Clinical trial NCT04631562
Conditions: Healthy
Keywords: ALXN1820 Properdin Pharmacodynamics Pharmacokinetics
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2021-01-13; Completion date: 2022-09-01
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1, randomized, double-blind, placebo-controlled single and multiple ascending dose study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of ALXN1820 administered subcutaneously (SC) (ALXN1820 SC) and intravenously (IV) (ALXN1820 IV).

Detailed description:
This study will include up to 10 different dosing cohorts, with each cohort consisting of 2 groups (ALXN1820 group, placebo group). Participants will be randomly assigned in a 3:1 ratio to each of these 2 groups, respectively, within all 10 cohorts, to receive either a single or multiple doses of ALXN1820 SC, a single dose of ALXN1820 IV, or a single or multiple doses of placebo.

The study will be conducted in healthy adult participants and will also include a multiple SC dose cohort in healthy participants of Japanese descent.

Arms: arm 1: Participants will receive ALXN1820 SC or ALXN1820 IV according to their assigned cohort. ALXN1820 SC will be evaluated in single and multiple ascending doses while ALXN1820 IV will be evaluated in a single dose cohort only. arm 2: Participants will receive Placebo SC or Placebo IV according to their assigned cohort.
Interventions: intervention 1: ALXN1820 SC intervention 2: ALXN1820 IV intervention 3: Placebo SC intervention 4: Placebo IV
Intervention descriptions: intervention 1: ALXN1820 SC will be administered as a manual SC push or SC infusion via a syringe pump. Doses will range from 12.5 milligrams (mg) to a maximum of 2250 mg. Multiple dosing duration will range from 3 to 5 weeks. intervention 2: ALXN1820 IV (450 mg) will be administered as an IV infusion. intervention 3: Placebo SC will be administered as a manual SC push or SC infusion via a syringe pump. intervention 4: Placebo IV will be administered as an IV infusion.

Protocol documents:
Prot_000.pdf: 
Protocol 
ALXN1820-HV-101 Amendment 1 (Global) 
Page 1 of 97 
Alexion Confidential 
TITLE PAGE 
Protocol Title: 
A Phase 1, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose 
Study of Subcutaneous and Intravenous ALXN1820 in Healthy Participants 
Protocol Number: ALXN1820-HV-101 
Amendment Number: 1 (Global) 
Compound: ALXN1820 
Study Phase: Phase 1 
Short Title:  
Safety, Pharmacokinetic, and Pharmacodynamic Study of ALXN1820 in Healthy Adult 
Participants 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 
121 Seaport Boulevard 
Boston, MA 02210 
USA 
Regulatory Agency Identifying Number(s): 
NCT: 04631562 
EudraCT: 2021-002472-39 
Approval Date: 06 Jul 2021 
Sponsor Signatory: 
Date 
Medical Monitor Name and Contact Information will be provided separately. 
12-Jul-2021 | 08:16:45 EDT
NCT #: NCT04631562


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INVESTIGATOR’S AGREEMENT 
I have read the 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 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Amendment 1 (06 Jul 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The main rationale for this amendment is a change in dose escalation rules to make Cohort 10 
independent of data from Cohort 9.  
Other changes implemented through this protocol amendment constitute removing monthly 
pregnancy testing for spouses/partners of male participants, revising exclusion criterion to allow 
for other vaccines during the study, revision of guidance for injection/infusion-associated 
reactions, and addition of COVID-19 risk assessment.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, Table 2 
It was clarified that dose in Cohort 7 will be 
determined based on the safety data up to 
Cohort 6 and interim PK/PD modeling with 
data up to Cohort 5. Dose in Cohort 10 will 
be determined based on safety data up to 
cohort 8 and interim PK/PD modeling with 
data up to Cohort 5. 
Updated to accurately reflect the 
decision for the dose in 
Cohorts 7 and 10. 
Section 1.1 Synopsis, 
Section 4.1 Overall Design, 
Section 4.3 Justification for 
Dose, and Section 6.6 Dose 
Modification 
Dependency on data from Cohort 9 for dose 
escalation to Cohort 10 was removed. 
Updated to accurately reflect that 
Cohort 9 is flexible and not 
required for dose escalation to 
Cohort 10. 
Section 1.1 Synopsis, 
Section 4.1 Overall Design, 
Section 6.6 Dose 
Modification 
“Optional” was added in relation to 
Cohort 7, and language around number of 
total cohorts was updated to reflect that. 
Wording added to clarify that 
Cohort 7 is optional.  
Section 1.1 Synopsis, 
Section 4.1 Overall Design 
Language amended regarding timing of 
dosing of participants to at least 48 hours 
after dosing of the sentinel pair. 
To clarify timing of dosing 
within cohorts. 
Section 1.1 Synopsis, 
Section 4.1 Overall Design 
Text stating the number of sites was 
replaced by the number of cohorts in the 
study and that all participants within each 
cohort will be recruited at a single site. 
To reflect the option to open 
additional sites and clarify that 
all participants within a cohort 
will be enrolled from a single 
site. 
Section 1.3 Schedule of 
Activities, Tables 4 - 11 
The following text has been added as a new 
footnote to accompany the row titled 
Immunogenicity (ALXN1820 ADA): 
“In case of any suspected case of 
hypersensitivity or anaphylaxis additional 
samples for the assessment of ADA may be 
collected at or near the time of the event” 
To allow collection of additional 
serum samples for assessment of 
potential ADA.  
Section 1.3 Schedule of 
Activities, Table 4, Table 6, 
and Table 9, Section 8.2.3.2 
The timing of the 24-hour Holter ECG was 
amended from “at Screening” to “up to 
3 months prior to Day 1”. 
To allow for flexibility of timing 
for the 24-hour Holter ECG. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities, Table 6, and 
Table 9, Section 8.2.3.2 
The option to use cardiac telemetry has 
been added for continuous monitoring from 
1 hour pre dose to 2 hours post first dose of 
study drug. 
To allow the option for use of 
cardiac telemetry should ECG 
not be available. 
Section 5.1 Inclusion Criteria 
Inclusion criterion 4 was revised to extend 
the upper range of BMI from 30 to 32 kg/m2 
To allow a broader range of 
potentially eligible participants 
without altering safety 
consideration for all participants. 
Section 5.1 Inclusion Criteria 
Inclusion criterion 9 was revised to detail 
the vaccination schedule for serogroup B 
meningococcal vaccination naïve 
participants and participants vaccinated 
more than 2 years and 6 months prior to 
dosing.  
To clarify the inclusion criteria 
regarding serogroup B 
meningococcal vaccination. 
Section 5.2 Exclusion Criteria 
Language specifying that immunization 
with inactivated or recombinant influenza 
vaccine is permitted was removed.  
Due to the COVID-19 pandemic, 
language for the exclusion 
criterion was revised to allow for 
other vaccines in addition to 
influenza vaccines. Only 
live-attenuated vaccines are 
excluded. 
Section 5.3 Lifestyle 
Considerations, Table 17 
Reference to the study plan for standard unit 
times for standard meals was removed. 
Corrected as the standard unit 
times for standard meals are not 
in the study plan. 
Section 8 Study Assessments 
and Procedures 
Clarification a participant’s procedures that 
are obtained prior to signing of the ICF may 
be utilized if consistent with site SOP 
Updated to align with practices at 
study site. 
Section 8.2.6 Pregnancy 
Monthly pregnancy tests for female 
spouses/partners of male participants was 
removed. 
Study assessments cannot be 
performed on female 
spouses/partners of male 
participants as they do not sign 
an ICF. 
Section 9.5 Safety Review 
Committee (SRC) 
Added Investigators from participating sites 
to the SRC membership, and the following 
sentence: 
“In the event a significant safety issue is 
identified, an ad hoc SRC meeting will be 
convened within 24 hours following its 
identification.” 
Clarified membership of the 
SRC, as well as trigger and 
timing for ad hoc SRC meetings. 
Section 10.3.3 Recording and 
Follow-Up of AE and/or SAE 
“Alexion” was added in the text in place of 
[X]. 
For clarification 
Section 10.4.2.2 Male 
Participants 
Time frame for following contraception 
guidance was updated from “up to 5 months 
after last dose” to “at least 5 months after 
last dose”. 
Updated to ensure contraception 
guidance is followed for a 
minimum of 5 months after last 
dose. 
Section 10.6 Appendix 6: 
Management of Potential 
Adverse Events During Study 
Drug Administration 
Updated to provide clarification on 
identification and treatment of 
infusion/injection-associated reactions. 
Updated to accurately reflect 
current practices. 
Section 10.7 Appendix 7: 
COVID-19 Risk Assessment 
Updated to provide guidance to study sites 
during COVID-19 pandemic. 
Updated to accurately reflect 
current practices. 
Section 10.9 Protocol 
Amendment History 
Table of document history was added. 
To accurately reflect the 
document history 


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Section # and Name 
Description of Change 
Brief Rationale 
Throughout the document 
Updated amendment number and date and 
incorporated minor editorial changes. 
Updated to reflect current 
amendment and sign-off date, 
and other minor changes. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................3 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................10 
LIST OF FIGURES .......................................................................................................................11 
1. 
PROTOCOL SUMMARY..........................................................................................12 
1.1. 
Synopsis ......................................................................................................................12 
1.2. 
Schema ........................................................................................................................17 
1.3. 
Schedule of Activities (SoA) ......................................................................................18 
2. 
INTRODUCTION ......................................................................................................35 
2.1. 
Study Rationale ...........................................................................................................35 
2.2. 
Background .................................................................................................................35 
2.2.1. 
Chemistry ....................................................................................................................35 
2.2.2. 
Nonclinical Pharmacology..........................................................................................36 
2.2.3. 
Toxicology ..................................................................................................................36 
2.3. 
Benefit/Risk Assessment ............................................................................................36 
2.3.1. 
Risk Assessment .........................................................................................................36 
2.3.1.1. 
Neisseria meningitidis Infections................................................................................37 
2.3.1.2. 
Immunogenicity and Hypersensitivity ........................................................................37 
2.3.1.3. 
Coronavirus Disease 2019 ..........................................................................................38 
2.3.2. 
Benefit Assessment .....................................................................................................38 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................38 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................40 
4. 
STUDY DESIGN .......................................................................................................41 
4.1. 
Overall Design ............................................................................................................41 
4.2. 
Scientific Rationale for Study Design ........................................................................43 
4.3. 
Justification for Dose ..................................................................................................44 
4.4. 
End of Study Definition ..............................................................................................49 
5. 
STUDY POPULATION .............................................................................................50 
5.1. 
Inclusion Criteria ........................................................................................................50 


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5.2. 
Exclusion Criteria .......................................................................................................51 
5.3. 
Lifestyle Considerations .............................................................................................53 
5.4. 
Screen Failures............................................................................................................54 
6. 
STUDY INTERVENTION.........................................................................................55 
6.1. 
Study Intervention Administered ................................................................................55 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................55 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................56 
6.4. 
Study Drug Compliance..............................................................................................57 
6.5. 
Concomitant Therapy .................................................................................................57 
6.5.1. 
Allowed Medicine and Therapy .................................................................................57 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................57 
6.6. 
Dose Modification ......................................................................................................58 
6.7. 
Intervention After the End of the Study......................................................................59 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................60 
7.1. 
Discontinuation of Study Intervention........................................................................60 
7.2. 
Stopping Criteria .........................................................................................................60 
7.2.1. 
Individual Stopping Rules ..........................................................................................60 
7.2.2. 
Cohort and Study Safety Stopping Rules ...................................................................61 
7.3. 
Participant Discontinuation/Withdrawal From the Study...........................................63 
7.4. 
Lost to Follow-up........................................................................................................63 
8. 
STUDY ASSESSMENTS AND PROCEDURES......................................................64 
8.1. 
Efficacy Assessments .................................................................................................64 
8.2. 
Safety Assessments .....................................................................................................64 
8.2.1. 
Physical Examination .................................................................................................64 
8.2.2. 
Vital Signs...................................................................................................................64 
8.2.3. 
Electrocardiograms .....................................................................................................65 
8.2.3.1. 
Safety Review of 12-lead Electrocardiograms ...........................................................65 
8.2.3.2. 
24-hour Holter Electrocardiograms/Real Time Display (Cardiac Telemetry) ...........65 
8.2.4. 
Clinical Laboratory Assessments................................................................................65 
8.2.5. 
Clinical Safety Laboratory Assessments ....................................................................66 
8.2.5.1. 
Virus Serology ............................................................................................................66 
8.2.5.2. 
Vaccine Titer...............................................................................................................66 


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8.2.5.3. 
Tuberculosis Testing ...................................................................................................66 
8.2.6. 
Pregnancy....................................................................................................................66 
8.2.7. 
Injection or Infusion Site Evaluation ..........................................................................66 
8.2.8. 
Injection/Infusion-associated Reactions .....................................................................67 
8.2.9. 
Vaccine and Antibiotic Prophylaxis ...........................................................................67 
8.2.10. 
Participant Safety Card ...............................................................................................68 
8.3. 
Adverse Events and Serious Adverse Events .............................................................68 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................68 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................69 
8.3.3. 
Follow-up of AEs and SAEs.......................................................................................69 
8.3.4. 
Regulatory Reporting Requirements for SAEs...........................................................69 
8.4. 
Treatment of Overdose ...............................................................................................69 
8.5. 
Pharmacokinetics ........................................................................................................70 
8.6. 
Pharmacodynamics .....................................................................................................70 
8.7. 
Genetics ......................................................................................................................71 
8.8. 
Biomarkers ..................................................................................................................71 
8.9. 
Immunogenicity ..........................................................................................................71 
8.10. 
Medical Resource Utilization and Health Economics ................................................71 
9. 
STATISTICAL CONSIDERATIONS .......................................................................72 
9.1. 
Statistical Hypotheses .................................................................................................72 
9.2. 
Sample Size Determination ........................................................................................72 
9.3. 
Populations for Analyses ............................................................................................72 
9.4. 
Statistical Analyses .....................................................................................................72 
9.4.1. 
Efficacy Analyses .......................................................................................................72 
9.4.2. 
Safety Analyses...........................................................................................................72 
9.4.2.1. 
ECG Analysis .............................................................................................................73 
9.4.3. 
Other Analyses............................................................................................................74 
9.4.3.1. 
Pharmacokinetic Analyses ..........................................................................................74 
9.4.3.2. 
Pharmacodynamic Analyses .......................................................................................74 
9.4.3.3. 
Immunogenicity Analysis ...........................................................................................75 
9.4.3.4. 
Interim Analyses .........................................................................................................75 
9.5. 
Safety Review Committee (SRC) ...............................................................................75 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................76 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.....................76 
10.1.1. 
Regulatory and Ethical Considerations.......................................................................76 
10.1.2. 
Financial Disclosure ...................................................................................................76 
10.1.3. 
Informed Consent Process ..........................................................................................77 
10.1.4. 
Data Protection ...........................................................................................................77 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................78 
10.1.6. 
Data Quality Assurance ..............................................................................................78 
10.1.7. 
Source Documents ......................................................................................................78 
10.1.8. 
Study and Site Start and Closure ................................................................................79 
10.1.9. 
Publication Policy .......................................................................................................79 
10.2. 
Appendix 2: Clinical Laboratory Tests.......................................................................81 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting........................................................................83 
10.3.1. 
Definition of AE .........................................................................................................83 
10.3.2. 
Definition of SAE .......................................................................................................83 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................84 
10.3.4. 
Reporting of SAEs ......................................................................................................85 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................87 
10.4.1. 
Definitions ..................................................................................................................87 
10.4.2. 
Contraception Guidance .............................................................................................87 
10.4.2.1. 
Female Participants .....................................................................................................87 
10.4.2.2. 
Male Participants ........................................................................................................88 
10.4.3. 
Collection of Pregnancy Information .........................................................................89 
10.5. 
Appendix 5: Biomarkers .............................................................................................90 
10.6. 
Appendix 6: Management of Potential Adverse Events During Study Drug 
Administration ............................................................................................................91 
10.7. 
Appendix 7: COVID-19 Risk Assessment .................................................................93 
10.8. 
Appendix 8: Abbreviations .........................................................................................94 
10.9. 
Protocol Amendment History .....................................................................................96 
11. 
REFERENCES ...........................................................................................................97 


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LIST OF TABLES 
Table 1: 
Mapping Objectives to Endpoints...............................................................................13 
Table 2: 
ALXN1820-HV-101 Dosing Cohorts.........................................................................14 
Table 3: 
Dosing Chart for Single Ascending Dose and Multiple Ascending Dose 
Regimens ....................................................................................................................15 
Table 4: 
Schedule of Activities – Screening Through Day 5 for Single-dose Cohorts 
1 - 7 .............................................................................................................................19 
Table 5: 
Schedule of Activities – Day 8 Through Day 127 for Single-dose Cohorts 1 - 
7 ..................................................................................................................................22 
Table 6: 
Schedule of Activities – Screening Through Day 5 (First Dose), Day 28 to 
33 (Last Dose) for Multiple-dose Cohorts 8 and 9 .....................................................23 
Table 7: 
Schedule of Activities – Day 7 Through Day 23 for Multiple-dose Cohorts 8 
and 9............................................................................................................................26 
Table 8: 
Schedule of Activities – Day 36 Through Day 155 for Multiple Dose 
Cohorts 8 and 9 ...........................................................................................................28 
Table 9: 
Schedule of Activities – Screening Through Day 5 (First Dose), Day 14 to 
19 (Last Dose) for Multiple-dose Cohort 10 ..............................................................29 
Table 10: Schedule of Activities – Day 7 Through Day 9 for Multiple-dose Cohort 10............32 
Table 11: Schedule of Activities – Day 22 Through Day 155 for Multiple Dose 
Cohorts 10 ...................................................................................................................34 
Table 12: Potential Risks and Mitigation Strategies ...................................................................38 
Table 13: Study ALXN1820-HV-101 Objectives and Endpoints ..............................................40 
Table 14:  ALXN1820-HV-101 Dosing Cohorts.........................................................................41 
Table 15: Dosing Chart for Single Ascending Dose and Multiple Ascending Dose 
Regimens ....................................................................................................................42 
Table 16:  Predicted ALXN1820 Exposure and Duration of Properdin and CAP 
Activity Inhibition.......................................................................................................48 
Table 17: Healthy Participant Lifestyle Considerations .............................................................53 
Table 18:  Dose Reference Chart for Study ALXN1820-HV-101...............................................55 
Table 19:  Study ALXN1820-HV-101 Dose Continuation/Escalation Decision Pathway..........58 
Table 20: Individual Stopping Rules ..........................................................................................61 
Table 21: Cohort and Study Stopping Rules...............................................................................62 
Table 22: Predicted ALXN1820 CAP Activity Inhibition and Duration of Antibiotic 
Prophylaxis Estimates .................................................................................................67 
Table 23: Protocol-Required Safety Laboratory Assessments ...................................................81 


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Table 24: Grading and Management of Allergic or Infusion-Related Reactions .......................92 
Table 25: Potential Risks and Mitigation Measures due to COVID-19 .....................................93 
Table 26: Abbreviations and Specialist Terms ...........................................................................94 
LIST OF FIGURES 
Figure 1: 
Study ALXN1820-HV-101 Schematic .......................................................................17 
 


Protocol 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, Randomized, Double-blind, Placebo-controlled, Single and Multiple 
Ascending Dose Study of Subcutaneous and Intravenous ALXN1820 in Healthy Participants 
Short Title: Safety, Pharmacokinetic and Pharmacodynamic Study of ALXN1820 in Healthy 
Adult Participants 
Rationale: ALXN1820 (anti-properdin/anti-serum albumin bispecific VHH antibody) is a novel 
properdin blocking agent being developed for the treatment of diseases involving dysregulated 
complement activity. The ALXN1820 molecule is bispecific, comprising a VHH antibody 
domain that binds and blocks properdin, connected via a linker to a VHH domain that binds 
serum albumin, thereby conferring an extended circulatory half-life to the molecule. ALXN1820 
formulation is designed for subcutaneous (SC) administration. The purpose of this first-in-human 
(FIH) 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 ALXN1820 administered SC (ALXN1820 SC) and a single 
dose of ALXN1820 administered intravenously (ALXN1820 IV). The study will be conducted in 
healthy adult participants and will also include a multiple SC dose cohort in healthy participants 
of Japanese descent. Data from this study are anticipated to help design future studies in patients 
with complement-mediated diseases. 


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Objectives and Endpoints 
Table 1: 
Mapping Objectives to Endpoints 
Objectives 
Endpoints 
Primary 
 
To assess the safety and tolerability of ALXN1820 SC 
and ALXN1820 IV 
Safety assessed by incidence of TEAEs and SAEs, 
physical examination, vital sign measurements, clinical 
laboratory, and electrocardiogram results 
 
Secondary 
 
To assess the single- and multiple-dose PK of 
ALXN1820 SC and single-dose PK of ALXN1820 IV 
 
Serum ALXN1820 single- and multiple-dose PK 
profiles and PK parameters 
 
To explore the PD effects of ALXN1820 SC and 
ALXN1820 IV 
Change in serum concentrations of total and free 
properdin over time 
 
Change in CAP activity using the Wieslab AP assay 
 
To assess the immunogenicity of ALXN1820 SC and 
ALXN1820 IV 
 
Incidence of anti-drug antibodies (ADAs) to 
ALXN1820 
To estimate the absolute bioavailability of 
ALXN1820 SC  
 
ALXN1820 PK parameters (AUC) SC versus IV will 
be compared 
 
To compare safety, tolerability, PK, PD, and 
immunogenicity of ALXN1820 SC between Japanese 
and non-Japanese healthy participants 
Quantitative assessment of safety, PK, PD parameters, 
and immunogenicity (ADA) between healthy 
non-Japanese participants and participants of Japanese 
descent 
 
Abbreviations: ADA = antidrug antibody; AP = alternative pathway; AUC = area under the concentration-time 
curve; CAP = complement alternative pathway; IV = intravenous; PD = pharmacodynamics(s); 
PK = pharmacokinetic(s); SAE = serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse 
event. 
Overall Design 
This is a Phase 1, randomized, double-blind, placebo-controlled study of single and multiple 
ascending doses of ALXN1820 SC and IV to be conducted in approximately 80 healthy adult 
participants (60 on ALXN1820, 20 on placebo) in up to 10 Cohorts. Eight participants will be 
randomly assigned in a 3:1 ratio to each cohort to receive either single or multiple doses of 
ALXN1820 SC (n = 6 per cohort), a single dose of ALXN1820 IV (n = 6 per cohort), or a single 
or multiple doses of placebo (n = 2 per cohort) (Table 2). The single dose portion of the study 
consists of up to 7 cohorts (Cohorts 1 to 7). Dosing in these cohorts will precede sequentially 
from 12.5 mg SC to a potential maximum dose of ≤ 2250 mg SC, including a single IV dose of 
450 mg (Cohort 5). The multiple dose portion of the study consists of 2 cohorts with doses of 
150 mg once weekly (QW) × 5 weeks in healthy participants (Cohort 8) and healthy participants 
of Japanese ethnicity (Cohort 9) and a higher dose (to be determined) administered as multiple 
doses QW × 3 weeks (Cohort 10). The multiple dose cohorts will be initiated after single dose 
Cohort 4 (450 mg SC) and Cohort 5 (450 mg IV). All participants within each cohort will be 
recruited at a single site. 
 


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Table 2: 
ALXN1820-HV-101 Dosing Cohorts 
Cohort 
N 
Study Drug 
Route of 
Administration 
Planned Dose 
(placeholders) 
Number of 
Doses/Dose 
Interval 
1 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
12.5 mg 
1 single dose 
2 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
50 mg 
1 single dose 
3 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
150 mg 
1 single dose 
4 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
450 mg 
1 single dose 
5 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
IV 
450 mg 
1 single dose 
6 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
1200 mg 
1 single dose 
7 
(optional) 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
TBDa 
(≤ 2250 mg) 
1 single dose 
8 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
150 mg 
QW × 5 
9 
8  
(6 active/2 placebo) 
Japanese 
participants 
ALXN1820 and 
placebo 
SC 
150 mg 
QW × 5 
10 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
TBDa 
QW × 3 
a Dose in Cohort 7 to be determined based on the safety data up to Cohort 6 and interim PK/PD modeling with data 
up to Cohort 5. Dose in Cohort 10 to be determined based on safety data up to cohort 8 and interim PK/PD 
modeling with data up to Cohort 5. 
Abbreviations: IV = intravenous; N = number of participants; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
QW = once weekly; SC = subcutaneous; TBD = to be determined. 
Details on timing of dosing in the cohorts are presented in Table 3. 
The first 2 participants randomized to each cohort will be dosed as a sentinel pair with at least 
1 participant on active treatment (either 1 participant on active treatment and 1 participant on 
placebo, or 2 participants on active treatment). This dosing strategy is justified given the large 
safety margin (approximately 20-fold at the highest planned dose) and the experience with 
properdin inhibition in healthy participants at Alexion. At the discretion of the Investigator, up to 
3 more participants will be dosed at least 48 hours after dosing of the sentinel pair, followed by 
dosing of the remaining participants in the cohort no earlier than the 4th day, as long as no 
suspension/stopping criteria have been met (Section 7.2). At no time will more than 
4 participants per cohort be dosed on a given day. The allowance for a maximum of 
4 participants/day/cohort is intended to provide flexibility should a fourth participant need to be 
added (eg, if replacement of a participant is required). The intention for this dosing strategy is to 
ensure limited number of healthy participants will receive a dose and regimen that have not been 
previously tested. The limit of ≤ 4 participants/day/cohort does not apply to dose and regimen 
that has been tested previously.  


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Table 3: 
Dosing Chart for Single Ascending Dose and Multiple Ascending Dose 
Regimens 
Cohort 
Route of Administration 
Number of participants dosed 
Day 1a 
 
Day 3 
 
Day 4 
 
1b, 2b, and 3b 
Manual SC or via SP 
2 
3 
3 
4b, 6c, 7c 
SC infusion via SP 
5d 
IV infusion 
8e, 9e 
Manual SC, QW × 5 
10f 
Manual SC or SC infusion via SP, 
QW × 3 
Note: At no time > 4 participants/cohort to be dosed on a given day for dose and regimen that have not been tested 
previously. 
a At least 1 participant on active treatment (either 1 participant on active treatment and 1 participant on placebo, or 
2 participants on active treatment). 
b Sequential dosing to occur in Cohorts 1 to 4, dependent on SRC review of safety data through Day 15 (336 hours) 
of previous cohort. 
c Dosing in Cohort 6 to be administered based on SRC review of interim safety data from the Day 15 (336 hours) 
assessment after dosing of Cohorts 4 and 5. Dosing in Cohort 7 to be determined based on SRC review of interim 
safety data from the Day 15 (336 hours) assessment after dosing of Cohort 6 and PK/PD data from Day 29 
(672 hours) assessment after dosing of Cohorts 4 and 5. 
d Dosing in Cohort 5 is dependent on Investigator review of safety data through Day 8 (168 hours) of Cohort 4. 
However, should there be safety findings of concern in previous cohorts, an SRC review will be conducted for 
Cohort 5 to determine if participants will be dosed at the planned dose of 450 mg IV or a lower dose. 
e Dosing in Cohorts 8 and 9 to be determined based on SRC review of all data from the Day 15 (336 hours) 
assessment for Cohorts 4 and 5. Dosing of Cohort 9 may start at the same time as Cohort 8 or later depending on 
scheduling at the clinical site 
f Dosing in Cohort 10 to be determined based on SRC review of all data from the Day 29 (672 hours) assessment 
for Cohort 8 and PK/PD data from Day 29 (672 hours) after dosing of Cohorts 4 and 5. 
Abbreviations: IV = intravenous; PD = pharmacodynamic; PK = pharmacokinetic; QW = once weekly; 
SC = subcutaneous; SP = syringe pump; SRC = safety review committee. 
At the Sponsor’s discretion, and after consultation with the Safety Review Committee (SRC), up 
to 18 additional participants across the entire study may be enrolled as replacement participants 
if a participant discontinues prior to Day 43 for reasons other than drug-related adverse events 
(AEs). 
Additional cohorts in healthy participants and patients may be added later if deemed necessary. 
These cohorts will only be added with a substantial amendment, and after regulatory agency and 
Ethics Committee (EC) approval. Screening for these cohorts can proceed prior to amendment 
approval, as long as the approved selection criteria apply. Randomization and dosing can only 
occur after approval of the amendment. 
Number of Participants: 
Approximately 80 participants (60 on active treatment, 20 on placebo) will be screened and 
randomly assigned to receive study drug or placebo to allow for study completion. 
Intervention Groups and Duration: 
The planned study duration is approximately 29 to 33 weeks: up to 79 days for screening and 
126 and 154 days for dosing and follow-up for the single dose and multiple dose cohorts, 


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respectively. Participants will be admitted to an inpatient facility during the Dosing and 
Follow-up Period (first 5 days for the single dose cohorts, and first 5 days after the first and last 
dose and 2 days after each other dose for the multiple-dose cohorts). Dosing will be staggered 
within and between cohorts, but the end of study for each individual participant is anticipated to 
be Day 127 and Day 155 for SAD and MAD cohorts, respectively, or the time point at which 
complement activity has normalized, if later than Day 127 or Day 155. 
Safety Review Committee: An SRC will be used to make dose escalation decisions. 
Statistical Analyses: 
Populations for Analysis 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Safety 
All participants who receive at least 1 dose of study drug 
Pharmacokinetic 
All participants who receive at least 1 dose of the study drug and have at least 
1 post-dose PK sample 
Pharmacodynamic 
All participants who receive at least 1 dose of study drug and who have 
evaluable properdin concentration data CAP or CCP activity data 
Immunogenicity 
All participants who have a predose and at least 1 postdose ADA sample 
collected that can be analyzed 
Abbreviations: ADA = antidrug antibody; CAP = complement alternative pathway; CCP = complement classical 
pathway; PK = pharmacokinetic(s). 
Safety Analysis 
All safety analyses will be performed on the Safety Population and will be reported by each 
cohort and treatment arm (ALXN1820 versus placebo). In addition, healthy participants on 
placebo treatment will be pooled together across cohorts. 
Safety analyses will include an analysis of all treatment-emergent AEs, electrocardiograms 
(ECG’s), 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 AEs and serious adverse events (SAEs) will be summarized, by 
System Organ Class (SOC) and Preferred Term for each cohort and treatment arm and overall, 
within each treatment arm, by relationship to study drug. Adverse events will also be 
summarized by cohort and by treatment arm, and overall, within each treatment arm, by severity. 
Serious AEs and AEs resulting in withdrawal from the study will be listed. Participants having 
multiple AEs within a category (eg, overall, SOC, Preferred Term) will be counted once in that 
category. For severity tables, a participant’s most severe event within a category will be counted. 
All concomitant medications will be coded using the World Health Organization Drug 
Dictionary, and the frequency and percentage of concomitant medications will be summarized. 
Pharmacokinetic Analysis 
The individual serum concentration data from participants who receive ALXN1820 SC or 
ALXN1820 IV with actual sampling dates and times, will be used to derive the PK parameters 
by noncompartmental analyses methods. 


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Pharmacodynamic Analysis 
The PD effects of all ALXN1820 SC and ALXN1820 IV doses administered will be evaluated 
by assessing changes in serum total and free properdin concentrations and complement 
alternative pathway (CAP) activity using the Weislab alternative pathway (AP) assay. In 
addition, complement classical pathway (CCP) activity and other measures of properdin activity 
over time may be considered as deemed appropriate (Section 8.6). 
Biomarker assays may be conducted as an exploratory analysis on collected samples. 
Immunogenicity Analysis 
Immunogenicity, as measured by incidence of anti-drug antibody (ADA) to ALXN1820 will be 
summarized.  
Interim Analyses 
An assessment of all available PK/PD data will be performed when all participants in Cohorts 4 
and 5 reach Day 29. These data will be used to project the exposure and duration of properdin 
and CAP activity inhibition (not to exceed 70 days) at the highest single dose planned in the 
study (Cohort 7) and the highest multiple dose in the study (Cohort 10). Further assessments of 
available data may be performed to inform Phase 2 study design in patients. Details of this 
analysis will be presented in the Statistical Analysis Plan (SAP). 
1.2. 
Schema 
Figure 1: 
Study ALXN1820-HV-101 Schematic  
 
Note: black arrow(s) indicate dose(s) given; red arrow indicates decision for dose escalation. 
Abbreviations: A = active (ALXN1820); D = day; IR = Investigator review; IV = intravenous; MAD = multiple 
ascending dose; N = number of participants; P = placebo; PD = pharmacodynamics; PK = pharmacokinetics; 


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QW = once weekly; SAD = single ascending dose; SC = subcutaneous; SRC = Safety Review Committee; 
TBD = to be determined. 
1.3. 
Schedule of Activities (SoA) 
As this is a FIH study, additional or fewer samples or assessments for safety, tolerability, PK, 
PD, and/or ADA may be taken or performed, or the timing of samples or assessments may be 
adjusted, in accordance with the evolving data and dosing schedule. The total blood volume will 
not exceed the study specified maximum blood volume (Section 8.2.4). 
Schedules of activities are presented for single-dose Cohorts 1 to 7 for Screening through Day 5 
in Table 4 and Day 8 through Day 127 in Table 5. 
Schedules of activities are presented for multiple-dose Cohorts 8 and 9 for Screening through 
Day 5 and Days 28 through 33 in Table 6, Day 7 through Day 23 in Table 7, and Day 36 through 
Day 155 in Table 8. Schedules of activities are presented for multiple-dose Cohort 10 for 
Screening through Day 5 and Days 14 through 19 in Table 9, Day 7 through Day 9 in Table 10 
and Day 22 through Day 155 in Table 11. 


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Table 4: 
Schedule of Activities – Screening Through Day 5 for Single-dose Cohorts 1 - 7 
Study Day 
Screening 
Day –1 
Day 1 
Day 2 
Day 3 
Day 5 
Assessmentsa 
Day –79  
to Day –2 
Admit 
Predose 
 
0 h 
(SOI) 
EOI 
30 min 
post 
SOIb 
2 h post 
SOI 
4 h post 
SOI 
8 h post 
SOI 
12 h 
post 
SOI 
24 h 
post 
SOI 
48 h 
post 
SOI 
96 h 
post 
SOI 
Status (OP or CRU) 
OP 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRUc 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MCV4 immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal 
serogroup B 
immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine titer 
(meningococcal 
serogroups A, C, 
W135, and Y)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height, weight, and 
BMIg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON®-TB 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistryh 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Serum albumin  
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Coagulation 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis B and C 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV (types 1 and 2) 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complement activityi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (via 
dipstick) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
measurementsk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECG 
X 
 
Xl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24-h Holter ECGm 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 4: 
Schedule of Activities – Screening Through Day 5 for Single-dose Cohorts 1 - 7 
Study Day 
Screening 
Day –1 
Day 1 
Day 2 
Day 3 
Day 5 
Assessmentsa 
Day –79  
to Day –2 
Admit 
Predose 
 
0 h 
(SOI) 
EOI 
30 min 
post 
SOIb 
2 h post 
SOI 
4 h post 
SOI 
8 h post 
SOI 
12 h 
post 
SOI 
24 h 
post 
SOI 
48 h 
post 
SOI 
96 h 
post 
SOI 
Randomizationn  
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PK samples 
 
 
X 
 
Xo 
 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum total 
and free properdin, 
CAP activity) 
 
 
X 
 
Xo 
 
X 
X 
X 
X 
X 
X 
X 
Exploratory 
biomarkersp 
 
 
X 
 
Xo 
 
 
 
 
 
X 
 
X 
Injection/infusion site 
evaluation  
 
 
X 
 
X 
X 
X 
X 
X 
X 
Xq 
 
 
Immunogenicity 
(ALXN1820 ADA)r 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Review safety cards 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Concomitant 
medications 
←Monitor continuously (after ICF is signed at Screening)→ 
Adverse eventst 
←Monitor continuously (after ICF is signed at Screening)→ 
Prophylactic antibiotic 
txu 
 
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the Study Operation Manual. 
b For Cohorts 6 and 7, assessments will be performed 1 hour after SOI. 
c Participant will be discharged from the CRU after completing all Day 5 assessments. Participants will be provided a “Study Participant ID card” with information for healthcare 
provider and participant on symptoms of meningitis infection. 
d Signed and dated IEC-approved ICF must be obtained before any study-specific screening procedures are performed. 
e For participants who do not have adequate documentation of prior MCV4 immunization or serogroup B vaccination, MCV4 immunization will be performed at least 56 days 
prior to dosing on Day 1, and vaccination for serogroup B meningococcal infections will be administered at least 56 days prior to Day 1 dosing with a booster administered at 
least 28 days prior to dosing on Day 1. 
f For participants with a documented vaccine titer indicating sufficient protection within 6 months prior to Screening, the titer does not need to be repeated. 
g Height and BMI only at Screening. 
h Non-fasting blood samples will be obtained. 
i Complement activity, confirmed by a suitable assay such as CAP ELISA/C5 (hemolysis) inhibition, will be performed at Screening to confirm participants do not have a 
complement deficiency.  
j Serum pregnancy test for all female participants of childbearing potential to confirm that a female participant is not pregnant prior to dosing. A urine pregnancy test can be 
performed if the Screening visit is within 3 weeks of Day 1 visit. 
k At Screening, supine and standing (orthostatic) blood pressures will be performed to exclude participants who are prone to orthostatic hypotension. 
l Predose triplicate 12-lead ECGs will be performed 3 times at approximately 2, 1, and 0.5 hours before the start of dosing. 


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m A 24-hour Holter ECG will be performed up to 3 months prior to Day 1 to exclude pre-existing ECG abnormalities. 
n Planned randomization may be up to 7 days prior to dosing on Day 1. 
o Collection of post-dose PK/PD samples are to be collected from the non-infused arm and not the administration line in IV administered cohorts 
p Collection of blood (for serum, citrated and K2-EDTA, or Plasma P100 plasma) and urine. 
q Injection/infusion site reaction evaluation will continue until the reaction is fully resolved. 
r In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the time of the event. 
s The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical study participant safety card at all times and to review the 
potential meningococcal infection risks of ALXN1820, and to address any safety concerns of the participant. 
t Collection of adverse events and serious adverse events will begin after ICF signing.  
u Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of Day -1 through 
Day 127, or until complement activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the discretion of the 
Investigator.  
Abbreviations: ADA = antidrug antibody; BMI = body mass index; C5 = complement component 5; CAP = complement alternative pathway; CRU = clinical research unit; 
ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; EOI = end of infusion/injection; h = hour; HIV = human immunodeficiency virus; ICF = informed 
consent form; ID = identity; IEC = Independent Ethics Committee; IV = intravenous; K2-EDTA = dipotassium ethylenediaminetetraacetic acid; MCV4 = tetravalent 
meningococcal conjugate vaccine; min = minutes; OP = outpatient; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SC = subcutaneous; SOI = start of infusion/injection; 
TB = tuberculosis; tx = treatment. 


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Table 5: 
Schedule of Activities – Day 8 Through Day 127 for Single-dose Cohorts 1 - 7 
Study Daya 
Day 8 
(168 h post 
SOI) 
Day 15 
Day 22 
Day 29 
Day 36 
Day 43 
Day 50 
Day 57 
Day 71 
Day 85 
Day 99 
Day 
127h/ET 
Window (days) 
0 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Status (OP or CRU) 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Physical examination 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECG 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
X 
Chemistryb 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Hematology 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Coagulation 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis (via dipstick) 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum pregnancy test 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
PK samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum total and free 
properdin, CAP activity) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarkersc 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Immunogenicity (ALXN1820 
ADA)e 
 
X 
 
X 
 
 
 
X 
 
X 
 
Xd 
Review safety cardf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously→ 
Adverse eventsg 
←Monitor continuously→ 
Prophylactic antibiotic txh 
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the Study Operations Manual. 
b Non-fasting blood samples will be obtained. 
c Collection of blood (for serum, citrated and K2-EDTA, or Plasma P100 plasma) and urine. 
d Participants who are ADA positive at Day 127/ET will be followed up to 1 year from the study drug administration or ADA titers return to baseline levels (whichever occurs 
first). 
e In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the event. 
f The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical study participant safety card at all times and to review the 
potential meningococcal infection risks of ALXN1820, and to address any safety concerns on the part of the participant 
g Collection of adverse events and serious adverse events will begin after ICF signing.  
h Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of Day -1 
through Day 127, or until complement activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the 
discretion of the Investigator. Follow-up will be extended until individual CAP activity has normalized.  
Abbreviations: ADA = antidrug antibody; CAP = complement alternative pathway; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; h = hour; 
ICF = informed consent form; K2-EDTA = dipotassium ethylenediaminetetraacetic acid; OP = outpatient; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SOI = start 
of infusion/injection; tx = treatment. 


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Table 6: 
Schedule of Activities – Screening Through Day 5 (First Dose), Day 28 to 33 (Last Dose) for Multiple-dose 
Cohorts 8 and 9 
Study Day 
Screening 
Day –1, 
28a 
Day 1, 29 
Day 2, 
30 
Day 3, 
31 
Day 5, 
33 
Assessmentsb 
Day –79  
to Day –2 
Admit 
Pre-
dose 
0 h 
(SOI) 
EOI 
30 min 
post SOI 
2 h 
post 
SOI 
4 h 
post 
SOI 
8 h 
post 
SOI 
12 h 
post 
SOI 
24 h 
post 
SOI 
48 h 
post 
SOI 
96 h 
post 
SOI 
Status (OP or CRU) 
OP 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRUc 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MCV4 immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal serogroup B 
immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine titer (meningococcal 
serogroups A, C, W135, and Y)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Height, weight, and BMIg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON®-TB test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistryh 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Serum albumin 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Coagulation 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV (types 1 and 2) screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complement activityi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (via dipstick) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurementsk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECG 
X 
 
Xl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac telemetrym 
 
 
←Monitor continuously→ 
 
 
 
 
 
 
24-h Holter ECGn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationo 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PK samples 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum total and free 
properdin, CAP activity) 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarkerp 
 
 
X 
 
 
 
 
 
 
 
X 
 
 


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Table 6: 
Schedule of Activities – Screening Through Day 5 (First Dose), Day 28 to 33 (Last Dose) for Multiple-dose 
Cohorts 8 and 9 
Study Day 
Screening 
Day –1, 
28a 
Day 1, 29 
Day 2, 
30 
Day 3, 
31 
Day 5, 
33 
Assessmentsb 
Day –79  
to Day –2 
Admit 
Pre-
dose 
0 h 
(SOI) 
EOI 
30 min 
post SOI 
2 h 
post 
SOI 
4 h 
post 
SOI 
8 h 
post 
SOI 
12 h 
post 
SOI 
24 h 
post 
SOI 
48 h 
post 
SOI 
96 h 
post 
SOI 
Injection/infusion site evaluation 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Xq 
 
 
Immunogenicity (ALXN1820 
ADA)r 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Review safety cards 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously (after ICF is signed at Screening)→ 
Adverse eventst 
←Monitor continuously (after ICF is signed at Screening)→ 
Prophylactic antibiotic txu 
 
←Antibiotic prophylaxis→ 
a Schedule for Days 7 – 23 provided in Table 7. 
b Permissible windows for study assessments are described in the Study Operations Manual. 
c Participant will be discharged from the CRU after completing all Day 5 or Day 33 assessments. Participants will be provided a “Study Participant ID card” with information for 
healthcare provider and participant on symptoms of meningitis infection. 
d Signed and dated IEC-approved ICF must be obtained before any study-specific screening procedures are performed. 
e For participants who do not have adequate documentation of prior MCV4 immunization or serogroup B vaccination, MCV4 immunization will be performed at least 56 days 
prior to dosing on Day 1, and vaccination for serogroup B meningococcal infections will be administered at least 56 days prior to Day 1 dosing with a booster administered at 
least 28 days prior to dosing on Day 1. 
f For participants with a documented vaccine titer indicating sufficient protection within 6 months prior to Screening, the titer does not need to be repeated. 
g Height and BMI only at Screening. 
h Non-fasting blood samples will be obtained. 
i Complement activity, confirmed by a suitable assay such as CAP ELISA/C5 (hemolysis) inhibition, will be performed at Screening to confirm participants do not have a 
complement deficiency. 
j Serum pregnancy test for all female participants of childbearing potential to confirm that a female participant is not pregnant prior to dosing. A urine pregnancy test can be 
performed if the Screening visit is within 3 weeks of Day 1 visit. 
k At Screening, supine and standing (orthostatic) blood pressures will be performed to exclude participants who are prone to orthostatic hypotension. 
l Predose triplicate 12-lead ECGs will be performed 3 times at approximately 2, 1, and 0.5 hours before the start of dosing. 
m Continuous cardiac monitoring from 1 hour pre-dose to 2 hours after the start of study drug administration. 
n A 24-hour Holter ECG will be performed up to 3 months prior to Day 1 to exclude pre-existing ECG abnormalities. 
o  Planned randomization may be up to 7 days prior to dosing on Day 1. 
p Collection of blood (for serum, citrated and K2-EDTA, or Plasma P100 plasma) and urine 
q Injection/infusion site reaction evaluation will continue until the reaction is fully resolved.  
r In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the time of the event. 
s The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical study participant safety card at all times and to review the 
potential meningococcal infection risks of ALXN1820, and to address any safety concerns of the participant. 
t Collection of adverse events and serious adverse events will begin after ICF signing.  


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u Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of Day -1 through 
Day 127, or until complement activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the discretion of the 
Investigator.  
Abbreviations: ADA = antidrug antibody; BMI = body mass index; C5 = complement component 5; CAP = complement alternative pathway; CRU = clinical research unit; 
ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; EOI = end of infusion/injection; h = hour; HIV = human immunodeficiency virus; ICF = informed 
consent form; ID = identity; IEC = independent ethics committee; MCV4 = tetravalent meningococcal conjugate vaccine; min = minutes; OP = outpatient; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); SC = subcutaneous; SOI = start of infusion/injection; TB = tuberculosis; tx = treatment.


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Table 7: 
Schedule of Activities – Day 7 Through Day 23 for Multiple-dose Cohorts 8 and 9 
Study Day 
Days 7, 
14, 21 
Days 8, 15, 22 
Days 9, 
16, 23 
Assessmentsa 
Admit  
Pre-
dose 
0 h 
(SOI) 
EOI 
30 min 
post SOI 
2 h post 
SOI 
4 h post 
SOI 
8 h post 
SOI 
12 h post 
SOI 
24 h post 
SOI 
Status (OP or CRU) 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRUb 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
Chemistryc 
X 
 
 
 
 
 
 
 
 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
X 
Serum pregnancy testd 
X 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
 
 
 
 
 
 
Urinalysis (via dipstick) 
X 
 
 
 
 
 
 
 
 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
Vital sign measurements 
X 
X 
 
X 
 
 
 
X 
 
X 
Triplicate ECG 
 
X 
 
X 
 
 
 
X 
 
X 
Cardiac telemetrye 
 
←Monitor continuously→ 
 
 
 
 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
PK samples 
 
X 
 
X 
 
 
 
X 
 
X 
PD panel (serum total and free properdin, 
CAP activity) 
 
X 
 
X 
 
 
 
X 
 
X 
Injection/infusion site evaluationf 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity (ALXN1820 ADA)g 
 
X 
 
 
 
 
 
 
 
 
Review safety cardh 
X 
X 
X 
Concomitant medications 
←Monitor continuously→ 
Adverse eventsi 
←Monitor continuously→ 
Prophylactic antibiotic txj 
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the Study Operations Manual. 
b Participant will be discharged from the CRU after completing all Day 9, Day 16 or Day 23 assessments. Participants will be provided a “Study Participant ID card” with 
information for healthcare provider and participant on symptoms of meningitis infection. 
c Non-fasting blood samples will be obtained. 
d Serum pregnancy test for all female participants of childbearing potential to confirm that a female participant is not pregnant prior to dosing. 
e Continuous cardiac monitoring from 1 hour pre-dose to 2 hours after the start of study drug administration. 
f Injection/infusion site reaction evaluation will continue until the reaction is fully resolved. 
g In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the time of the event. 
h The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical trial participant safety card at all times and to review the 
potential meningococcal infection risks of ALXN1820, and to address any safety concerns of the participant. 
i Collection of adverse events and serious adverse events will begin after ICF signing.  


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j Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of Day -1 
through Day 155, or until complement activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the 
discretion of the Investigator.  
Abbreviations: ADA = antidrug antibody; CAP = complement alternative pathway; CRU = clinical research unit; ECG = electrocardiogram; EOI = end-of-infusion/injection; 
h = hour; ICF = informed consent form; ID = identity; min = minutes; OP = outpatient; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SOI = start of 
infusion/injection; tx = treatment. 
 


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Table 8: 
Schedule of Activities – Day 36 Through Day 155 for Multiple Dose Cohorts 8 and 9 
Study Daya 
Day 36 
(168 h post 
SOI) 
Day 43 
Day 50 
Day 57 
Day 71 
Day 85 
Day 99 
Day 113 
Day 127 
Day 141 
Day 
155h/ET 
Window (Day) 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Status (OP or CRU) 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Abbreviated physical exam 
(optional) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECG 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
Chemistryb 
X 
 
 
X 
 
 
 
 
 
 
X 
Hematology 
X 
 
 
X 
 
 
 
 
 
 
X 
Coagulation 
X 
 
 
X 
 
 
 
 
 
 
X 
Urinalysis (via dipstick) 
X 
 
 
X 
 
 
 
 
 
 
X 
Serum pregnancy test 
X 
 
 
X 
 
X 
 
X 
 
 
X 
PK samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum total and free 
properdin, CAP activity) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarkersc 
 
 
 
X 
 
 
 
 
 
 
X 
Immunogenicity (ALXN1820 
ADA)d 
 
 
X 
 
X 
 
X 
 
X 
 
Xe 
Review safety cardf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously→ 
Adverse eventsg 
←Monitor continuously→ 
Prophylactic antibiotic txh 
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the Study Operations Manual. 
b Non-fasting blood samples will be obtained. 
c Collection of blood (for serum, citrated and K2-EDTA, or Plasma P100 plasma) and urine. 
d In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the time of the event. 
e Participants who are ADA positive at Day 155/ET will be followed up to 1 year from the study drug administration or ADA titers return to baseline levels (whichever occurs 
first). 
f The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical trial participant safety card at all times and to review the 
potential meningococcal infection risks of ALXN1820, and to address any safety concerns on the part of the participant. 
g Collection of adverse events and serious adverse events will begin after ICF signing. 
h Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units) through Day 155 or until complement 
activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the discretion of the Investigator. Follow-up will 
be extended until individual CAP activity has normalized.  
Abbreviations: ADA = antidrug antibody; CAP: Complement alternative pathway; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; h = hour; 
ICF = informed consent form; K2-EDTA = dipotassium ethylenediaminetetraacetic acid; OP = outpatient; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SOI = start 
of infusion/injection; tx = treatment. 
 


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Table 9: 
Schedule of Activities – Screening Through Day 5 (First Dose), Day 14 to 19 (Last Dose) for Multiple-dose 
Cohort 10 
Study Day 
Screening 
Day –1, 
14a 
Day 1, 15 
Day 2, 
16 
Day 3, 
17 
Day 
5, 19 
Assessmentsb 
Day –79  
to Day –2 
Admit 
Pre-
dose 
0 h 
(SOI) 
EOI 
30 min 
post SOI 
2 h 
post 
SOI 
4 h 
post 
SOI 
8 h 
post 
SOI 
12 h 
post 
SOI 
24 h 
post 
SOI 
48 h 
post 
SOI 
96 h 
post 
SOI 
Status (OP or CRU) 
OP 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRUc 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MCV4 immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal serogroup B 
immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccine titer (meningococcal 
serogroups A, C, W135, and Y)f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Height, weight, and BMIg 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON®-TB test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistryh 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Serum albumin 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Coagulation 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV (types 1 and 2) screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complement activityi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testj 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis (via dipstick) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurementsk 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECG 
X 
 
Xl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac telemetrym 
 
 
←Monitor continuously→ 
 
 
 
 
 
 
24-h Holter ECGn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationo 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PK samples 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum total and free 
properdin, CAP activity) 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 


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Table 9: 
Schedule of Activities – Screening Through Day 5 (First Dose), Day 14 to 19 (Last Dose) for Multiple-dose 
Cohort 10 
Study Day 
Screening 
Day –1, 
14a 
Day 1, 15 
Day 2, 
16 
Day 3, 
17 
Day 
5, 19 
Assessmentsb 
Day –79  
to Day –2 
Admit 
Pre-
dose 
0 h 
(SOI) 
EOI 
30 min 
post SOI 
2 h 
post 
SOI 
4 h 
post 
SOI 
8 h 
post 
SOI 
12 h 
post 
SOI 
24 h 
post 
SOI 
48 h 
post 
SOI 
96 h 
post 
SOI 
Exploratory biomarkerp 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Injection/infusion site evaluation 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Xq 
 
 
Immunogenicity (ALXN1820 
ADA)r 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Review safety cards 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously (after ICF is signed at Screening)→ 
Adverse eventst 
←Monitor continuously (after ICF is signed at Screening)→ 
Prophylactic antibiotic txu 
 
←Antibiotic prophylaxis→ 
a Schedule for Days 7 – 9 provided in Table 10. 
b Permissible windows for study assessments are described in the Study Operations Manual. 
c Participant will be discharged from the CRU after completing all Day 5 or Day 19 assessments. Participants will be provided a “Study Participant ID card” with information 
for healthcare provider and participant on symptoms of meningitis infection. 
d Signed and dated IEC-approved ICF must be obtained before any study-specific screening procedures are performed. 
e For participants who do not have adequate documentation of prior MCV4 immunization or serogroup B vaccination, MCV4 immunization will be performed at least 56 days 
prior to dosing on Day 1, and vaccination for serogroup B meningococcal infections will be administered at least 56 days prior to Day 1 dosing with a booster administered at 
least 28 days prior to dosing on Day 1. 
f For participants with a documented vaccine titer indicating sufficient protection within 6 months prior to Screening, the titer does not need to be repeated. 
g Height and BMI only at Screening. 
h Non-fasting blood samples will be obtained. 
i Complement activity, confirmed by a suitable assay such as CAP ELISA/C5 (hemolysis) inhibition, will be performed at Screening to confirm participants do not have a 
complement deficiency. 
j Serum pregnancy test for all female participants of childbearing potential to confirm that a female participant is not pregnant prior to dosing. A urine pregnancy test can be 
performed if the Screening visit is within 3 weeks of Day 1 visit. 
k At Screening, supine and standing (orthostatic) blood pressures will be performed to exclude participants who are prone to orthostatic hypotension. 
l Predose triplicate 12-lead ECGs will be performed 3 times at approximately 2, 1, and 0.5 hours before the start of dosing. 
m A 24-hour Holter ECG will be performed up to 3 months prior to Day 1 to exclude pre-existing ECG abnormalities. 
n Continuous cardiac monitoring from 1 hour pre-dose to 2 hours after the start of study drug administration. 
o  Planned randomization may be up to 7 days prior to dosing on Day 1. 
p Collection of blood (for serum, citrated and K2-EDTA, or Plasma P100 plasma) and urine 
q Injection/infusion site reaction evaluation will continue until the reaction is fully resolved. 
r In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the time of the event. 
s The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical study participant safety card at all times and to review the 
potential meningococcal infection risks of ALXN1820, and to address any safety concerns of the participant. 
t Collection of adverse events and serious adverse events will begin after ICF signing.  


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Table 9: 
Schedule of Activities – Screening Through Day 5 (First Dose), Day 14 to 19 (Last Dose) for Multiple-dose 
Cohort 10 
Study Day 
Screening 
Day –1, 
14a 
Day 1, 15 
Day 2, 
16 
Day 3, 
17 
Day 
5, 19 
Assessmentsb 
Day –79  
to Day –2 
Admit 
Pre-
dose 
0 h 
(SOI) 
EOI 
30 min 
post SOI 
2 h 
post 
SOI 
4 h 
post 
SOI 
8 h 
post 
SOI 
12 h 
post 
SOI 
24 h 
post 
SOI 
48 h 
post 
SOI 
96 h 
post 
SOI 
u Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of Day -1 
through Day 155, or until complement activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the 
discretion of the Investigator.  
Abbreviations: ADA = antidrug antibody; BMI = body mass index; C5 = complement component 5; CAP = complement alternative pathway; CRU = clinical research unit; 
ECG = electrocardiogram; ELISA = enzyme-linked immunosorbent assay; EOI = end of infusion/injection; h = hour; HIV = human immunodeficiency virus; ICF = informed 
consent form; ID = identity; IEC = independent ethics committee; MCV4 = tetravalent meningococcal conjugate vaccine; min = minutes; OP = outpatient; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); SC = subcutaneous; SOI = start of infusion/injection; TB = tuberculosis; tx = treatment. 


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Table 10: 
Schedule of Activities – Day 7 Through Day 9 for Multiple-dose Cohort 10 
Study Day 
Day 7 
Day 8 
Day 9 
Assessmentsa 
Admit  
Pre-
dose 
0 h 
(SOI) 
EOI 
30 min 
post SOI 
2 h post 
SOI 
4 h post 
SOI 
8 h post 
SOI 
12 h post 
SOI 
24 h post 
SOI 
Status (OP or CRU) 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRUb 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
Chemistryc 
X 
 
 
 
 
 
 
 
 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
X 
Serum pregnancy testd 
X 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
 
 
 
 
 
 
 
 
 
Urinalysis (via dipstick) 
X 
 
 
 
 
 
 
 
 
X 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
Vital sign measurements 
X 
X 
 
X 
 
 
 
X 
 
X 
Triplicate ECG 
 
X 
 
X 
 
 
 
X 
 
X 
Cardiac telemetrye 
 
←Monitor continuously→ 
 
 
 
 
Study drug administration 
 
 
X 
 
 
 
 
 
 
 
PK samples 
 
X 
 
X 
 
X 
X 
X 
X 
X 
PD panel (serum total and free properdin, 
CAP activity) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Injection/infusion site evaluation 
 
X 
 
X 
X 
X 
X 
X 
X 
Xf 
Immunogenicity (ALXN1820 ADA)g 
 
X 
 
 
 
 
 
 
 
 
Review safety cardh 
X 
 
X 
Concomitant medications 
←Monitor continuously→ 
Adverse eventsi 
←Monitor continuously→ 
Prophylactic antibiotic txj 
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the Study Operations Manual. 
b Participant will be discharged from the CRU after completing all Day 9 assessments. Participants will be provided a “Study Participant ID card” with information for healthcare 
provider and participant on symptoms of meningitis infection. 
c Non-fasting blood samples will be obtained. 
d Serum pregnancy test for all female participants of childbearing potential to confirm that a female participant is not pregnant prior to dosing. 
e Continuous cardiac monitoring from 1 hour pre-dose to 2 hours after the start of study drug administration. 
f Injection/infusion site reaction evaluation will continue until the reaction is fully resolved. 
g In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the time of the event. 
h The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical trial participant safety card at all times and to review the 
potential meningococcal infection risks of ALXN1820, and to address any safety concerns of the participant. 
i Collection of adverse events and serious adverse events will begin after ICF signing.  
j Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of Day -1 through 
Day 155, or until complement activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the discretion of the 


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Investigator.  
Abbreviations: ADA = antidrug antibody; CAP = complement alternative pathway; CRU = clinical research unit; ECG = electrocardiogram; EOI = end-of-infusion/injection; 
h = hour; ICF = informed consent form; ID = identity; min = minutes; OP = outpatient; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SOI = start of infusion/injection; 
tx = treatment.


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Table 11: 
Schedule of Activities – Day 22 Through Day 155 for Multiple Dose Cohorts 10 
Study Daya 
Day 22 
(168 h po
st SOI) 
Day 
29 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Day 
71 
Day 
85 
Day 
99 
Day 
113 
Day 
127 
Day 
141 
Day 
155h/ET 
Window (Day) 
 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Status (OP or CRU) 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviated physical exam 
(optional) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECG 
X 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
Chemistryb 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Hematology 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Coagulation 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Urinalysis (via dipstick) 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Serum pregnancy test 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
PK samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum total and free 
properdin, CAP activity) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory biomarkersc 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Immunogenicity (ALXN1820 
ADA)e 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xd 
Review safety cardf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously→ 
Adverse eventsg 
←Monitor continuously→ 
Prophylactic antibiotic txh 
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the Study Operations Manual. 
b Non-fasting blood samples will be obtained. 
c Collection of blood (for serum, citrated and K2-EDTA, or Plasma P100 plasma) and urine. 
d Participants who are ADA positive at Day 155/ET will be followed up to 1 year from the study drug administration or ADA titers return to baseline levels 
(whichever occurs first). 
e In case of any suspected case of hypersensitivity or anaphylaxis additional samples for the assessment of ADA may be collected at or near the time of the event. 
f The Investigator or qualified designee will meet with the participant at each visit to ensure they carry the clinical trial participant safety card at all times and to 
review the potential meningococcal infection risks of ALXN1820, and to address any safety concerns on the part of the participant. 
g Collection of adverse events and serious adverse events will begin after ICF signing. 
h Participants will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units) through Day 155 or until 
complement activity has normalized (as determined by CAP assay). If penicillin is not tolerated, second line antibiotics will be initiated at the discretion of the 
Investigator. Follow-up will be extended until individual CAP activity have normalized. 
Abbreviations: ADA = antidrug antibody; CAP: complement alternative pathway; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; 
h = hour; ICF = informed consent form; K2-EDTA = dipotassium ethylenediaminetetraacetic acid; OP = outpatient; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s); SOI = start of infusion/injection; tx = treatment. 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
ALXN1820 (anti-properdin/anti-serum albumin bispecific VHH antibody) is a novel properdin 
blocking agent being developed for the treatment of diseases involving dysregulated complement 
alternative pathway (CAP) activity. The ALXN1820 molecule is bispecific, comprising a VHH 
antibody domain that binds and blocks properdin connected via a linker to a VHH domain that 
binds serum albumin, thereby conferring an extended circulatory half-life to the molecule. 
ALXN1820 binds to properdin with a high affinity to prevent stabilization of the CAP C3 and C5 
convertases that cleave C3 and C5 into their activation products. Quantitative blockade of 
properdin has been shown to be safe in human based on experience with the properdin binding 
antibody ALXN1510 (see Section 4.3). There is a need to provide patients the opportunity for 
self-administration and an extended dose interval with complement pathway inhibitors. With this 
goal in mind, ALXN1820 was designed to enable SC self-administration. 
The purpose of this FIH study is to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), and immunogenicity of single ascending doses and multiple ascending 
doses of ALXN1820 administered SC (ALXN1820 SC) and bioavailability of a single dose of 
ALXN1820 administered intravenously (ALXN1820 IV). The study will be conducted in healthy 
adult participants and will also include a multiple SC dose cohort in healthy participants of 
Japanese descent. Data from this study are anticipated to help inform the design of future studies 
in patients with complement-mediated diseases. 
2.2. 
Background 
A detailed description of the chemistry, pharmacology, and toxicology data available for 
ALXN1820 is provided in the Investigator’s Brochure (IB). 
2.2.1. 
Chemistry  
ALXN1820 is a recombinant, humanized VHH bispecific antibody that binds to human 
properdin and serum albumin. The antibody consists of a single polypeptide chain of 256 amino 
acids, which is comprised of an anti-albumin domain at the N-terminus that is fused to a 
C-terminal anti-properdin domain via a 15 amino acid linker. The variable region domains that 
form the serum albumin and properdin binding sites consist of llama complementarity 
determining regions grafted into human germline frameworks. Within the framework regions, 
llama residues at 11 positions were left unchanged to maintain antigen binding, aqueous 
solubility, and overall stability. There are 2 intrachain disulfide bonds, one disulfide bond 
localized in each VHH domain. The theoretical average molecular mass of the antibody is 
27,350.2 Da. At pH 7.4, ALXN1820 exhibited a binding dissociation constant (KD) of 323 pM 
for human properdin and KD of 439 pM for human serum albumin. The IC50 for blockade of 
human CAP hemolysis by ALXN1820 (20% v/v final serum) was 29 nM. ALXN1820 blocked 
C3 fragment, properdin and C9 deposition onto a myeloperoxidase substrate by human serum 
(20%v/v) with IC50 values of approximately 20 nM (C3), 15 nM (properdin) and 19 nM (C9). 


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2.2.2. 
Nonclinical Pharmacology  
In a study of the potency of blockade of in vitro CAP hemolysis by ALXN1820 using sera across 
a range of species, significant species cross reactivity was observed only when using sera from 
cynomolgus and rhesus macaque. CAP hemolytic activities in the sera of mouse, rat, guinea pig, 
minipig, beagle and rabbit were not inhibited by the highest concentration of ALXN1820 
examined (> 100 μg/mL). The IC50 for blockade of cynomolgus CAP hemolysis by ALXN1820 
(20% v/v final serum) was 47 nM. ALXN1820 exhibited a binding KD of 2.9 nM for cynomolgus 
properdin and KD of 2.1 nM for cynomolgus serum albumin. ALXN1820 blocked C3 fragment, 
properdin and C9 deposition onto a myeloperoxidase substrate by cynomolgus monkey serum 
(20%v/v) with IC50 values of approximately 11 nM (C3), 9 nM (properdin) and 17 nM (C9). The 
lack of species cross reactivity beyond primates described above, prevented testing of the 
biologic activity of ALXN1820 in traditional rodent models of diseases involving dysregulated 
complement activity. Collectively therefore, the nonclinical in vitro and in vivo studies to assess 
the pharmacologic, PK, PD and toxicologic properties of ALXN1820 are being performed in 
cynomolgus monkeys. 
2.2.3. 
Toxicology  
Nonclinical safety profile of ALXN1820 has been evaluated in an in vitro Good Laboratory 
Practice (GLP) tissue cross reactivity (TCR) study and in both a non-GLP and GLP in vivo study 
in cynomolgus monkeys. In the GLP toxicology study ALXN1820 was administered both by IV 
administration (up to single dose of 100 mg/kg) and SC administration (up to 6 weekly doses of 
300 mg/kg/week). ALXN1820 did not demonstrate any non-specific binding to human tissues in 
the TCR study. Based on the absence of any adverse systemic or local toxicity in cynomolgus 
monkeys, 300 mg/kg/week was considered the no observed adverse effect level (NOAEL) for SC 
administration and 100 mg/kg was considered as the NOAEL for IV administration of 
ALXN1820. Systemic exposures (Cmax and AUC0-168hr of 9,220 µg/mL and 1,230,000 µg∙hr/mL, 
respectively), after the last dose at the NOAEL in the SC group, yielded exposure multiples of 
40-fold to the Cmax and 37-fold to the AUC0-168hr to the projected exposures at the highest 
anticipated human dose of 1200 mg (Table 16). Antidrug antibodies were only observed in 1 
monkey (out of a total of 40 monkeys) administered with ALXN1820 and did not have any 
impact on systemic exposure or toxicity profile. 
2.3. 
Benefit/Risk Assessment 
This is a healthy participant study, and there is no direct benefit to study participants. Identified 
and potential risks are described below. More detailed information about the known and 
expected benefits and risks and reasonably expected AEs of ALXN1820 may be found in the IB. 
2.3.1. 
Risk Assessment 
This study is the first human exposure to ALXN1820, and as there is no clinical experience to 
date, the potential risks are based on the class of the molecule and its mechanism of action. No 
potential risks were identified from the repeat dose toxicity study in cynomolgus monkeys with 
ALXN1820 after 6 weekly SC doses up to 300 mg/kg/week or after a single IV dose up to 
100 mg/kg. 


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2.3.1.1. 
Neisseria meningitidis Infections 
Increased susceptibility to infection with Neisseria (N.) meningitidis is a known risk associated 
with properdin deficiency and has been well described with properdin deficient patients 
(Figueroa, 1991). Similar to properdin deficiency, the main risk associated with the use of 
ALXN1820 (properdin inhibitor) is the risk of meningococcal infections. Specific risk mitigation 
measures are in place to address this risk. All participants must be vaccinated against 
meningococcal infections at least 56 days before the time of initiating study drug and should 
receive treatment with appropriate prophylactic antibiotics during the duration of reduced 
complement activity.  
Clinically, the risk of N. meningitidis is mitigated in patients with properdin deficiency by 
vaccinating all patients against N. meningitidis with tetravalent meningococcal conjugate 
(MCV4) and serogroup B vaccines before dosing. In this clinical study, participants will 
experience an induced transient state of properdin deficiency, therefore participants will receive 
the MCV4 vaccination at least 56 days prior to dosing with ALXN1820 (if not vaccinated with 
MCV4 within the last 2 years and 6 months, or if adequate documentation to verify previous 
vaccination is unavailable). A titer to MCV4 will be established prior to enrollment to confirm 
immunization status. Participants who are not already vaccinated for serogroup B meningococcal 
infections will also receive that vaccination at least 56 days prior to Day 1 dosing with a booster 
administered at least 28 days prior to dosing on Day 1. 
In addition to vaccination against N. meningitidis with MCV4 and the serogroup B vaccine, all 
participants will be treated with prophylactic antibiotics (oral penicillin V 500 mg twice daily) 
for the duration of reduced complement activity. Unless the Investigator and Sponsor agree to an 
alternative regimen, all participants will take prophylactic antibiotics (oral penicillin V 500 mg 
twice daily) until complement activity has normalized. Penicillin is the drug of choice in 
eradication of N. meningitidis in carriers, as supported by the following: 
1. High levels of resistance to penicillin caused by plasmid-encoded β-lactamases are rarely 
encountered in meningococcal strains (Yazdankhah, 2004). 
2. Antibiotic prophylaxis with orally administered penicillin V 500 mg twice daily has been 
provided in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical 
hemolytic uremic syndrome (aHUS) patients with eculizumab by some physicians and is 
generally well-tolerated (Kelly, 2011; Leeds Teaching Hospitals NHS Trust, 2013). 
If penicillin is not tolerated, or the participant has a known penicillin allergy, second-line 
antibiotics will be initiated at the discretion of the Investigator. 
2.3.1.2. 
Immunogenicity and Hypersensitivity 
ALXN1820 has the potential to be immunogenic and may be associated with hypersensitivity 
reactions. Some healthy participants are also known to have pre-existing antibody to VHH 
antibodies. Antibodies to ALXN1820 have been observed in 14 of 100 healthy participant serum 
samples tested in an in vitro screening assay.  
Monitoring of immunogenicity for ALXN1820 is in place for this study as specified in the SoA 
(Section 1.3). 


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Table 12: 
Potential Risks and Mitigation Strategies 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Treatment with ALXN1820 
Meningococcal infection 
ALXN 1820 blocks properdin which 
can result in increased susceptibility to 
Neisseria meningitidis, likely with 
fulminant clinical manifestations.  
 
Participants must be vaccinated against 
all available serotypes of N. meningitidis 
(A, C, Y, W 135, and B). However, 
vaccination may not be sufficient to 
prevent meningococcal infection.  
Participants will be put on prophylactic 
antibiotics for the entire Treatment Period 
until CAP activity returns to baseline 
(See Sections 1.3, 2.3.1.1 and 8.2.9) 
 
Participants will be provided a safety card 
to carry at all times and for 5 months after 
the final dose of ALXN1820. 
 
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.  
Algorithm for hypersensitivity reaction 
management; Stopping rules and 
staggered dosing 
 
 
Abbreviation: CAP = complement alternative pathway. 
2.3.1.3. 
Coronavirus Disease 2019  
The SARS-COV-2 disease (COVID-19) global pandemic is active in many countries at the time 
of this protocol. Given this unique circumstance, specific consideration has been given to the 
risks and benefits of the study as they may be related to COVID-19, and the global and local 
changes that exist as a result of the pandemic. This assessment is described in Section 10.7, 
Appendix 7. 
2.3.2. 
Benefit Assessment 
This is a healthy participant study, and there is no direct benefit to study participants. 
2.3.3. 
Overall Benefit: Risk Conclusion 
This is the first time that ALXN1820 will be administered to humans. Healthy participants are 
the appropriate population for this study, as they will enable PK and PD assessments without the 
potential of confounding effects due to other disease activity, comorbidities, or medications. This 
study has been designed to minimize risk to participants; there is strict inclusion/exclusion 
criteria with a robust safety monitoring and risk mitigation plan in place. This dosing strategy is 


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justified given the large safety margin and the experience with complete properdin inhibition in 
healthy participants at Alexion (Section 4.3). An SRC, consisting of the Investigator, Medical 
Monitor, safety physician, study statistician and clinical pharmacologist, will evaluate the 
available study data at prespecified time points for participant safety and make recommendations 
on dose escalation, dose modification, or termination of the study. The single and multiple SC 
and IV doses to be studied in healthy participants in this study are predicted to be within the 
safety exposure margins established from a cynomolgus monkey 6-week GLP toxicology study. 
The data obtained from this healthy participant study may inform future clinical studies in 
patients. 


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3. 
OBJECTIVES AND ENDPOINTS 
The study objectives and corresponding endpoints are presented in Table 13. 
Table 13: 
Study ALXN1820-HV-101 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To assess the safety and tolerability of ALXN1820 SC 
and ALXN1820 IV 
Safety assessed by incidence of TEAEs and SAEs, 
physical examination, vital sign measurements, clinical 
laboratory, and electrocardiogram results 
 
Secondary 
 
To assess the single- and multiple-dose PK of 
ALXN1820 SC and single-dose PK of ALXN1820 IV 
 
Serum ALXN1820 single- and multiple-dose PK 
profiles and PK parameters 
 
To explore the PD effects of ALXN1820 SC and 
ALXN1820 IV 
Change in serum concentrations of total and free 
properdin over time  
 
Change in CAP activity using the Wieslab AP assay 
 
To assess the immunogenicity of ALXN1820 SC and 
ALXN1820 IV 
 
Incidence of treatment-emergent ADAs to ALXN1820 
To estimate the absolute bioavailability of 
ALXN1820 SC  
 
ALXN1820 PK parameters (AUC) SC versus IV will 
be compared 
 
To compare safety, tolerability, PK, PD, and 
immunogenicity of ALXN1820 SC between Japanese 
and non-Japanese healthy participants 
Quantitative assessment of safety, PK, PD parameters, 
and immunogenicity (ADA) between healthy non-
Japanese participants and participants of Japanese 
descent 
 
Abbreviations: ADA = antidrug antibody; AP = alternative pathway; AUC = area under the concentration-time 
curve; CAP = complement alternative pathway; IV = intravenous; PD = pharmacodynamics(s); 
PK = pharmacokinetic(s); SAE = serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse 
event. 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 1, randomized, double-blind, placebo-controlled single and multiple ascending 
dose study designed to evaluate the safety, tolerability, PK, PD, and immunogenicity of 
ALXN1820 administered SC (ALXN1820 SC) and IV (ALXN1820 IV). ALXN1820 SC will be 
evaluated in single and multiple ascending doses while ALXN1820 IV will be evaluated in a 
single dose only. A total of 80 healthy adult participants (60 on ALXN1820, 20 on placebo) will 
be enrolled in up to 10 cohorts. All participants within each cohort will be recruited at a single 
site. 
Eight participants will be randomly assigned in a 3:1 ratio to each cohort to receive either a 
single or multiple doses of ALXN1820 SC, a single dose of ALXN1820 IV (n = 6 per cohort), or 
a single or multiple doses of placebo (n = 2 per cohort). Details on dosing are presented in 
Table 14. 
Table 14:  
ALXN1820-HV-101 Dosing Cohorts 
Cohort 
N 
Study Drug 
Route of 
Administration 
Planned Dose 
(placeholders) 
Number of 
Doses/Dose 
Interval 
1 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
12.5 mg 
1 single dose 
2 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
50 mg 
1 single dose 
3 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
150 mg 
1 single dose 
4 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
450 mg 
1 single dose 
5 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
IV 
450 mg 
1 single dose 
6 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
1200 mg 
1 single dose 
7 
(optional) 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
TBDa 
(≤ 2250 mg) 
1 single dose 
8 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
150 mg 
QW × 5 
9 
8  
(6 active/2 placebo) 
Japanese 
participants 
ALXN1820 and 
placebo 
SC 
150 mg 
QW × 5 
10 
8  
(6 active/2 placebo) 
ALXN1820 and 
placebo 
SC 
TBDa 
QW × 3a  
a Dosing in Cohorts 7 and 10 to be determined based on the observed data up to Cohort 5 and PK/PD modeling. 
Abbreviations: IV = intravenous; N = number of participants; PD = pharmacodynamic (s); PK = pharmacokinetic(s); 
QW = once weekly; SC = subcutaneous; TBD = to be determined. 
Details on timing of dosing in the cohorts are presented in Table 15. 
The first 2 participants randomized to each cohort will be dosed as a sentinel pair with at least 
1 participant on active treatment (either 1 participant on active treatment and 1 participant on 
placebo, or 2 participants on active treatment). This dosing strategy is justified given the large 


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safety margin (approximately 20-fold at the highest planned dose) and the experience with 
properdin inhibition in healthy participants at Alexion. At the discretion of the Investigator, up to 
3 more participants will be dosed at least 48 hours after dosing of the sentinel pair, followed by 
dosing of the remaining participants in the cohort no earlier than the 4th day, as long as no 
suspension/stopping criteria have been met (Section 7.2). At no time will more than 
4 participants per cohort be dosed on a given day. The allowance for a maximum of 
4 participants/day/cohort is intended to provide flexibility should a 4th participant need to be 
added (eg, if replacement of a participant is required). The intention for this dosing strategy is to 
ensure a limited number of healthy participants will receive a dose and regimen that have not 
been previously tested. The limit of ≤ 4 participants/day/cohort does not apply to the dose and 
regimens tested previously. 
The timing and dependencies of the dosing cohorts are in Table 15 and in Figure 1. Enrollment 
may be stopped at the discretion of the SRC. Should they be required, dose modifications are 
described in Table 19. 
Table 15: 
Dosing Chart for Single Ascending Dose and Multiple Ascending Dose 
Regimens 
Cohort 
Route of Administration 
Number of participants dosed 
Day 1a 
 
Day 3 
 
Day 4 
 
1b, 2b, and 3b 
Manual SC or via SP 
2 
3 
3 
4b, 6c, 7c 
SC infusion via SP 
5d 
IV infusion 
8e, 9e 
Manual SC, QW × 5 
10f 
Manual SC or SC infusion via SP, 
QW × 3 
Note At no time > 4 participants/cohort to be dosed on a given day for dose and regimen that have not been tested 
previously. 
a At least 1 participant on active treatment (either 1 participant on active treatment and 1 participant on placebo, or 
2 participants on active treatment).  
b Sequential dosing to occur in Cohorts 1 to 4, dependent on SRC review of safety data through Day 15 (336 hours) 
of previous cohort. 
c Dosing in Cohort 6 to be administered based on SRC review of interim safety data from the Day 15 (336 hours) 
assessment after dosing of Cohorts 4 and 5. Dosing in Cohort 7 to be determined based on SRC review of interim 
safety data from the Day 15 (336 hours) assessment after dosing of Cohort 6 and PK/PD data from Day 29 
(672 hours) assessment after dosing of Cohorts 4 and 5. 
d Dosing in Cohort 5 is dependent on Investigator review of safety data through Day 8 (168 hours) of Cohort 4. 
However, should there be safety findings of concern in previous cohorts, an SRC review will be conducted for 
Cohort 5 to determine if participants will be dosed at the planned dose of 450 mg IV or a lower dose. 
e Dosing in Cohorts 8 and 9 to be determined based on SRC review of all data from the Day 15 (336 hours) 
assessment for Cohorts 4 and 5. Dosing of Cohort 9 may start at the same time as Cohort 8 or later depending on 
scheduling at the clinical site 
f Dosing in Cohort 10 to be determined based on SRC review of all data from the Day 29 (672 hours) assessment 
for Cohort 8 and PK/PD data from Day 29 (672 hours) after dosing of Cohorts 4 and 5. 
Abbreviations: IV = intravenous; PD = pharmacodynamic; PK = pharmacokinetic; QW = once weekly; 
SC = subcutaneous; SP = syringe pump; SRC = safety review committee. 
An SRC, consisting of the Investigator, Medical Monitor, safety physician, study statistician and 
clinical pharmacologist, will evaluate the available study data at prespecified time points for 
participant safety and make recommendations on dose escalation, dose modification, or 


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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). At the Sponsor’s discretion, and after consultation with the SRC, up to 18 additional 
participants across the entire study may be enrolled as replacement participants if a participant 
discontinues prior to Day 43 for reasons other than drug-related AEs. 
The highest single-dose cohort (Cohort 7) will be optional and determined based on SRC review 
of interim safety data from Day 15 (336 hours) assessment after dosing of Cohort 6 and PK/PD 
data from Day 29 (672 hours) after dosing of Cohorts 4 and 5 (450 mg SC and IV, respectively). 
Based on properdin and CAP activity, the highest dose administered in this study will not exceed 
2250 mg or the NOAEL exposure established in the GLP toxicology study, whichever is lower. 
For comparison with NOAEL exposure, instead of using the common practice of the mean 
predicted AUC0-168 and Cmax of all participants in a cohort, the upper limit of the 95% 
prediction interval (PI) of the model predicted AUC0-168 and Cmax will be used. This approach 
will ensure that each participant in this cohort will have a lower exposure than the NOAEL 
exposure. The highest dose will have on average ≤ 70 days complete inhibition of properdin and 
CAP activity. 
Dosing in the multiple-dose Cohort 10 will start after SRC review of all available data through 
Day 29 (672 hours) for Cohort 8 (ALXN1820 150 mg SC weekly for 5 weeks) and all available 
data from the single dose cohorts at the time of the SRC meeting. The final dose will be 
determined based on the interim PK/PD modeling using PK/PD data from Day 29 (672 hours) 
after dosing of Cohorts 4 and 5. Administration of ALXN1820 to participants in Cohort 10 is 
expected to completely inhibit properdin and CAP activity during the dosing period. The dose 
regimen determined for this cohort will not exceed the NOAEL exposure established in the GLP 
toxicology study. For comparison with NOAEL exposure, instead of using the common practice 
of the mean predicted AUC0-168 and Cmax of all participants in a cohort, the upper limit of the 
95% prediction interval (PI) of the model predicted AUC0-168 and Cmax will be used. This 
approach will ensure that each participant in this cohort will have an exposure lower than the 
NOAEL exposure. 
Additional cohorts in healthy participants and patients may be added later if deemed necessary. 
These cohorts will only be added as part of a substantial amendment to the protocol, and after 
SRC review and regulatory agency and EC approval. Screening for these cohorts can proceed 
prior to amendment approval, as long as the approved selection criteria apply. Randomization 
and dosing can only occur after approval of the amendment. 
All ALXN1820 dose levels/dosing regimens can be adjusted in accordance with safety, 
tolerability, and PK/PD data collected up to the decision-making time point (see Table 19 for 
dose escalation rules). As used here, the term “dosing regimen” includes (1) the dose level 
administered, (2) the number of doses administered each day, (3) the interval between individual 
doses, and (4) the duration of dosing, i.e., the total number of doses administered. Accordingly, 
these can be adjusted individually or in combination. 
4.2. 
Scientific Rationale for Study Design 
As this is the first time ALXN1820 will be dosed in humans, a randomized, double-blind, 
placebo-controlled, single- and multiple ascending dose design was chosen for initial assessment 
of the safety, tolerability, PK/PD, and immunogenicity of ALXN1820 SC and ALXN1820 IV. 


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The ALXN1820 IV cohort will provide the reference arm for assessing ALXN1820 SC absolute 
bioavailability. 
This study is being conducted in healthy participants, not patients, so that the assessments are not 
confounded by disease activity, comorbidities, or concomitant medications. A sentinel dosing 
paradigm is being used since this is the first administration of ALXN1820 to healthy 
participants. 
The ALXN1820 multiple-dose SC cohorts will assess safety, tolerability, PK/PD, and 
immunogenicity after multiple doses of ALXN1820 administration. The ALXN1820 
multiple-dose SC cohort in participants of Japanese ethnicity will assess safety, tolerability, 
PK/PD, and immunogenicity after multiple doses of ALXN1820 administration in participants of 
Japanese ethnicity and comparison of safety and PK/PD between Japanese and non-Japanese 
participants. 
The expected terminal elimination half-life for the highest SC dose being evaluated in this study 
is expected to be approximately 24 days. The 126 and 154-day washout periods for the single 
and multiple dose cohorts, respectively, correspond to more than 5 half-lives, at which point 
ALXN1820 is expected to be nearly completely eliminated from the systemic circulation and 
complement activity restored to normal levels in the study participants. 
As this is a FIH study, placebo control is implemented in each cohort. Due to the difficulty of 
providing a matching placebo, participants randomized to placebo will receive an equivalent 
volume of normal saline (SC administration) or 5% dextrose or glucose (IV administration) at 
the same injection/infusion rate as the active treatment. To ensure double-blinded conditions, the 
pharmacist preparing the study drug and the physician(s) administering the active treatment or 
placebo will be unblinded to treatment assignment. All other study personnel will remain blinded 
to treatment assignment, unless pre-specified in the protocol. All necessary steps will be taken to 
avoid inadvertent unblinding. 
4.3. 
Justification for Dose 
The proposed doses in this study are justified based on the experience of properdin deficient 
patients reported in the literatures and Alexion’s own nonclinical and clinical experience with 
other properdin inhibitors (ALXN1510 and ALXN1610). 
A number of individuals have been described in the literature with properdin deficiency 
(Figueroa, 1991; Fijen, 1996). Properdin deficiency is an X-linked recessive disease that occurs 
in males. The main clinical characteristic of properdin deficiency is significant risk of 
meningococcal infection. Recurrent meningococcal infection is rare possibly in part because the 
CCP remains intact and can be activated by antibodies elicited in the initial meningococcal 
infection. Properdin-deficient patients respond well to meningococcal vaccination (Fijen, 1998). 
Obligate carrier females had approximately half the normal level of properdin but normal AP 
activity and no increased risk of meningococcal infection (Densen, 1987). 
Alexion has previously conducted nonclinical and clinical studies with other properdin 
inhibitors, ALXN1510 and ALXN1610. ALXN1510 is a full-length IgG1 monoclonal antibody 
(mAb) that binds and blocks properdin. A FIH healthy participant SAD study of ALXN1510 was 
conducted with 6 dose cohorts from 0.1 to 20 mg/kg administered as IV infusions 
(Study ALXN1510-HV-101). A total of 48 participants (36 active and 12 placebo) were enrolled 


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with 8 participants (6 active and 2 placebo) in each of the 6 cohorts. ALXN1510 was well 
tolerated up to the highest dose tested (20 mg/kg) with no SAEs. Adverse events (AEs) were 
mild (mostly Grade 1). Risk of Neisseria infection in this study was mitigated by a combination 
of immunizations (ACWY and Serogroup B) and antibiotic prophylaxis. At doses > 1 mg/kg a 
complete inhibition (defined as < 20% of the baseline value) of CAP-mediated hemolysis was 
observed. At doses above 10 mg/kg, the complete inhibition of CAP hemolysis persisted for 
22 to 36 days post dose, returning to baseline (defined as > 80% of the baseline value) around 
36 to 50 days post dose. There was no effect on hemolysis mediated through CCP at any dose 
level in this study. Antidrug antibody against ALXN1510 was observed in only one of 
36 ALXN1510-treated participants in this study at the lowest dose cohort starting around Day 90 
and was not associated with any clinical sequelae or accelerated clearance. 
A 26-week, QW IV GLP toxicology study with 8-week recovery period performed in rhesus 
monkeys with ALXN1510 was conducted in parallel with the FIH healthy volunteer study 
ALXN1510-HV-101. In this study, poor tolerability was observed which was due to significant 
immunogenicity towards ALXN1510 with subsequent deposition of immune complexes and was 
unrelated to inhibition of free properdin and CAP-mediated hemolysis. ALXN1610, derived 
from ALXN1510 by removing 19 murine back mutations from ALXN1510 and replacing the 
aglyco-Ig1-Fc with a G2-G4 Fc, had substantially reduced ADA levels and was well tolerated in 
a 26-week QW toxicology study in rhesus monkeys up to the highest dose tested (100 mg/kg) 
where complete inhibition of free properdin and CAP-mediated hemolysis was achieved. 
A PK/PD model of ALXN1820 was developed using data from the following: 
• a non-GLP single dose and a GLP multiple dose toxicology PK/PD study in 
cynomolgus monkeys  
• in vitro binding of ALXN1820 to human properdin  
• the relationship between in vitro human properdin and CAP activity 
The ALXN1820 PK/PD model was based and refined upon the PK/PD model used in the 
ALXN1510 FIH study. ALXN1510 PK/PD model was a semi-mechanistic target-mediated drug 
disposition model, incorporating ALXN1510, human properdin, binding kinetics of ALXN1510 
to human properdin, and in vitro properdin vs. CAP hemolysis relationship. ALXN1510 PK/PD 
model was used to predict the ALXN1510 PK, properdin inhibition and duration of CAP 
hemolysis inhibition for the ALXN1510 FIH single ascending dose study with reasonable 
accuracy when compared to the observed data. The ALXN1820 PK/PD model in cynomolgus 
monkeys was scaled to simulate ALXN1820 concentrations and the inhibition of properdin and 
CAP activity in humans, which in turn were used to estimate exposure and select a starting dose 
that will produce a minimal on-target pharmacologic effect. 
A summary of the predicted exposure, safety margin, duration of inhibition of properdin, and 
CAP activity for ALXN1820 based on the PK/PD model described above is provided in 
Table 16. Based on the results of PK/PD modeling for ALXN1820, a single dose of 12.5 mg 
ALXN1820 SC is expected to result in < 50% inhibition of free properdin. This dose is 
considered as the minimally anticipated biologically effective dose (MABEL) based upon studies 
of individuals that exhibit heterozygous deficiency in properdin (Bathum, 2006; Densen, 1987). 
In these studies, obligate carrier females had approximately half the normal level of properdin 
but normal CAP activity; no meningococcal infections were reported. In addition, given 


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Alexion’s previous clinical study experience with ALXN1510 as described above, a 
50% inhibition of free properdin would have little impact on the CAP activity. The MABEL dose 
is estimated to occupy only about 0.02 - 0.03% of human serum albumin on a molar basis at 
Cmax. 
Single SC doses will be escalated by 4-fold from 12.5 mg to 50 mg and by 3-fold from 50 mg to 
150 mg and from 150 mg to 450 mg and by 2.67-fold from 450 mg to 1200 mg. At 1200 mg SC, 
ALXN1820 is predicted to produce complete inhibition of properdin (> 99.6% from the baseline) 
and CAP activity (> 80% from the baseline) for about 68 days and 67 days, respectively. The 
properdin and CAP activity are expected to return to 80% of baseline levels by 92 days and 
84 days, respectively. The predicted exposure at the 1200 mg dose is around 1/37 of the 
predicted NOAEL exposure, based on the NOAEL in the toxicology study (300 mg/kg). At this 
dose, the occupancy of human serum albumin at the Cmax is approximately 1.12% to 1.69%. 
A single dose of 450 mg will be administered by the IV route (Cohort 5) to healthy participants 
after completion of the 450 mg SC cohort (Cohort 4) to estimate the absolute bioavailability of 
ALXN1820 following SC administration (Table 16). Given the high SC bioavailability in the 
cynomolgus monkey, the SC bioavailability in humans is expected to be close to 100%. Hence, 
the exposure of ALXN1820 following a 450 mg IV dose is anticipated to be similar to that 
following a 450 mg SC dose. Dosing of Cohort 5 will start based on the Investigator’s review of 
all available safety data through Day 8 (168 hours) for Cohort 4. However, in case there are 
safety findings in previous cohorts, an SRC review will be conducted and dosing for Cohort 5 
may be started at the planned dose of 450 mg IV or at a lower dose than 450 mg IV. 
The highest single-dose cohort (Cohort 7) will be determined based on SRC review of interim 
safety data from the Day 15 (336-hour) assessment after dosing of Cohort 6 and PK/PD data 
from Day 29 (672 hours) after dosing of Cohorts 4 and 5. As shown in Table 16, for participants 
in Cohort 4 and 5 (450 mg SC and IV, respectively), properdin is projected to be completely 
suppressed for 39 days, and CAP activity is projected to be completely suppressed for 
approximately 39 days. The interim PK/PD data from the 450 mg SC and IV doses would be 
sufficient for prediction of higher doses in which an extended duration of inhibition of properdin 
and CAP activity is expected. The highest dose administered in this study will not exceed 
2250 mg or the NOAEL exposure established in the GLP toxicology study, whichever is lower. 
For comparison with NOAEL exposure, instead of using the common practice of the mean 
predicted AUC0-168 and Cmax of all participants in a cohort, the upper limit of the 95% PI of the 
model predicted AUC0-168 and Cmax will be used. This approach will ensure that each participant 
in this cohort will have an exposure lower than the NOAEL exposure. The highest dose also will 
have on average ≤ 70 days complete inhibition of properdin and CAP activity. The limit of 
70 days of complete inhibition is selected to enable evaluation of extended dosing intervals (eg, 
Q8W), leveraging our previous nonclinical (up to 6-month monkey toxicology data) and clinical 
(up to 36 days of complete inhibition of properdin and CAP hemolysis in human) experience 
with other antiproperdin inhibitors (ALXN1510 and ALXN1610), and properdin deficiency 
patients as described above. As shown in Table 16, a 1200 mg dose of ALXN1820 (Cohort 6) is 
projected to suppress properdin and CAP activity for approximately 68 days. If this level of 
suppression is confirmed based on the observed data and interim PK/PD analysis, Cohort 7 may 
not be initiated. 


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Three MAD cohorts will also be included in this study. The first 2 multiple-dose cohorts 
(Cohorts 8 and 9) will receive 150 mg SC weekly for 5 doses. These cohorts will start after SRC 
review of all available data through Day 15 for the 450 mg SC and IV single-dose cohort 
(Cohorts 4 and 5) and administration of ALXN1820 is predicted to provide a duration of 
complete inhibition of properdin and CAP activity of approximately 67 and 66 days, 
respectively, following the first dose, with properdin and CAP activity returning to baseline level 
approximately 91 and 83 days, respectively, after the first dose. The binding to human serum 
albumin is predicted to be approximately 0.51% to 0.77% at the Cmax after the last dose. Cohort 9 
will assess the safety, tolerability, PK, PD, safety, and immunogenicity of ALXN1820 at a dose 
level of 150 mg SC weekly for 5 doses in participants of Japanese descent. 
Study drug administration in Cohort 10 will start after the completion of the Day 29 SRC 
assessment of the safety and tolerability of Cohort 8 in conjunction with all available safety, 
tolerability, and PK/PD data from the single-dose cohorts. The dose will be determined based on 
the interim PK/PD modeling using PK/PD data from Day 29 after dosing of Cohorts 4 and 5. 
Administration of ALXN1820 to participants in Cohort 10 is expected to completely inhibit 
properdin and CAP activity during the dosing period. The dose regimen determined for this 
cohort will not exceed the NOAEL exposure established in the GLP toxicology study. For 
comparison with NOAEL exposure, instead of using the common practice of the mean predicted 
AUC0-168 and Cmax of all participants in a cohort, the upper limit of the 95% PI of the model 
predicted AUC0-168 and Cmax will be used. This approach will ensure that each participant in this 
cohort will have an exposure lower than the NOAEL exposure. The dose regimen also will have 
on average ≤ 70 days complete inhibition of properdin and CAP activity. 


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Table 16:  
Predicted ALXN1820 Exposure and Duration of Properdin and CAP Activity Inhibition 
Cohort 
Planned 
Dose 
Predicted 
AUChuman (0-168h) 
(h × µg/mL) 
Predicted 
Cmax 
(µg/mL) 
Expected 
Safety 
Margin 
for AUC 
Expected 
Safety 
Margin 
for Cmax 
Duration 
of 
≥ 99.6% 
Properdin 
Inhibition 
(Days) 
Time of 
Properdin 
Return to 
80% 
Baseline  
(Days) 
Duration of 
Complete 
Inhibition 
of CAP 
Activity 
(Days) 
Time of 
CAP 
Activity 
Return to 
80% 
Baseline 
(Days) 
Max Free 
and 
Partially 
Free 
Properdin 
Inhibition 
(%) 
Maximum 
Albumin 
Occupancy 
(%) 
1 
12.5 mg SC 
503 
4 
2447 
2460 
0 
4 
0 
0 
44 
0.02 - 0.03 
2 
50 mg SC 
1685 
12 
730 
771 
4 
14 
4 
9 
99.717 
0.06 - 0.09 
3 
150 mg SC 
4414 
31 
279 
300 
16 
33 
16 
26 
99.936 
0.15 - 0.23 
4 
450 mg SC 
12579 
88 
98 
105 
39 
62 
39 
54 
99.981 
0.43 - 0.64 
5 
450 mg IV 
17271 
178 
71 
52 
39 
61 
39 
53 
99.995 
0.87 - 1.30 
6 
1200 mg SC 
32984 
230 
37 
40 
68 
92 
67 
84 
99.993 
1.12 - 1.69 
7 
TBDa (≤ 2250 mg SC) 
8 and 9 
150 mg SC 
QW × 5 
4414  
(after the 1st dose) 
31  
(after the 
1st dose) 
73 
(after the 
5th dose) 
88 
(after the 
5th dose) 
67  
(after the 
1st dose) 
91  
(after the 1st 
dose) 
66 
(after the 1st 
dose) 
83  
(after the 1st 
dose) 
99.936 
0.51 – 0.77 
16802  
(after the 5th dose) 
105 
(after the 
5th dose) 
39 
(after the 
5th dose) 
63 
(after the 5th 
dose) 
38 
(after the 5th 
dose) 
55  
(after the 5th 
dose) 
10 
TBDa 
SC QW × 3 
8497  
(after the 1st dose) 
59 
(after the 
1st dose) 
54 
(after the 
3rd dose) 
64 
(after the 
3rd dose) 
65 
(after the 
1st dose) 
90  
(after the 1st 
dose) 
65  
(after the 1st 
dose) 
81  
(after the 1st 
dose) 
 99.97 
0.71 – 1.06 
22901  
(after the 3rd dose) 
145 
(after the 
3rd dose) 
51  
(after the 
3rd dose) 
76  
(after the 3rd 
dose) 
51 
(after the 3rd 
dose) 
67  
(after the 3rd 
dose) 
a Dose will be determined based on the interim PK/PD analysis using the PK/PD limits specified in Sections 4.1 and 4.3. 
Note: Expected safety margin for AUC = AUCcyno (0-168h) after last dose/AUChuman (0-168h). 
Abbreviations: AUC = area under the concentration-time curve; AUCcyno (0-168h) after last dose = area under the concentration-time curve from time 0 through 168 hours after the last 
dose in cynomolgus monkeys; AUChuman (0-168h) = area under the concentration-time curve from time 0 through 168 hours in humans; CAP = complement alternative pathway; 
Cmax = maximum concentration; IV = intravenous; Max = maximum; PD = pharmacodynamic(s); PK = pharmacokinetic(s); QW = once weekly; SC = subcutaneous; TBD = to 
be determined. 


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4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the SoA (Section 1.3). 
The end of the study is defined as the date the last participant completes the last visit as shown in 
the SoA (Section 1.3). 


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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 the following 
criteria apply: 
Age 
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants who are healthy as determined by medical evaluation with no clinically 
significant or relevant abnormalities as determined by medical history, physical 
examination, vital signs, 12-lead ECG, and clinical laboratory evaluation (hematology, 
biochemistry, coagulation, and urinalysis) that is reasonably likely to interfere with 
participation in or ability to complete the study, or to potentially confound interpretation 
of study results, as assessed by the Investigator and Sponsor Medical Monitor. 
3. Cohort 9 only: Participants of Japanese descent (defined as those participants whose 
parents and grandparents are both Japanese and who have spent less than 5 years outside 
of Japan). 
Weight 
4. Body weight within 50 – 100 kg (inclusive), and body mass index (BMI) within the range 
17 – 32 kg/m2, (inclusive). 
Sex 
5. Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. Female 
participants of childbearing potential and male participants with female partners of 
childbearing potential must be willing to follow protocol-specified contraception 
guidance while on treatment and for at least 5 months after last dose of study drug 
(described in Section 10.4). 
Other Inclusion Criteria 
6. Serum albumin above lower limit of the normal range (local laboratory) at Screening. 
7. QT interval corrected using the Fridericia’s formula (QTcF) ≤ 450 msec at Screening and 
prior to dosing on Day 1. 
8. Documented vaccination with MCV4 at least 56 days and not more than 2 years and 
6 months prior to dosing. Documentation must include a positive titer to confirm an 
immune response before study drug administration. 
9. Documented vaccination with serogroup B meningococcal vaccine at least 56 days and 
not more than 2 years and 6 months prior to dosing. For participants not previously 


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vaccinated with serogroup B meningococcal vaccine, vaccination at least 56 days prior to 
dosing on Day 1, with a booster administered at least 28 days prior to dosing on Day 1, 
with at least 28 days between the first and second injections. For participants vaccinated 
more than 2 years and 6 months prior to dosing, a booster administrated at least 28 days 
prior to dosing on Day 1. 
Informed Consent 
10. Capable of giving signed informed consent as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Current or recurrent disease (eg, cardiovascular, hematologic, neurologic, endocrine, 
immunologic, rheumatologic, renal, hepatic or gastrointestinal, or other conditions) that 
could affect clinical assessments or clinical laboratory evaluations. 
2. Current or relevant history of physical or psychiatric illness that is not stable or may 
require a change in treatment, use of prohibited therapies during the study, make the 
participant unlikely to fully comply with the requirements of the study or complete the 
study, or, any condition that presents undue risk from the study drug or study procedures. 
3. Any other significant disease or disorder which, in the opinion of the Investigator, may 
put the participant at risk. 
4. History of any Neisseria infection. 
5. History of unexplained, recurrent infection, or infection requiring treatment with systemic 
antibiotics within 90 days prior to dosing on Day 1. 
6. History of complement deficiency or complement activity below the reference range as 
evaluated at Screening. 
7. History of malignancy with the exception of a nonmelanoma skin cancer or carcinoma 
in-situ of the cervix that has been treated with no evidence of recurrence within 5 years. 
8. Positive test for hepatitis B surface antigen (HbsAg) or human immunodeficiency virus 
antibody (HIV Ab) at Screening. 
9. Acute or chronic hepatitis C virus infection (evidenced by antibody titer). 
10. Active systemic bacterial, viral, or fungal infection within 14 days prior to dosing. 
11. History of latent or active tuberculosis (TB) or exposure to endemic areas within 8 weeks 
prior to the Screening Visit. 
12. History of significant allergic reaction to any product, including documented history of 
allergy to penicillin or cephalosporin. 
 
 


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Prior/Concomitant Therapy 
13. Use of prescription medications (excluding oral contraceptives) within 7 days prior to 
dosing on Day 1, except with prior approval of the Sponsor. 
14. Regular use of nonprescription, over-the-counter medications, including herbal remedies 
and supplements, within 7 days prior to dosing on Day 1. Multivitamins and paracetamol 
(acetaminophen) ≤ 2 g per day are allowed. 
Prior/Concurrent Clinical Study Experience 
15. Participation (ie, last protocol-required study visit) in a clinical study within 90 days or 5 
half-lives of the investigational agent, whichever is longer, before initiation of dosing on 
Day 1. 
16. Participation in more than 1 clinical study of a mAb, or participation (ie, last 
protocol-required study visit) in a clinical study of a mAb within the 6 months or 5 half-
lives of the mAb, whichever is longer, prior to Screening, during which the participant 
was exposed to the active study drug. 
Diagnostic assessments 
17. Positive or indeterminate QuantiFERON®-TB test indicating possible TB infection. 
18. Presence of fever (confirmed body temperature > 37.6°C) within 14 days prior to dosing 
on Day 1. 
19. Serum creatinine greater than the upper limit of normal (ULN) of the reference range of 
the testing laboratory at Screening or on Day -1. 
20. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN of the 
reference range of the testing laboratory at Screening or > 1.5 × ULN of the reference 
range of the testing laboratory on Day -1. 
21. Any clinically significant abnormal hematological parameters (per the Investigator’s 
discretion with agreement of the Sponsor). 
22. Positive urine drug toxicology screen at Screening or on Day -1. 
23. Alcohol consumption within 48 hours prior to study drug administration or positive 
alcohol breath test on Day -1. 
24. Donation of plasma within 7 days prior to dosing on Day 1. Donation or loss (excluding 
volume drawn at Screening) of more than 400 mL of blood within the last 16 weeks prior 
to dosing on Day 1. 
Other Exclusions 
25. Female participants who are pregnant or breastfeeding. 
26. Participants who are in intimate and prolonged contact with (defined as living under the 
same roof, living in dormitory-style accommodations, or providing personal care to) 
people younger than 2 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); congenital complement, 


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properdin, factor D, or primary antibody deficiencies; acquired complement deficiencies 
(eg, those receiving eculizumab); or HIV. 
27. Participants who are one of the following: 
a. Professionals who are exposed to environments of greater risk for meningococcal 
disease. 
b. Research, industrial, and clinical laboratory personnel who are routinely exposed to 
N. meningitidis. 
c. Military personnel during recruit training (military personnel may be at increased risk 
of meningococcal infection when accommodated in close quarters). 
d. Daycare center workers. 
e. Those living on a college or university campus. 
f. Those who plan to travel during the course of the study to or have travelled to 
endemic areas for meningococcal meningitis (eg, India, Sub-Saharan Africa, Saudi 
Arabia) within 6 months prior to dosing. 
28. Immunization with a live-attenuated vaccine 28 days prior to dosing on Day 1 or planned 
vaccination during the course of the study (except for the vaccination planned by the 
study protocol).  
29. Major surgery or hospitalization within 90 days prior to dosing on Day 1. 
30. History of allergy or hypersensitivity to excipients of ALXN1820 (eg, polysorbate 80) 
31. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing 
products in any form (eg, gum, patch, electronic cigarettes) within 24 hours prior to the 
planned first day of dosing (Former smokers may be permitted to enroll at the 
Investigator’s discretion). Unwilling to comply with the smoking restrictions detailed in 
Section 5.3. 
32. 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 abuse within the 2 years 
before Screening. Alcohol abuse is defined as regular weekly intake of more than 
14 units (for both males and females. 
5.3. 
Lifestyle Considerations 
Table 17: 
Healthy Participant Lifestyle Considerations 
Items participants must not 
consume or do 
When participants must stop 
When participants can restart 
Food containing poppy seeds 
Within 24 hours prior to admission 
to the inpatient facility 
After study completion/last visit. 
Consume meals/snacks/water while 
confined in the inpatient facility. 
Meals/snacks/water provided by the 
study personnel will be allowed. 
Standard meals will be provided at 
the standard unit times, and meals 
should be completed each time. 
While confined to the inpatient 
facility. 
After discharge from the facility  


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Table 17: 
Healthy Participant Lifestyle Considerations 
Items participants must not 
consume or do 
When participants must stop 
When participants can restart 
Caffeine-containing or xanthine-
containing products (eg, coffee, tea, 
cola drinks, and chocolate).  
From 24 hours before admission 
through discharge from the 
inpatient facility and 24 hours 
before each study follow-up visit. 
After discharge from the facility 
and after each study follow-up visit. 
Alcohol 
From 24 hours before admission 
through discharge from the 
inpatient facility and 24 hours 
before each study follow-up visit. 
After discharge from the facility 
and after each study follow-up visit. 
Tobacco in any form (eg, smoking 
or chewing) or other 
nicotine-containing products in any 
form (eg, gum, patch, electronic 
cigarettes).  
From 24 hours before admission 
through discharge from the 
inpatient facility. 
After discharge from the facility. 
Strenuous physical activity.  
48 hours before blood draws for 
clinical safety laboratory testing. 
After blood draws for clinical 
safety laboratory testing. 
Participants should not start new 
physical training activities during 
the study until study completion 
(last visit). 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study drug due to failure to meet eligibility criteria. 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 and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details (eg, failed eligibility criteria), and any AEs, 
including any SAEs and any related concomitant medication, occurring during the screening 
period. 
Participants who do not meet the criteria for participation in this study (ie, screen failures) may 
be rescreened. Any abnormal laboratory parameter(s) results outside of the reference range at 
Screening may be repeated per the Investigator’s discretion for the purpose of further 
determining eligibility. 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1. 
Study Intervention Administered 
The study drug composition and doses to be administered in this study are presented in Table 18. 
Placebo will be commercially available normal saline for SC administration, and 5% dextrose or 
glucose for IV administration. Placebo will be sourced from the site.  
Table 18:  
Dose Reference Chart for Study ALXN1820-HV-101 
Characteristics 
ALXN1820 SC 
ALXN1820 IV 
Dosage formulation 
ALXN1820 is formulated at pH 5.4 and 
each vial contains 300 mg of ALXN1820 
in 20 mM sodium acetate, 250 mM 
sucrose, and 0.05% polysorbate-80. 
The concentration is 150 mg/mL. 
ALXN1820 is formulated at pH 5.4 and 
each vial contains 300 mg of ALXN1820 
in 20 mM sodium acetate, 250 mM 
sucrose, and 0.05% polysorbate-80. The 
concentration is 150 mg/mL. 
Unit dose 
strength(s)/dosage 
level(s) 
12.5 mg, 50 mg, 150 mg, 300 mg, 450 mg, 
1200 mg, and a dose that will not exceed 
2250 mg 
 
450 mg 
Route of 
administration 
SC 
IV 
Dosing instructions 
The SC doses will be administered as a 
manual SC push (for doses ≤ 300 mg) or as 
a SC infusion via a syringe pump (for 
doses > 300 mg).  
 
ALXN1820 IV will be administered as an 
IV infusion 
Packaging and 
labeling 
Each vial will be packaged into a kit. 
There will be 1 vial per kit. Both vials and 
kits will be labeled according to the 
protocol and local regulatory requirements. 
Each vial will be packaged into a kit. 
There will be 1 vial per kit. Both vials and 
kits will be labeled according to the 
protocol and local regulatory 
requirements. 
Manufacturer 
Alexion  
Alexion 
Abbreviations: IV = intravenous; 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. ALXN1820 is to be stored at 2 - 8°C. 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. 


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3. The pharmacy staff at the Investigator’s site will be responsible for study drug 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and 
final disposition records). The site's pharmacy will assemble the supplies into individual, 
labelled participant dose syringes and perform Qualified Person certification of the 
assembled product. 
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. 
For all cohorts, dosing will be double-blinded to active versus placebo. Participants will be 
randomly assigned in a 3:1 ratio to active treatment or placebo. 
During dosing, the participants and on site medical/nursing staff at the study center, and the 
Sponsor will be blinded to study drug assignment. The pharmacy staff preparing the SC/IV doses 
will not be blinded, nor will the study drug administrator(s), while all other study center staff 
involved in the safety evaluations will remain blinded to study drug assignment. Because the 
appearance of the placebo does not match that of the active study drug, a masking technique will 
be used at the time of administration (see pharmacy manual for details). 
Sponsor staff will be unblinded only when necessary (eg, to monitor that the SC/IV dosing are 
being prepared appropriately, to determine reportability of SAEs, and evaluate PK/PD data for 
dose escalation decisions), and will refrain from sharing any information on study drug 
assignment with the study center staff or others at the Sponsor, especially with regard to 
assessment and reporting of safety. An unblinded study drug administrator will administer study 
drug; an appropriate unblinded physician or senior pharmacy staff member will review CAP 
activity results and make decisions regarding antibiotic treatment. 
In the event of an emergency, an envelope for each participant containing his or her study drug 
assignment will be available from the pharmacy staff preparing the study drugs. There is no 
antidote to reverse the effects of ALXN1820; therefore, unblinding would not be helpful in the 
planning of participant treatment for a given event. 
Except for reasons stated above, unblinding should only be considered for the safety of the 
participant. If unblinding is deemed necessary by the Investigator, the Investigator can unblind 
the participant’s treatment allocation using the envelope available from the secure location 
accessible to the clinical 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 participant’s 
treatment allocation. When an AE is serious, unexpected, and related, the blind will be broken by 
the Sponsor only for that specific participant. 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. 


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6.4. 
Study Drug Compliance 
Participants will be administered study drug in a controlled setting 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 intervention 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 
intervention. 
For additional information on study intervention compliance and management, refer to the 
Pharmacy Manual. 
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 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1. 
Allowed Medicine and Therapy 
Multivitamins, contraceptives, and paracetamol (ie, acetaminophen, at doses of ≤ 2 g/day) are 
permitted for use during the study at the Investigator’s discretion. Topical skin products should 
not be administered at the site of study drug injection from 24 hours prior until 24 hours 
following study drug administration. Participants are also permitted to receive a booster vaccine, 
if required. 
See Section 8.2.9 for details on administration and duration of treatment with prophylactic 
antibiotics that are required concomitant medication to mitigate the risk of N. meningitidis 
infection associated with complement inhibition. 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor if required. Concomitant procedures are not allowed 
unless medically indicated. 
6.5.2. 
Disallowed Medicine and Therapy 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days or 5 half-lives (whichever is longer) before the 
start of study intervention until completion of the follow-up visit, unless, in the opinion of the 
Investigator and Alexion, the medication will not interfere with the study. 


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6.6. 
Dose Modification 
Decisions to continue or modify dosing will be made by the Investigator and/or SRC after review 
of the blinded data as described in Table 19. The SRC may also make recommendations 
regarding safety issues, study conduct, or study suspension. 
Table 19:  
Study ALXN1820-HV-101 Dose Continuation/Escalation Decision Pathway 
Dosing 
Decision 
Responsible 
Party 
Data to be Reviewed 
Documentation/Communication 
Methods 
Continuation 
from the 
sentinel 
participant to 
the remaining 
participants 
Investigator 
A minimum of 48 hours post-dose 
safety and tolerability data from the 
sentinel participant. 
The Investigator will document the 
decision in an email to the Sponsor. 
The email does not require the 
Sponsor’s response, unless there is 
disagreement with the Investigator’s 
decision. 
Dose escalation 
from Cohort 1 to 
2, Cohort 2 to 3, 
Cohorts 3 to 4 
SRC 
All available data up to a minimum 
of 336 hours post-dose safety and 
tolerability data from at least 7 
participants (of whom at least 5 will 
have received treatment) from the 
previous cohort.  
The SRC will document the decision 
on the escalation/progression 
approval form.  
Proceed to 
Cohort 5 
Investigator 
or SRC 
A minimum of 168 hours post-dose 
safety and tolerability data from at 
least 7 participants (of whom at least 
5 will have received treatment) from 
Cohort 4.  
The Investigator will document the 
decision in an email to the Sponsor. 
The email does not require the 
Sponsor’s response, unless there is 
disagreement with the Investigator’s 
decision. 
In case there are safety findings in 
previous cohorts, an SRC review will 
be conducted and dosing for Cohort 5 
may be started at the planned dose of 
450 mg IV or a lower dose. 
Escalation to 
Cohort 6 
SRC 
All available data up to a minimum 
of 336 hours post-dose safety and 
tolerability data from at least 7 
participants (of whom at least 5 will 
have received treatment) from each 
of cohorts 4 and 5.  
The SRC will document the decision 
on the escalation/progression 
approval form.  
Escalation to 
Cohort 7 
(optional)  
SRC 
All available data up to a minimum 
of 336 hours post-dose safety and 
tolerability data from at least 7 
participants (of whom at least 5 will 
have received treatment) from 
Cohort 6 and 672 hours post-dose 
PK/PD data for Cohorts 4 and 5 
from at least 7 participants (of whom 
at least 5 will have received 
treatment) from each cohort. 
Cohort 7 may not be initiated based 
on SRC review.  
The SRC will document the decision 
on the escalation/progression 
approval form.  


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Table 19:  
Study ALXN1820-HV-101 Dose Continuation/Escalation Decision Pathway 
Dosing 
Decision 
Responsible 
Party 
Data to be Reviewed 
Documentation/Communication 
Methods 
Proceed to 
Cohort 8 and 9 
SRC 
All available data up to a minimum 
of 336 hours post-dose safety and 
tolerability data from at least 
7 participants (of whom at least 5 
will have received treatment) from 
Cohorts 4 and 5. 
The SRC will document the decision 
on the escalation/progression 
approval form. 
Escalation to 
Cohort 10 
SRC 
All available data up to a minimum 
of 672 hours post-dose safety and 
tolerability data from at least 
7 participants (of whom at least 5 
will have received treatment) from 
Cohort 8, and 672 hours post-dose 
PK/PD data for Cohorts 4 and 5 
from at least 7 participants (of whom 
at least 5 will have received 
treatment) from each cohort. 
The SRC will document the decision 
on the escalation/progression 
approval form. 
Abbreviations: IV = intravenous; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SRC = Safety Review 
Committee. 
6.7. 
Intervention After the End of the Study 
This is a healthy participant study and no follow-up intervention is planned. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) the study intervention. If the study intervention is definitively discontinued, the 
participant should remain in the study to be evaluated for safety follow-up. See the SoA for data 
to be collected at the time of discontinuation of study intervention and follow-up and for any 
further evaluations that need to be completed. 
Participants should be considered for discontinuation from intervention if any of the following 
occur during the study: 
• Serious hypersensitivity reaction; 
• Severe uncontrolled infection; 
• Use of disallowed medication as defined in Section 6.5; 
• Pregnancy or planned pregnancy; or 
• Alexion or the Investigator deems it is necessary for the participant. 
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.2. 
Stopping Criteria 
7.2.1. 
Individual Stopping Rules 
Study drug administration to an individual participant will be continued, delayed, temporarily 
suspended, or discontinued immediately (if applicable) and permanently if AEs related to the 
study drug occur as detailed in Table 20: 


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Table 20: 
Individual Stopping Rules 
Adverse Events Related to ALXN1820 
Actiona 
Moderate (CTCAE Grade II except for injection site 
reactions, QT interval prolongation, hematology, and 
liver function, which are specified below) 
Study drug administration may be continued, delayed, 
temporarily suspended, or discontinued in accordance 
with Investigator’s clinical judgment, in consultation 
with the Sponsor  
Injection site reactions: 
Moderate (CTCAE Grade II) 
Study drug administration will be discontinued if not 
reduced at least to Grade 1 by the time of next dose 
QT interval prolongation:  
A prolongation of the uncorrected QT interval of 
greater than 500 ms, using consistent, technically 
valid triplicate ECG 
Study drug administration will be discontinued 
Hematology: 
Hb drop to absolute values of < 10 g/dL (100 g/L) 
Platelet count drop to absolute values of 
< 75,000/mm3 
Severe (CTCAE Grade III) 
CTCAE Grade IV 
Or 
Serious  
Or 
Hy’s law: 
ALT or AST value > 3 × ULN together with bilirubin 
increase > 2 × ULN, without other evidence of 
cholestasis 
Or 
ALT or AST value > 8 × ULN 
ALT or AST value > 3 × ULN, and symptomatic 
 
a Actions are only relevant for multiple dosing regimens where additional doses are planned for administration. 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common 
Terminology Criteria for Adverse Events; ECG = electrocardiogram; Hb = hemoglobin; IV = intravenous; ULN = 
upper limit of normal. 
7.2.2. 
Cohort and Study Safety Stopping Rules 
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 (Table 21): 


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Table 21: 
Cohort and Study Stopping Rules 
Adverse Events Related to ALXN1820 
Showing Signs 
of 
Reversibility 
Number of Participants 
Action 
Moderate (CTCAE Grade II except for injection site reactions, 
QT interval prolongation, hematology, and liver function, 
which are specified below) 
Yes 
≥ 3 in 1 SOC 
≥ 4 total in different SOCs 
Cohort: Dosing of the remainder of the cohort suspended 
Study: Dosing of equal or higher doses suspended 
 
Dosing of lower dose levels can continue 
Continuation of dosing of equal or higher doses requires a 
substantial amendmentb 
No 
≥ 2 total in different SOCs 
Injection site reactions: 
Moderate (CTCAE Grade II) 
Noa 
≥ 3 
QT interval prolongation:  
A prolongation of the uncorrected QT interval of greater than 
500 msec, using consistent, technically valid triplicate ECG 
NA 
≥ 2 
Hematology: 
Hemoglobin drop to absolute values of < 10g/dL (100 g/L). 
Platelet count drop to absolute values of < 75,000/mm3 
NA 
≥ 2 
Severe (CTCAE Grade III) 
NA 
2 
Study suspended (all dosing [lower, equal or higher doses] 
suspended) 
 
Continuation of the cohort or study requires a substantial 
amendmentb 
CTCAE Grade IV 
Or 
Serious  
Or 
Hy’s law: 
ALT or AST value > 3 × ULN together with bilirubin increase 
> 2 × ULN, without other evidence of cholestasis 
Or 
ALT or AST value > 8 × ULN 
ALT or AST value > 3 × ULN, and symptomatic 
NA 
1 
a For injection-site reactions, a cohort and/or the study will be suspended when ≥ 3 participants are observed. If all but 1 affected participant show signs of recovery (at least to 
Grade 1), cohort and study continuation can then proceed. If ≥ 2 participants remain at Grade 2 after the minimum data review period, the period of observation should be 
extended for up to 168 hours. If all but 1 affected participant show sign of recovery (at least to Grade 1), cohort and study continuation can then proceed. If ≥ 2 affected 
participants remain at Grade 2 after the first 168-hour extension period, the SRC will make the decision to either prolong further the observation period up to a maximum of 
another 168 hours, or suspend the remainder of the cohort and study. At the end of the second extension period, if all but 1 participant show sign of recovery (at least to Grade 1), 
cohort and study continuation can then proceed. If, however, ≥ 2 affected participants remain at Grade 2, cohort and study will be suspended. 
b A substantial amendment may include an amendment to the protocol, the ICF, or other study-related documents as appropriate. 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; 
Hb = hemoglobin; ICF = informed consent form; IV = intravenous; NA = not applicable; SOC = System Organ Class; SRC = Safety Review Committee; ULN = upper limit of 
normal. 
 


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7.3. 
Participant Discontinuation/Withdrawal From the Study 
All efforts should be made to ensure participants are willing to comply with study participation 
prior to conducting the screening procedures. The study staff should notify Alexion and their site 
monitor of all study withdrawals as soon as possible. The reason for participant discontinuation 
must be recorded in the source documents and eCRF. 
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. See SoA (Section 1.3) 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 intervention 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. 
In order to meet minimum data requirements for SRC meetings, participants who withdraw 
consent from the study within the first 14 days may be replaced. At the Sponsor’s discretion, and 
after consultation with the SRC, up to 18 additional participants may be enrolled as replacement 
participants if a participant discontinues prior to Day 43 for reasons other than drug-related AEs. 
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 
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, email, 
3 telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• 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 are handled as part of Section 10.1.8. 


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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 intervention. 
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. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA, if consistent with site SOP. 
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 Examination 
A complete physical examination will include, at a minimum, assessments of the general 
appearance; skin; head, ears, eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal 
cavity; limbs; central nervous system; and musculoskeletal system. Weight will also be measured 
and recorded. 
Height and BMI will be recorded at Screening only. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
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 (tympanic or oral), 
respiratory rate, supine blood pressure, and pulse. Orthostatic (standing) blood pressure will only 
be measured at Screening. 
The timing of vital sign measurements is described in the SoA (Section 1.3). 
Out of range blood pressure or pulse measurements will be repeated at the Investigator’s 
discretion. Confirmed, clinically significant vital sign measurements will be recorded as AEs. 


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8.2.3. 
Electrocardiograms 
Triplicate 12-lead ECGs will be recorded at the time points described in the SoA (Section 1.3) to 
obtain heart rate, PR, QRS, and QT intervals. 12-lead ECG recordings will be made after the 
participants have been resting in a supine position for at least 10 minutes. 
At each time point at which triplicate ECGs are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession but no more than 2 minutes apart. 
8.2.3.1. 
Safety Review of 12-lead Electrocardiograms 
All recorded ECGs will be reviewed by the Investigator or qualified designee. 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 will be followed to resolution. 
8.2.3.2. 
24-hour Holter Electrocardiograms/Real Time Display (Cardiac Telemetry) 
Holter recording will be performed up to 3 months prior to Day 1, and telemetry will be used on 
dosing days as specified in Section 1.3. Electrocardiogram telemetry will be monitored by the 
Investigator or qualified member of clinical staff. This will allow the extraction of 10-second 
12-lead ECG data files, which can be transferred onto the MUSE. All ECG files so acquired will 
then be analyzed and over-read using the same process as for any other 12-lead ECG. The ECG 
Holter/telemetry reports will be archived with study documents.  
8.2.4. 
Clinical Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency. Clinical and laboratory assessments will be 
performed by a local laboratory to assess safety. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator 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 performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 


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The maximum total blood volume collected from participants participating in this study will not 
exceed 500 mL every 16 weeks. 
8.2.5. 
Clinical Safety Laboratory Assessments 
8.2.5.1. 
Virus Serology 
Blood samples collected at Screening will be analyzed for HIV-1, HIV-2, HbsAg, hepatitis B 
core antibody (anti-HBc IgG + IgM, if IgG positive), and hepatitis C virus antibody titers. 
8.2.5.2. 
Vaccine Titer 
A titer against meningococcal serogroups A, C, W135, and Y will be performed at Screening 
(Section 1.3). Titer measurements will be used to exclude participants without a confirmed 
immune response. For participants with a documented vaccine titer indicating sufficient 
protection within 6 months prior to Screening, the titer does not need to be repeated. 
8.2.5.3. 
Tuberculosis Testing 
Serum samples for a QuantiFERON®-TB test will be obtained at Screening as specified in the 
SoA (Section 1.3). 
8.2.6. 
Pregnancy 
No studies of ALXN1820 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. Refer to Section 10.4 
for additional details. 
Following the last study visit, female participants are required to perform a monthly pregnancy 
test until at least 5 months after the last dose. For the convenience of the participant, a serum 
sample will be collected when there is a clinic visit, otherwise, urine test need to be done at home 
(when there is no clinic visit) and the result is to be reported to the Sponsor within 3 days. 
Pregnancy data from female participants and female spouses/partners of male participants will be 
collected from the signing of the ICF until the outcome of the pregnancy is known, which might 
occur after the last follow-up visit. Any female participant who becomes pregnant while 
participating in the study will be discontinued from the study intervention. If a pregnancy is 
reported, the Investigator must immediately inform Alexion within 24 hours of awareness of the 
pregnancy and follow the procedures outlined in Section 10.4. 
8.2.7. 
Injection or Infusion Site Evaluation 
Injection/infusion of antibodies has been associated with injection/infusion reactions, with onset 
typically during or shortly after completion of the injection/infusion. For this reason, participants 
will be carefully observed during each injection/infusion. 
Subcutaneous injection/infusion or IV infusion-site evaluations will be performed at the time 
points specified in the SoA (Section 1.3). Injection/infusion site reactions will not be recorded as 
AEs unless deemed clinically significant. 


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8.2.8. 
Injection/Infusion-associated Reactions 
Injection/infusion-associated reactions are defined as systemic AEs (eg, fever, chills, flushing, 
alterations in heart rate and blood pressure, dyspnea, nausea, vomiting, diarrhea, and generalized 
skin rashes) occurring during or within 24 hours of the start of IV or SC injection/infusion that 
are assessed by the Investigator to be related to the study drug. 
8.2.9. 
Vaccine and Antibiotic Prophylaxis 
To mitigate the risk of N. meningitidis infection associated with complement inhibition, all 
participants in this study will be administered the following: 
1. A MCV4 vaccination at least 56 days prior to dosing of ALXN1820 on Day 1 (if not 
vaccinated with MCV4 within the last 2 years and 6 months, or if participants have been 
previously vaccinated but there is not adequate documentation to verify prior 
vaccination). 
2. Two injections of the serogroup B meningococcal vaccine. The first injection must be 
administered at least 56 days prior to dosing on Day 1, with a booster administered at 
least 28 days prior to dosing on Day 1, with at least 28 days between the first and second 
injections. 
3. Prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 
1 × 106 units) until complement activity has normalized (as determined by CAP assay). If 
penicillin is not tolerated, or the participant has a penicillin allergy, second-line 
antibiotics will be initiated at the discretion of the Investigator. 
The first dose of antibiotic will be administered orally on Day -1 in the evening, prior to the 
Day 1 (dose administration) of study drug. For the outpatient portion of the study, participants 
will be instructed to take the antibiotic approximately at the same times (twice daily) on each 
scheduled day. A suitable system (such as text messaging) will be used for daily monitoring of 
participants’ compliance with the antibiotic prophylaxis regimen. 
Table 22: 
Predicted ALXN1820 CAP Activity Inhibition and Duration of Antibiotic 
Prophylaxis Estimates 
Cohort  Planned Dose  
Duration of 
Complete Inhibition 
of CAP Activity 
(Days After First 
Dose)  
Time of CAP 
Activity Return to 
80% Baseline 
(Days After First 
Dose)  
Anticipated 
Antibiotic 
Prophylaxis 
Duration (Days) 
1  
12.5 mg SC 
0 
0 
22 
2  
50 mg SC 
4 
9 
29 
3 
150 mg SC 
16 
26 
43 
4  
450 mg SC 
39 
54 
57 
5 
450 mg IV 
39 
53 
57 
6  
1200 mg SC 
67 
84 
85 
7  
TBD (≤ 2250 mg SC) 
 
 
 
8 and 9 
150 mg SC QW × 5 in 
healthy participants 
and participants of 
Japanese descent 
66 (after the 1st dose) 
83 (after the 1st dose) 
113 


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Cohort  Planned Dose  
Duration of 
Complete Inhibition 
of CAP Activity 
(Days After First 
Dose)  
Time of CAP 
Activity Return to 
80% Baseline 
(Days After First 
Dose)  
Anticipated 
Antibiotic 
Prophylaxis 
Duration (Days) 
10  
TBD mg SC QW × 3 
 
 
113 
Abbreviations: CAP = complement alternate pathway; IV = intravenous; QC = once weekly; SC = subcutaneous; 
TBD = to be determined 
Analysis of serum samples to establish actual complement activity will be performed using a 
CAP assay (Wieslab AP assay). The analysis will take place continuously and the results will be 
used in an interim PK/PD model to update the predicted duration of CAP inhibition. Results will 
be used to confirm that complement activity has returned to normal; once confirmed, 
prophylactic antibiotic treatment can be stopped. Antibiotics will be continued in all participants 
in a cohort, until complement activity for every participant in the cohort has normalized, in order 
to preserve blinding. All participants will be closely monitored for signs of infection throughout 
the study. 
8.2.10. 
Participant Safety Card  
Participants will always also be provided a safety card to carry with them. Risk of 
meningococcal infection will be explained and discussed with participants during the informed 
consent process, occurring at the Screening Visit. In order to increase the risk awareness and 
promote quick disclosure of any potential signs or symptoms of infection experienced by the 
participants during the course of the study, additional discussion and explanation of the potential 
risks, signs, and symptoms, as described in the ICF, will take place at specific time points 
throughout the study as noted in the SoA (Section 1.3). 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.3. 
All AEs will be reported to the Investigator or qualified designee by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative). 
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 intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.3 (Appendix 3). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the last follow-up visit. 
All SAEs will be recorded and reported to Alexion or the designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). The 
Investigator will submit any updated SAE data to Alexion within 24 hours of it being available. 


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Investigators are not obligated to actively seek AE or SAE data after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify 
Alexion. 
8.3.2. 
Method of Detecting AEs and SAEs  
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 AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each 
participant at subsequent visits/contacts. All SAEs will be followed up 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 SAEs 
Prompt notification of an SAE by the Investigator to Alexion is essential so that legal obligations 
and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
Alexion has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. Alexion 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, institutional review boards (IRBs)/IECs, and Investigators. 
Suspected unexpected serious adverse reactions (SUSARs) must be reported according to local 
regulatory requirements and Alexion policy and forwarded 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 will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4. 
Treatment of Overdose 
For this study, any dose of study intervention greater than that specified in the protocol will be 
considered an overdose. Any blinded dose greater than that specified in the protocol will be 
considered a suspected overdose. There is no specific treatment or antidote for overdose. 
Overdoses are medication errors that are not considered AEs unless there is an untoward medical 
occurrence resulting from the overdose. 
In the event of an overdose or suspected overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 


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2. Closely monitor the participant for any AE/SAE. 
3. Obtain a plasma sample for PK/PD analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
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 ALXN1820 
as specified in the SoA (Section 1.3). Additional samples may be collected at additional time 
points during the study if warranted and agreed upon between the Investigator and Alexion. The 
total blood volume will not exceed the volume limit for healthy participants (Section 8.2.4). 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 ALXN1820. Samples collected for 
analyses of ALXN1820 serum concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study. 
• Samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to dysregulated complement activity. 
Study intervention 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 
Whole blood samples will be collected for measurement of serum total and free properdin 
concentrations, CAP activity, CCP activity, and potentially other measures of complement 
activation as specified in the SoA (Section 1.3). Additional samples may be collected at 
additional time points during the study if warranted and agreed upon between the Investigator 
and Alexion. The total blood volume will not exceed the blood volume limit for healthy 
participants (Section 8.2.4). 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 PD of ALXN1820. Samples collected for analyses of 
ALXN1820 concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study. Unused samples may be retained for a period of up to 
5 years to perform additional assessments as necessary. 


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8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Collection of samples for biomarker research (eg, exploratory) is also part of this study. See 
Section 10.5, Appendix 5 for details. 
The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA (Section 1.3): 
• Blood 
• Urine 
Samples will be collected for testing that may include, but are not limited to, markers of 
complement dysregulation (eg, Factor Ba), vascular inflammation (eg, soluble tumor necrosis 
factor receptors), and endothelial activation/damage (eg, soluble vascular cell adhesion 
molecule-1, thrombomodulin). 
8.9. 
Immunogenicity  
Antibodies to ALXN1820 (ADAs) will be evaluated in whole blood samples collected from all 
participants according to the SoA (Section 1.3) 
Serum samples will be screened for ADAs that bind to ALXN1820. If the screen is positive, the 
sample will be analyzed using a confirmatory ADA assay and the titer of confirmed positive 
samples will be reported. The detection and characterization of antibodies to ALXN1820 will be 
performed using a validated assay method by or under the supervision of the Sponsor. Samples 
may be further characterized to determine the titer and the presence of neutralizing antibodies (as 
an exploratory analysis) if deemed necessary. Additional samples may be collected during the 
study if warranted and agreed upon between the Investigator and the Sponsor. 
Subjects who remain ADA positive for ALXN1820 at the end of the study will be requested 
return to the clinic for blood collection to assess ADA for up to a year following the end of the 
study or until ADA returns to baseline levels (for a maximum of 3 follow-up visits). 
The actual date and time (24-hour clock time) of each sample will be recorded. Samples may be 
banked for a period of up to 5 years in order to perform additional safety assessments, as 
necessary. 
Detailed instructions on the procedure for collecting, processing, storing, and shipping serum 
samples for immunogenicity analysis will be provided in the laboratory manual. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics data will not be evaluated in this study. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
Not applicable. 
9.2. 
Sample Size Determination 
The sample size is based on PK considerations. A sample size of up to 80 participants 
(8 participants per cohort) will be enrolled. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Safety 
All participants who receive at least 1 dose of study drug 
Pharmacokinetic 
All participants who receive at least 1 dose of the study drug and have at least 
1 post-dose PK sample. 
Pharmacodynamic 
All participants who receive at least 1 dose of study drug and who have 
evaluable properdin concentration, CAP or CCP activity data 
Immunogenicity 
All participants who have a predose and at least 1 postdose ADA sample 
collected 
Abbreviations: ADA = antidrug antibody; CAP = complement alternative pathway; CCP = complement classical 
pathway; PK = pharmacokinetic(s). 
9.4. 
Statistical Analyses 
In general, descriptive statistics for continuous variables will include number of nonmissing 
values, arithmetic mean, standard deviation, median, minimum, and maximum. Descriptive 
statistics for PK parameters will include number of observations, arithmetic mean, standard 
deviation, arithmetic coefficient of variation (% CV), median, minimum, maximum, geometric 
mean, and geometric %CV. Categorical variables will be summarized using percentages and 
frequency counts, by cohort and time point. 
A statistical analysis plan (SAP) will be developed and finalized before first data cutoff/database 
lock and will further describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data as appropriate. This section is a 
high-level summary of the planned statistical analyses of the primary and secondary endpoints. 
9.4.1. 
Efficacy Analyses 
No efficacy analyses will be performed for this study. 
9.4.2. 
Safety Analyses 
The primary endpoint for the study is safety and tolerability. 
All safety analyses will be performed on the Safety Population and will be reported by each 
cohort and treatment arm (ie, ALXN1820 or placebo). In addition, healthy participants on 
placebo treatment will be pooled together across cohorts. 


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Safety analyses will include an analysis of all treatment-emergent AEs, 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 AEs and SAEs will be summarized, by SOC and Preferred Term for each cohort and treatment 
arm and overall, within each treatment arm, and by relationship to study drug. Adverse events 
will also be summarized by cohort and treatment arm, and overall, within each treatment arm, 
and by severity. Serious AEs and AEs resulting in withdrawal from the study will be listed. 
Participants having multiple AEs within a category (eg, overall, SOC, Preferred Term) will be 
counted once in that category. For severity tables, a participant’s most severe 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 and 
treatment arm, and overall within placebo treated healthy participants. Laboratory parameter 
values will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE, v5.0, published 27 Nov 2017). Shift tables by cohort and treatment arm 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 postdose during the study. 
All concomitant medications will be coded using the World Health Organization Drug 
Dictionary, and the frequency and percentage of concomitant medications will be summarized. 
9.4.2.1. 
ECG Analysis 
Intensive cardiac assessments will be performed in the Safety Population using food effects on 
ECG to establish assay sensitivity. Analysis of drug related QT/QTc interval changes relative to 
plasma PK concentrations will be conducted on all dose regimens. The principles of this analysis 
follow the statistical methods described by Garnett et al. (Garnett, 2018). The ECG utilized for 
this analysis requires adjudication by qualified cardiologists in accordance with principles set out 
in the International Conference on Harmonisation (ICH) E14 guideline and subsequent Q&A 
documents. All ECG recordings will be in triplicate and compliant with the correct recording and 
manual adjudication of ECG in thorough QT/QTc studies. The ECG analyses will be based on 
adjudicated selected triplicates from each time point. 
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 and treatment arm. 
An outlier analysis will be performed that will summarize the absolute count, frequency and 
percentage of participants who meet any of the following outlier criteria at each visit by cohort 
and treatment arm: 
• QT, QTcF interval > 450 msec 
• QT, QTcF interval > 480 msec 
• QT, QTcF interval > 500 msec 
• QT, QTcF interval increases from baseline > 30 msec 


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• QT, QTcF interval increases from baseline > 60 msec 
Detailed analysis will be specified in the SAP or a separate ECG analysis plan. 
9.4.3. 
Other Analyses  
9.4.3.1. 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Population and will be reported by cohort and 
study intervention within each cohort (ie, ALXN1820 or placebo). 
The individual serum concentration data from participants who receive ALXN1820 SC or 
ALXN1820 IV with actual sampling dates and times will be used to derive the PK parameters by 
noncompartmental analyses methods. 
The following PK parameters as appropriate and data permitting will be derived:  
Parameters Dosing 
Regimen 
Definitions 
Cmax 
SD, MD 
Maximum observed serum concentration 
tmax 
SD, MD 
Time to maximum observed serum concentration 
AUCt 
SD, MD 
Area under the serum concentration versus time curve from time 0 to the last 
quantifiable concentration  
AUCtau 
MD 
Area under the concentration-time curve during the dosing interval 
AUC0-∞ 
SD 
Area under the concentration-time curve from time 0 (dosing) to time infinity 
t½ 
SD, MD 
Terminal elimination half-life 
λz 
SD, MD 
Terminal-phase elimination rate constant 
CL or CL/F 
SD 
Total body clearance or apparent clearance 
Vd or Vd/F 
SD 
Volume of distribution or apparent volume of distribution 
F 
SD 
Absolute bioavailability 
Rac 
MD 
Accumulation ratio 
Abbreviations: SD = single-dose; MD = multiple-dose 
The absolute bioavailability for the ALXN1820 SC cohorts will be defined by the ratio of the 
geometric means for the AUC0-∞ (area under the concentration-time curve from time 0 [dosing] 
to time infinity) parameter for the ALXN1820 SC cohort over the ALXN1820 IV cohort. For the 
absolute bioavailability estimates, a 95% CI for each of the ratio of the geometric means will be 
provided. 
Additional details will be provided in the SAP. 
9.4.3.2. 
Pharmacodynamic Analyses 
All PD analyses will be performed on the PD Population and will be reported by cohort and 
study intervention within each cohort (ie, ALXN1820 or placebo). 
The PD effects of all ALXN1820 SC and ALXN1820 IV doses administered will be evaluated 
by assessing changes in serum total and free properdin concentrations and CAP activity using the 
Weislab AP assay. In addition, an exploratory assessment of CCP activity and other measures of 
properdin activity over time may be considered as deemed appropriate. 
Biomarker assays may be conducted as an exploratory analysis on collected samples. 


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9.4.3.3. 
Immunogenicity Analysis 
For assessment of immunogenicity, the incidence of confirmed positive ADAs will be 
summarized. Additionally, following confirmation of positive ADAs, samples will be assessed 
for ADA titer and presence of neutralizing antibodies (if possible). 
9.4.3.4. 
Interim Analyses 
Interim assessments will be performed as follows: 
1. An assessment of all available PK/PD and immunogenicity data will be performed when 
all participants in Cohorts 4 and 5 reach Day 29. These data will be used to project the 
exposure and duration of properdin and CAP activity inhibition (not to exceed 70 days) at 
the highest single dose planned in the study (Cohort 7) and the highest multiple dose in 
the study (Cohort 10). 
2. CAP activity will be continuously analyzed and will be used to estimate the time of CAP 
activity returning to baseline for each individual participant based on PK/PD modeling. 
Refer to a separate PK/PD analysis plan for further details on the interim assessments. 
Further assessments of available data may be performed to inform Phase 2 study design in 
patients. Details of this analysis will be presented in the SAP. 
No formal interim analysis for futility is planned. 
9.5. 
Safety Review Committee (SRC)  
An SRC, consisting of Investigators from participating sites, Safety physician, 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. In the event a significant safety issue is identified, an ad hoc SRC 
meeting will be convened within 24 hours following its identification (see SRC charter for 
description of membership, schedule of meetings, data required for each safety review, and 
requirements for documenting meeting discussions and outcome). 


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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, IB, 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 
− 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. 


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10.1.3. 
Informed Consent Process 
• It is the responsibility of the Investigator to obtain signed (written or electronic 
signature) informed consent from all study participants prior to any study-related 
procedures including screening assessments. 
• The Investigator or his/her representative will explain the nature of the study 
(including but not limited to the objectives, potential benefits and risks, 
inconveniences, and the participant’s rights and responsibilities) to the participant or 
his/her legally authorized representative, defined according to local and country 
regulations where the study is taking place, and answer all questions regarding the 
study. 
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent or a certified translation if applicable, that meets the requirements of 21 CFR 
50, local regulations, EU General Data Protection Regulation (GDPR), 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 signed (written or electronic) 
informed consent was obtained before the participant was screened in the study and 
the date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the informed consent form(s). 
• Participants must be reconsented to the most current version of the informed consent 
form(s) during their participation in the study. 
• A copy of the signed (written or electronic) informed consent documentation (ie, a 
complete set of participant information sheets and fully executed signature pages) 
must be provided to the participant or the participant’s legally authorized 
representative, as applicable. This document may require translation into the local 
language. Signed (written or electronic) consent [or assent] forms must remain in 
each participant’s study file and must be available for verification at any time. 
• 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. 
• Participants must be informed that their 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 participants who will be required to give consent for their 
data to be used as described in the informed consent 


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• Participants must be informed that their 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 EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed 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 eCRF. 
• 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 eCRF 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 2 years after the last marketing 
application approval, or if not approved, 2 years following the discontinuance of the 
study intervention, 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. 


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Data reported on 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. Source documents are filed at the Investigator’s site. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented. 
Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at the sole discretion of Alexion. Study sites will be closed after the study is completed or 
following the decision to close or terminate the study. A study site is considered closed when all 
participants have completed the end of study or early discontinuation visit, all data have been 
collected and entered into electronic data capture (EDC) system, all required documents and 
study supplies have been collected, and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by 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 intervention development 
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. 
10.1.9. 
Publication Policy 
• Where possible, primary manuscripts reporting results of the primary efficacy 
endpoint or the final results will be submitted for publication within 12 to 18 months 
of the primary evaluation date or end of study, whichever is earlier. 
• Investigators who participate as authors in manuscripts derived from 
Alexion-sponsored studies will agree to the prerequisites as outlined in the Alexion 
author engagement agreement prior to engaging in manuscript development. 
• The Investigator agrees to submit proposals for new manuscripts (whether or not the 
proposed analyses are derived from protocol-specified endpoints) to Alexion for 
review and consideration. All manuscripts or abstracts emanating from approved 
proposals are to be submitted to Alexion for review before submission to the 
journal/society. This allows Alexion to protect proprietary information and to provide 
comments. 


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− The proprietary nature of some development work may preclude publication. In 
some cases, it may be necessary to delay a publication to allow Alexion to ensure 
protection of intellectual property. 
• In general, primary publications, including congress and journal publications, 
containing the protocol-specified results of a study should occur prior to the 
publication of individual study site results or case reports. Alexion’s policy prohibits 
duplicate publication, whereby the same results must not be published in multiple 
peer-reviewed journal manuscripts. 
− Encore congress publications may be appropriate to allow communication of 
research findings to relevant audience and geographical regions. 
• Alexion will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, Alexion will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a Coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements and per the Alexion 
Publication Policy. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 23 will be performed by the local 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. 
• Pregnancy testing: Women of childbearing potential should only be enrolled after a 
negative serum pregnancy test result at Screening. Additional urine pregnancy testing 
will be standard for the protocol unless serum testing is required by site policies, local 
regulation, or IRB/IEC and should be performed per the time points specified in the 
SoA (Section 1.3). 
Table 23: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
• Platelet count  
• Red blood cell (RBC) count 
• Hemoglobin 
• Hematocrit 
• RBC indices (MCV, MCH, %reticulocytes) 
• White blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
Clinical 
chemistrya 
• Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) 
• Alkaline phosphatase  
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) 
• Blood urea nitrogen (optional) 
• Calcium  
• Creatinine 
• Creatine kinase 
• Hemoglobin A1C 
• Potassium 
• Sodium 
• Serum albumin 
• Total and direct bilirubin 
• Total protein 
• Urea 
Coagulation 
• Prothrombin time, partial thromboplastin time, international normalized ratio 
Routine 
urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
by dipstick 
• Microscopic examination (if any leucocytes, more than a trace protein, nitrites, and 
blood [if not menstruating] are abnormal) 
Complement 
activity 
• Change in CAP activity using the Wieslab AP assay  
• Change in CCP and LP activities 
Other 
screening tests 
• Serum QuantiFERON®-TB test 
• Alcohol breath and urine drug screen (to include at minimum: amphetamines, 
barbiturates, benzodiazepines cocaine, opiates, phencyclidine, methamphetamine, 3,4 


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Table 23: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
methylenedioxy-methamphetamine, methadone, and tetrahydrocannabinol 
[cannabinoids]) 
• Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)b  
• Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
• Human immunodeficiency virus (HIV)-1 and HIV-2 antibodies, hepatitis B surface 
antigen (HbsAg), anti-HBc IgG + IgM (if IgG positive) and hepatitis C virus 
antibodies (anti-HCV) 
• Vaccine titer (meningococcal serogroups A, C, W135, and Y) 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.2. All events of ALT ≥ 3 × upper limit of normal (ULN) and bilirubin 
≥ 2 × ULN (> 35% direct bilirubin) or ALT ≥ 3 × ULN and international normalized ratio (INR) > 1.5, if INR 
measured which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).  
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
Abbreviations: CAP = complement alternative pathway; CCP = complement classical pathway; HIV= human 
immunodeficiency virus; IEC = Independent Ethics Committee; IRB = Institutional Review Board; LP = lectin 
pathway; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; SAE = serious adverse event. 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study 
intervention, whether or not considered related to the study intervention. 
• 
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 intervention. 
 
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 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.  
 
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 (eg, hospitalization for elective 
surgery if planned before the signing the ICF, admissions for social reasons or for convenience).  
• 
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.  
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what 
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result 
of a medication error.  
• 
Cases of pregnancy that occur during maternal or paternal exposure to study intervention are to be reported 
within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be collected for 
regulatory reporting and safety evaluation.  
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 


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An SAE is defined as any untoward medical occurrence that, at any dose: 
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 
was 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 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
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. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
Recording of AE and/or SAE 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to Alexion 
in lieu of completion of the AE/SAE eCRF 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 one 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) 
• 
Grade 4: Life-threatening 
• 
Grade 5: Fatal 
 


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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study intervention 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: There is no reasonable possibility the study intervention caused the AE. 
 
The AE has a more likely alternative etiology; it may be due to underlying or 
concurrent illness, complications, concurrent treatments, or effects of another 
concurrent drug. 
 
The event does not follow a reasonable temporal relationship to administration of the 
study intervention. 
− 
Related: There is a reasonable possibility the study intervention caused the AE. 
 
The AE has a temporal relationship to the administration of the study intervention. 
 
The event does not have a likely alternative etiology. 
 
The event corresponds with the known pharmaceutical profile of the study 
intervention. 
 
There is improvement on discontinuation and/or 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 intervention administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for marketed 
products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to the Sponsor or designee. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the SAE data to the 
Sponsor 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 AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by the Sponsor or designee 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. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Sponsor or designee with a copy of any post-mortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to Sponsor or designee within 24 hours of receipt of the 
information. 
10.3.4. 
Reporting of SAEs  
SAE Reporting to Sponsor or Delegate via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours 
awareness. 
• 
SAEs will be reported using the Safety Reporting Form and submitted to Alexion Global Drug Safety 
(GDS). The Investigator must complete, sign, and date the SAE pages, verify the accuracy of the 


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SAE Reporting to Sponsor or Delegate via Paper Safety Reporting Form 
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:
or Fax: 
 
• 
Additional follow-up information, if required or available, should be entered into the eCRF and sent to 
Alexion GDS within 24 hours of the Investigator or study site staff becoming aware of this additional 
information via the reporting process outlined above. 
• 
For all SAEs, the Investigator must provide the following: 
− 
Appropriate and requested follow-up information in the time frame detailed above 
− 
Causality of the SAE(s) 
− 
Treatment of/intervention for the SAE(s) 
− 
Outcome of the SAE(s) 
− 
Medical records and laboratory/diagnostic information 
• 
All paper forms and follow-up information submitted to Alexion GDS must be accompanied by a cover 
page signed by the Investigator. 
• 
Paper source documents and/or reports should be kept in the appropriate section of the study file. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
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. 
10.4.2. 
Contraception Guidance 
10.4.2.1. Female Participants 
Female participants 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 8.2.9), 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: 
− Oral 


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− 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 for at least 5 months after last dose. 
10.4.2.2. 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 for at least 5 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 5 months after 
last dose. 
Male participants must not donate sperm and female participants must not donate ova for at least 
5 months after last dose. 


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10.4.3. 
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 participant’s female sexual partner of childbearing 
potential becomes or is found to be pregnant while being treated or exposed to study 
drug, the Investigator must submit the “Pregnancy Reporting and 
Outcome/Breastfeeding” form to Alexion or designee via the same method as SAE 
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 
reported (via the “Pregnancy Reporting and Outcome Form/Breastfeeding” form) and 
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 8.2.6). 
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 


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10.5. 
Appendix 5: Biomarkers 
• Whole blood samples will be collected for biomarker analyses and the data will be 
used for research (eg, exploratory) related to ALXN1820. The samples may also be 
used to develop tests/assays including diagnostic tests related to ALXN1820 and/or 
others of this study intervention class. 
• The samples may be analyzed as part of a multistudy assessment of biomarkers in the 
response to ALXN1820 to understand study disease or related conditions. Analyses 
may be done to establish normal range of values for biomarkers which may include, 
but are not limited to, markers of complement dysregulation (eg, Factor Ba), vascular 
inflammation (eg, soluble tumor necrosis factor receptors), and endothelial 
activation/damage (eg, soluble vascular cell adhesion molecule-1, thrombomodulin). 
• The results of biomarker analyses may be reported in the clinical study report or in a 
separate study summary. 
• Alexion or designee will store the samples obtained for biomarker analyses in a 
secure storage space with adequate measures to protect confidentiality. 
• The samples will be retained while research on ALXN1820 continues but no longer 
than 5 years or other period as per local requirements. 


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10.6. 
Appendix 6: Management of Potential Adverse Events During Study 
Drug Administration 
Infusion/injection-associated reactions are a potential risk with the use of therapeutic protein 
products; these reactions can be nonimmune or immune mediated (eg, hypersensitivity 
reactions). Signs and symptoms may include headache, fever, facial flushing, pruritus, myalgia, 
nausea, chest tightness, dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, 
shivers, hypertension, lightheadedness, hypotension, palpitations, and somnolence. Signs and 
symptoms of hypersensitivity or allergic reactions may include hives, swollen face, eyelids, lips, 
or tongue, or trouble with breathing. An acute infusion reaction algorithm will be used to manage 
infusion-associated reactions (See Study Operation Manual). 
All infusion/injection-associated reactions will be reported to the Investigator and qualified 
designee. The Investigator and qualified designee are responsible for detecting, documenting, 
and recording events that meet the definition of AE or SAE and remain responsible for following 
up events that are serious, considered related to the study drug or study procedures, or that 
caused the participant to discontinue ALXN1820. 
Definitions and procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are 
outlined in Section 10.3.  
Before study drug administration, the treating physician and other appropriate personnel must 
make certain that medication (ie, adrenaline, inhaled beta agonists, antihistamines, 
corticosteroids) and other equipment to treat anaphylaxis are readily available. The infusion must 
be stopped immediately if Grade ≥ 3 allergic/hypersensitivity reactions (including drug fever) or 
Grade ≥ 3 cytokine release syndrome/acute infusion reaction occurs. Alexion must be notified 
within 24 hours of any infusion reaction requiring interruption or discontinuation of study drug. 
Participants who experience a reaction during the administration of study drug should be treated 
according to institutional guidelines.  
For a Grade 2 infusion reaction, the infusion should be temporarily stopped and treatment with 
an antihistamine and acetaminophen/paracetamol/NSAIDs may be considered. If the 
participant’s signs and symptoms have resolved (with or without administration of the above 
medication), the infusion may be restarted. However, the participant should be infused at a 
slower rate and be monitored closely for any signs and symptoms of infusion reactions during 
the remainder of the infusion. Participants experiencing an infusion reaction should be observed 
in the clinic until resolution of the reaction, or until the Investigator determines the participant is 
no longer at risk. Participants who experience a severe reaction during administration of study 
drug resulting in discontinuation of study drug should undergo all scheduled safety, PK, and PD 
evaluations required by the protocol, if possible.  
If anaphylaxis occurs, please follow local guidance for the management. In the event that there is 
no local guidance, please see suggested management as follow: 
Administration of epinephrine (1/1000, 0.3 mL to 0.5 mL, or equivalent) should be considered. 
In the case of bronchospasm, treatment with an inhaled beta agonist also should be considered. 
Participants administered an antihistamine for the treatment or prevention of an infusion reaction 
should be given appropriate warnings about drowsiness and impairment of driving ability before 
being discharged from the center. 


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Table 24: 
Grading and Management of Allergic or Infusion-Related Reactions 
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Infusion-related 
reaction 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, non-
steroidal anti-
inflammatory drugs 
[NSAIDs], narcotics, 
IV fluids): 
prophylactic 
medications indicated 
for ≤ 24 hours 
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement, 
hospitalization indicated 
for clinical sequelae 
Life-threatening 
consequences; 
urgent 
intervention 
required 
Death 
Allergic 
reaction 
Transient 
flushing or 
rash, drug 
fever < 38.0°C. 
Intervention 
not indicated 
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, 
IV fluids): 
prophylactic 
medications indicated 
for ≤ 24 hours 
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement, 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
urgent 
intervention 
required 
Death 
Anaphylaxis 
– 
– 
Symptomatic 
bronchospasm, with or 
without urticarial; 
parenteral intervention 
indicated; 
allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent 
intervention 
required 
Death 
Cytokine 
release 
syndrome 
Mild reaction: 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or infusion 
interruption indicated 
but responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, 
IV fluids): 
prophylactic 
medications indicated 
for ≤ 24 hours 
Prolonged (eg, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement, 
hospitalization indicated 
for clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
Death 
Abbreviations: IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs 
Source: NCI CTCAE Version 5.0. 
 


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10.7. 
Appendix 7: COVID-19 Risk Assessment 
ALXN1820 blocks properdin, which could result in immunosuppression; therefore, there is a 
theoretical concern that the risk for infection may be higher than in study participants who are 
not on immunosuppression. However, there is no specific data to inform this risk further. The 
Principal Investigator will balance the risk/benefit considerations in their participants, taking 
these factors into account. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 25. 
Table 25: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Healthcare institution 
availability for 
non-COVID-19 
related activities  
COVID-19 may impact the workload of healthcare 
institutions globally and may reduce staff availability 
to perform non-urgent activities and non-COVID-19 
related activities. 
During the time that the 
COVID-19 pandemic is active, 
Alexion will not open study 
sites or enroll new participants 
at sites unless they have the 
resourcing and capabilities to 
implement the study as per 
protocol. 
Data quality and 
integrity 
Lack of availability of site personnel to perform 
study assessments and capture study- specific data in 
a timely manner and to maintain adequate quality 
standards. 
Lack of availability of site personnel to ensure 
adequate and continuous chain of custody, storage 
conditions, and monitoring for investigational 
product and biological samples. 
Inability of study monitors and quality personnel to 
conduct in-person visits to exercise adequate 
oversight of study execution at investigational sites. 
Missing data (COVID-19 pandemic may impact 
study visit schedules, and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the 
COVID-19 pandemic is active, 
Alexion will only open study 
sites that report enough 
personnel capacity to 
sufficiently conduct clinical 
study- related activities.  
During this timeframe, site 
capacity will be reviewed by the 
site Investigator and the study 
Medical Monitor prior to 
Screening. Each site is also 
evaluated for the capacity to 
perform remote monitoring 
visits and remote source data 
verification. 
During the time that the 
COVID-19 pandemic is active, 
it will be important to capture 
specific information in the 
eCRF that explains the reason 
the data are missing (eg, missed 
study visits or participant study 
discontinuations due to 
COVID-19). 
Abbreviations: COVID-19 = Coronavirus Disease 2019; eCRF = electronic case report form


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10.8. 
Appendix 8: Abbreviations 
Table 26: 
Abbreviations and Specialist Terms 
Abbreviation or 
Term 
Explanation 
ADA 
antidrug antibody 
AE 
adverse event  
AP 
alternative pathway 
AST 
aspartate aminotransferase 
AUC0-∞ 
area under the concentration-time curve from time 0 (dosing) to time infinity 
AUC0-168 
area under the concentration-time curve from time 0 to 168 hours 
BMI 
body mass index  
C5 
complement component 5 
CAP 
complement alternative pathway 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax  
maximum observed serum concentration  
CONSORT 
Consolidated Standards of Reporting Trials 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
% CV 
coefficient of variation 
ECG 
electrocardiogram  
eCRF 
electronic case report form 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice  
GDS 
Global Drug Safety 
GDPR 
General Data Protection Regulation 
GLP 
Good Laboratory Practice 
HBc 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
independent ethics committee 
Ig 
immunoglobulin 
IRB 
institutional review board 
IV 
intravenous(ly)  
KD 
dissociation constant 
mAb 
monoclonal antibody  
MABEL 
minimally anticipated biologically effective dose 
MAD 
multiple ascending dose 
MCV4 
tetravalent meningococcal conjugate vaccine  
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PI 
prediction interval 
PK 
pharmacokinetic(s) 


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Table 26: 
Abbreviations and Specialist Terms 
Abbreviation or 
Term 
Explanation 
QTcF 
QT interval corrected using the Fridericia’s formula 
QW 
once weekly 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TMDD 
target-mediated drug disposition 
ULN 
upper limit of normal  


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10.9. 
Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the Table of Contents. 
DOCUMENT HISTORY 
Document 
Type of 
Amendment 
(Global or 
Country-specific) 
Date 
Summary of Key Changes in the 
Amendment 
Original 
protocol 
Not applicable 
09 Oct 2020 
Not applicable 
 
 


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11. 
REFERENCES 
Bathum L, Hansen H, Teisner B, et al. Association between combined properdin and mannose-
binding lectin deficiency and infection with Neisseria meningitidis. Mol Immunol. 
2006;43(5):473-479. 
Densen P, Weiler JM, Griffiss JM, Hoffmann LG. Familial properdin deficiency and fatal 
meningococcemia. Correction of the bactericidal defect by vaccination. N Engl J Med. 
1987;316(15):922-926. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin 
Microbiol Rev. 1991;4(3):359-395. 
Fijen CA, van den Bogaard R, Daha MR, Dankert J, Mannens M, Kuijper EJ. Carrier detection 
by microsatellite haplotyping in 10 properdin type 1-deficient families. Eur J Clin Invest. 
1996;26(10):902-906. 
Fijen CA, Kuijper EJ, Drogari-Apiranthitou M, Van LY, Daha MR, Dankert J. Protection against 
meningococcal serogroup ACYW disease in complement-deficient individuals vaccinated with 
the tetravalent meningococcal capsular polysaccharide vaccine. Clin Exp Immunol. 
1998;114(3):362-369. 
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. J 
Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
Kelly RJ, Hill A, Arnold LM, et al. Long-term treatment with eculizumab in paroxysmal 
nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117(25):6786-
6792. 
Leeds Teaching Hospitals NHS Trust KCHNFT. National Specialised Commissioning Team 
(NSCT) Service Specification Paroxysmal Nocturnal Haemoglobinuria (PNH). 2013. 
Yazdankhah SP, Caugant DA. Neisseria meningitidis: an overview of the carriage state. J Med 
Microbiol. 2004;53(Pt 9):821-832. 
 

SAP_001.pdf: 
NCT #: NCT04631562


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1820-HV-101 
SAP Version: 2.0, 28 November 2022 
 
 
This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 2 of 39 
 
Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
27-Aug-2021 
Initial Release Version  
2.0 
28-Nov-2022 
Added a sentence explaining that for Cohort 7, doses 
higher than 2250 mg will require SRC review and 
regulatory agency and EC approval prior to implementing 
a substantial amendment to the protocol, and for cohort 10, 
any increase in total number of doses or change in dosing 
interval will require SRC review and regulatory agency and 
EC approval prior to implementing a substantial 
amendment to the protocol. 
Added a sentence noting that Alexion will be performing a 
safety analysis of Cohort 6. 
Removed the subgroup analysis, as no subgroup 
analysis is being performed, instead all Japanese 
subjects were enrolled to one cohort (cohort 9). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1820-HV-101 
SAP Version: 2.0, 28 November 2022 
 
 
This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 3 of 39 
 
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
 
 
 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
 
 
 
 
Signature 
 
Date (DD-Mmm-
YYYY) 
Alexion Pharmaceuticals, Inc. Approval 
 
 
 
Name, Title 
Sponsor Contact 
 
Date (DD-Mmm-
YYYY) 
 
29-Nov-2022 | 11:35 EST
Nov 30, 2022
Nov 30, 2022
Nov 30, 2022


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1820-HV-101 
SAP Version: 2.0, 28 November 2022 
 
This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 4 of 39 
Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
Glossary of Abbreviations ................................................................................................... 7 
Purpose ............................................................................................................................ 11 
Study Objectives .............................................................................................................. 12 
Study Details/Design ........................................................................................................ 13 
Endpoints ......................................................................................................................... 17 
Analysis Sets .................................................................................................................... 18 
General Aspects for Statistical Analysis ........................................................................... 19 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1820-HV-101 
SAP Version: 2.0, 28 November 2022 
 
 
This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 5 of 39 
 
 
Participant Disposition, Demographic, Other Baseline Characteristics and Medication .... 21 
 
Pharmacokinetics ............................................................................................................. 23 
 
Pharmacodynamics .......................................................................................................... 28 
 
Safety ............................................................................................................................... 29 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1820-HV-101 
SAP Version: 2.0, 28 November 2022 
 
 
This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 6 of 39 
 
 
Immunogenicity ................................................................................................................ 35 
 
Interim Analyses ............................................................................................................... 36 
 
Changes from Analysis Planned in Protocol ..................................................................... 37 
 
Reference List .................................................................................................................. 38 
 
Quality Control ................................................................................................................. 39 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1820-HV-101 
SAP Version: 2.0, 28 November 2022 
 
 
This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 7 of 39 
 
 
Glossary of Abbreviations 
Abbreviation 
Description 
%AUCextrap 
AUC extrapolated from time t to infinity as a percentage of total AUC∞ 
λz 
 
Apparent terminal-phase elimination rate constant 
ADA 
Antidrug Antibody 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
ANOVA 
Analysis of Variance 
AP 
Alternative Pathway 
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the serum concentration versus time curve 
AUCt 
Area under the serum concentration versus time curve from time 0 to the last 
quantifiable concentration  
AUCt_n 
Dose-normalized AUCt 
AUC∞ / AUCinf 
Area under the serum concentration versus time curve from zero to infinity  
AUC∞_n / AUCinf_n 
Dose-normalized AUC∞ / AUCnf 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CAP 
Complement Alternative Pathway 
CCP 
Complement Classical Pathway 
CFB 
Change From Baseline 
CI 
Confidence Interval 
CL/F 
Apparent Oral Clearance 
CLP 
Complement Lectin Pathway  
Cmax 
Maximum Observed Concentration  
Cmax_n 
Dose-normalized Cmax 
COVID-19 
Coronavirus Disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 


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CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
EOS 
End of Study  
ET 
Early Termination 
Frel 
Relative bioavailability between test and reference treatments 
FSH 
Follicle-stimulating Hormone 
GMR 
Geometric Mean Ratio 
HbA1c 
Glycated Hemoglobin 
hCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IGS 
Immunogenicity Set 
IQR 
Interquartile Range 
IP 
Investigational Product 
IV 
Intravenous 
MAD 
Multiple Ascending Dose 
Max 
Maximum 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
MCV4 
Tetravalent Meningococcal Conjugate Vaccine 
MD 
Multiple-Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
N/A 
Not Applicable 
NAb 
Neutralizing Antibodies 
NCI 
National Cancer Institute 
PD 
Pharmacodynamic(s) 
PDS 
Pharmacodynamic Set 
PK 
Pharmacokinetic(s)  


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PKS 
Pharmacokinetic Set 
PT 
Preferred Term 
Q1 
1st Quartile 
Q3 
3rd Quartile 
QC 
Quality Control 
QTcF 
QT interval corrected for heart rate using Fredericia’s formula 
QW 
Once Weekly 
RBC 
Red Blood Cell 
RNA 
Ribonucleic Acid 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Single Dose 
STD 
Standard Deviation 
SGPT 
Serum Glutamic-pyruvic Transaminase 
SGOT 
Serum Glutamic-oxaloacetic Transaminase 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
SS 
Safety Set 
t½ 
Terminal Elimination Half-life  
TBD 
To Be Determined 
TEAE 
Treatment-emergent Adverse Event 
TERAE 
Related Treatment-emergent Adverse Event 
TESAE 
Treatment-emergent Serious Adverse Event 
TFL 
Table, Figure and Listing 
tmax 
Time to Maximum Concentration  
ULN 
Upper Limit of Normal 


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Vd/F 
Apparent Volume of Distribution  
WBC 
White Blood Cell 
WHO 
World Health Organization 


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Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies which will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and is responsible for the production and quality 
control of all tables, figures and listings. 
 
Timings of Analyses 
The primary analysis of safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD) and 
immunogenicity is planned after all participants complete the final study visit or terminate early from the 
study. The immunogenicity analysis will summarize the presence of confirmed positive antidrug antibodies 
(ADAs). Additionally, following confirmation of positive ADAs, samples will be assessed for ADA titer and 
presence of neutralizing antibodies (if possible). 
An interim analysis of all available safety and toleratbility data will be performed by Alexion when all 
participants in Cohort 6 reach Day 15. This analysis will be used to support regulatory activity which is 
outside the scope of this SAP and will not be performed by Syneos Health. 
An interim analysis, of all available PK/PD data, will be performed when all participants in Cohorts 4 and 5 
reach Day 29. This data will be used to project the exposure and duration of properdin and Complement 
Alternative Pathway (CAP) activity inhibition (not to exceed 70 days) at the highest single dose planned in 
the study (Cohort 7) and the highest multiple dose in the study (Cohort 10). Doses higher than 2250 mg (in 
Cohort 7) and an increase in total number of doses or change in dosing interval (in Cohort 10) will require 
SRC review and regulatory agency and EC approval prior to implementing a substantial amendment to the 
protocol. Further assessments of available data may be performed to inform Phase 2 study design in 
patients. The interim analysis is outside the scope of this SAP and will not be performed by Syneos Health. 
A safety review committee (SRC), consisting of the Investigator, Safety Physician, 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. A further description of the SRC analyses can be found in the SRC charter Version 1.0 dated 31-
Mar-2021.  


Statistical Analysis Plan for Interventional Studies 
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Study Objectives 
Objective 
Endpoints 
Primary 
To assess the safety and tolerability of ALXN1820 
subcutaneous (SC) and ALXN1820 intravenous 
(IV) 
Safety assessed by incidence of treatment-
emergent adverse events (TEAEs) and serious 
adverse events (SAEs), physical examination, vital 
sign measurements, clinical laboratory, and 
electrocardiogram results 
Secondary 
To assess the single- and multiple-dose PK of 
ALXN1820 SC and single-dose PK of ALXN1820 
IV 
Serum ALXN1820 single- and multiple-dose PK 
profiles and PK parameters 
 
To explore the PD effects of ALXN1820 SC and 
ALXN1820 IV 
Change in serum concentrations of total and free 
properdin over time. 
Change in CAP activity using the Wieslab AP 
assay. 
To assess the immunogenicity of ALXN1820 SC 
and ALXN1820 IV 
Incidence of ADAs to ALXN1820 
To estimate the absolute bioavailability of 
ALXN1820 SC 
ALXN1820 PK parameters (AUC) SC versus IV will 
be compared 
To compare safety, tolerability, PK, PD, and 
immunogenicity of ALXN1820 SC between 
Japanese and non-Japanese healthy participants  
Quantitative assessment of safety, PK, PD 
parameters, and immunogenicity (ADA) between 
healthy non-Japanese participants and participants 
of Japanese descent 
Abbreviations: ADA = antidrug antibody; AP = alternative pathway; AUC = area under the concentration-time curve; 
CAP = complement alternative pathway; IV = intravenous; PD = pharmacodynamics(s); PK = pharmacokinetic(s); 
SAE = serious adverse event; SC = subcutaneous; TEAE = treatment-emergent adverse 
event. 


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Study Details/Design 
 
Brief Description 
This is a Phase 1, randomized, double-blind, placebo-controlled single and multiple ascending dose study 
designed to evaluate the safety, tolerability, PK, PD, and immunogenicity of ALXN1820 administered SC 
(ALXN1820 SC) and IV (ALXN1820 IV). ALXN1820 SC will be evaluated in single and multiple ascending 
doses while ALXN1820 IV will be evaluated in a single dose only. A total of 80 healthy adult participants 
(60 on ALXN1820, 20 on placebo) will be enrolled in up to 10 cohorts. All participants within each cohort 
will be recruited at a single site. 
 
Eight participants will be randomly assigned in a 3:1 ratio to each of 10 cohorts to receive either a single or 
multiple doses of ALXN1820 SC, a single dose of ALXN1820 IV (n = 6 per cohort), or a single or multiple 
doses of placebo (n = 2 per cohort). The dosing cohorts are presented in Table 1. 
 
 
Table 1: ALXN1820-HV-101 Dosing Cohorts 
 
 
a Dose in Cohort 7 to be determined based on the safety data up to Cohort 6 and interim PK/PD modeling with data 
up to Cohort 5. Dose in Cohort 10 to be determined based on safety data up to cohort 8 and interim PK/PD modeling 
with data up to Cohort 5.  
Abbreviations: IV = intravenous; N = number of participants; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
QW = once weekly; SC = subcutaneous; TBD = to be determined.  
 
If it is seen during the interim PK/PD analysis that Cohort 6 (ALXN1820 1200 mg dose) suppresses 
properdin and CAP activity for approximately 68 days, it may be decided not to initiate Cohort 7. 


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The first two participants randomized to each cohort will be dosed as a sentinel pair with at least 1 
participant on active treatment (either 1 participant on active treatment and 1 participant on placebo, or 2 
participants on active treatment). This dosing strategy is justified given the large safety margin 
(approximately 20-fold at the highest planned dose) and the experience with properdin inhibition in healthy 
participants at Alexion. At the discretion of the Investigator, up to 3 more participants will be dosed 48 hours 
after dosing of the sentinel pair, followed by dosing of the remaining participants in the cohort no earlier 
than the 4th day, as long as no suspension/stopping criteria have been met. At no time will more than 4 
participants per cohort be dosed on a given day. The allowance for a maximum of 4 participants/day/cohort 
is intended to provide flexibility should a 4th participant need to be added (e.g., if replacement of a participant 
is required). The intention for this dosing strategy is to ensure a limited number of healthy participants will 
receive a dose and regimen that have not been previously tested. The limit of ≤ 4 participants/day/cohort 
does not apply to the dose and regimens tested previously. 
The timing of dosing cohorts is presented in Figure 1.  
Figure 1: ALXN1820-HV-101 Schematic 
 
 
Note: black arrow(s) indicate dose(s) given; red arrow indicates decision for dose escalation. 
Abbreviations: A = active (ALXN1820); D = day; IR = Investigator review; IV = intravenous; MAD = multiple 
ascending dose; N = number of participants; P = placebo; PD = pharmacodynamics; PK = pharmacokinetics; QW = 
once weekly; SAD = single ascending dose; SC = subcutaneous; SRC = Safety Review Committee; TBD = to be 
determined. 
 
Participant Selection 
Inclusion and exclusion criteria will be confirmed at Screening. 


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Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol 
waivers or exemptions, is not permitted. 
Refer to Section 5 of the Protocol for a complete list of requirements for inclusion and exclusion of 
participants. 
 
Determination of Sample Size 
The sample size is based on PK considerations. A sample size of up to 80 participants (8 participants per 
cohort) will be enrolled. 
 
Treatment Assignment and Blinding 
• 
This is a double-blind study where, in order to minimize selection bias in treatment assignment, 
each participant will be randomly assigned in a 3:1 ratio to active treatment or placebo. 
• 
Eligible participants who meet all inclusion and no exclusion criteria included in the study will be 
assigned unique study participant numbers for enrollment and randomization. 
• 
The participants, on site medical/nursing staff at the study center, Syneos health biostatistics and 
the Sponsor will be blinded to study drug assignment throughout the study. The pharmacy staff 
preparing the SC/IV doses will not be blinded, nor will the study drug administrator(s). 
• 
A masking technique will be used at the time of study drug administration due to the appearance 
of the placebo not matching that of the active study drug. 
 
Administration of Study Medication 
The study drug composition and doses to be administered in this study are presented in Table 2. Placebo 
will be commercially available normal saline for SC administration, and 5% dextrose or glucose for IV 
administration. Placebo will be sourced from the site. 
 
Table 2: Details of Study Medication Administration 
 


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Study Procedures and Flowchart 
Refer to Section 1.3 of the Protocol for the Schedule of Activities and refer to Section 4.1 for the timing 
and dependencies of the dosing cohorts. 
 
 


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Endpoints   
 
Primary Endpoint 
The primary endpoint for the study is to assess the safety and tolerability of ALXN1820 SC and ALXN1820 
IV. Safety is assessed by incidence of treatment-emergent adverse events (TEAEs) and serious adverse 
events (SAEs), physical examination, vital sign measurements, clinical laboratory, and electrocardiogram 
results. 
 
Secondary Endpoints 
• 
Serum ALXN1820 single- and multiple-dose PK profiles and PK parameters; 
• 
Change in serum concentrations of total and free properdin over time; 
• 
Change in CAP activity using the Wieslab AP assay; 
• 
Incidence of ADAs to ALXN1820; 
• 
ALXN1820 PK parameters (AUC) SC versus IV will be compared to estimate the absolute 
bioavailability of ALXN1820 SC; 
• 
Quantitative assessment of safety, PK, PD parameters, and immunogenicity (ADA) between 
healthy non-Japanese participants and participants of Japanese descent. 
 


Statistical Analysis Plan for Interventional Studies 
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Analysis Sets 
 
Enrolled Set 
The Enrolled Set will include all participants who agree to participate in the study following completion of 
the informed consent process and who satisfy the inclusion/exclusion criteria and are randomized. Unless 
specified otherwise, this set will be used for participant listings and summaries of participant disposition.  
 
Safety Set  
The Safety Set (SS) will include all participants who receive at least 1 dose of study drug. Participants will 
be analyzed according to treatment received. The SS will be used for all analyses of safety endpoints.  
 
Pharmacokinetic Set  
The Pharmacokinetic Set (PKS) will include all participants who receive at least 1 dose of study drug and 
have at least 1 post-dose PK concentration measured. Serum concentrations will be summarized for all 
participants in the PKS. The exclusions from summary statistics for serum concentrations and/or PK 
parameters will be defined based on review of protocol deviations (if any) prior to database lock by PK 
scientist and study statistician at the discretion of the sponsor. Pharmacokinetic analyses will be performed 
using the PKS. 
 
Pharmacodynamic Set 
The Pharmacodynamic Set (PDS) will include all participants who receive at least 1 dose of study drug and 
have evaluable properdin concentration, CAP or Complement Classical Pathway (CCP) activity data. 
Pharmacodynamic analyses will be performed using the PDS. 
 
Immunogenicity Set 
The Immunogenicity Set (IGS) will include all participants who have a predose and at least 1 postdose ADA 
sample collected. Immunogenicity analyses will be performed using the IGS. 
 
 


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General Aspects for Statistical Analysis 
 
General Methods 
• 
In general, descriptive statistics for continuous variables will include the number of non-missing values 
(n), arithmetic mean, 95% confidence interval (CI) of the mean, standard deviation (STD), 1st quartile 
(Q1), median, 3rd quartile (Q3), minimum, maximum, and interquartile range (IQR). Categorical 
variables will be summarized using percentages and frequency counts. Descriptive statistics and 
percentages and frequency counts will be summarized by cohort and study intervention within each 
cohort, where appropriate. 
• 
For the summary statistics of continuous variables, unless specified otherwise, the minimum and 
maximum will be presented to the same number of decimal places as the raw data, mean, median, 
Q1 and Q3. The IQR will be presented to one more decimal place than the raw data and the STD will 
be presented to two more decimal places than the raw data. 
• 
All statistical analyses will be conducted using SAS® for Windows® Version 9.4 or higher; 
• 
All relevant participant data will be included in listings. All participants entered into the database will 
be included in participant data listings. 
In general, the tables will include all cohorts and study intervention within each cohort and a total column 
as follows (see table shells for further details): 
• 
Cohort 1: ALXN1820 12.5 mg SC  
• 
Cohort 2: ALXN1820 50 mg SC  
• 
Cohort 3: ALXN1820 150 mg SC  
• 
Cohort 4: ALXN1820 450 mg SC  
• 
Cohort 5: ALXN1820 450 mg IV  
• 
Cohort 6: ALXN1820 1200 mg SC  
• 
Cohort 7: ALXN1820 TBD (≤ 2250 mg SC)  
• 
Cohort 8: ALXN1820 150 mg SC QW x 5  
• 
Cohort 9: ALXN1820 150 mg SC QW x 5 Japanese Descent 
• 
Cohort 10: ALXN1820 TBD SC QW x 3  
• 
All Cohorts Placebo 
• 
All Cohorts ALXN180 Total 
 
 
Key Definitions 
End of Study (EOS)  
The EOS for each participant is defined as the date the participant completes the last visit or date of 
discontinuation.  EOS for each individual participant is anticipated to be Day 127 and Day 155 for single 
ascending dose (SAD) and multiple ascending dose (MAD) cohorts, respectively, or the time point at 
which complement activity has normalized, if later than Day 127 or Day 155. 
 
 


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Trial day 
If the event date ≥ date of first dose of investigational product (IP), trial day = event date – date of first 
dose of IP + 1. 
If the event date < date of first dose of IP, trial day = event date – date of first dose of IP. 
 
Nominal Time 
Nominal time is the scheduled measurement time relative to time 0. Time 0 is the time of study drug dosing 
on Day 1.  
 
Baseline Value 
Baseline is defined as the last non-missing assessment (including repeated and unscheduled 
assessments) prior to treatment on Day 1, unless otherwise specified.  
 
Change from Baseline (CFB) 
CFB = Post-baseline value – Value at baseline 
 
Missing Data 
For participants who are withdrawn from the study prior to the end of the study, all data collected up to the 
point of discontinuation will be used for analysis. There will be no imputation for missing data, unless 
otherwise specified.  
 
Visit Windows 
If there are multiple planned assessments for any study procedure at a given time point the latest non-
missing value will be used for summarization, unless specified otherwise. Unscheduled assessments will 
be listed and will be used to flag baseline visit if this is the last non-missing assessment before the first 
dose of study drug, but unscheduled assessments will not be included in the summarization. 
 
Pooling of Centers 
Not Applicable. 
 
Subgroups 
Not Applicable. 


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Participant Disposition, Demographic, Other Baseline Characteristics 
and Medication 
 
Participant Disposition and Withdrawals 
Listings of treatment assignments, including the participant’s identification and date of randomization will 
be presented. 
The following frequencies (number and percent) will be displayed for all screened participants: participants 
randomized, screen failures with reasons and COVID-19 related reasons for screen failure.  
 
The analysis sets will be summarized with counts and percentages by cohort and study intervention within 
each cohort and overall. This table will include the following: number of participants in the Enrolled Set, 
number of participants in the Safety Set, reasons for exclusion from the Safety Set, number of participants 
in the PK/PD sets, reasons for exclusion from the PK/PD sets, number of participants in the Immunogenicity 
Set and reasons for exclusion from the Immunogenicity Set. 
 
The frequencies, number and percent, will be displayed for all participants in the Enrolled Set: participants 
who received treatment for each cohort, participants who completed the study, participants who 
discontinued early, participants who discontinued due to COVID-19 and study duration in days. The 
denominators will be the number of enrolled participants.  
The number and percent of participants who discontinued early will also be presented by reason for early 
discontinuation, also for all participants combined. The denominators will be the number of participants who 
received the treatments. 
Completion/discontinuation status, inclusion/exclusion criteria definitions and inclusion/exclusion criteria 
violations will be listed by participant.  
A listing of participants excluded from the analysis sets will also be generated. 
 
Protocol Deviations 
Protocol deviation management at Syneos Health is detailed in Protocol Deviation and Non-compliance 
Management (3101.W02). For details on the process for defining analysis datasets refer to (Blind) Data 
Review and Definition of Analysis Sets SOP (3911). 
All protocol deviations recorded in Clinical Trial Management System (CTMS) will be listed. The Protocol 
deviation criteria are graded as not important or important. Important protocol deviations and important 
protocol deviations related to COVID-19 will be summarized by the number and percentage of participants 
for the Safety Set.  
 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including sex, female child-bearing potential, race, ethnicity, 
Japanese Descent, age, height, body weight, and body mass index (BMI) will be summarized on the Safety 
Set using standard descriptive statistics. No formal statistical comparisons between populations will be 
performed. Demographics and informed consent data will be listed for all participants in the Enrolled Set.  
Height (in cm) = height (in inches) * 2.54 


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Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = Weight(kg)/[Height(m)2] 
 
Medical History and Concomitant Diseases 
Medical history will be coded using MedDRA version 23.1 and summarized for the Safety Set, presenting 
the number and percentages of participants within each preferred term (PT) grouped by the system organ 
class (SOC). A participant with multiple occurrences of an event in a PT is counted only once. Medical 
history will be listed by participant.  
 
Medication 
The WHO Drug Dictionary, WhoDrugGlobalB3 Sep 2020, will be used to classify prior and concomitant 
medications by therapeutic class and drug name.  
Prior medication is defined as any medication taken before the date of the first dose of study treatment. 
Concomitant medication is defined as any medication taken on or after the date of the first dose of study 
treatment.  
The use of prior and concomitant medications will be summarized by the number and percentage of 
participants for the Safety Set. If a participant took a specific medication multiple times or took multiple 
medications within a specific therapeutic class, that participant would be counted only once for the coded 
drug name or therapeutic class. 
Tetravalent Meningococcal Conjugate Vaccine (MCV4) and Meningococcal Serogroup B immunization 
results will be summarized for the Safety Set, presenting the number and percentages of participants who 
received the MCV4 and Meningococcal Serogroup B immunizations by timing (i.e. prior to consent or after 
consent). MCV4 and Meningococcal Serogroup B immunization results will be listed by participant. 
 
Extent of Exposure 
Exposure data will be summarized by total dose administered (mg), total volume administered (mL) and 
the number of interruptions (SC Infusion/IV) by cohort. Exposure will be listed by participant. 
 
Treatment Compliance  
Compliance of IP (%) intake will be calculated as follows: 
• 
(Total dose (mg) that the participant actually received and took / total expected dose (mg) that the 
participant was meant to receive) x 100 
 


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Pharmacokinetics 
Pharmacokinetic analyses will be performed using the PK Set and will be reported by cohort. 
PK parameters will be calculated using noncompartmental methods with Phoenix® WinNonlin® (Certara 
USA Inc., Princeton, New Jersey) Version 8.0 or higher. Calculations of individual PK parameters will be 
based on individual serum concentration data from participants who receive ALXN1820 SC or ALXN1820 
IV with actual sampling dates and times. 
 
PK/PD Sampling Schedule  
Whole blood samples for PK analysis and pharmacodynamic (PD)/ biomarkers will be collected at various 
different timepoints for different cohorts. The timing of sampling may be altered during the course of the 
study based on newly available data to ensure appropriate monitoring.  
 
Serum PK Endpoint 
The following PK parameters will be derived from the serum concentrations of ALXN1820: 
For the single dose cohorts 1-7, PK parameters will be derived on Day 1. 
For the multiple dose cohort 8, PK parameters will be derived on Day 1 and 29. 
For the multiple dose cohorts 8 and 9, PK parameters will also be derived on Day 8, 15 and 22 (when 
possible using limited sampling schedule up to 24h*). 
For the multiple dose cohort 10, PK parameters will be derived on Day 1, 8 (when possible using limited 
sampling schedule up to 24h*) and 15. 
 * Only selected PK parameters might be derived due to limited sampling up to 24 h such as Cmax, tmax, 
and AUC0-24 etc. 
Refer to Section 1.3 of the Protocol for the full sample schedule. 
Parameters 
Dosing 
Definition 
Cmax  
SD, MD 
Maximum observed serum concentration 
tmax  
SD, MD 
Time to maximum observed serum concentration 
AUCt  
SD, MD 
Area under the serum concentration versus time curve from time 0 to the 
last quantifiable concentration 
AUCtau 
MD 
Area under the concentration-time curve during the dosing interval 
AUC0-∞ 
SD, MD 
Area under the concentration-time curve from time 0 (dosing) to time 
infinity 
t½ 
SD, MD 
Terminal elimination half-life 
λz 
SD, MD 
Terminal-phase elimination rate constant 
CL or CL/F 
SD, MD 
Total body clearance or apparent clearance 
Vd or Vd/F 
SD, MD 
Volume of distribution or apparent volume of distribution 
F 
SD 
Absolute bioavailability 
Rac  
MD 
Accumulation Ratio 
Abbreviations: MD = Multiple-dose; SD = Single dose 


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Note: tau is the dosing interval for steady-state data, i.e., the time between doses (tau = 1 week). 
The absolute bioavailability for the ALXN1820 SC cohorts will be defined by the ratio of the geometric 
means for the AUC0-∞ parameter for the ALXN1820 SC cohort over the ALXN1820 IV cohort. For the 
absolute bioavailability estimates, a 95% CI for each of the ratio of the geometric means will be provided. 
The primary PK parameters will be summarized by overall treatment and the sub treatment category ADA 
status (at least one positive/negative). Boxplots will present PK levels by ADA status and by healthy non-
Japanese participants and participants of Japanese descent. Some PK parameters may not be calculated 
for all or some subjects, at the discretion of the pharmacokineticist, 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 report. 
 
Presentation of Concentration Data 
 
Handling of Missing Data 
Missing concentration data for all participants who are administered scheduled study treatments will be 
considered as non-informative missing and will not be imputed. No concentration estimates will be provided 
for missing sample values. 
For the derivation of AUC and for the individual serum concentration versus time curves, the following rules 
will apply: 
• 
Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose Day 1 
samples will be treated as zero; 
• 
The sampling time of pre-dose samples relative to dosing will also be treated as zero; 
• 
BLQ’s between two quantifiable samples will be set to missing; 
• 
The first BLQ after the last measurable sample will be set to missing; any subsequent BLQ’s will 
be set to zero.  
For serum concentration summary, the following rules will apply: 
• 
All BLQ values will be set to zero; 
• 
No further imputation will be applied to any missing values. 
 
Listing and Presentation of Individual PK Data 
The actual and nominal sampling times of PK blood sample collection will be listed for each participant and 
will include the deviation in time from the protocol scheduled time (i.e., nominal time), if applicable. 
All measured concentrations will be presented in original precisions (i.e., significant figures) and units as 
reported by Bioanalytical lab – e.g. ng/mL. 
Serum concentrations and time deviation data will be presented in a data listing by participant. 


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Summary of PK Concentrations by Matrix  
Serum concentration data will be summarized separately by time point for each cohort/actual treatment, 
using the following descriptive statistics: number of participants, arithmetic mean, STD, CV, geometric 
mean, geometric CV, median, minimum, and maximum.  
Mean (STD) serum concentration versus scheduled time profiles will be presented in figures on both linear 
and semilogarithmic scales. Individual serum concentration versus actual time profiles will be presented 
similarly. 
 
PK Parameters Derivation 
• 
The apparent Cmax and the corresponding tmax will be read directly from the concentration-time plot 
(observed data). 
• 
AUCt will be calculated using the log-linear trapezoidal interpolation rule for extravascular model. 
• 
The terminal elimination rate constant (λz) will be determined by log linear regression obtained on 
at least the 3 last quantifiable concentrations and will not include Cmax; t1/2 is calculated by the 
program as ln2/λz; 
• 
The AUC∞ will be calculated by the program as AUC∞ = AUCt + AUCextrap where last is the sampling 
time point of the last measurable concentration (tlast). AUCextrap is calculated by the program as: 
Clast/λz, where Clast is the observed concentration at time tlast and λz is the elimination rate constant 
during the apparent terminal elimination phase; AUC∞ will only be presented for participants with a 
reliable λz; 
• 
CL will be calculated by program as (dose/AUC∞); 
• 
Vd will be calculated by the program as (dose/AUC∞)/λz.  
The following PK acceptance criteria will be applied to assess the reliability of elimination parameters: 
• 
Number of points to calculate λz is greater than or equal to 3 excluding Cmax point; 
• 
The adjusted square of the correlation coefficient or coefficient of determination (Rsquare adjusted) 
for the goodness of fit of the regression line through the data points must be ≥ 0.80; 
• 
AUCextrap ≤20%. 
Unreliable PK parameters will be listed but flagged and excluded from summary. 
 
PK Parameters Summarization 
Pharmacokinetic parameters derived from serum concentrations will be presented in data listings and 
summarized separately by cohort/actual treatment using the following descriptive statistics: number of 
participants, arithmetic mean, STD, arithmetic CV, geometric mean, geometric CV, median, minimum, and 
maximum. 


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Planned Statistical Models for PK Parameters and Concentrations 
The primary PK analysis will be based on the PK Set. 
For the cohort 4 versus cohort 5 evaluation of the absolute bioavailability, the PK parameters (Cmax, AUCt, 
and AUC∞) will be evaluated using an ANOVA statistical model with cohort, treatment, and sequence as 
the fixed effects, and participant-participant (sequence) as a random effect, using the natural logarithms of 
the data. Confidence intervals (CI, 90%) will be constructed for the least squares geometric mean ratio 
(GMR) for the cohort 4 versus cohort 5 for all 3 parameters using the natural log-transformed data. The 
GMRs and associated 90% confidence limits will be exponentiated back to the original scale.  
The within-participant CV for the Cmax, AUCt, and AUC∞ will be estimated using the mean squared error 
from the ANOVA.  
In addition, the geometric means and the associated 95% CIs of Cmax, AUCt, and AUC∞ will be reported for 
each treatment. 
The evaluation of relative bioavailability, will be done for cohort 9 versus cohort 8 (for a comparison of non-
Japanese versus Japanese descent). 
All secondary analyses will be based on the PK Set. 
Dose-proportionality will be assessed across all single dose (SD) cohorts (Cohort 1 (12.5 mg), Cohort 2 (50 
mg), Cohort 3 (150 mg), Cohort 4 (450 mg), Cohort 6 (1200 mg) and Cohort 7 (≤ 2250 mg) ALXN1820) 
graphically and by using a power model (Smith, 2000; Newlands, 2006; EMA, 2010).  
The following dose-normalized PK parameters will be assessed for dose proportionality: Cmax_n, AUCt_n 
and AUC∞_n. The log (PK parameters) will be included as a response variable and log (dose) will be 
included as a fixed effect in the power model. 
The form of the model is as follows:  
PK Parameter = eα × Doseβ × eϵ, where Dose ≥ 0, and eϵ represents the associated error. Thus, perfect 
dose proportionality is met when β=1 (ignoring error). This becomes a linear relationship following a natural-
log transformation, to which a linear regression will be fit by ordinary least squares (OLS):  
ln(PK Parameter) = α + β × ln(Dose) + ϵ, where Dose > 0, and ϵ represents the associated error.  
 
The estimate of β together with a 90%CI will be provided (for each PK parameter model), and this will be 
used to quantify dose proportionality. According to Hummel et al. (2009), the following criterion may be 
used for exploratory dose proportionality evaluations: If the (two-sided) 90% CI for β is wholly contained 
within the interval, [1+ln(0.5)/ln(ρ), 1+ln(2)/ln(ρ)], then dose proportionality is suggested across the 
investigated dose range. Here, ρ is defined as the ratio of the highest to lowest dose. This interval criterion 
will be reported along with the corresponding 90% CI estimate for β (presented to three decimal places). 
log(PK Parameter) = mu + beta*log(Dose) 
*where beta = 1 indicates perfect dose proportionality. Estimation of beta, along with its 90% CI, will be 
provided. 
 


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Deviation from Analyses Planned in Protocol 
Not applicable. 
 
 
 


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Pharmacodynamics 
Samples collected for the assessment of ALXN1820 concentration will be retained and may be analyzed 
in the future.  
Samples for measurement of serum total and free properdin concentrations, CAP activity, CCP activity, 
CLP (complement lectin pathway) activity and potentially other measures of complement activation as 
specified in Section 1.3 of the Protocol will be used for the PD analysis described in this SAP/section. 
Serum samples will be collected as defined in Section 1.3 of the Protocol.  
 
Endpoint(s) 
• 
Change in serum concentrations of total and free properdin over time; 
• 
Change in CAP activity using the Wieslab AP assay; 
• 
Subgroup analysis of the PD parameters between healthy non-Japanese participants and 
participants of Japanese descent. 
 
 
Analysis of the Endpoint 
Pharmacodynamic analyses will be performed using the PD Set. 
Missing concentration data for all participants who are administered scheduled study treatments will be 
considered as non-informative missing and will not be imputed. No concentration estimates will be provided 
for missing sample values. 
For the serum concentrations, actual values, changes from baseline and percentages change from baseline 
will be summarized by time point for each treatment using the following descriptive statistics: number of 
participants, arithmetic mean, STD, CV, geometric mean, geometric CV, median, minimum, and maximum. 
Mean (STD) serum concentration (change from baseline and percentage change from baseline) versus 
scheduled time profiles will be presented in figures. 
Individual serum concentration (change from baseline and percentage change from baseline) versus 
scheduled time profiles will be presented similarly. 
Serum concentrations, change from baseline and percentage change from baseline will be presented in a 
data listing by participant. 
 
 


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Safety 
The population used for safety analyses will be the Safety Set (SS).  
Safety analyses will include an analysis of all adverse events (AEs), Electrocardiograms (ECGs), clinical 
laboratory data, physical examinations, vital sign measurements and injection/infusion site evaluation 
measurements using descriptive statistics.  
No inferential statistical analyses are planned on the safety parameters of this study.  
 
Adverse Events  
AEs for all participants in the Safety Set will be included in the AE summaries.  
Adverse events will be summarized by SOC and PT for each cohort, study intervention within each cohort 
and overall, based on the MedDRA dictionary version 23.1.  
If the relationship to study drug is missing for TEAEs, then the relationship will be counted as related to 
study product for the summary tables. Missing severity for TEAEs will be counted as Grade 3.  
Treatment-emergent AEs are defined as AEs which commence on or after first study drug administration, 
or those that first occur before first study drug administration but worsen in frequency or severity after first 
study drug administration. 
If the start date of an AE is partially or completely missing, the date will be compared as far as possible with 
the date of the start of administration of study drug. The AE will be assumed to be treatment-emergent if it 
cannot be definitively shown that the AE did not occur or increase in severity during the treatment period 
(worst case approach). The following general rules will be used: 
• 
If the start day is missing but the start month and year are complete, an AE will not be considered 
as being treatment-emergent only if the start month/year is before the month/year of the first 
study drug administration; 
• 
If the start day and month are missing but the start year is complete, an AE will not be considered 
as being treatment-emergent only if the start year is before the year of the first Study Drug 
administration; 
• 
If the start date is completely missing, an AE will be considered treatment-emergent unless the 
stop date is before the first study drug administration. 
Time since first/last dose will be calculated as the difference between the event start date/time and the 
date/time of the first/last dose prior to start. Time since first/last dose will be expressed in days, hours and 
minutes. If time is missing, duration will be calculated as the difference between the start date and dosing 
date plus 1 and expressed in days. Time since first/last dose and duration will only be calculated when both 
dates are complete. 
Duration will be calculated for AEs that resolve as the difference between the resolution date and onset 
date plus 1 and expressed in days. Should an AE have a short duration (i.e. < 24 hours), the duration will 
be calculated as the difference between the resolution time and the onset time. 


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The summary tables will include the number of participants and the number of events. Percentages will be 
based on the number of participants. Repeat AE summary tables will be created to display percentages 
based on the number of events. For summaries by SOC and PT, a participant will be counted once at the 
SOC level and once at each PT within the SOC level.  
For summaries by SOC, PT and maximum Common Terminology Criteria for Adverse Events (CTCAE) 
grading, a participant will be counted once at the highest CTCAE grading for which the event occurred at 
the SOC level and the highest CTCAE grading for each unique PT within that SOC level. Therefore, 
participants may only contribute once to each PT and once to each SOC level.  
The summaries presenting frequency of AEs by SOC and PT will be ordered by overall descending 
frequency of SOC and then, within a SOC, by overall descending frequency of PT.  
The following tables will be provided: 
• 
An overall summary of the number and percentage of participants reporting TEAEs, serious 
TEAEs (TESAEs), TEAEs leading to death, TEAEs leading to withdrawal of study drug, TESAEs 
leading to withdrawal of study drug, TEAEs by relationship, TESAEs by relationship and TEAEs 
by CTCAE grade; 
• 
TEAEs overall by system organ class and preferred term;  
• 
TEAEs by maximum CTCAE grading, overall and by system organ class and preferred term;  
• 
TEAEs by strongest relationship to study medication, overall and by system organ class and 
preferred term;  
• 
TEAEs overall by system organ class; 
• 
TEAEs overall by preferred term; 
• 
Related TEAEs (TERAEs), overall by preferred term;   
• 
TESAEs overall by system organ class and preferred term;  
• 
TESAEs by maximum CTCAE grading, overall and by system organ class and preferred term; 
• 
TESAEs by strongest relationship to study medication, overall and by system organ class and 
preferred term;  
Only TEAEs (or TESAEs, as applicable) will be included in the summary tables, however we will generate 
separate listings for treatment-emergent and non-treatment-emergent AEs. Additional listings will be 
provided for deaths, serious adverse events, AEs resulting in withdrawal from the study and AEs resulting 
is study drug withdrawal. 
 
Laboratory Evaluations 
Safety laboratory samples for hematology, chemistry, urinalysis and coagulation will be collected at various 
different timepoints for different cohorts.  


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Samples for pregnancy test, alcohol breath test, urine drug screen, FSH, HIV (types 1 and 2) screen, 
hepatitis B and C screen will collected. 
Refer to Section 1.3 of the Protocol for the schedule of activities indicating when the respective samples 
are taken for each cohort. 
The following parameters will be included: 
Hematology: Platelet count, Red blood cell (RBC) count, Hemoglobin, Hematocrit, RBC indices (MCV, 
MCH, %reticulocytes), White blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils). 
Clinical chemistry: Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), 
Alkaline phosphatase, Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT), Blood urea nitrogen (optional), Calcium, Creatinine, Creatine kinase, Hemoglobin A1C, 
Potassium, Sodium, Serum albumin, Total and direct bilirubin, Total protein, Urea. 
 
Urinalysis: Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick, Microscopic examination (if any leucocytes, more than a trace protein, nitrites, and 
blood [if not menstruating] are abnormal). 
Coagulation: Prothrombin time, partial thromboplastin time, international normalized ratio. 
Serology: Human immune deficiency virus (HIV)-1 and HIV-2 antibodies, hepatitis B surface antigen 
(HbsAg), anti-HBc + IgM (if IgG positive) and anti-hepatitis C virus with confirmation by hepatitis C virus 
Ribonucleic acid (RNA). 
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of childbearing 
potential), Follicle-stimulating hormone estradiol (as needed in women of non-childbearing potential only).  
 
Alcohol breath and urine drug screen: amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, 
methamphetamine, 
3,4-methylenedioxy-methamphetamine, 
methadone, 
and 
tetrahydrocannabinol [cannabinoids]. 
Other tests: Serum QuantiFERON®-TB test, Vaccine titer (meningococcal serogroups A, C, W135, and Y). 
Laboratory parameter values will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE).  
All summaries will be based on results in SI (standard international system of units) units and will be output 
in the order listed above.  
Toxicity grading following the NCI CTCAE grades version 5.0 will also be derived for laboratory variables 
where applicable (see list below). Note, where gradings require investigator/clinical input, this will not be 
considered and only the numeric criteria will be used for the assignments. If this results in the criteria for 
more than one grade being met, the highest (worst) CTCAE grade will be assigned. For creatinine only, the 
criteria based on the upper limit of normal (ULN) will be used (changes compared to the baseline value will 
not be used), e.g., CTCAE defines Grade 1 as > ULN - 1.5 x ULN or > 1 - 1.5 x baseline. Only the ULN – 
1.5 x ULN criterion will be used (and not the baseline criterion). 


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The following parameters are CTCAE gradable: 
• Hematology: Absolute neutrophil count (neutrophil), total leukocytes (Leukocytes), hemoglobin (only do 
the grading for Anemia, no grading for Hemoglobin increased), platelet count, Lymphocyte.  
• Coagulation: International normalized ratio.  
• Chemistry: Alanine aminotransferase albumin, alkaline phosphatase, aspartate aminotransferase, total 
bilirubin, creatinine, gamma-glutamyl transferase, glucose (only do the grading the Hypoglycemia, no 
grading for Hyperglycemia), creatine kinase. 
Actual values and changes from baseline (screening) in hematology, coagulation, clinical chemistry, and 
urinalysis will be summarized by treatment. 
Shift tables for hematology, clinical chemistry and coagulation from baseline CTCAE toxicity for each visit 
and to the maximum CTCAE grade on treatment for each parameter will be provided. Participants with both 
a non-missing baseline and at least one non-missing post-baseline grade will be included in the shift tables. 
Unscheduled data will be included in the worst case across all scheduled and unscheduled visits after the 
first dose of study treatment. This means that if there are CTCAE grades derived from both unscheduled 
and scheduled visits data per test per participant then the highest grade will be summarized.  
For non-CTCAE gradable tests, a shift table will be provided showing shifts relative to the normal ranges. 
This summary of normal range category changes illustrates the number and percentage of participants who 
fall into specified categories (Decrease to Low, Change to Normal or No Change, Increase to High) by 
comparing the baseline normal range category to the planned time normal range category and the worst-
case normal range category. The worst-case post-baseline row will be used to summarize the participants’ 
overall worst-case normal range category change. The determination of the worst-case takes into account 
both planned and unscheduled assessments. Only laboratory tests which cannot be graded per CTCAE v. 
5.0 specified criteria will be included.  
Participants with missing baseline value are to be assumed to have normal baseline value. Worst-case can 
be either High or Low. If a participant has a Decrease to Low and an Increase to High during the same time 
interval, then the participant is counted in both the ‘Decrease to Low’ and ‘Increase to High’ categories. If a 
participant was high at baseline and decreases to Low during the time interval, then the participant is 
counted in the ‘Decrease to Low’ category. Likewise, if a participant was Low at baseline and increases to 
High during the time interval, then the participant is counted in the ‘Increase to High’ category. Participants 
are only counted in the ‘Change to Normal or No Change’ category if they are: 
• 
Normal at baseline and have no normal range High and no normal range Low values during the 
time interval 
• 
High at baseline and do not change to Low during the time interval 
• 
Low at baseline and do not change to High during the time interval Shift tables by treatment will be 
produced for these laboratory parameters. These tables will summarize the number of participants 


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with each baseline grade relative to the reference ranges and changes to the worst highest grade 
assessed post-dose during the study. 
All events of ALT ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 ×ULN (> 35% direct bilirubin) which 
may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE. Optional outputs may be 
created if it is seen that ALXN1820 causes liver injury. For these optional outputs, liver function results will 
be presented in a summary table and eDISH (evaluation of drug-induced serious hepatotoxicity) plots. 
All laboratory results, as well as CTCAE grades will be included in data listings. Abnormal results for 
hematology, clinical chemistry, urinalysis and coagulation will be listed separately. Laboratory results for 
serology, pregnancy and FSH, urine drug screen, alcohol breath test, QuantiFERON Tuberculosis test and 
MC4 Vaccine Titer will be listed only. 
 
Vital Signs  
Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (bpm), respiratory rate 
(breaths per minute) and temperature (degree Celsius) will be measured at different timepoints as per the 
schedule of events (Section 1.3) in the Protocol. 
Actual values and changes from baseline in vital sign measurements will be summarized by treatment. 
Note temperature will be reported in centigrade. Any conversions required will be as follows: 
Temperature (in °C) = 5/9 (Temperature [in °F]-32). 
All vital signs will be provided in data listings. 
 
ECG 
The ECG parameters include heart rate, PR, RR, QRS, QT, and corrected QTcF intervals.  
Analysis of drug related QT/QTc interval changes relative to serum PK concentrations will be conducted on 
all dose regimens. The principles of this analysis follow the statistical methods described by Garnett et al. 
(Garnett, 2018). All ECG recordings will be in triplicate and compliant with the correct recording and manual 
adjudication of ECG in thorough QT/QTc studies. The ECG analyses will be based on adjudicated selected 
triplicates from each time point. 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.  The 
average of the triplicate ECG readings will be used to derive QT/QTc at all visits (i.e. both pre- and post-
baseline visits). An outlier analysis will be performed that will summarize the absolute count, 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 


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• 
QT, QTcF interval increases from baseline > 60 msec 
Actual values and change from baseline of these average ECGs will be summarized by treatment.  
All ECG parameters, including all single ECG measurements, but also the mean value and overall ECG 
evaluation will be provided in data listings. 
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 will be followed to resolution. The 24-hour Holter 
ECG recording results will be provided in data listings. 
 
If deemed necessary, a separate concentration-QT analysis may be performed by Alexion. The 
concentration-QT analysis is not within the scope of this SAP. 
 
Physical Examination 
A full physical examination will be performed at different timepoints as per the schedule of events (Section 
1.3) in the Protocol. 
A symptom-driven physical examination of relevant body systems may be performed at other times, at the 
Investigator’s discretion.  
Physical examination data will be listed. 
 
Injection or Infusion Site Evaluation 
Subcutaneous injection/infusion or IV infusion-site evaluations will be performed at the time points specified 
in the schedule of events (Section 1.3) in the Protocol. Injection/infusion site reactions will not be recorded 
as AEs unless deemed clinically significant. 
The severity (grade) of the injection/infusion site evaluation will be summarized by treatment and 
visit/timepoint. 
Injection/infusion site evaluation data will be listed. 
 


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Immunogenicity 
The population used for immunogenicity analyses will be the Immunogenicity Set (IGS). 
The immunogenicity analyses will include an analysis of ADAs using descriptive statistics. The results will 
summarize the difference between healthy non-Japanese participants and participants of Japanese 
descent. 
Whole blood samples will be screened for ADAs that bind to ALXN1820. If the screen is positive, the sample 
will be analyzed using a confirmatory ADA assay and the titer of confirmed positive samples will be reported.  
The actual date and time (24-hour clock time) of each sample will be recorded. Refer to Section 1.3 of the 
Protocol for the schedule of activities indicating when the ADA samples are taken for each cohort. 
ADA and Neutralizing Antibodies (NAb) data reporting:  
• 
Incidence, titer, duration, time to detection, pre-existing ADA; 
• 
PK concentration or parameter by immunogenicity response; 
• 
PD response by immunogenicity response; 
• 
Individual data listing or spaghetti plots with ADA category overlaid. 
For ADA categories and participants, summary of individual plots of PK, PD, ADA and NAb titer time course 
to better understand the clinical impact of immunogenicity at a subject level. 
 
 


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Interim Analyses 
Interim assessments will be performed as follows: 
• 
An assessment of all available PK/PD data will be performed when all participants in Cohorts 4 and 
5 reach Day 29. These data will be used to project the exposure and duration of properdin and 
CAP activity inhibition (not to exceed 70 days) at the highest single dose planned in the study 
(Cohort 7) and the highest multiple dose in the study (Cohort 10). 
• 
CAP activity will be continuously analyzed and will be used to estimate the time of CAP activity 
returning to baseline for each individual participant based on PK/PD modeling. 
The interim analysis is outside the scope of this SAP. 


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Changes from Analysis Planned in Protocol 
Not Applicable. 


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This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 38 of 39 
 
 
Reference List 
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. J 
Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Alexion Pharmaceuticals, Inc.; Protocol No.: ALXN1820-HV-101 
SAP Version: 2.0, 28 November 2022 
 
 
This document is confidential. 
SAP Version: SAP 2.0, 28-Nov-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 39 of 39 
 
 
Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
Developing Statistical Programs SOP (3907). 
Syneos Health Developing Statistical Programs SOP (3907), Conducting the Transfer of Biostatistical 
Deliverables SOP (3908) and the SAS Programming and Validation Plan describes the quality control 
procedures that are performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs produce the output by 
checking for their logic, efficiency and commenting and by review of the produced output.  
Syneos Health SOP Pharmacokinetic and Related Data Analysis (3913) describes the process for the 
interaction between the Biostatistics and Pharmacokinetics departments for the analysis of pharmacokinetic 
and pharmacodynamic data.  
 
 


ALXN1820-HV-101_Final_Version_SAP_2.0_28
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