no predefined sample collection on the same day. 
The detection and characterization of antibodies to ALXN1830 will be performed using a 
validated assay method by or under the supervision of Alexion. All samples collected for 
detection of ADA will also be evaluated for ALXN1830 serum concentration to enable 
interpretation of the antibody data. All samples that are confirmed positive for ADA will be 
evaluated for the presence of neutralizing antibodies. Samples may be stored for a maximum of 
5 years (or according to local regulat
at a facility selected by Alexion to enable further analysis of immune responses to ALXN1830. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics data, associated with medical encounters, will 
not be collected as a part of this study.  
Page 64 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses
No statistical hypothesis will be tested for this study. 
9.2. 
Sample Size Determination 
Up to 56 participants will be enrolled. Participants will be randomly assigned in a 6:2 ratio to up 
to 7 planned cohorts to receive either single or multiple doses of ALXN1830 SC (n = 6 per 
cohort) or single or multiple doses of PBO (n = 2 per cohort). Of these 7 cohorts, 1 cohort is 
optional; a dose to be determined (based on the safety of the predetermined doses) in the MAD. 
Progression to the next dosing cohort will be gated by review of initial dosing data by an SRC. 
Formal sample size calculation has not been performed. The number of participants has been 
chosen based on feasibility and are considered adequate to meet the study objectives. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Table 15: 
Populations for Analyses 
Population 
Description 
Enrolled set 
All participants who sign the ICF 
Safety set 
All participants who receive at least 1 dose of study drug. Participants will be 
analyzed according to the study drug they actually received. 
PK analysis set 
All participants who have sufficient serum ALXN1830 concentration data to 
evaluate PK parameters. Participants will be analyzed according to the study 
drug they actually received.  
PD analysis set 
All participants who have sufficient serum IgG data to evaluate PD effects. 
Participants will be analyzed according to the study drug they actually 
received. 
Abbreviations: ICF = informed consent form; IgG = immunoglobulin G; PD = pharmacodynamics; 
PK = pharmacokinetics. 
9.4. 
Statistical Analyses 
The Statistical Analysis Plan (SAP) will be developed and approved before database lock and 
will describe the participant populations to be included in the analyses, and procedures for 
accounting for missing data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints.  
9.4.1. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Safety analyses will include an analysis of all TEAEs, AESIs, ECGs, clinical laboratory data, 
physical examinations, and vital sign measurements using descriptive statistics. No inferential 
statistical analyses are planned on the safety parameters of this study. The prevalence of TEAEs 
and SAEs will be summarized, by System Organ Class (SOC) and Preferred Term for each 
Page 65 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
cohort and overall, by relationship to study drug. Adverse events will also be summarized by 
cohort and overall, by severity. Serious AEs and TEAEs resulting in study discontinuation will 
be listed. Participants having multiple TEAEs within a category (eg, overall, SOC, Preferred 
event within a category will be counted. 
Changes from baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
cell blood count with differential, and urinalysis) will be summarized by each cohort. Laboratory 
parameter values will be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE). Shift tables by cohort will be produced for these laboratory parameters. These 
tables will summarize the number of participants with each baseline grade relative to the 
reference ranges and changes to the worst highest grade assessed post-dose during the study. 
The ECG parameters will be measured at the specified time points, including heart rate, PR, RR, 
QRS, QT, and corrected QTcF intervals. The average of the triplicate ECG readings at the time 
points collected will be calculated, and changes from pretreatment baseline values will be 
assessed by each cohort. 
An outlier analysis will be performed that will summarize the frequency and percentage of 
participants who meet any of the following outlier criteria at each visit by cohort: 
QT, QTcF interval > 450 msec 
QT, QTcF interval > 480 msec 
QT, QTcF interval > 500 msec 
QT, QTcF interval increases from baseline > 30 msec 
QT, QTcF interval increases from baseline > 60 msec 
All concomitant medications will be coded using the current version of the WHO Drug 
Dictionary, and the frequency and percentage of concomitant medications will be summarized. 
9.4.2. 
Other Analyses 
All PK analyses will be performed on the PK Population and all PD analyses will be performed 
on the PD Population. Pharmacokinetic, PD, immunogenicity (secondary analyses), and 
biomarker exploratory analyses will be described in the statistical analysis plan (or the PK 
analysis plan, as applicable), and finalized before database lock. 
9.5. 
Interim Analyses 
No interim analyses are planned. 
Page 66 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight
Considerations
10.1.1. 
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
Applicable ICH Good Clinical Practice (GCP) Guidelines. 
Applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB / IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
The Investigator will be responsible for the following: 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
Notifying the IRB/IEC of deviations from the study protocol or GCP as defined 
by UK legislation as a serious breach or as required by IRB/IEC procedures. 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations. 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 
Page 67 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.1.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.  
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative defined according to local and country 
regulations where the study is taking place will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
ally 
authorized representative. 
Participants who are rescreened are required to sign a new ICF (see Section 5.4).  
10.1.4. 
Data Protection 
Participants will be assigned a unique identifier by Alexion. Any participant records 
or datasets that are transferred to Alexion will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participant must be informed that his/her personal study-related data will be used 
by Alexion in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data 
to be used as described in the informed consent.  
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
Alexion, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the European Union website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
Page 68 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.1.6. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed CRF or eCRF 
unless transmitted to Alexion 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 CRF.  
The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
Alexion 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 CRF by authorized site personnel are accurate, complete, and 
verifiable 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.  
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for a minimum of 25 years after study 
completion, unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of Alexion. No records may be transferred to another location or party 
without written notification to Alexion. 
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. The Investigator or designee will 
prepare and maintain adequate and accurate source documents (eg, medical records, 
ECGs, AE and concomitant medication reporting, raw data collection forms) 
designed to record all observations and other pertinent data for each participant.  
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Alexion or its designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of Alexion. The study site will be closed upon study 
Page 69 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
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 the study site by Alexion 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, Alexion's procedures, or GCP guidelines. 
Inadequate recruitment of participants by the Investigator. 
Discontinuation of further study drug development. 
If the study is prematurely terminated, Alexion shall promptly inform the investigators, the 
IECs/IRBs, the regulatory authorities, and any contract research organization(s) used in the study 
of the reason for termination, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participants and should assure appropriate participant 
therapy and/or follow-up.  
10.1.9. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 
Page 70 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 16 will be performed by the central laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 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. 
Page 71 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Table 16: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
RBC count 
Hemoglobin 
Hematocrit 
RBC indices: 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin 
% Reticulocytes 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
chemistry 
BUN 
Chloride 
Potassium 
Bicarbonate 
Sodium 
Glucose 
AST 
ALT 
Alkaline phosphatase 
Gamma glutamyltransferase 
HbA1C (Screening only) 
Urea 
Total and direct bilirubin 
Total protein 
Albumin 
Creatinine 
Creatine phosphokinase 
Coagulation 
International normalized ratio, partial thromboplastin time, prothrombin time 
Routine 
urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase 
Microscopic examination (if any leucocytes, more than a trace protein, nitrites, and blood [if 
not menstruating] are abnormal) 
Other screening 
tests 
Alcohol breath and urine drug screen (to include at minimum: amphetamines, 
barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, methamphetamine, 
3,4-methylenedioxy-methamphetamine, methadone, and tetrahydrocannabinol 
[cannabinoids]) 
IgG concentration 
HIV-1 and HIV-2 antibodies, HBsAg, anti-HBC IgG + IgM (if IgG positive), and 
anti-HCV with confirmation by HCV RNA 
Serum hCG pregnancy test (as needed for women of childbearing potential) 
FSH (postmenopausal females only)
IRR 
In the event of an IRR, it is recommended to collect a blood sample for assessment 
of tryptase, histamine, CRP, cytokines, and complement as soon as the IRR is 
observed (prior to administering any IRR medication), and 2 hours, 24 hours and 
7 days (prior to the next dose of study drug) after onset of the IRR.
Signs of infection 
If a subject shows signs of infection, the following investigations should be included: 
Blood cultures (taken prior to start of antibiotics) 
Routine profile
Pneumovax 23 
titer
Pneumovax 23 vaccine titers (refer to Section 6.5.3) 
Abbreviations: ALT = alanine transaminase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
FSH = follicle stimulating hormone; CRP = C-reactive protein; HBsAg = hepatitis B surface antigen; 
hCG = human chorionic gonadotropin; HCV = hepatitis C virus; RNA = ribonucleic acid; gonadotropin; 
HIV = human immunodeficiency virus; Ig = immunoglobulin; IRR = infusion-related reaction; RBC = red blood 
cells; WBC = white blood cells. 
Investigators must document their review of each laboratory safety report. Laboratory/analyte 
results that could unblind the study will be reviewed by dedicated unblinded staff at the 
investigative sites or other blinded personnel until the study has been unblinded. 
Page 72 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Adverse Event Definition 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study drug, whether or not considered related to the study drug. 
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 drug. 
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). 
New conditions detected or diagnosed after study drug administration even though it may have been 
present before the start of the study. 
Signs, symptoms, or the clinical sequelae which may or may not be to a suspected drug-drug 
interaction. 
Events NOT Meeting the AE Definition 
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.
10.3.2. 
Adverse Reaction Definition 
Adverse Reaction Definition 
An AR is any TEAE that is considered to have a causal relationship to the study drug.
10.3.3. 
Serious Adverse Event Definition 
An SAE is defined as an AE that, at any dose: 
1.
Results in death
2.
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.
3.
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
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the
ccurred or was necessary, the AE should 
be considered serious.
Page 73 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
An SAE is defined as an AE that, at any dose: 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4.
Results in persistent disability/incapacity
The term disability me
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.
5.
Is a congenital anomaly/birth defect
6.
Other situations:
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 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.
10.3.4. 
Suspected Unexpected Adverse Reaction Definition 
Suspected Unexpected Serious Adverse Reactions Definition 
Suspected unexpected serious adverse reactions are serious events that are not listed in the IB and that the 
Investigator identifies as related to study drug or procedure. The US 21CFR312.32 and EU Clinical Trial 
Directive 2001/20/EC and the associated detailed guidance documents or national regulatory requirements 
in participating countries require the reporting of SUSARs. Alexion has procedures that will be followed 
for the recording and expedited reporting of SUSARs that are consistent with global regulations and the 
associated detailed guidance documents. Suspected unexpected serious adverse reactions will be reported to 
the national competent authority and IECs where applicable.
10.3.5. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
Adverse Event and Serious Adverse Event 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 or SAE information in the CRF. 
Alexion in lieu of completion of the AE/SAE CRF page. 
There may be instances when copies of medical records for certain cases are requested by Alexion. 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 Alexion. 
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.
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 from National Cancer Institute CTCAE v5.0, published 
27 Nov 2017:  
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
Grade 3: Severe (incapacitating, with inability to perform normal activities)
Page 74 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Adverse Event and Serious Adverse Event Recording 
Grade 4: Life-threatening 
Grade 5: Fatal 
Changes in the severity of an AE should be documented to allow an assessment of the AE duration at each 
level of intensity to be evaluated. Adverse events characterized as intermittent require documentation of 
onset and duration of each episode, if the severity of the intermittent event changes. 
Assessment of Causality 
The Investigator is obligated to assess the relationship between the study drug and each occurrence 
of each AE or SAE. An Investigator causality assessment must be provided for all AEs (both 
nonserious and serious). This assessment must be recorded in the eCRF and on any additional 
forms, as appropriate. The definitions for the causality assessments are as follows: 
Not related (unrelated): There is no causal association with study drug  
Related: There is causal (temporal) association to the study drug. Other conditions (concurrent 
illness, concurrent medication reaction, or progression/expression of disease state) do not 
appear to explain the event; the event corresponds with the known pharmaceutical profile; 
improvement on discontinuation; reappearance on rechallenge.  
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 drug administration will be considered and 
investigated. 
This protocol will use the current IB as the Reference Safety Document. The expectedness and 
reporting criteria of an SAE will be determined by Alexion, based on the Reference Safety 
Document. The Investigator will also consult the IB 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 Alexion. However, it is very important that the 
Investigator always makes an assessment of causality for every event before the initial 
transmission of the SAE data to Alexion or designee. 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting requirements. 
Follow-up of Adverse Events and Serious Adverse Events 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Alexion 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 health care professionals. 
New or updated information will be recorded in the originally completed eCRF. 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of the 
information.
10.3.6. 
Reporting of Serious Adverse Events 
Serious Adverse Event Reporting to Alexion or Designee via Paper Case Report Form 
All AEs must be assessed by the Investigator to determine if they meet criteria for an SAE. All SAEs 
must be reported to Alexion or designee immediately, or within 24 hours of the Investigator and/or 
study site staff becoming aware of the event, regardless of the presumed relationship to the study 
drug.
Page 75 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Serious Adverse Event Reporting to Alexion or Designee via Paper Case Report Form 
The Investigator must complete, sign, and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a copy via email or 
facsimile to the contact information provided below: 
Email: 
 
Facsimile: 
 
Additional follow-up information, if required or available, should be entered into the CRF and sent to 
Sponsor within 24 hours of the Investigator or study site staff becoming aware of this additional 
information via the reporting process outlined above. These reporting timelines need to be followed 
for all initial SAE cases and follow-up versions of the initial cases. 
For all SAEs, the Investigator must provide the following: 
Appropriate and requested follow-up information in the time frame detailed above 
Causality of the serious event(s) 
Treatment of/intervention for the SAE(s) 
Outcome of the serious event(s) 
Redacted medical records and laboratory/diagnostic information 
If applicable, additional information such as relevant medical records should be submitted to Alexion 
via the email address or facsimile number noted above. 
All forms and follow-up information submitted to Alexion (eg, discharge summary) should be kept 
in the appropriate section of the study file.
Page 76 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.4. 
Appendix 4: Infusion Related Reactions  Definitions of Severity 
Levels and Management Algorithm  
Level 1:  
Constitutional symptoms only, up to and including 
CTCAE Grade 2 and requiring either no treatment or 
symptomatic treatment only.  
 39  C with 1 g paracetamol 
(maintenance therapy thereafter allowed) - if not, 
count as Level 3.
Vigilant supportive care: 
Antipyretics and analgesics as required. 
Antihistamines for pruritus as required. 
Close observation  keep on telemetry. 
Level 2b:  
Dyspnoea on moderate exertion, which is associated 
with any other constitutional symptoms. 
OR any of: 
Evidence of haemodynamic instability (isolated 
hypotension not requiring intervention is however 
permitted) that responds to 1 L of fluids, infused 
rapidly.
Vigilant supportive care: 
Analgesics/antipyretics as required.  
Antihistamines for pruritus as required; 
consider oral corticosteroids. 
Close observation  keep on telemetry. 
PI informed urgently. 
PI to consider referral to acute hospital if multiple 
clinical features at this level are present. 
Level 3: Any of the following: 
Vomiting or diarrhoea requiring hospitalisation for 
rehydration (CTCAE grade 3). 
Haemodynamic instability (isolated hypotension not 
requiring intervention is however permitted) that does 
not respond to 1 L of fluids, infused rapidly. 
Fever > 40  C (CTCAE grade 3)/rigors that do not 
reduce to  39  C/stop after 1 g of paracetamol. 
Dyspnoea on minimal exertion. 
Any respiratory, coagulation, other neurological, or 
cardiovascular signs/symptoms. 
Urgent transfer to acute hospital (999 transport may 
be necessary): 
May require intensive organ function 
monitoring, vasopressor support, IV fluid 
replacement, oxygen. 
Specialist referral advised. 
Specialists to consider use of tocilizumab. 
PI informed urgently. 
Vigilant supportive care required until participant 
transported: 
Analgesics as required.  
IV fluids, oxygen therapy. 
Close observation  keep on telemetry. 
Level 4: 
Any sign/symptom at CTCAE Grade 4. 
Level 2a:  
Constitutional symptoms up to and including CTCAE 
Grade 3 including vomiting (provided that no IV 
infusion and/or hospitalisation required). 
Note: anorexia > grade 2 unlikely in the context of this 
healthy participant trial. 
 39  C with 1 g paracetamol 
(maintenance therapy thereafter allowed) 
 if not, 
count as Level 3. 
No haemodynamic instability (isolated, spurious  
hypotension not requiring intervention is however 
permitted). 
Isolated dyspnoea on moderate exertion without any 
other constitutional symptoms .
Page 77 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Level (see 
algorithm 
above for 
explanation on 
levels): 
DECISION 1 
Individuals: 
DECISION 2 
Continuation within a 
dosing regimen: 
DECISION 3 
Study progression: 
Level 1  
(Mild to 
moderate, not 
serious) 
Continue as per 
protocol 
Continue as per protocol 
Continue as per protocol 
Level 2a 
(Severe, not 
serious) 
Study drug 
administration 
will be 
discontinued 
1 participant: Continue as 
per protocol. 
 2 participants: Dosing 
of the remainder of the 
dosing regimen stopped. 
Continuation and 
extension requires 
substantial amendment.  
1 participant: Continue as per protocol. 
 2 participants: Dose escalation and 
progression to study parts with an equal or 
higher dose stopped. Dosing regimens on 
lower dose levels can continue. Progression 
to successive cohorts or study parts is 
permitted only with doses below this current 
level (at which this toxicity was observed). 
Escalation or progression to study parts with 
an equal or higher dose requires substantial 
amendment. 
Level 2b 
(Severe, not 
serious) 
Study drug 
administration 
will be 
discontinued 
 1 participant: Dosing of 
the remainder of the 
dosing regimen stopped. 
Continuation and 
extension requires 
substantial amendment. 
 1 participant: Dose escalation and 
progression to study parts with an equal or 
higher dose stopped. Dosing regimens on 
lower dose levels can continue. Progression 
to successive cohorts or study parts is 
permitted only with doses below this current 
level (at which this toxicity was observed). 
Escalation or progression to study parts with 
an equal or higher dose requires substantial 
amendment.
Level 3 (Severe, 
serious AR) 
Study drug 
administration 
will be 
discontinued 
Level 4 
(Life-
threatening. 
serious AR) 
Study drug 
administration 
will be 
discontinued 
 1 participant: Dosing of 
the remainder of the 
dosing regimen stopped. 
Continuation and 
extension requires 
substantial amendment.
Study stopped (ie this dosing regimen and 
all ongoing dosing regimens including those 
at lower doses, and upcoming dosing 
regimens, are immediately stopped). 
Continuation of the study requires a 
substantial amendment.
Abbreviations: AR = adverse reaction
Page 78 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.5. 
Appendix 5: United Kingdom Resuscitation Council Anaphylaxis 
Algorithm  
Abbreviations: ECG = electrocardiogram; IM = intramuscular; IV =intravenous 
Page 79 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.6. 
Appendix 6 Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the Following Categories are Not Considered Women of Childbearing Potential 
1. Premenopausal female with one of the following:
Documented hysterectomy 
Documented bilateral salpingectomy 
Documented bilateral oophorectomy 
records, medical examination, or medical history interview. 
2. 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, as per local laboratory reference ranges, 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. 
Female participants 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 who are documented as being of non-childbearing potential are exempt from 
contraception requirements. 
Female participants of childbearing potential, if heterosexually active, must use highly effective 
contraception as defined below. Antibiotic prophylaxis may be administered during this study 
(see Section 6.5.3), which can compromise the efficacy of hormonal contraception. Therefore, 
participants using hormonal contraception must also use barrier contraception (eg, condom or 
diaphragm with spermicide) for the duration of antibiotic prophylaxis. 
Highly effective contraceptive methods for females are as follows: 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation as follows: 
Page 80 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Oral 
Intravaginal 
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation as 
follows: 
Oral 
Injectable 
Implantable 
Intrauterine device 
Intrauterine hormone-releasing system 
Bilateral tubal occlusion 
Vasectomized male partner (with documented evidence of azoospermia if possible) 
Sexual abstinence (in line with the preferred and usual lifestyle of the participant) 
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 treatments. 
Calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal do NOT meet the 
definition of abstinence. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical trial and the preferred and usual lifestyle of the participant.  
Participants must use an appropriate form of highly effective contraception as stated for females 
of childbearing potential who are sexually active, from one complete menstrual cycle prior to the 
first intercourse with a male and continue until at least 3 months after last dose. 
Male Participants 
To prevent transfer of study drug to a male or female partner or fetus/baby, all male participants 
including those who have had a vasectomy (even with documented evidence of azoospermia) 
must agree to use a barrier method (male condom) during intercourse with a male or female 
partner from the time of screening to at least 3 months after last dose. 
Male participants, if sexually active and with a female spouse or partner of childbearing potential 
or a pregnant or breastfeeding spouse or partner, must agree to use barrier contraception (male 
condom). Barrier contraception is required even with documented medical assessment of surgical 
success of a vasectomy. Female spouses or partners of male participants who are of childbearing 
potential must use highly effective contraception as defined above. 
Contraception for all cohorts must start during Screening and continue for at least 3 months after 
last dose.  
Male participants must not donate sperm and female participants must not donate ova until at 
least 3 months after last dose. 
Page 81 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for all female participants and any 
female spouse/partner of a male participant, who become pregnant. Exposure during 
pregnancy (also referred to as exposure in utero) can be the result of either maternal 
exposure or transmission of drug product via semen following paternal exposure. 
If a female participant or a male 
 female sexual partner of childbearing 
potential becomes or is found to be pregnant while being treated or exposed to study 
 and 
reporting (Section 10.3). When the outcome of the pregnancy becomes known, the 
form should be updated and submitted to Alexion or designee. If additional follow-up 
is required, the Investigator will be requested to provide the information. 
Exposure of an infant to a Sponsor product during breastfeeding must also be 
reporte
any AEs experienced by the infant must be reported to Alexion or designee via 
facsimile or email. 
A pregnancy in and of itself is not regarded as an AE unless there is a suspicion that 
the study drug may have interfered with the effectiveness of a contraceptive 
medication. However, complications of pregnancy and abnormal outcomes of 
pregnancy are AEs and may meet the criteria for an SAE (eg, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly). Elective abortions without complications should not be reported as AEs 
(Section 8.3.5). 
Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
Page 82 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.7. 
Appendix 7: Justification for Protective Measures 
This study has adopted a comprehensive approach to minimize the potential risk of infection in 
healthy participants, which emerges from theoretical concerns associated with reduced total IgG. 
Protective measures have been implemented including vaccination/confirmation of vaccination, 
 300 mg/dL 
(the lower bound of the mild-moderate range), and prophylactic antibiotic or IVIG treatment 
when warranted further mitigate the risk of infection.   
To mitigate AEs, which are associated with anti-FcRn agents and other Igs (eg, headache), this 
study proposes to implement premedication and hydration measures. 
10.7.1. 
IgG Lowering and the Potential Risk of Infection 
ALXN1830 is an anti-FcRn mAb that blocks recycling of IgG antibodies, reducing the total IgG 
in circulation, including potentially pathogenic IgG autoantibodies associated with multiple 
autoimmune diseases. Thus, reduction in IgG level is used to measure the anti-FcRn PD activity 
of ALXN1830.  
Chronic deficiency of Ig across multiple Ig classes can be associated with an increased risk of 
infections (eg, in patients with known hypogammaglobulinemia due to primary causes and for 
secondary reasons due to iatrogenic intervention in patients treated with broadly active therapies, 
such as rituximab or plasma exchange). For example, rituximab has been documented to widely 
deplete the B-cell population and affect other Ig classes, while plasma exchange removes all 
types of serum proteins (Marco et al, 2014). Likewise, hereditary hypogammaglobulinemia is 
generally characterized by persistent deficiency of both IgG and other Ig (IgA or IgM) due to 
inadequate production of gamma globulin. Other immune system disorders, such as common 
variable immunodeficiency are characterized by lower percentages of memory and isotype 
switched-memory B cells; increased infection susceptibility; chronic recurrent, persistent 
infections; and insufficient immune responses to most vaccines, which in turn is also underlined 
by low levels of IgG and at least 1 other subclass of Ig, such as IgA or IgM documented by 
laboratory investigations (Filion et al, 2019).  
In contrast to the broadly active agents and immune system disorders discussed above, 
ALXN1830 is highly specific in reducing IgG in circulation. ALXN1830 has no effect on IgM or 
IgA levels, and it is also not expected to affect the catabolism of complement, cytokines, or other 
proteins involved in the immune response, or affect pre-existing cellular immunity  
(Rath et al, 2015). Thus, most of the immune system repertoire has been shown to be unaffected 
by ALXN1830 treatment, maintaining an immunocompetent host. This is supported by prior 
experience with anti-FcRn therapeutics in healthy participants, which has shown no increase in 
infection risk despite a significant reduction in tIgG.  
The lack of infection risk following anti-FcRn treatment is likely due to both the specificity and 
transient nature of the IgG reduction, which returns to baseline relatively rapidly after 
discontinuation of treatment. Specifically, in a single dose and 4-week multiple dose study of the 
anti-FcRn antibody M281 in healthy participants (n = 50), tIgG was reduced by 85% compared 
to baseline, and at least 50% of participants experienced a decrease of IgG to < 200 mg/dL over 
the 2 highest SAD and both MAD cohorts, with no SAEs and few moderate AEs. The incidence 
Page 83 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
of infection-related AEs in this study was similar between the drug-treated groups and PBO, and 
IgG levels returned to within 20% to 25% of baseline levels within 56 days (Ling et al, 2019).  
Similarly, in a 4-week multiple dose study in healthy participants (n = 62) using the anti-FcRn, 
efgartigimod, tIgG was decreased on average by approximately 75%, with some individuals 
showing reductions of up to 85%. There was no increase in infections due to efgartigimod 
treatment, and IgG levels returned to baseline within 8 weeks after the last dose 
(Ulrichts et al, 2018). Also, in a SAD study in healthy participants (n = 48) of the anti-FcRn, 
rozanolixizumab, IgG levels were reduced by up to 47.6% and returned to baseline within 57 
days post dose, with little or no TEAEs reported (Kiessling et al, 2017). Recently, in a SAD and 
4-week MAD study of RVT-1401, total IgG was reduced by up to > 75%, with all AEs being
mild to moderate in severity and no participants requiring premature discontinuation due to AEs
(Collins et al, 2019).
Finally, in the previous SAD and MAD studies of ALXN1830 in healthy participants, an IgG 
lowering of up to 64% was observed (in the 20 mg/kg MAD cohort) with no increased risk of 
infection, and the IgG levels returned to baseline levels 43 days after the last dose. In total, 
studies with five different anti-FcRn therapeutics (M281, efgartigimod, rozanolixizumab, 
RVT-1401, and ALXN1830) in well over 200 healthy participants have generally shown no 
increased risk of infection, and there have been no cases of severe or serious infections reported 
following anti-FcRn treatment. 
In summary, treatment with ALXN1830 is known to lead to a specific reduction of IgG, but not 
of IgA or IgM, and the IgG lowering is a transient effect with a robust, predictable and consistent 
return to baseline in healthy participants. Prior experience with anti-FcRn therapies suggests a 
low risk of infection even with lowering of IgG to below 200 mg/dL. There have been no cases 
of severe or serious infections reported following anti-FcRn treatment in healthy participants.  
10.7.1.1. IgG Level Stopping Rule 
 300 mg/dL was chosen based on generally used 
classifications of IgG lowering and the prior experience with anti-FcRn treatments discussed 
- 
600 
 
 100 mg/dL). 
Participants with IgG levels of 200 to 400 mg/dL and total Ig level of 400 to 600 mg/dL are 
considered to have adequate antibody levels to convey humoral immunity, but this is less likely 
if total Ig levels are less than 400 mg/dL or serum IgG levels are less than 200 mg/dL 
(Agarwal, 2007). Prior experience with anti-FcRn therapeutics in healthy participants showed no 
increased risk of evidence of infection despite reduction in IgG less than 200 mg/dL. Thus, 
isolated reduction of IgG to levels as low as 200 mg/dL in the presence of normal IgA and IgM 
levels and normal cellular elements of immunity (white blood cell [WBC]/differential) would 
most likely maintain an immunocompetent status. However, to avoid IgG reductions below the 
mild-moderate range, we will utilize a more conservative level of 300 mg/dL as the threshold for 
individual and cohort level stopping rules. 
To further ensure the IgG nadir would not drop below 300 mg/dL, the inclusion criteria for IgG 
 1000 mg/dL, higher than the lower limit of normal. Since the proposed dosing 
regimens of ALXN1830 are not expected to lower IgG levels more than ~ 70% as predicted by 
PK/PD modeling, the IgG levels should remain above 300 mg/dL. Furthermore, the IgG nadir is 
Page 84 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
a transient phenomenon, with IgG levels rising back towards baseline in a relatively rapid 
timeframe.  
In addition, if there is any reason to believe the participant is at risk of infection or exhibits 
evidence/signs of infection, we offer an antibiotic prophylaxis as an additional layer of risk 
mitigation against potential infections. Finally, IVIG replacement will be considered only if IgG 
is profoundly low, ie, below 100 mg/dL, and this low nadir is sustained for more than 7 days 
despite discontinuation of ALXN1830, which again would be an extremely unlikely event as 
discussed above. 
10.7.1.2. Evidence of Immunity/Vaccination 
To mitigate the risk of sinopulmonary infections associated with anti-FcRN targeted IgG 
reduction therapy, healthy participants will have current vaccinations against pneumococcus and 
seasonal influenza, evidenced by documents showing that vaccinations occurred in the relevant 
time w
Public Health England, 2016). Further details are 
provided in Section 6.5.3. These vaccinations are based on the recommended from Chapter 7 of 
sation of Individuals with Underlying 
10.7.2. 
Hydration 
Adverse events of anti-FcRn agents and other Ig are commonly reported to be associated with 
headaches (Robak et al, 2010; Ling et al, 2019; Kiessling et al, 2017). Similarly, in ALXN1830 
studies, both in patients and healthy participants, headaches (mild to moderate in grade) occurred 
in both SAD and MAD dose regimens with or without nonprescription analgesics. In the case of 
Ig, multiple mechanistic factors have been postulated, such as osmolality, volume load, total 
volume infused, rate of infusion, concentration, and total dose of the Ig infused, which were 
shown to affect infusion tolerability (Vo et al, 2006). Hydration was considered to be an 
important factor for improvement of infusion-induced headaches (Feldmeyer et al, 2010). To 
ensure adequate hydration, it is recommended that study participants drink approximately 2 L 
(women)/2.5 L (men) of water every day during the 3 days preceding and following an infusion 
treatment (National Academies of Sciences, Engineering, and Medicine, 2004). 
Page 85 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
10.8. 
Appendix 8: Abbreviations 
Abbreviation 
Explanation 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
AR 
adverse reaction 
AUC 
area under the concentration-time curve 
biw 
twice weekly 
BMI 
body mass index 
BP 
blood pressure 
CIC 
circulating immune complexes 
CL 
clearance 
CRF 
case report form 
CRP 
C-reactive protein
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
day 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOI 
end of infusion 
EOS 
end of study 
ET 
early termination 
F 
bioavailability 
FcRn 
neonatal crystallizable fragment receptor 
FSH 
follicle stimulating hormone 
GCP
Good Clinical Practice
GLP
good laboratory practice
GMP
Good Manufacturing Practices
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
HRT
hormonal replacement therapy
IB
IC
immune complex
ICF
informed consent form
IEC
independent ethics committee
Ig
immunoglobulin
IgA
immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IMP
investigational medicinal product
IRB
institutional review board
IRR
infusion related reaction
IV
intravenous
IVIG
intravenous immunoglobulin
mAb
monoclonal antibody
MAD
multiple ascending dose
MG
myasthenia gravis
NAb
neutralizing antibody
NOAEL
no observed adverse effect level
Page 86 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Abbreviation 
Explanation 
OP 
outpatient 
PBO 
placebo 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PV 
Pemphigus Vulgaris 
q2w 
every 2 weeks 
QTcF 
qw 
weekly 
SAD 
single ascending dose 
SAE 
serious adverse event 
SC 
subcutaneous 
SoA 
schedule of activities 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WAIHA 
warm autoimmune hemolytic anemia 
WBC 
white blood cell 
WHO 
World Health Organization 
Page 87 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
11.
REFERENCES
Filion CA, Taylor-Black S, Maglione PJ, Radigan L, Cunningham-Rundles C. Differentiation of 
common variable immunodeficiency from IgG deficiency. J Allergy Clin Immunol Pract. 
2019;7(4): 1277-1284. 
Agarwal S, Cunningham-Rundles C. Assessment and clinical interpretation of reduced IgG 
values. Ann Allergy Asthma Immunol. 2007;99(3): 281-283. 
Baker K, Qiao SW, Kuo T, et al. Immune and non-immune functions of the (not so) neonatal Fc 
receptor, FcRn. Semin Immunopathol. 2009;31(2): 223-236. 
Blumberg RS, Lencer WI. Antibodies in the breakdown lane. Nat Biotechnol. 2005; 23(10): 
1232-1234. 
Collins J, Jones L, Michele Snyder, et al. RVT-1401, A novel anti-FcRn monoclonal antibody is 
well tolerated in healthy subjects and reduces plasma IgG following subcutaneous or intravenous 
administration (P5.2-079). Neurology. 2019;92 (Suppl 15). 
FDA. Guidance for Industry, Clinical/Medical, Guidance for Industry: Immunogenicity 
assessment for therapeutic protein product. 2014. 
Feldmeyer L, Benden C, Haile SR, et al. Not all intravenous immunoglobulin preparations are 
equally well tolerated. Acta Derm Venereol. 2010;90(5): 494-497. 
Hunley TE, Corzo D, Dudek M, et al. Nephrotic syndrome complicating alpha-glucosidase 
replacement therapy for Pompe disease. Pediatrics. 2004;114(4): e532-535. 
Kiessling P, Lledo-Garcia, R, Watanabe S, et al. The FcRn inhibitor rozanolixizumab reduces 
human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9(414). 
Ling LE, Hillson JL, Tiessen RG, et al. M281, an anti-FcRn antibody: Pharmacodynamics, 
pharmacokinetics, and safety across the full range of IgG reduction in a first-in-human study. 
Clin Pharmacol Ther. 2019;105(4): 1031-1039. 
Liu L, Garcia AM, Santoro H, et al. Amelioration of experimental autoimmune myasthenia 
gravis in rats by neonatal FcR blockade. J Immunol. 2007;178(8): 5390-5398. 
Marco H, Smith RM, Jones RB, et al. The effect of rituximab therapy on immunoglobulin levels 
in patients with multisystem autoimmune disease. BMC Musculoskelet Disord. 2014;15: 178. 
Mezo AR, McDonnell KA, Hehir CA, et al. Reduction of IgG in nonhuman primates by a 
peptide antagonist of the neonatal Fc receptor FcRn. Proc Natl Acad Sci U S A. 2008;105(7): 
2337-2342. 
National Academies of Sciences, Engineering, and Medicine. 2004. Available at: 
http://www.nationalacademies.org/ Accessed on 23 Sep 2019. 
National Health Service. Alcohol units - Alcohol support. NHS England: NHS Digital. 2018. 
Nixon AE, Chen J, Sexton DJ, et al. Fully human monoclonal antibody inhibitors of the neonatal 
fc receptor reduce circulating IgG in non-human primates. Front Immunol. 2015;6: 176. 
Public Health England. Immunisation of individuals with underlying medical conditions: the 
green book, chapter 7. Published 20 March 2013. Last updated 29 September 2016. 
Page 88 of 89 
Alexion Confidential 


ALXN1830-HV-105 Amendment 2 
24 January 2020 
Pyzik M, Rath T, Lencer WI, Baker K, Blumberg RS. FcRn: The architect behind the immune 
and nonimmune functions of IgG and albumin. J Immunol. 2015;194(10): 4595-4603. 
Rath T, Baker K., Pyzik M, Blumberg RS. Regulation of immune responses by the neonatal Fc 
receptor and its therapeutic implications. Front Immunol. 2015;5: 664. 
Robak T, Mainau C, Pyringer B, et al. Efficacy and safety of a new intravenous immunoglobulin 
10% formulation (octagam® 10%) in patients with immune thrombocytopenia. Hematology. 
2010;15(5): 351-359. 
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 
2007;7(9): 715-725. 
Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: 
updated guidelines for reporting parallel group randomised trials. Ann Intern Med. 
2010;152(11): 726-732. 
Ulrichts P, Guglietta A, Dreier T, et al. Neonatal Fc receptor antagonist efgartigimod safely and 
sustainably reduces IgGs in humans. J Clin Invest. 2018:128(10); 4372-4386. 
Vo AA, Cam V, Toyoda M, et al. Safety and adverse events profiles of intravenous 
gammaglobulin products used for immunomodulation: a single-center experience. Clin J Am Soc 
Nephrol. 2006; 1(4): 844-852. 
Page 89 of 89 
Alexion Confidential 

SAP_001.pdf: 
Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 1 of 19 
 ALXN1830-HV-105 
EUDRACT NUMBER: 2019 003496 18 
RPL STUDY CODE: C19015 
STATISTICAL ANALYSIS PLAN 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single 
and Multiple Ascending Dose Study of Subcutaneous ALXN1830 in 
Healthy Participants 
FINAL VERSION 1.0, 24MAR2021 
Prepared by: 
 
Signature
 
Richmond Pharmacology  
Date.......
Reviewed by:
 
Signature
 
Richmond Pharmacology 
Date.......
Approved by:  
 
Signature
 
Alexion Pharmaceuticals, Inc. 
Date.......
 Alexion 
Confidential
NCT #: NCT05254613


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 2 of 19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
or Specialist 
Term  
Explanation 
%CV 
Coefficient of Variation 
ADA 
Antidrug Antibodies 
AE 
Adverse Event 
AESI 
Adverse events of special interest 
AUC 
Area under the Concentration Time Curve 
AUC0-
Area under the Serum Concentration versus Time Curve 
from Time Zero Extrapolated to Infinity 
AUC0-t 
Area under the Serum Concentration versus Time Curve 
from Time Zero to the Last Quantifiable Concentration 
AUCtau 
Area under the Serum Concentration during the dosing 
interval 
BLQ 
Below the Level of Quantification 
BDRM 
Blind Data Review Meeting 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CL 
Total Body Clearance 
CL/F 
Apparent total clearance 
Cmax 
Maximum Observed Serum Concentration 
COVID-19 
Novel Coronavirus (previously 2019 n-CoV) 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IRR 
Infusion-related Reactions 
z
Terminal Elimination Rate Constant 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing Antibody 
PD 
Pharmacodynamic(s) 
PDF 
Portable Document Format 
PK 
Pharmacokinetic(s) 
QTcF 
QT interval corrected us
RPL 
Richmond Pharmacology Ltd 
RTF 
Rich Text Format 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard Deviation 
SAD 
Single Ascending Dose
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment-Emergent Adverse Event 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 3 of 19 
t½ 
Terminal Elimination Half-Life 
TFLs 
Tables, Figures and Listings 
Tmax 
Time to Maximum Observed Serum Concentration 
Vd 
Volume of Distribution 
Vd/F 
Apparent Volume of Distribution 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 4 of 19 
Table of Contents 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................ 2 
1.
INTRODUCTION .............................................................................. 6 
Early Termination of Study ..................................................................... 6 
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................. 6 
2.1 
Study objectives ........................................................................... 6 
2.2 
Endpoints .................................................................................... 6 
3.
TRIAL DESIGN ................................................................................ 7 
3.1 
Overall Design ............................................................................. 7 
3.2 
Duration of Study ......................................................................... 8 
3.3 
Sample Size ................................................................................ 9 
3.4 
Randomization and Blinding ........................................................... 9 
3.5 Early Termination .......................................................................... 10 
4.
STATISTICAL ANALYSES ................................................................. 10 
4.1 
Interim Analysis ......................................................................... 11 
4.2 
Analysis Populations.................................................................... 11 
4.3 
Subject Disposition ..................................................................... 12 
4.4 
Demographic Characteristics ........................................................ 12 
4.5 
Baseline and Other Safety Characteristics ....................................... 13 
4.6 
Inclusion and Exclusion Criteria .................................................... 13 
4.7 
Protocol Deviations ..................................................................... 13 
4.8 
Medical History .......................................................................... 13 
4.9 
Study Drug Administration ........................................................... 13 
4.10 
Prior and Concomitant Medications ............................................. 13 
4.11 
Infusion Site (Pain) Evaluation ................................................... 14 
4.12 
Safety Analysis ........................................................................ 14 
4.12.1 Adverse Events ........................................................................ 14 
4.12.2 Laboratory Data ....................................................................... 15 
4.12.3 Electrocardiograms ................................................................... 15 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 5 of 19 
4.12.4 Telemetry and Holter ................................................................. 16 
4.12.5 Vital Signs ............................................................................... 16 
4.12.6 Physical Examination ................................................................. 16 
4.13 
Pharmacokinetic Analysis .......................................................... 16 
4.13.1 Values Below the Limit of Quantification and Missing Values ............. 17 
4.13.2 Pharmacokinetic Parameters ....................................................... 17 
4.14 
Pharmacodynamic Analyses ....................................................... 18 
4.15 Immunogenicity Analyses ............................................................. 19 
4.17 Methods for Withdrawals, Missing Data and Outliers .......................... 19 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 6 of 19 
1.
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to define the variables and 
analysis methodology to address the study objectives. 
The protocol dated 24 January 2020, Amendment 2 was used to prepare this SAP. 
Pharmacokinetic (PK) parameters calculations and statistical analyses will be the 
responsibility of Richmond Pharmacology Ltd (RPL). Tables, figures, and listings 
(TFLs) will be produced using Statistical Analysis System (SAS), Version 9.4 or 
higher. 
Early Termination of Study 
ALXN1830-HV-105 was placed on hold in FEB2020 and the decision was made by 
Alexion in FEB2021 to prematurely discontinue the study due to Covid-19. Twelve 
subjects were enrolled and completed the study. There are no further subject visits 
expected. The study has been terminated and no additional subjects will be dosed 
under this protocol. 
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1 
Study objectives 
The objectives of this study are: 
Primary 
To assess the safety and tolerability of single and multiple doses of 
ALXN1830 SC. 
Secondary 
To assess the PK of single and multiple doses of ALXN1830 SC. 
To explore the PD effects of single and multiple doses of ALXN1830 SC. 
To assess the immunogenicity of ALXN1830 SC. 
2.2 
Endpoints 
Primary 
Safety assessed by the incidence and relatedness of TEAEs, SAEs, AESIs, 
physical examination, vital sign measurements, clinical laboratory and ECG 
results. 
Secondary 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 7 of 19 
ALXN1830 PK profiles and PK parameters. 
Change in IgG levels. 
Measurement of ADA levels and Nabs. 
3.
TRIAL DESIGN
This is a Phase 1 study in up to 56 healthy adult participants (42 on active 
treatment, 14 on placebo) conducted at a single site in the United Kingdom. Eight 
participants will be randomly assigned in a 6:2 ratio to each of up to 7 cohorts to 
receive either single or multiple doses of ALXN1830 SC (n = 6 per cohort) or single 
or multiple doses of placebo (n = 2 per cohort). Cohort 7 is optional. If Cohort 6 
is terminated early due to safety or IgG stopping rules, then Cohort 7 may be 
dosed at a < 1500 mg lower weekly dose for 4 doses. If Cohort 6 does not reach 
the expected IgG reduction, and no safety or IgG stopping rules are met, then 
Cohort 7 may be dosed at higher dose > 1500 mg (but not to exceed 2250 mg) 
weekly for 4 doses).  
3.1 
Overall Design 
Initially, the first 4 participants randomized to each cohort will be dosed with 3 
participants on ALXN1830 and 1 participant on placebo. The dosing will be 
staggered, with an interval of at least 3 days for the SAD cohorts and at least 7 
days for the MAD cohorts, before dosing the rest of the participants in the cohort. 
The shorter interval of staggered dosing for the SAD cohorts compared to the MAD 
cohorts is considered appropriate as the expected PK exposure of the ALXN1830 
SC doses will be a fraction of that of the IV dose demonstrated to be safe and well 
tolerated in previous IV studies. The reduction of IgG after a single SC dose will 
be well within the observed IgG reduction observed in previous IV studies; and in 
general, there will be low risk of immunogenicity and infusion related reactions 
after a single dose. All participants will be observed during the drug administration 
and for 2 hours after dosing for safety and participants will be encouraged to 
report any discomfort immediately, especially within 24 hours post dosing. At no 
time will more than 4 participants per cohort be dosed on a given day.  
A Safety Review Committee (SRC), consisting of the Investigator, safety monitor, 
medical monitor, study statistician, and clinical pharmacologist, will evaluate the 
study data at prespecified time points for participant safety and make 
recommendations on dose escalation, dose modification, or termination of the 
study. Relevant safety data from any other studies ongoing with ALXN1830 will 
fter consultation with 
the SRC, additional participants may be enrolled as replacement participants if a 
participant discontinues within 3 weeks of the last dose for reasons other than 
drug-related AEs. 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 8 of 19 
Table 1: ALXN1830-HV-105 Dosing Cohorts 
Cohort (n) 
Regimen/Route of 
Administration 
Study Drug (N) 
1 
1 Single dose SC 
ALXN1830 750 mg (6 active/2 placebo) 
2 
1 Single dose SC 
ALXN1830 1500 mg (6 active/2 placebo) 
3 
1 Single dose SC 
ALXN1830 up to 2250 mg (6 active/2 
placebo) 
4 
8 doses biw SC 
ALXN1830 300 mg (6 active/2 placebo) 
5 
12 doses qw SC 
ALXN1830 750 mg (6 active/2 placebo) 
6 
4 doses qw SC 
ALXN1830 1500 mg (6 active/2 placebo) 
7 (Optional) 
4 or 12 doses qw SC 
ALXN1830 2250mg (6 active/2 placebo) 
Abbreviations: biw = twice weekly; qw = weekly; SC = subcutaneous. 
3.2 
Duration of Study 
The planned study duration is approximately 183 days: up to 42 days for screening 
and approximately 141 days for dosing and follow up. 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 9 of 19 
Figure 1: Study ALXN1830-HV-105 Schematic 
3.3 
Sample Size 
Up to 56 participants will be enrolled. Participants will be randomly assigned in a 
6:2 ratio to up to 7 planned cohorts to receive either single or multiple doses of 
ALXN1830 SC (n = 6 per cohort) or single or multiple doses of placebo (n = 2 per 
cohort). Cohort 7 is optional.  
Progression to the next dosing cohort will be gated by review of initial dosing data 
by an SRC.  
Formal sample size calculation has not been performed. The number of 
participants has been chosen based on feasibility and are considered adequate to 
meet the study objectives. 
3.4 
Randomization and Blinding 
This is a double-blind study. Eligible participants who meet all inclusion and no 
exclusion criteria will be assigned unique numbers for enrollment and 
randomization. 
On Day 1 participants will be assigned a randomization number in ascending 
to one of the 7 cohorts of the study, according to the randomization schedule 
generated prior to the study by the Statistics Department at Alexion (or designee). 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 10 of 19 
Participants will be randomly assigned in a 6:2 ratio to receive ALXN1830 or 
ned study 
drug throughout the course of the study. To maintain this blind, site's pharmacy 
staff will be responsible for the reconstitution and dispensation of all study drug. 
3.5 Early Termination 
Due to the outbreak of COVID-19, it was decided by the Sponsor as per study 
protocol section 7.5 that the study will be discontinued. Prior to termination, 8 
subjects from Cohort 1 and 4 subjects from Cohort 2 were dosed. The statistical 
analyses outlined in this SAP will be presented for Cohort 1, single dose SC 
ALXN1830 750 mg (6 active/2 placebo) and Cohort 2, single dose SC ALXN1830 
1250mg (3 active/1 placebo). The statistical analysis described, and the 
associated summary tables may not be presented due to the unavailability of data 
where necessary. In these cases, a blank table with corresponding table 
 match the criteria for this 
4.
STATISTICAL ANALYSES
In general, descriptive statistics for continuous variables will include number of 
non-missing values (n), arithmetic mean, standard deviation (SD), median, 
minimum, and maximum.  
Descriptive statistics for PK parameters will include number of observations (n), 
arithmetic mean, standard deviation (SD), arithmetic coefficient of variation 
(%CV), geometric mean, geometric %CV, median, minimum and maximum.  
Categorical variables will be summarized using frequency counts and percentages. 
For all tables, except PK parameter tables, descriptive statistics for minimum and 
maximum will be presented with the same decimal digits as the original data, and 
with 1 more decimal place than the original data for mean and median; SD will be 
reported with 2 more decimal places than the original data.  
PK parameters will be presented as follows in the listing: 
Parameters 
Definitions 
Cmax 
Maximum observed serum concentration 
tmax 
Time to maximum observed serum concentration 
AUCt 
Area under the concentration-time curve from time 0 to the last 
quantifiable concentration  
AUC0-
Area under the concentration-time curve from time 0 (dosing) to 
time infinity 
t½ 
Terminal elimination half-life 
z
Terminal-phase elimination rate constant 
CL/F 
Total body clearance or apparent clearance 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 11 of 19 
Vd/F 
Volume of distribution or apparent volume of distribution 
Cmax and Tmax will be presented as given in the raw data; AUCt, AUC0-
z , t1/2, 
CL/F, and Vd/F data permitting, will be presented with 3 significant figures, where 
appropriate in the tables, listings or figures. The rounding of pharmacokinetic 
results will be undertaken only after the final calculation of PK parameters. 
Descriptive statistics for PK parameters will be presented to 3 significant figures 
for all parameters. Due to early termination, the particular pharmacokinetic 
parameters to be derived will be determined based on the available concentration 
data.  
The analyses will be produced for cohorts 1 and 2. They will be presented by 
treatment group (dose levels and placebo). Placebo subjects will be pooled across 
cohorts. All collected data will be presented in by-subject listings. Listings will be 
ordered by treatment group and subject number and will include all randomized 
subjects. 
Baseline will be defined as the last non-missing value among assessments 
including unscheduled visits recorded prior to first administration of study drug. 
Changes from baseline values will be calculated as the post-baseline assessment 
value minus the baseline value. Only observed values from scheduled time points 
will be used to create summary tables (except for baseline). 
Early Termination (ET) visits will be recoded to ET visits where necessary and 
reported as ET. 
Deviations from the planned analyses mentioned in this SAP will be described in 
the final clinical study report (CSR). 
Page layout of the TFLs will be in landscape mode and will be provided in Microsoft 
Word file format. Final TFLs will additionally be created as bookmarked PDF. 
Further details of page layout will be provided in the TFL shell document. Individual 
RTF files for tables may be provided to assist medical writing. RTF files will not be 
compiled into a single document. 
4.1 
Interim Analysis 
No Interim analyses are planned. 
4.2 
Analysis Populations 
Inclusion and exclusion from each analysis set will be decided at the Blind Data 
Review Meeting (BDRM) prior to database lock. Further exclusions may be made 
from PK/PD/Immunogenicity sets based on the concentrations of ALXN1830. 
Enrolled Population 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 12 of 19 
The enrolled population will consist of all participants who sign the ICF and were 
randomized. 
Safety Population 
The safety population will consist of all participants who receive at least 1 dose of 
study drug. Participants will be analyzed according to the study drug they 
received. 
PK Population 
The PK population will consist of all participants who have at least one post-dose 
measurable serum ALXN1830 concentration data to evaluate PK parameters. 
Participants will be analysed according to the study drug they received. 
PD Population 
The PD population will consist of all participants who have at least one serum IgG 
data to evaluate PD effects. Participants will be analysed according to the study 
drug they received. 
Immunogenicity Population 
The immunogenicity population will consist of all participants who have ADA 
sample collected. 
4.3 
Subject Disposition 
All subjects will be included in the summary of subject disposition. The summary 
will present the overall number of subjects enrolled, the number of subjects by 
treatment group and overall, the frequency and percentage of subjects 
randomized and treated, and who completed or discontinued from the study, along 
with reason for discontinuation.  
Furthermore, the number and percentage of subjects in each study population will 
be tabulated. Discontinued subjects will be listed. Subject assignment to study 
populations will be listed.  
Screen Failures will not be listed or included in summary tables. 
4.4 
Demographic Characteristics 
Individual subject demographics (including age, sex, race and ethnicity) and body 
measurement data (height, body weight and body mass index (BMI)) at baseline 
will be listed and summarized by each treatment group and overall, for the safety 
population and the PK population. If the remaining populations are different from 
the safety population by more than 5%, separate demographic tables will be 
produced.  
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 13 of 19 
Height will be measured in centimeters and weight in kilograms. BMI will be given 
in kg/m2.  
4.5 
Baseline and Other Safety Characteristics 
Data collected from vaccine and antibiotic prophylaxis, vaccine titer, virus 
serology, serum pregnancy test, alcohol breath test and urine drug screen will be 
listed by subject. 
4.6 
Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria will be listed together with the overall eligibility 
for each subject. 
4.7 
Protocol Deviations 
The final review of protocol deviations will be performed at the BDRM prior to 
database lock. The protocol deviations will be listed and summarized by deviations 
category.  
4.8 
Medical History 
Medical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary Version 22.0 (or higher) and listed individually. 
Surgical histories will be listed separately. 
4.9 
Study Drug Administration 
Study drug administration data will be listed individually. 
4.10 Prior and Concomitant Medications 
All prior and concomitant medications will be coded using the World Health 
Organization Drug Dictionary version March 1, 2018 (or higher) and will be listed 
individually. The frequency and percentage of prior and concomitant medications 
will be summarized by Anatomical Therapeutic Chemical and Preferred Name. 
Separate tables will be given for prior and concomitant medications. Prior 
medications are defined as those for which the end date and time is prior to the 
date, and time of first study drug administration. Concomitant medications are 
defined as those with start date and time on or after the date and time of first 
study drug administration, or ongoing medications with start date and time prior 
to the first study drug administration. The end date and time of concomitant 
medications may fall on or after the date and time of first study drug 
administration. Non-pharmacologic therapies and procedures and prophylactic 
antibiotic treatment will be listed. 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 14 of 19 
In case of partially missing start (end) date or time, the available information will 
be used, as much as possible, to classify the medication as prior or concomitant. 
4.11 Infusion Site (Pain) Evaluation 
Data from the infusion site evaluations and from pain at infusion/injection site will 
be listed individually. Infusion site evaluations will be summarized by treatment 
group. 
4.12 Safety Analysis 
Safety analyses will be performed on the safety population and will be reported at 
each time point by treatment group.  
Safety analyses will include an analysis of all TEAEs, AESIs, ECGs, clinical 
laboratory data, physical examinations, and vital sign measurements using 
descriptive statistics. No inferential statistical analyses are planned on the safety 
parameters of this study.  
4.12.1 Adverse Events 
A Treatment-Emergent Adverse Event (TEAE) is any adverse event that 
commences after the start of administration of study drug. 
An AESI is an AE of scientific or medical concern specific to the Sponsor or the 
product or program, for which ongoing monitoring and rapid communication by 
the Investigator to the Sponsor may be appropriate. 
The AESIs for ALXN1830 include the following: 
Any infusion-related reactions (IRRs) equal to or higher than Grade 3; or 
any IRR that may jeopardize the participant and requires immediate 
intervention to prevent it from leading to severe outcomes. 
Potential cases of any delayed hypersensitivity reactions, equal to or higher 
than Grade 2. 
The incidence of TEAEs and AESIs (after dosing) will be summarized using the 
safety population. The MedDRA dictionary Version 22.0 (or higher) will be used to 
classify all AEs reported during the study by System Organ Class (SOC) and 
Preferred Term. A summary of TEAEs including the incidence of subjects who 
experienced TEAEs (number and percentage of subjects) and incidence of TEAEs 
(number of events) will be presented for each treatment group and overall, by 
severity and by relationship to study drug.  
TEAEs, AESIs and serious TEAEs will be summarized by SOC and Preferred Term 
for each treatment group and overall, and by relationship to study drug.  
Subjects having multiple AEs within a category (e.g., overall, SOC and Preferred 
Term) will be counted once in that category. For severity tables, a subject's most 
severe event within a category will be counted. For relationship tables, a subject's 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 15 of 19 
event with greatest relationship to study drug within a category will be counted. 
In each table, SOC and Preferred Term will be presented in descending order of 
overall incidence rate (alphabetical order will be used in case of equal rates).  
All adverse events will be listed. Serious TEAEs will be listed. 
4.12.2 Laboratory Data 
Clinical 
laboratory 
parameters 
(including 
blood 
chemistry, 
hematology, 
coagulation, urinalysis and other laboratory results) will be listed and abnormal 
parameters will be flagged as high (H) or low (L) according to reference ranges. 
Absolute (observed) values and changes from baseline (continuous variables) will 
be summarized for each parameter and scheduled time point by treatment group. 
The last non-missing lab value will be used for summary analysis if repeated 
measurements are made at any time point.  
In the listings, the values will be displayed as originally 
reported by the laboratory. 
Laboratory parameter values will be graded according to the Common 
Terminology Criteria for Adverse Events v5.0. Non-protocol parameters will only 
be listed, in a separate listing, if required.  
4.12.3 Electrocardiograms 
ECG parameters will be measured at the specified time points and will include 
formula (QTcF)(QTcF=QT/RR^1/3). The variables will be listed individually. 
Three or more replicate measurements are taken at each protocol time point and 
the arithmetic mean of the evaluable/available measurements will be taken as the 
measurement to be used for summary statistics. Arithmetic mean values will also 
be included into the listings.  
For ECG variables, the change from baseline will be derived using the arithmetic 
mean value of each time-point triplicate minus the arithmetic mean of baseline 
triplicate values. The baseline is the arithmetic mean of all pre-dose 
measurements observed prior to dosing on Day 1. 
Absolute (observed) values and changes from baseline in the ECG variables will 
be summarized by treatment group and time point. 
An outlier analysis will be performed that will summarize the frequency and 
percentage of subjects who meet any of the following outlier criteria at each visit 
by treatment group: 
QT, QTcF interval > 450 msec 
QT, QTcF interval > 480 msec 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 16 of 19 
QT, QTcF interval > 500 msec 
QT, QTcF interval increases from baseline > 30 msec 
QT, QTcF interval increases from baseline > 60 msec 
The summary of outliers for QT and QTcF will be presented using the following 
groupings: 
> 500 msec
And the corresponding group for QT and QTcF interval increases: 
> 60 msec
4.12.4 Telemetry and Holter 
Cardiac telemetry and Holter data will be listed individually. 
4.12.5 Vital Signs 
Vital signs data (systolic and diastolic blood pressure, heart rate, temperature, 
oxygen saturation and respiration rate) will be listed for individual subjects. 
Summary statistics of absolute (observed) values and changes from baseline will 
be calculated and presented for each parameter at scheduled time point by 
treatment group. 
4.12.6 Physical Examination 
Physical examination data will be listed individually. 
4.13 
Pharmacokinetic Analysis 
All serum concentration data may be listed for each individual subject and 
summarized at each time point by treatment group. Individual and mean 
concentrations versus time on linear and semi-log scales may be presented 
graphically. Individual concentration plots will be based on actual sampling time 
relative to the actual start of dosing time. Overlaid individual plots by treatment 
group will be presented using graphically using nominal time. PK parameters will 
be summarized by treatment group. The PK population will be used to conduct all 
PK analysis. 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 17 of 19 
4.13.1 Values Below the Limit of Quantification and Missing Values 
Parameter Estimation 
Concentrations that are below limit of quantitation (BLQ) and are associated with 
time-points prior to the first quantifiable concentration in a profile are replaced 
with zero for the non-compartmental analysis. A BLQ value between two non-BLQ 
values will be set as missing for the estimation of the pharmacokinetic parameters. 
Any BLQ value that occurs after the last quantifiable concentration will be set as 
zero. If more than one BLQ values occur in succession between two non BLQ 
values, the situation will be considered on a case-by-case basis. 
Summary Statistics 
When calculating the mean or median value for a concentration at a given time 
point, all BLQ values will be set to half the Lower Limit of Quantification, except 
when an individual BLQ falls between two quantifiable values, in which case it will 
be omitted. 
Samples with no reportable value due to a bioanalytical issue or missing samples 
will be set to missing and will not be included in the PK calculations. 
For tabulation, graphical representation, and calculation purposes, all samples 
with no reportable value (or missing samples) observed after dosing will be set to 
missing. 
4.13.2 Pharmacokinetic Parameters 
Individual ALXN1830 serum concentration data along with actual dosing and 
sampling times will be used to derive pharmacokinetic (PK) parameters by non-
compartmental analysis (NCA) using Phoenix WinNonlin software (Version 6.3 or 
higher). If actual sampling or dosing times are missing, then the nominal times 
will be used. Dose-normalized parameters will be derived using the actual dose; 
the nominal dose will be used if the actual dose is not available. PK parameters 
will be summarized by cohort. 
Descriptive statistics for PK parameters will include number of observations (n), 
arithmetic mean (mean), standard deviation (SD), arithmetic coefficient of 
variation (%CV), geometric mean, geometric coefficient of variation (%CV), 
median, minimum and maximum. 
The following PK parameters will be derived for each subject in Cohorts 1 and 2: 
-
Cmax (µg/mL): Maximum observed serum concentration
-
Tmax (h): Time to maximum observed serum concentration
-
AUC0-Tlast (h*µg/mL): Area under the serum concentration versus time
curve from time zero (dosing) to the last quantifiable concentration
-
AUC0-  (h*µg/mL): Area under the serum concentration versus time
curve from time zero (dosing) extrapolated to infinity
-
z (1/h): Apparent terminal-phase elimination rate constant
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 18 of 19 
o
Only those data points that are judged to describe the terminal log-
linear decline will be used in the regression
o
A minimum number of 3 data points in the terminal phase will be
z, with the line of regression starting at any post-
Cmax data point (Cmax should not be part of the regression slope)
-
t½ (h): Terminal elimination half-life
o 
z
-
CL/F (L/h): Apparent total clearance
o
Calculated as dose/AUC
-
Vd/F (L): Apparent volume of distribution during the terminal phase
o
C
z*AUC ) 
Some PK parameters may not be calculated for all or some subjects if the 
concentration data are not deemed to be amenable to evaluation. Explanations for 
PK parameters that could not be estimated will be provided in the CSR. 
Additional PK parameters may be calculated, as appropriate. 
4.14 
Pharmacodynamic Analyses 
The pharmacodynamic endpoints will be evaluated using the PD population as 
follows: 
Actual values, changes and percent changes in IgA, IgG and IgM 
concentration over time. 
Actual values, change and percent change IgG subtypes (1-4) over time. 
Actual values, change and percent change in CIC over time. 
PD data will be listed for each individual subject and absolute (observed) values 
as well as changes and percent changes from baseline will be summarized at each 
time point by treatment group. For summary statistics, BLQ values will be 
assigned a value of half the Lower Limit of Quantification. 
Individual and mean percent change from baseline versus time profiles may be 
presented graphically for each PD parameter. Individual plots will be based on 
actual sampling time relative to dosing time. The mean plots will be based on 
nominal time. More figures may be presented if necessary. 
Baseline is defined as the last observed (scheduled or unscheduled) value 
collected prior to first dose administration. If a baseline value is missing, no 
change from baseline is to be calculated and the subject excluded from the 
summary statistics for change from baseline. 
 Alexion 
Confidential


Statistical Analysis Plan
C19015 (ALXN1830-HV-105) SAP Final v1.0 24MAR2021.docx
Page 19 of 19 
4.15 Immunogenicity Analyses 
Immunogenicity, as measured by ADA to ALXN1830 (all formulations), will be 
listed, and summarized over time by treatment group using the Immunogenicity 
population.  
A summary of the number and proportion of patients who are ever positive and 
always negative will also be provided by treatment group. 
4.17 Methods for Withdrawals, Missing Data and Outliers 
The individual serum concentration data and the actual timing of study drug 
administration and blood sampling will be used throughout the analyses. If there 
is any doubt about the actual time at which a sample was taken, then the 
scheduled time will be used. For PK data analysis, please see Section 4.13.1 
regarding the handling of missing values. For PD data analysis, there will be no 
imputation for missing values. 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
AEs with unknown start date/time will be assumed to be treatment-emergent 
unless the end date/time is known to be before the first administration of study 
drug. Otherwise, missing or partial dates will be listed as such. 
There will be no further imputation of missing data (i.e., subjects who prematurely 
discontinue from the study will not be included in summary statistics or analyses 
beyond the time of discontinuation).  
Depending on the extent of missing values, the appropriateness of the methods 
described for handling missing data may be reassessed prior to database lock (to 
examine the sensitivity of results to handling of missing data). 
 Alexion 
Confidential