Clinical trial NCT05565092
Conditions: Sickle Cell Disease (SCD)
Keywords: Sickle Cell Disease ALXN1820 SCD
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2023-02-22; Completion date: 2024-01-09
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to assess the safety and tolerability of ALXN1820 SC (subcutaneous) in participants with SCD (Sickle Cell Disease).

Detailed description:

Arms: arm 1: Participants will receive 300 milligrams (mg) once weekly (QW). arm 2: Participants will receive 600 mg once every 4 weeks (Q4W). arm 3: Participants will receive 300 mg once every 2 weeks (Q2W).
Interventions: intervention 1: ALXN1820
Intervention descriptions: intervention 1: ALXN1820 will be administered subcutaneously.

Protocol documents:
Prot_002.pdf: 
Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
TITLE PAGE 
Protocol Title: 
A Phase 2a, Randomized, Open-Label Study to Evaluate Multiple Dosing Regimens of 
Subcutaneous ALXN1820 in Adult Patients with Sickle Cell Disease 
Protocol Number: ALXN1820-SCD-201 
Amendment Number: 1.0 
Compound: ALXN1820 
Study Phase: Phase 2a 
Short Title:  
Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Study of ALXN1820 in Adult Patients 
with Sickle Cell Disease 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 
121 Seaport Boulevard 
Boston, MA 02210 
USA 
Regulatory Agency Identifying Number(s): 
NCT: 
Pending 
EudraCT: 
2022-001615-74 
Approval Date: 22 August 2022 
Sponsor Signatory: 
 
, Clinical Development Sciences 
Date 
Medical Monitor Name and Contact Information will be provided separately. 
Alexion Confidential
Page 1 of 93
23-Aug-2022 | 09:48:42 EDT
NCT #: NCT05565092


Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
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 International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Guidelines for Good 
Clinical Practice (GCP), 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  
_____________________________________ 
Primary Site Address of Investigator  
_______________ 
Date 
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 1.0 (22 August 2022) 
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 purpose of this global protocol amendment is to clarify the individual and study 
stopping rules as well as the inclusion/exclusion criteria. These and other changes are described 
in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Intervention Groups and Duration 
has been changed. The text indicated 
in bold font has been added:  
The end of study (EOS) for each 
individual patient is anticipated to be 
Day 211 (210 days) or the 
timepoint at which complement 
activity has returned to a normal 
range or 80% of baseline if later 
than Day 211. 
The EOS for each individual patient 
is anticipated to be Day 169 (168 
days) or the timepoint at which 
complement activity has returned 
to a normal range or 80% of 
baseline if later than Day 169. 
Included to further enhance safety 
measures.   
1.2 Schema 
Footnote a has been added to the 
schema. See text indicated in bold 
font below. 
a Follow-up Period may be longer 
than 18 weeks for those patients 
whose complement activity has not 
returned to the normal range or 
80% of baseline. 
Included to further enhance safety 
measures.   
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities, Table 6 
and Table 8 
Table caption has been changed. The 
text indicated in strikethrough has 
been deleted and the text indicated in 
bold has been added.  
Table 6: Schedule of Activities – 
Day 99 tThrough Day 211End of 
Follow-up Period, Cohorts 1 and 2 
Table 8: Schedule of Activities – 
Day 57 tThrough Day 169End of 
Follow-up Period for Multiple 
dDose Follow-up (Optional Cohort 
3) 
Updated as a result of the changes 
made to the Follow-up Period to 
enhance patient safety.    
1.3 Schedule of 
Activities, Table 6 
and Table 8 
Day 211 (Table 6) and Day 169 
(Table 8) column titles have been 
changed. Text indicated in 
strikethrough has been deleted. 
Day 211/EOS/ET/Unscheduled 
Day 169/EOS/ET/Unscheduled 
Updated as a result of the changes 
made to the Follow-up Period to 
enhance patient safety.    
1.3 Schedule of 
Activities, Table 6 
and Table 8 
Text in bold has been added. Added 
“Complement Activity Follow-up” 
column (with a time window of 
± 14 days) with the following 
footnote: 
If CAP activity has not returned to 
a normal range or 80% of the 
baseline level at the end of the 
Follow-up Period, patients may 
have additional Follow-up Visits 
every 12 weeks until CAP activity 
has been confirmed to either have 
returned to a normal range or 
80% of the baseline level. This visit 
may be completed at home.   
Included to further enhance safety 
measures.   
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Inclusion Criterion 7 has been 
changed. The text indicated in bold 
font has been added; text indicated in 
strikethrough has been deleted: 
Patients receiving hydroxyurea must 
have been on a stable dose for 
≥ 3 months prior to providing 
informed consent, with no 
anticipated need for dose adjustment 
during the study. For patients who 
previously used hydroxyurea but are 
not currently on hydroxyurea 
treatment (due to 
non-responsiveness, intolerance, or 
unwillingness to take 
hydroxyurea), hydroxyurea 
treatment must be stopped have 
been discontinued at least 30 days 
prior to providing informed consent. 
Included to define the conditions under 
which being “not currently on 
hydroxyurea treatment” is acceptable 
for study participation.  
5.2 Exclusion 
Criteria  
Added Exclusion Criterion 7. The 
text in bold font has been added:  
History of complement deficiency. 
Included to further enhance the safety 
of the participants allowed in the 
study.  
5.2 Exclusion 
Criteria  
Added Exclusion Criterion 8. The 
text in bold font has been added:  
History of N meningitidis, S 
pneumoniae, or H influenzae 
infection. 
Included to further enhance the safety 
of the participants allowed in the 
study.  
7.2 Stopping Criteria 
Section 7.2 has been changed. The 
text in bold font has been added and 
the text in strikethrough has been 
deleted: 
7.2 Stopping Criteria 
7.2.1. Individual Stopping Rules 
Participants should be considered for 
discontinuation from intervention if 
any of the following occur during the 
study: 
• Serious hypersensitivity reaction;
• Grade 3 or higher injection site
reactions;
• Severe uncontrolled infection;
Included individual and study stopping 
rules to further enhance safety 
measures.  
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Section # and Name 
Description of Change 
Brief Rationale 
• Serious N meningitidis, S
pneumoniae, or H influenzae
infections;
• Use of disallowed medication as
defined in Section 6.5.2;
• Pregnancy or planned pregnancy;
or
• Any AE, laboratory abnormality,
or intercurrent illness which, in
the judgment of the Investigator
or Alexion, presents a substantial
clinical risk to the patient with
continued study drug dosing.
7.2.2 Study Stopping Criteria 
Rules 
Please see Section 7.1 
The study may be terminated at 
the recommendation of the DMC, 
if the following occur and are 
deemed to be related to the study 
drug:  
•
Two or more meningococcal
infections;
• Two or more serious
(≥ Grade 3) pneumococcal
infections;
• Two or more serious
(≥ Grade 3) H influenzae
infections;
• One meningococcal,
pneumococcal, or H influenzae
infection resulting in a fatal
outcome.
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Section # and Name 
Description of Change 
Brief Rationale 
10.1.9 Study and Site 
Start and Closure 
Text indicated in strikethrough has 
been deleted and text indicated in 
bold has been added.  
A study site is considered closed 
when all participants have completed 
the EOS the last study visit or Early 
Discontinuation Visit, all data have 
been collected and entered into the 
electronic data capture system, all 
required documents and study 
supplies have been collected and 
reconciled, and a study-site closure 
visit has been performed. 
Removed reference to EOS Visit 
because the protocol no longer has a 
clearly demarked EOS Visit.  
10.10 
Protocol Amendment 
History 
New section added. 
For completeness. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been 
summarized. 
Abbreviations: AE = adverse event; CAP = complement alternative pathway; EOS = end of study; DMC = Data 
Monitoring Committee 
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................3 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
1.
PROTOCOL SUMMARY ..........................................................................................14 
1.1. 
Synopsis ......................................................................................................................14 
1.2. 
Schema ........................................................................................................................19 
1.3. 
Schedule of Activities (SoA) ......................................................................................19 
2.
INTRODUCTION ......................................................................................................34 
2.1. 
Study Rationale ...........................................................................................................34 
2.2. 
Background .................................................................................................................34 
2.2.1. 
Chemistry ....................................................................................................................34 
2.2.2. 
Nonclinical Pharmacology ..........................................................................................35 
2.2.3. 
Toxicology ..................................................................................................................35 
2.3. 
Benefit/Risk Assessment ............................................................................................35 
2.3.1. 
Risk Assessment .........................................................................................................35 
2.3.1.1. 
Neisseria meningitidis Infections ...............................................................................36 
2.3.1.2. 
Immunogenicity and Hypersensitivity ........................................................................36 
2.3.1.3. 
Coronavirus Disease 2019 ..........................................................................................37 
2.3.2. 
Benefit Assessment .....................................................................................................38 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................38 
3.
OBJECTIVES AND ENDPOINTS ............................................................................39 
4.
STUDY DESIGN .......................................................................................................40 
4.1. 
Overall Design ............................................................................................................40 
4.2. 
Scientific Rationale for Study Design ........................................................................41 
4.3. 
Justification for Dose ..................................................................................................42 
4.4. 
End of Study Definition ..............................................................................................43 
5.
STUDY POPULATION .............................................................................................44 
5.1. 
Inclusion Criteria ........................................................................................................44 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
5.2. 
Exclusion Criteria .......................................................................................................45 
5.3. 
Lifestyle Considerations .............................................................................................46 
5.4. 
Screen Failures ............................................................................................................46 
6.
STUDY INTERVENTION ........................................................................................47 
6.1. 
Study Intervention Administered ................................................................................47 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................47 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................48 
6.4. 
Study Intervention Compliance ..................................................................................48 
6.5. 
Concomitant Therapy .................................................................................................48 
6.5.1. 
Allowed Medicine and Therapy .................................................................................48 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................49 
6.6. 
Dose Modification ......................................................................................................49 
6.7. 
Intervention After the End of the Study .....................................................................49 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................50 
7.1. 
Discontinuation of Study Intervention ........................................................................50 
7.2. 
Stopping Criteria .........................................................................................................50 
7.2.1. 
Individual Stopping Rules ..........................................................................................50 
7.2.2. 
Study Stopping Rules .................................................................................................50 
7.3. 
Participant Discontinuation/Withdrawal From the Study ...........................................50 
7.4. 
Lost to Follow-Up .......................................................................................................51 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................52 
8.1. 
Efficacy Assessments .................................................................................................52 
8.1.1. 
Change in Complement Biomarkers ...........................................................................52 
8.1.2. 
Change in Biomarkers Related to VOC ......................................................................52 
8.1.3. 
Change in Hemoglobin ...............................................................................................53 
8.1.4. 
Markers of Hemolysis .................................................................................................53 
8.1.5. 
Assessment of VOC ....................................................................................................53 
8.2. 
Safety Assessments .....................................................................................................53 
8.2.1. 
Physical Examination .................................................................................................53 
8.2.2. 
Vital Signs ..................................................................................................................53 
8.2.3. 
Electrocardiograms .....................................................................................................54 
8.2.3.1. 
Safety Review of 12-lead Electrocardiograms ...........................................................54 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
8.2.4. 
Clinical Laboratory Assessments ...............................................................................54 
8.2.5. 
Clinical Safety Laboratory Assessments ....................................................................54 
8.2.5.1. 
Virus Serology ............................................................................................................54 
8.2.6. 
Pregnancy ...................................................................................................................55 
8.2.7. 
Injection Site Evaluation .............................................................................................55 
8.2.8. 
Injection-associated Reactions ....................................................................................55 
8.2.9. 
Vaccine and Antibiotic Prophylaxis ...........................................................................55 
8.2.10. 
Participant Safety Card ...............................................................................................56 
8.3. 
Adverse Events and Serious Adverse Events .............................................................56 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................56 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................56 
8.3.3. 
Follow-Up of AEs and SAEs ......................................................................................56 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................57 
8.4. 
Treatment of Overdose ...............................................................................................57 
8.5. 
Pharmacokinetics ........................................................................................................57 
8.6. 
Pharmacodynamics .....................................................................................................58 
8.7. 
Genetics ......................................................................................................................58 
8.8. 
Biomarkers ..................................................................................................................58 
8.9. 
Immunogenicity Assessments ....................................................................................59 
8.10. 
Health Economics Data and/or Medical Resource Utilization ...................................59 
8.11. 
Other Assessments and Procedures ............................................................................59 
9.
STATISTICAL CONSIDERATIONS .......................................................................60 
9.1. 
Statistical Hypotheses .................................................................................................60 
9.2. 
Sample Size Determination ........................................................................................60 
9.3. 
Populations for Analyses ............................................................................................60 
9.4. 
Statistical Analyses .....................................................................................................60 
9.4.1. 
Efficacy Analyses .......................................................................................................61 
9.4.1.1. 
Change in Complement Biomarkers ...........................................................................61 
9.4.1.2. 
Change in Hemoglobin ...............................................................................................61 
9.4.1.3. 
Time to Hemoglobin Response ..................................................................................61 
9.4.1.4. 
Markers of Hemolysis .................................................................................................61 
9.4.1.5. 
Exploratory Analysis of Change in Biomarkers Related to VOC ..............................61 
9.4.2. 
Exploratory Assessment of VOC ................................................................................61 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
9.4.3. 
Safety Analyses ..........................................................................................................62 
9.4.3.1. 
ECG Analysis .............................................................................................................62 
9.4.4. 
Other Analyses ............................................................................................................63 
9.4.4.1. 
Pharmacokinetic Analyses ..........................................................................................63 
9.4.4.2. 
Pharmacodynamic Analyses .......................................................................................63 
9.4.4.3. 
Immunogenicity Analysis ...........................................................................................63 
9.4.4.4. 
Exploratory Analysis ..................................................................................................63 
9.5. 
Interim Analyses .........................................................................................................63 
9.6. 
Data Monitoring Committee .......................................................................................63 
9.7. 
Safety Review Committee ..........................................................................................64 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................65 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................65 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................65 
10.1.2. 
Financial Disclosure ...................................................................................................65 
10.1.3. 
Informed Consent Process ..........................................................................................66 
10.1.4. 
Data Protection ...........................................................................................................66 
10.1.5. 
Committees Structure .................................................................................................67 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................67 
10.1.7. 
Data Quality Assurance ..............................................................................................67 
10.1.8. 
Source Documents ......................................................................................................68 
10.1.9. 
Study and Site Start and Closure ................................................................................68 
10.1.10. 
Publication Policy .......................................................................................................69 
10.1.11. 
Good Clinical Practice Compliance ............................................................................70 
10.2. 
Clinical Laboratory Tests ...........................................................................................71 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................73 
10.3.1. 
Definition of AE .........................................................................................................73 
10.3.2. 
Definition of SAE .......................................................................................................74 
10.3.3. 
Recording and Follow-up of AE and/or SAE .............................................................75 
10.3.4. 
Reporting of SAEs ......................................................................................................77 
10.4. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................79 
10.4.1. 
Definitions ..................................................................................................................79 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
10.4.2. 
Contraception Guidance .............................................................................................80 
10.4.2.1. 
Guidance for Female Participants ...............................................................................80 
10.4.2.2. 
Guidance for Male Participants ..................................................................................81 
10.4.3. 
Collection of Pregnancy Information .........................................................................82 
10.4.3.1. 
Male Participants with Partners Who Become Pregnant ............................................82 
10.4.3.2. 
Female Participants Who Become Pregnant ...............................................................83 
10.5. 
Biomarkers ..................................................................................................................84 
10.6. 
Management of Potential Adverse Events During Study Drug 
Administration ............................................................................................................85 
10.7. 
COVID-19 Risk Assessment ......................................................................................86 
10.8. 
COVID-19 Vaccine Risk Assessment ........................................................................87 
10.9. 
Abbreviations ..............................................................................................................88 
10.10. 
Protocol Amendment History .....................................................................................91 
11.
REFERENCES ...........................................................................................................92 
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
LIST OF TABLES 
Table 1: 
Mapping Objectives to Endpoints for Patients with Sickle Cell Disease ...................14 
Table 2: 
ALXN1820-SCD-201 Dosing Cohorts .......................................................................15 
Table 3: 
Schedule of Activities – Screening Through Day 85 (Cohort 1) – QW 
Dosing .........................................................................................................................20 
Table 4: 
Schedule of Activities – Screening Through Day 85 (Cohort 2) – Q4W 
Dosing .........................................................................................................................23 
Table 5: 
Optional PK/PD Sampling for Intensive PK/PD for Subset of Patients in 
Cohort 1 and 2 ............................................................................................................26 
Table 6: 
Schedule of Activities – Day 99 Through End of Follow-up Period, Cohorts 
1 and 2 .........................................................................................................................27 
Table 7: 
Schedule of Activities – Screening Through Day 43 (Optional Cohort 3) – 
Q2W Dosing ...............................................................................................................29 
Table 8: 
Schedule of Activities – Day 57 Through End of Follow-up Period for 
Multiple Dose Follow-up (Optional Cohort 3) ...........................................................32 
Table 9: 
Potential Risks and Mitigation Strategies ...................................................................37 
Table 10: Mapping Objectives to Endpoints for Patients with Sickle Cell Disease ...................39 
Table 11: ALXN1820-SCD-201 Dosing Cohorts .......................................................................40 
Table 12: Dose Reference Chart for Study ALXN1820-SCD-201 ............................................47 
Table 13: Protocol-required Laboratory Assessments ................................................................71 
Table 14: Potential Risks and Mitigation Measures due to COVID-19 .....................................86 
Table 15: Potential Risks and Mitigation Measures due to COVID-19 Vaccine .......................87 
Table 16: Abbreviations and Specialist Terms ...........................................................................88 
LIST OF FIGURES 
Figure 1: 
Study ALXN1820-SCD-201 Schematic for Cohorts 1, 2, and 3 ................................19 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title: A Phase 2a, Randomized, Open-label Study to Evaluate Multiple Dosing 
Regimens of Subcutaneous ALXN1820 in Adult Patients with Sickle Cell Disease 
Short Title: Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Study of ALXN1820 in 
Adult Patients with Sickle Cell Disease 
Rationale: ALXN1820 (anti-properdin/anti-serum albumin bispecific single variable domain on 
a heavy chain [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 study is to evaluate the safety, tolerability, efficacy, 
pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple doses and 
dosing regimens of ALXN1820 SC in patients with Sickle Cell Disease (SCD). 
The study will include up to 3 cohorts. Data from this study are anticipated to help design future 
studies in patients with SCD and other complement-mediated diseases. 
Objectives and Endpoints 
Table 1: 
Mapping Objectives to Endpoints for Patients with Sickle Cell Disease 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of 
ALXN1820 SC in patients with SCD  
Safety assessed by incidence of TEAEs and 
SAEs, physical examination, vital sign 
measurements, clinical laboratory, and 
electrocardiogram results through Day 211 
(Cohorts 1 and 2) and through Day 169 (Optional 
Cohort 3) 
Secondary 
To assess the multiple-dose PK of ALXN1820 SC 
Serum ALXN1820 multiple-dose PK profiles 
through Day 211 (Cohorts 1 and 2) and through 
Day 169 (Optional Cohort 3) 
To assess the PD effects of ALXN1820 SC 
Change in serum concentrations of total and free 
properdin over time through Day 211 (Cohorts 1 
and 2) and through Day 169 (Optional Cohort 3) 
Change in CAP activity using the Wieslab AP 
assay through Day 211 (Cohorts 1 and 2) and 
through Day 169 (Optional Cohort 3) 
To assess the effect of ALXN1820 on 
complement biomarkers 
Change from baseline in complement biomarkers 
through Week 12 (Cohorts 1 and 2) 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Table 1: 
Mapping Objectives to Endpoints for Patients with Sickle Cell Disease 
Objectives 
Endpoints 
To assess the effect of ALXN1820 on hemolysis 
Change from baseline in hemoglobin levels at 
Week 12 (Cohorts 1 and 2) 
Change from baseline in hemolysis markers (eg, 
lactate dehydrogenase, reticulocytes, and 
bilirubin) and hemopexin at Week 12 (Cohorts 1 
and 2) 
To assess the immunogenicity of ALXN1820 SC 
Incidence of ADAs to ALXN1820 through 
Day 211 (Cohorts 1 and 2) and through Day 169 
for Optional Cohort 3 
Exploratory 
To explore the effect of ALXN1820 on vaso-
occlusion markers 
Change from baseline in VOC related biomarkers 
through Week 12 (Cohorts 1 and 2) 
To explore the clinical efficacy of ALXN1820 SC 
in SCD 
VOC events (rate of VOC, time to first VOC) 
through Week 12 (Cohorts 1 and 2) 
Abbreviations: ADA = antidrug antibody; AP = alternative pathway; CAP = complement alternative 
pathway; PD = pharmacodynamics(s); PK = pharmacokinetic(s); SAE = serious adverse event; 
SC = subcutaneous; SCD = sickle cell disease; TEAE = treatment-emergent adverse event; 
VOC = vaso-occlusive crisis. 
Overall Design 
This is a Phase 2a study, with up to 3 multiple dose cohorts of open-label ALXN1820 SC in 
adult patients with SCD (HbSS and HbSß0-thalassemia). 
The study will be conducted in up to 30 adult patients with SCD enrolled in up to 3 open-label 
cohorts (Cohorts 1, 2 and 3 [optional]) to receive multiple SC doses of open-label ALXN1820. 
ALXN1820 will be administered as described in Table 2. 
Table 2: 
ALXN1820-SCD-201 Dosing Cohorts 
Cohort 
N 
Study Drug 
Route of 
Administration 
Planned Dose 
Number of 
Doses/Dose 
Interval 
1 
Up to 12 
maximum of 6 on 
stable dose of 
hydroxyurea 
ALXN1820 
SC 
300 mg 
QW × 13 
2 
Up to 12 
maximum of 6 on 
stable dose of 
hydroxyurea 
ALXN1820 
SC 
600 mg 
Q4W × 4 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Table 2: 
ALXN1820-SCD-201 Dosing Cohorts 
Cohort 
N 
Study Drug 
Route of 
Administration 
Planned Dose 
Number of 
Doses/Dose 
Interval 
3 
(optional) 
Up to 6 
maximum of 3 on 
stable dose of 
hydroxyurea 
ALXN1820 
SC 
300 mg 
Q2W × 4 
Abbreviations: N = number of participants; QW = once weekly; Q2W = once every 2 weeks; 
Q4W = once every 4 weeks; SC = subcutaneous; SCD = Sickle Cell Disease. 
The dose and dosing interval for Cohorts 1 and 2 was determined using cumulative safety data, 
an interim PK/PD analysis from participants enrolled in Study ALXN1820-HV-101, and data 
from the 6-month Good Laboratory Practice (GLP) toxicology study in monkeys. Optional 
Cohort 3 will be initiated after evaluation of safety and PK/PD data from Cohorts 1 and 2, at 
Alexion's discretion. 
Cohort 1 and Cohort 2 will run in parallel, and patients will be randomized 1:1 to either of the 
cohorts on determination of eligibility. The decision to initiate Optional Cohort 3 will be made at 
Alexion’s discretion and will be based on analysis of PK/PD and safety after at least 8 patients 
from Cohorts 1 and 2 (4 from each cohort) have enrolled. Furthermore, enrollment of Optional 
Cohort 3 will start after Cohorts 1 and 2 are fully enrolled. Each cohort will be stratified to 
ensure patients with SCD who are treated with a stable dose of hydroxyurea and patients with 
SCD who are not currently treated with hydroxyurea are included. The Treatment Period will be 
12 weeks for Cohorts 1 and 2, and 6 weeks for Cohort 3. For patients who were previously 
treated with hydroxyurea but are not currently on hydroxyurea, treatment must have been 
stopped at least 30 days prior to providing informed consent.  
At Alexion’s discretion, and after consultation with the Data Monitoring Committee (DMC), 
additional participants with SCD may be enrolled as replacement participants if a participant 
discontinues during the Dosing Period for reasons other than drug-related adverse events (AEs). 
Disclosure Statement This is an open-label, parallel group intervention study with up to 
3 treatment arms. 
Number of Participants: 
Up to 30 adult patients with SCD (HbSS and HbSß0-thalassemia) will be enrolled in up to 
3 cohorts and will receive multiple open-label SC doses of ALXN1820. The cohorts will enroll 
both patients with SCD who are being treated with a stable dose of hydroxyurea and patients 
with SCD who are not currently treated with hydroxyurea. For patients who were previously 
treated with but are not currently on hydroxyurea, treatment must have been stopped at least 
30 days prior to providing informed consent. 
Intervention Groups and Duration: 
The planned study duration is approximately 38 weeks for Cohorts 1 and 2: up to 56 days 
(8 weeks) for Screening, 84 days (12 weeks) for the Treatment Period, and 126 days (18 weeks) 
for the Follow-up Period. Patients will attend outpatient visits during the Treatment and Follow-
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Protocol Amendment 1.0 
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up Period with the option to stay at the inpatient facility. The end of study (EOS) for each 
individual patient is anticipated to be Day 211 (210 days) or the timepoint at which complement 
activity has returned to a normal range or 80% of baseline if later than Day 211.  
The planned study duration is approximately 32 weeks for optional Cohort 3: up to 56 days 
(8 weeks) for Screening, 42 days (6 weeks) for the Treatment Period, and 126 days (18 weeks) 
for the Follow-up Period. Patients will attend outpatient visits during the Treatment and Follow-
up Period with the option to stay at the inpatient facility. The EOS for each individual patient is 
anticipated to be Day 169 (168 days) or the timepoint at which complement activity has returned 
to a normal range or 80% of baseline if later than Day 169.  
A schematic view of the study is presented in Figure 1. 
Data Monitoring Committee: This study will use an independent DMC to monitor safety and to 
perform the planned interim analyses of the study.  
Statistical Analyses – All Cohorts:  
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 
Enrolled Set 
All participants who sign the ICF and passed inclusion/exclusion criteria. 
Full Analysis Set 
(FAS) 
All participants in the Enrolled Set who have been randomized and received 
at least 1 dose of study drug. 
Per Protocol Set 
(PPS) 
All participants in the Enrolled Set without any major protocol deviation. 
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; ICF = informed consent form; 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.  
Safety analyses will include an analysis of all treatment-emergent adverse events (TEAEs), 
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. AEs will also be 
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Protocol Amendment 1.0 
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summarized by cohort and overall by severity. SAEs 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. 
Efficacy Analysis 
Absolute and percentage change from baseline in complement biomarkers, hemoglobin and 
hemolysis markers will be evaluated at the end of the Treatment Period (12 weeks) for Cohort 1 
and Cohort 2. Time to hemoglobin response (defined as an increase in hemoglobin levels of 
> 1g/dL from baseline) will be evaluated at the end of the Treatment Period (12 weeks) for
Cohort 1 and Cohort 2.
Pharmacokinetic Analysis 
The individual serum concentration data from participants who receive ALXN1820 SC with 
actual sampling dates and times, will be used to characterize the PK by population PK analysis 
approach. 
Pharmacodynamic Analysis 
The PD effects of all ALXN1820 SC doses administered will be evaluated by assessing changes 
in serum total and free properdin concentrations and complement alternative pathway (CAP) 
activity using the Wieslab alternative pathway (AP) assay. In addition, complement classical 
pathway activity and other measures of properdin activity over time may be considered as 
deemed appropriate (Section 8.6). 
Immunogenicity Analysis 
Immunogenicity, as measured by incidence of antidrug antibody (ADA) to ALXN1820 will be 
summarized.  
Exploratory Analysis 
Additional exploratory analyses on biomarker assays and clinical efficacy endpoints may be 
conducted. Details of these analyses will be presented in the statistical analysis plan (SAP). 
Interim Analysis 
An interim analysis may be performed after at least12 patients from Cohorts 1 and 2 (6 from 
each cohort) have enrolled and completed the Treatment Period (12 weeks). Details of this 
analysis will be presented in the SAP.  
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Protocol Amendment 1.0 
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1.2. 
Schema 
Figure 1: 
Study ALXN1820-SCD-201 Schematic for Cohorts 1, 2, and 3  
a Follow-up Period may be longer than 18 weeks for those patients whose complement activity has not returned to 
the normal range or 80% of baseline.  
Abbreviations: N = number of participants; QW = once weekly; Q2W = once every 2 weeks; Q4W = once every 
4 weeks; SCD = sickle cell disease 
Note: Optional Cohort 3 will be initiated at Alexion’s discretion and will be based on analysis of PK/PD and safety 
after at least 8 patients from Cohorts 1 and 2 (4 from each cohort) have enrolled. Furthermore, enrollment of 
Optional Cohort 3 will start after Cohorts 1 and 2 are fully enrolled. 
1.3. 
Schedule of Activities (SoA) 
The SoA for once weekly (QW) dosing for multiple-dose Cohort 1 for Screening through Day 85 
is presented in Table 3.  
The SoA for once every 4 weeks (Q4W) dosing for multiple-dose Cohort 2 for Screening 
through Day 85 is presented in Table 4. 
Table 5 presents the SoA for intensive PK/PD sampling for a subset of participants in Cohorts 1 
and 2. Table 6 presents the SoA for Cohorts 1 and 2 for Day 99 through the end of the Follow-up 
Period. 
The SoA for once every 2 weeks (Q2W) dosing for optional multiple-dose Cohort 3 for 
Screening through Day 43 is presented in Table 7. Table 8 presents the SoA for Cohort 3 for Day 
57 through the end of the Follow-up Period.  
a
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Protocol Amendment 1.0 
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Table 3: 
Schedule of Activities – Screening Through Day 85 (Cohort 1) – QW Dosing 
Study Day 
Screening 
Day –56 to 
Day –1
Day 
1 
Day 
8 
Day 15 
Day 22 
Day 29 
Day 36 
Day 43 
Day 50 
Day 57 
Day 64 
Day 71 
Day 78 
Day 85 
Window (Day) 
NA 
NA 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
Informed consenta 
X 
Eligibility criteriab 
X 
X 
Randomizationc 
X 
Confirmation of or 
administration of 
meningococcal 
vaccinationd 
X 
Confirmation of or 
administration of HiB 
and S pneumoniae 
vaccination  
X 
Medical history and 
demographics 
X 
Physical examination 
X 
X 
Abbreviated physical 
examination 
X 
X 
X 
Height, weight, and 
BMIe
X 
X 
X 
X 
X 
Hematologyf 
X 
X 
X 
X 
X 
Clinical chemistryf 
X 
X 
X 
X 
X 
Coagulationf 
X 
X 
X 
X 
X 
Hepatitis B and C 
screen 
X 
HIV (types 1 and 2) 
screen 
X 
Serum/urine pregnancy 
testg 
X 
X 
X 
X 
X 
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Protocol Amendment 1.0 
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Table 3: 
Schedule of Activities – Screening Through Day 85 (Cohort 1) – QW Dosing 
Study Day 
Screening 
Day –56 to 
Day –1
Day 
1 
Day 
8 
Day 15 
Day 22 
Day 29 
Day 36 
Day 43 
Day 50 
Day 57 
Day 64 
Day 71 
Day 78 
Day 85 
Window (Day) 
NA 
NA 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
Urinalysis (including 
spot urine) 
X 
X 
X 
X 
X 
Vital sign 
measurementsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECGi 
X 
X 
X 
X 
X 
X 
Study drug 
administration QW 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samplesj 
X 
X 
X 
X 
X 
X 
X 
Blood sample for PD 
panelj,k 
X 
X 
X 
X 
X 
X 
X 
Injection site reactionl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkersm 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
(ALXN1820 ADA)n 
X 
X 
X 
X 
Assessment of VOCo 
X 
←Monitor continuously→ 
Review patient diaryp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review safety cardq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
←Monitor continuously (after ICF is signed)→ 
Adverse eventsr 
←Monitor continuously (after ICF is signed)→ 
a Signed and dated IEC-approved informed consent must be obtained before any study-specific screening procedures are performed. 
b Eligibility will be assessed at Screening and Day 1. 
c Randomization will occur following confirmation of all eligibility requirements. 
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Protocol Amendment 1.0 
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22 August 2022 
Table 3: 
Schedule of Activities – Screening Through Day 85 (Cohort 1) – QW Dosing 
d  To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients will be vaccinated with MCV4 and serogroup B meningococcal vaccinations at least 14 days 
before dosing, if not already vaccinated within 3 years before the first dose (or per national/local guidelines). Participants who initiate study intervention treatment less than 14 
days after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until at least 2 weeks after vaccination. Every effort should be 
made to start the meningococcal vaccination series at least 14 days prior to randomization. 
e Height and BMI only at Screening. 
f Non-fasting blood samples will be obtained. 
g Serum pregnancy test is required for all female participants of childbearing potential (ie, have achieved menarche) to confirm that a female participant is not pregnant prior to 
first dosing. A urine pregnancy test can be performed if the Screening visit is within 3 weeks of Day 1 visit. A urine (or serum if required by local site policy) pregnancy test is to 
be performed at all other required timepoints.  
h At Screening, supine and standing (orthostatic) blood pressures will be performed. 
i Predose triplicate 12-lead ECGs will be performed on Day 1 only and will be performed 3 times at approximately 2, 1, and 0.5 hours before the start of dosing (If this schedule is 
not feasible, ECGs performed with at least 20 min apart is acceptable). If the scheduled dosing is delayed, predose ECGs performed within 4 hours of dosing do not need to be 
repeated. Postdose ECGs will be performed within 30 min before PK/PD sample collection.  
j PK and PD samples are collected at pre-dose and between 2 and 4 hours post dose. 
k PD samples will be collected to assess serum total and free properdin and CAP activity. 
l Injection site reaction evaluation will be conducted on dosing days and if a reaction occurs, the evaluation will continue until the reaction is fully resolved.
m Blood samples for biomarkers will be collected 2 times prior to receiving the first dose (collect once during Screening and then again at Day 1 pre-dose, the 2 collections should
be at least 2 weeks apart). Collection of blood (for serum, citrated and K2-EDTA, or P100 plasma) and urine. 
n 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. 
o If a VOC occurs, samples will be collected as per unscheduled visit.
p The patient will record symptoms of VOC in a paper diary throughout the study. The Investigator or qualified designee will review the patient diary at every visit.
q 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. 
r Collection of adverse events and serious adverse events will begin after ICF signing. 
Abbreviations: ADA = antidrug antibody; BMI = body mass index; CAP = complement alternative pathway; ECG = electrocardiogram; HiB = Haemophilus influenzae type B; 
HIV = human immunodeficiency virus; ICF = informed consent form; IEC = Independent Ethics Committee; K2-EDTA = dipotassium ethylenediaminetetraacetic acid; 
MCV4 = tetravalent meningococcal conjugate vaccine; NA = not applicable; PD = pharmacodynamic(s); PK = pharmacokinetic(s); QW = once weekly; VOC = vaso-occlusive 
crisis. 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Table 4: 
Schedule of Activities – Screening Through Day 85 (Cohort 2) – Q4W Dosing 
Study Day 
Screening 
Day –56 to 
Day –1
Day 1 
Day 15 
Day 29 
Day 43 
Day 57 
Day 71 
Day 85 
Window (Day) 
NA 
NA 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Informed consenta 
X 
Eligibility criteriab 
X 
X 
Randomizationc 
X 
Confirmation of or 
administration of meningococcal 
vaccinationd 
X 
Confirmation of or 
administration of HiB and 
S pneumoniae vaccination 
X 
Medical history and 
demographics 
X 
Physical examination 
X 
X 
Abbreviated physical 
examination 
X 
X 
X 
Height, weight, and BMIe 
X 
X 
X 
X 
X 
Hematologyf 
X 
X 
X 
X 
X 
Clinical chemistryf 
X 
X 
X 
X 
X 
Coagulationf 
X 
X 
X 
X 
X 
Hepatitis B and C screen 
X 
HIV (types 1 and 2) screen 
X 
Serum/urine pregnancy testg 
X 
X 
X 
X 
X 
Urinalysis (including spot urine) 
X 
X 
X 
X 
X 
Vital sign measurementsh 
X 
X 
X 
X 
X 
X 
X 
X 
Triplicate ECGi 
X 
X 
X 
X 
X 
X 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Table 4: 
Schedule of Activities – Screening Through Day 85 (Cohort 2) – Q4W Dosing 
Study Day 
Screening 
Day –56 to 
Day –1
Day 1 
Day 15 
Day 29 
Day 43 
Day 57 
Day 71 
Day 85 
Window (Day) 
NA 
NA 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Study drug administration Q4W 
X 
X 
X 
X 
PK samplesj 
X 
X2 
X 
X 
X 
X 
X 
Blood sample for PD panel j,k 
X 
X 
X 
X 
X 
X 
X 
Injection site reactionl 
X 
X 
X 
X 
X 
X 
X 
Biomarkerm 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity (ALXN1820 
ADA)n
X 
X 
X 
X 
Assessment of VOCo 
X 
←Monitor continuously→ 
Review patient diaryp 
X 
X 
X 
X 
X 
X 
X 
X 
Review safety cardq 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously (after ICF is signed at Screening)→ 
Adverse eventsr 
←Monitor continuously (after ICF is signed at Screening)→ 
a Signed and dated IEC-approved informed consent must be obtained before any study-specific screening procedures are performed. 
b Eligibility will be assessed at Screening and Day 1. 
c Randomization will occur following confirmation of all eligibility requirements. 
d To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients will be vaccinated with MCV4 and serogroup B meningococcal vaccinations at least 14 days 
before dosing, if not already vaccinated within 3 years before the first dose (or per national/local guidelines). Participants who initiate study intervention treatment less than 14 
days after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until at least 2 weeks after vaccination. Every effort should be 
made to start the meningococcal vaccination series at least 14 days prior to randomization. 
e Height and BMI only at Screening. 
f Non-fasting blood samples will be obtained. 
g Serum pregnancy test is required for all female participants of childbearing potential (ie, have achieved menarche) to confirm that a female participant is not pregnant prior to 
first dosing. A urine pregnancy test can be performed if the Screening visit is within 3 weeks of Day 1 visit. A urine (or serum if required by site policy) local pregnancy test is to 
be performed at all other required timepoints.  
h At Screening, supine and standing (orthostatic) blood pressures will be performed. 
i Predose triplicate 12-lead ECGs will be performed on Day 1 only and will be performed 3 times at approximately 2, 1, and 0.5 hours before the start of dosing (If this schedule is 
not feasible, ECGs performed with at least 20 min apart is acceptable). If the scheduled dosing is delayed, predose ECGs performed within 4 hours of dosing do not need to be 
repeated. Postdose ECGs will be performed within 30 min before PK/PD sample collection. 
j PK and PD samples are collected at pre-dose and between 2 and 4 hours post dose. 
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Protocol Amendment 1.0 
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22 August 2022 
Table 4: 
Schedule of Activities – Screening Through Day 85 (Cohort 2) – Q4W Dosing 
k PD samples will be collected to assess serum total and free properdin and CAP activity. 
l Injection site reaction evaluation will be conducted on dosing days and if a reaction occurs, the evaluation will continue until the reaction is fully resolved.
m Blood samples for biomarkers will be collected two times prior to receiving the first dose (collect once during Screening and then again at Day 1 pre-dose, the 2 collections
should be at least 2 weeks apart). Collection of blood (for serum, citrated and K2-EDTA, or P100 plasma) and urine. 
n 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. 
o If a VOC crisis occurs, samples will be collected as per unscheduled visit.
p The patient will record symptoms of VOC in a paper diary throughout the study. The Investigator or qualified designee will review the patient diary at every visit.
q 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. 
r Collection of adverse events and serious adverse events will begin after ICF signing. 
Abbreviations: ADA = antidrug antibody; BMI = body mass index; CAP = complement alternative pathway; ECG = electrocardiogram; HiB = Haemophilus influenzae type B; 
HIV = human immunodeficiency virus; ICF = informed consent form; IEC = Independent Ethics Committee; K2-EDTA = dipotassium ethylenediaminetetraacetic acid; 
MCV4 = tetravalent meningococcal conjugate vaccine; NA = not applicable; PD = pharmacodynamic(s); PK = pharmacokinetic(s); Q4W = once every 4 weeks; VOC = vaso-
occlusive crisis. 
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Table 5: 
Optional PK/PD Sampling for Intensive PK/PD for Subset of Patients in Cohort 1 and 2 
Study Daya
Day 2 
(24 hours post Day 1 
dose (± 4 hours) 
Day 4 
(72 hours post Day 1 
dose, 
± 24 hours) 
Day 86 
(24 hours post Day 85 
dose (± 4 hours) 
Day 88 
(72 hours post Day 85 
dose, 
± 24 hours) 
Day 92 
(168 hours post Day 85 
dose, 
± 24 hours) 
PK samples 
X 
X 
X 
X 
X 
Blood sample for PD panelb 
X 
X 
X 
X 
X 
a A subset of Cohort 1 and 2 patients may undergo a more intensive PK/PD sampling specified in this table. All other assessments are to be performed per Table 3, Table 4, 
and Table 6. 
b PD samples will be collected to assess serum total and free properdin and CAP activity.  
Abbreviations: CAP = complement alternative pathway; PD = pharmacodynamic(s); PK = pharmacokinetic(s). 
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Protocol Amendment 1.0 
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22 August 2022 
Table 6: 
Schedule of Activities – Day 99 Through End of Follow-up Period, Cohorts 1 and 2 
Study Day
Day 99 
Day 127a 
Day 155 
Day 183a 
Day 211 /ET/ 
Unscheduled  
Complement 
Activity 
Follow-upb 
Window (Day) 
± 3 
± 3 
± 3 
± 3 
± 3 
±14 
Physical examination 
X 
Abbreviated physical examination 
X 
X 
Vital sign measurements 
X 
X 
X 
Triplicate ECG 
X 
X 
X 
Hematologyc 
X 
X 
X 
Clinical chemistryc 
X 
X 
X 
Coagulationc 
X 
X 
X 
Urinalysis (including spot urine) 
X 
X 
X 
Serum/urine pregnancy test 
X 
X 
X 
PK samples 
X 
X 
X 
Blood samples for PD panel 
(serum total and free properdin, CAP activity) 
X 
X 
X 
X 
Biomarkersd 
X 
X 
X 
Immunogenicity (ALXN1820 ADA)e 
X 
X 
Assessment of VOCf 
←Monitor continuously→ 
Review patient diaryg 
X 
X 
X 
X 
X 
X 
Review safety cardh 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously→ 
Adverse eventsi 
←Monitor continuously→ 
a Visit may be performed remotely (phone or video calls). 
b If CAP activity has not returned to a normal range or 80% of the baseline level at the end of the Follow-up Period, patients may have additional Follow-up Visits every 12 weeks 
until CAP activity has been confirmed to either have returned to a normal range or 80% of the baseline level. This visit may be completed at home. 
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Protocol Amendment 1.0 
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Table 6: 
Schedule of Activities – Day 99 Through End of Follow-up Period, Cohorts 1 and 2 
c Non-fasting blood samples will be obtained. 
d Collection of blood (for serum, citrated and K2-EDTA, or P100 plasma) and urine. 
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 Assessment of VOC must be performed by a healthcare provider. 
g The patient will record symptoms of VOC in a paper diary throughout the study. The Investigator or qualified designee will review the patient diary at every visit.  
h 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. 
i Collection of adverse events and serious adverse events will begin after ICF signing 
Abbreviations: ADA = antidrug antibody; CAP = complement alternative pathway; ECG = electrocardiogram; ET = early termination; ICF = informed consent form; 
K2-EDTA = dipotassium ethylenediaminetetraacetic acid; PD = pharmacodynamic(s); PK = pharmacokinetic(s); VOC = vaso-occlusive crisis. 
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Protocol Amendment 1.0 
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22 August 2022 
Table 7: 
Schedule of Activities – Screening Through Day 43 (Optional Cohort 3) – Q2W Dosing 
Study Day 
Screening Day –56 to 
Day –1
Day 1 
Day 15 
Day 29 
Day 43 
Window (Day) 
NA 
NA 
± 3 
± 3 
± 3 
Informed consenta 
X 
Eligibility criteriab 
X 
X 
Randomizationc 
X 
Confirmation of or administration of 
meningococcal vaccinationd 
X 
Confirmation of or administration of 
HiB and S pneumoniae vaccination  
X 
Medical history and demographics 
X 
Physical examination 
X 
X 
Abbreviated physical examination 
X 
Height, weight, and BMIe 
X 
X 
X 
Hematologyf 
X 
X 
X 
Clinical chemistryf 
X 
X 
X 
Coagulationf 
X 
X 
X 
Hepatitis B and C screen 
X 
HIV (types 1 and 2) screen 
X 
Serum/urine pregnancy testg 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
Vital sign measurementsh 
X 
X 
X 
X 
X 
Triplicate ECGi 
X 
X 
X 
X 
Study drug administration Q2W 
X 
X 
X 
X 
PK samplesj 
X 
X 
X 
X 
Blood sample for PD panel j,k 
X 
X 
X 
X 
Injection site reactionl 
X 
X 
X 
X 
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Protocol Amendment 1.0 
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22 August 2022 
Table 7: 
Schedule of Activities – Screening Through Day 43 (Optional Cohort 3) – Q2W Dosing 
Study Day 
Screening Day –56 to 
Day –1
Day 1 
Day 15 
Day 29 
Day 43 
Window (Day) 
NA 
NA 
± 3 
± 3 
± 3 
Biomarkerm 
X 
X 
X 
X 
X 
Immunogenicity (ALXN1820 ADA)n
X 
X 
X 
Assessment of VOCo 
X 
←Monitor continuously→ 
Review patient diaryp 
X 
X 
X 
X 
X 
Review safety cardq 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously (after ICF is signed at Screening)→ 
Adverse eventsr 
←Monitor continuously (after ICF is signed at Screening)→ 
a Signed and dated IEC-approved informed consent must be obtained before any study-specific screening procedures are performed. 
b Eligibility will be assessed at Screening and Day 1. 
c Randomization will occur following confirmation of all eligibility requirements. 
d To reduce the risk of meningococcal infection (Neisseria meningitidis), all patients will be vaccinated with MCV4 and serogroup B meningococcal vaccinations at least 14 days 
before dosing, if not already vaccinated within 3 years before the first dose (or per national/local guidelines). Participants who initiate study intervention treatment less than 14 
days after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until at least 2 weeks after vaccination. Every effort should be 
made to start the meningococcal vaccination series at least 14 days prior to randomization. 
e Height and BMI only at Screening. 
f Non-fasting blood samples will be obtained 
g Serum pregnancy test is required for all female participants of childbearing potential (ie, have achieved menarche) to confirm that a female participant is not pregnant prior to 
first dosing. A urine pregnancy test can be performed if the Screening Visit is within 3 weeks of Day 1 Visit. A urine (or serum if required by site policy) local pregnancy test is 
to be performed at all other required timepoints.  
h At Screening, supine and standing (orthostatic) blood pressures will be performed. 
i Predose triplicate 12-lead ECGs will be performed on Day 1 only and will be performed 3 times at approximately 2, 1, and 0.5 hours before the start of dosing (If this schedule is 
not feasible, ECGs performed with at least 20 min apart is acceptable). If the scheduled dosing is delayed, predose ECGs performed within 4 hours of dosing do not need to be 
repeated. Postdose ECGs will be performed within 30 min before PK/PD sample collection. 
j PK and PD samples are collected at pre-dose and between 2 and 4 hours post dose. 
k PD samples will be collected to assess serum total and free properdin and CAP activity. 
l Injection site reaction evaluation will be conducted on dosing days and if a reaction occurs, the evaluation will continue until the reaction is fully resolved.
m Blood samples for biomarkers will be collected 2 times prior to receiving the first dose (collect once during Screening and then again at Day 1 pre-dose, the 2 collections should
be at least 2 weeks apart). Collection of blood (for serum, citrated and K2-EDTA, or P100 plasma) and urine. 
n 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. 
o If a VOC crisis occurs, samples will be collected as per unscheduled visit.
p The patient will record symptoms of VOC in a paper diary throughout the study. The Investigator or qualified designee will review the patient diary at every visit.
q 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. 
r Collection of adverse events and serious adverse events will begin after ICF signing. 
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Table 7: 
Schedule of Activities – Screening Through Day 43 (Optional Cohort 3) – Q2W Dosing 
Abbreviations: ADA = antidrug antibody; BMI = body mass index; CAP = complement alternative pathway; ECG = electrocardiogram; HiB = Haemophilus influenzae type B; 
HIV = human immunodeficiency virus; ICF = informed consent form; IEC = Independent Ethics Committee; K2-EDTA = dipotassium ethylenediaminetetraacetic acid; 
MCV4 = tetravalent meningococcal conjugate vaccine; NA = not applicable; PD = pharmacodynamic(s); PK = pharmacokinetic(s); Q2W = every 2 weeks; VOC = vaso-
occlusive crisis.  
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Table 8: 
Schedule of Activities – Day 57 Through End of Follow-up Period for Multiple Dose Follow-up 
(Optional Cohort 3) 
Study Day
Day 57 
Day 85 a 
Day 113 
Day 141a 
Day 169 /ET/ 
Unscheduled  
Complement 
Activity 
Follow-upb 
Window (Day) 
± 3 
± 3 
± 3 
± 3 
± 3 
±14 
Physical examination 
X 
Abbreviated physical examination 
X 
X 
Vital sign measurements 
X 
X 
X 
Triplicate ECG 
X 
X 
X 
Clinical chemistryc 
X 
X 
X 
Hematologyc 
X 
X 
X 
Coagulationc 
X 
X 
X 
Urinalysis 
X 
X 
X 
Serum/urine pregnancy test 
X 
X 
X 
PK samples 
X 
X 
X 
Blood samples for PD panel (serum total and free 
properdin, CAP activity) 
X 
X 
X 
X 
Biomarkersd 
X 
X 
X 
Immunogenicity (ALXN1820 ADA)e 
X 
X 
Assessment of VOCf,g 
←Monitor continuously→ 
Review patient diaryg 
X 
X 
X 
X 
X 
X 
Review safety cardh 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←Monitor continuously→ 
Adverse eventsi 
←Monitor continuously→ 
a Visit may be performed remotely (phone or video calls). 
b If CAP activity has not returned to a normal range or 80% of the baseline level at the end of the Follow-up Period, patients may have additional Follow-up Visits every 12 weeks 
until CAP activity has been confirmed to either have returned to a normal range or 80% of the baseline level. This visit may be completed at home. 
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Table 8: 
Schedule of Activities – Day 57 Through End of Follow-up Period for Multiple Dose Follow-up (Optional Cohort 3) 
c Non-fasting blood samples will be obtained. 
d Collection of blood (for serum, citrated and K2-EDTA, or Plasma P100 plasma) and urine. 
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 Assessment of VOC must be performed by a healthcare provider. 
g The patient will record symptoms of VOC in a paper diary throughout the study. The Investigator or qualified designee will review the patient diary at every visit.  
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 on the part of the participant. 
i Collection of adverse events and serious adverse events will begin after ICF signing. 
Abbreviations: ADA = antidrug antibody; CAP: complement alternative pathway; ECG = electrocardiogram; ET = early termination; ICF = informed consent form; K2-
EDTA = dipotassium ethylenediaminetetraacetic acid; PD = pharmacodynamic(s); PK = pharmacokinetic(s); VOC = vaso-occlusive crisis. 
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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 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 
complement component C3 (C3) and complement component C5 (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). ALXN1820 is currently being evaluated in an ongoing Phase 1 study in healthy 
adult participants (Study ALXN1820-HV-101), and doses and dosing regimens for participants 
in this study were determined using cumulative safety data and an interim PK/PD analysis from 
participants enrolled in the ongoing Phase 1 study as well as data from the 6-month GLP 
toxicology in monkeys. 
The purpose of this study in patients with SCD is to evaluate the safety, tolerability, efficacy, 
PK, PD, and immunogenicity of multiple doses and dosing regimens of ALXN1820 administered 
subcutaneously (ALXN1820 SC). 
The study will include up to 3 cohorts with multiple SC doses and dosing regimens of open-label 
ALXN1820 in adult patients with SCD. Data from this study are anticipated to help design future 
studies in patients with SCD and other 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, 1 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 complement component C9 (C9) deposition onto a myeloperoxidase substrate by
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human serum (20%v/v) with IC50 values of approximately 20 nM (C3), 15 nM (properdin) and 
19 nM (C9). 
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 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 GLP tissue cross 
reactivity (TCR) study and in both a non-GLP and GLP in vivo studies in cynomolgus monkeys. 
In GLP toxicology studies ALXN1820 was administered by intravenous (IV) administration (up 
to single dose of 100 mg/kg) and SC administration (up to 26 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 (maximum observed serum concentration [Cmax] and area under 
the concentration-time curve from time 0 to 168 hours [AUC0-168] of 8,570 µg/mL and 
1,160,000 µg∙hr/mL, respectively), after the last dose at the NOAEL in the SC group, yielded 
exposure multiples of ~30-fold to the projected exposures at the anticipated human dose of 
300 mg QW. Antidrug antibodies, when observed in a very small number of monkeys, did not 
have any impact on systemic exposure or toxicity profile. 
2.3. 
Benefit/Risk Assessment 
There may be potential benefits to patients with SCD (See Section 2.3.2). 
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. Potential risk mitigation strategies are described in Table 9. 
2.3.1. 
Risk Assessment 
Besides the first-in-human (FIH) Phase 1 Study ALXN1820-HV-101 in healthy participants, this 
study is the second human exposure to ALXN1820 and the first exposure to patients with SCD. 
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As there is limited 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 26 weekly SC doses up to 
300 mg/kg/week or after a single IV dose up to 100 mg/kg and no safety concerns in healthy 
participants have been identified as of 11 Mar 2022 after 5 weekly SC doses up to 150 mg or 
after a single SC dose of 1200 mg.  
2.3.1.1. 
Neisseria meningitidis Infections 
Increased susceptibility to infection with Neisseria 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 expected to be the risk of meningococcal infections. Specific risk 
mitigation measures are in place to address this risk. 
Clinically, the risk of N. meningitidis is mitigated in patients with properdin deficiency by 
vaccinating all patients against N. meningitidis with tetravalent meningococcal conjugate vaccine 
(MCV4) and serogroup B vaccines before dosing.  
Patients will be vaccinated with MCV4 and serogroup B meningococcal vaccinations at least 
14 days before dosing, if not already vaccinated within 3 years before the first dose (or per 
national/local guidelines). Participants who initiate study intervention treatment less than 14 days 
after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic 
antibiotics until at least 2 weeks after vaccination. Every effort should be made to start the 
meningococcal vaccination series at least 14 days prior to randomization. 
Additionally, participants may be treated with prophylactic antibiotics at the Investigator’s 
discretion.  
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 9: 
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.
Prophylactic antibiotics will be used 
at the investigator's discretion. 
Timing for meningococcal 
vaccinations can be mandated per 
local/national guidelines. 
(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 
2.3.1.3. 
Coronavirus Disease 2019  
The SARS-COV-2 disease (coronavirus disease 2019 [COVID-19]) global pandemic is active in 
many countries at the time of this protocol amendment. 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. 
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2.3.2. 
Benefit Assessment 
The potential benefit of ALXN1820 treatment for SCD is being measured by assessments of 
anemia and hemolysis. An increase in hemoglobin by ≥ 1g/dL from baseline is considered 
clinically meaningful. In addition, a positive treatment effect would also be shown by a decrease 
in hemolysis, including improvements in the serum levels of markers of hemolysis (ie, lactate 
dehydrogenase [LDH], indirect bilirubin, and haptoglobin). Other exploratory endpoints 
(vaso-occlusive crisis [VOC], etc.) may be assessed. 
2.3.3. 
Overall Benefit: Risk Conclusion 
ALXN1820 has been and is being evaluated in an ongoing Phase 1 Study ALXN1820-HV-101. 
Study ALXN1820-SCD-201 is the second human exposure to ALXN1820.  
Study ALXN1820-SCD-201 will be conducted in patients with SCD, and dosing will be initiated 
based on review of safety, tolerability, and PK/PD data from Study ALXN1820-HV-101. The 
doses administered in the current study are expected to produce exposure lower than the highest 
exposure tested in Study ALXN1820-HV-101, and the expected exposure in patients will be 
lower than the NOAEL exposure established in 6-week and 6-month GLP monkey toxicology 
studies. Strict inclusion/exclusion criteria, with a robust safety monitoring and risk mitigation 
plan are in place. A DMC will evaluate the available study data at prespecified time points for 
participant safety and make recommendations on dose modification or termination of the study. 
The selected doses are intended to deliver complete inhibition of properdin, providing potential 
benefit of ALXN1820 to patients with SCD, with a positive benefit/risk ratio.  
The data obtained from this study is expected to inform future clinical studies in patients with 
SCD. 
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3.
OBJECTIVES AND ENDPOINTS
The study objectives and corresponding endpoints are presented in Table 10. 
Table 10: 
Mapping Objectives to Endpoints for Patients with Sickle Cell Disease 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of 
ALXN1820 SC in patients with SCD  
Safety assessed by incidence of TEAEs and 
SAEs, physical examination, vital sign 
measurements, clinical laboratory, and 
electrocardiogram results through Day 211 
(Cohorts 1 and 2) and through Day 169 (Optional 
Cohort 3) 
Secondary 
To assess the multiple-dose PK of ALXN1820 SC 
Serum ALXN1820 multiple-dose PK profiles 
through Day 211 (Cohorts 1 and 2) and through 
Day 169 (Optional Cohort 3) 
To assess the PD effects of ALXN1820 SC 
Change in serum concentrations of total and free 
properdin over time through Day 211 (Cohorts 1 
and 2) and through Day 169 (Optional Cohort 3) 
Change in CAP activity using the Wieslab AP 
assay through Day 211 (Cohorts 1 and 2) and 
through Day 169 (Optional Cohort 3) 
To assess the effect of ALXN1820 on 
complement biomarkers 
Change from baseline in complement biomarkers 
through Week 12 (Cohorts 1 and 2) 
To assess the effect of ALXN1820 on hemolysis 
Change from baseline in hemoglobin levels at 
Week 12 (Cohorts 1 and 2) 
Change from baseline in hemolysis markers (eg, 
lactate dehydrogenase, reticulocytes, and 
bilirubin) and hemopexin at Week 12 (Cohorts 1 
and 2) 
To assess the immunogenicity of ALXN1820 SC 
Incidence of ADAs to ALXN1820 through 
Day 211 (Cohorts 1 and 2) and through Day 169 
for Optional Cohort 3 
Exploratory 
To explore the effect of ALXN1820 on vaso-
occlusion markers 
Change from baseline in VOC related biomarkers 
through Week 12 (Cohorts 1 and 2) 
To explore the clinical efficacy of ALXN1820 SC 
in SCD 
VOC events (rate of VOC, time to first VOC) 
through Week 12 (Cohorts 1 and 2) 
Abbreviations: ADA = antidrug antibody; AP = alternative pathway; CAP = complement alternative 
pathway; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SAE = serious adverse event; 
SC = subcutaneous; SCD = sickle cell disease; TEAE = treatment-emergent adverse event; 
VOC = vaso-occlusive crisis. 
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4.
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 2a study, with up to 3 multiple dose cohorts of open-label ALXN1820 SC in 
adult patients with SCD (HbSS and HbSß0-thalassemia). 
The study will be conducted in up to 30 adult patients with SCD enrolled in up to 3 open-label 
cohorts (Cohorts 1, 2 and 3 [optional]) to receive multiple SC doses of open-label ALXN1820. 
ALXN1820 will be administered as described in Table 11. 
Table 11: 
ALXN1820-SCD-201 Dosing Cohorts 
Cohort 
N 
Study Drug 
Route of 
Administration 
Planned Dose 
Number of 
Doses/Dose 
Interval 
1 
Up to 12 
maximum of 6 on 
stable dose of 
hydroxyurea 
ALXN1820 
SC 
300 mg 
QW × 13 
2 
Up to 12 
maximum of 6 on 
stable dose of 
hydroxyurea 
ALXN1820 
SC 
600 mg 
Q4W × 4 
3 
(optional) 
Up to 6 
maximum of 3 on 
stable dose of 
hydroxyurea 
ALXN1820 
SC 
300 mg 
Q2W × 4 
Abbreviations: N = number of participants; QW = once weekly; Q2W = once every 2 weeks; Q4W = 
once every 4 weeks; SC = subcutaneous. 
The dose and dosing intervals for Cohorts 1 and 2 were determined using cumulative safety data, 
an interim PK/PD analysis from participants enrolled in Study ALXN1820-HV-101, and data 
from the 6-month GLP toxicology study in monkeys. Optional Cohort 3 will be initiated after 
evaluation of safety and PK/PD data from Cohorts 1 and 2.  
Cohort 1 and Cohort 2 will run in parallel, and patients will be randomized 1:1 to either of the 
cohorts on determination of eligibility. The decision to initiate Optional Cohort 3 will be made at 
Alexion’s discretion and will be based on analysis of PK/PD and safety after at least 8 patients 
from Cohorts 1 and 2 (4 from each cohort) have enrolled. Furthermore, enrollment of Optional 
Cohort 3 will start after Cohorts 1 and 2 are fully enrolled. Each cohort will be stratified to 
ensure patients with SCD who are treated with a stable dose of hydroxyurea and patients with 
SCD who are not currently treated with hydroxyurea are included. For patients who were 
previously treated with hydroxyurea but are not currently on hydroxyurea, treatment must be 
stopped at least 30 days prior to providing informed consent.  
This study will use an independent DMC to monitor safety and to perform the planned interim 
analyses of the study. At Alexion’s discretion, and after consultation with the DMC, additional 
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participants with SCD may be enrolled as replacement participants if a participant discontinues 
during the Dosing Period for reasons other than drug related AEs.  
4.2. 
Scientific Rationale for Study Design 
The initial indication for ALXN1820 will be SCD. SCD affects about 20 to 25 million people 
worldwide (Aliyu, 2008) and in the US, approximately 100,000 people are affected (Hassell, 
2010). The prevalence of SCD newborns and SCD carriers in the EU is approximately 1 to 5 in 
10,000 and 1 in 150, respectively (Engert, 2016). The few available life expectancy estimates for 
SCD patients in the US or EU vary widely from 45 to 65 years which is approximately 20 years 
lower than the general population (Gardner, 2016; Lubeck, 2019; Payne, 2020; Platt, 1994). 
SCD is a group of inherited disorders. A mutation in the β-hemoglobin gene is responsible for 
the synthesis of sickle hemoglobin (HbS). The most common genotypes in SCD are HbSS, 
HbSC, and HbSβ+ thalassemia. The most common clinical manifestations of SCD are chronic 
hemolysis and VOC (Kato, 2018; Pecker, 2021). 
HbS has abnormal physicochemical properties and is prone to polymerization under low oxygen 
concentration causing deformation of red blood cells (RBCs) with the characteristic sickle shape. 
Sickling has numerous adverse outcomes on RBCs and on multiple organs. Sickled RBCs have 
limited life span due to hemolysis. Hemolysis is thought to occur principally through 
extravascular phagocytosis (approximately 2/3) and intravascular (approximately 1/3) hemolysis, 
which leads to anemia. Intravascular hemolysis of sickle RBCs leads to release of free 
hemoglobin, which in turn activates CAP (via free heme) and depletes nitric oxide, contributing 
to endothelial damage. Hemolysis and sickling of the RBCs leads to endothelial cell activation 
with increased adhesion molecule expression and activation of neutrophils, monocytes, and 
platelets (Kato, 2018). VOC, as a result of these processes, leads to obstruction of blood flow to 
vital organs such as the kidneys, liver, lungs, and heart, promoting ischemia, acute episodes of 
pain, and necrosis. The ensuing ischemic/reperfusion injury leads to the generation of reactive 
oxygen species. This in turn leads to a chronic inflammatory state (Kato, 2018; Piel, 2017). 
Patients also have increased vulnerability to infections, particularly from encapsulated bacteria, 
as a result of functional or actual asplenia. Together, these mechanisms contribute to the 
development of chronic organ damage including sickle nephropathy, pulmonary hypertension, 
avascular necrosis of the bone, chronic lung disease, and shortened life expectancy (Kato, 2018). 
Universal newborn screening is established in the US to enable early diagnosis and treatment of 
infants with SCD to reduce morbidity and mortality. It is recommended that all infants with 
HbSS and HbSβ0-thalassemia receive penicillin prophylaxis and 23-valent-pneumococcal 
polysaccharide vaccine to prevent invasive pneumococcal disease (Kato, 2018; Pecker, 2021). 
Hydroxyurea, RBC transfusion, and opioids are the treatments commonly used to manage the 
symptoms of SCD. There are several approved novel drugs for the treatment of sickle cell 
complications in recent years: L-glutamine (Endari®), voxelotor (Oxbryta®), and crizanlizumab 
(Adakveo®). However, none of these treatments addresses both anemia (hemolysis) and VOC. 
The only curative treatment option for SCD is hematopoietic stem cell transplantation. However, 
this is reserved for severe patients due to the risk of life-threatening complications  
(Pecker, 2021). 
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Recently, much attention has been given to the role of the innate immune system in SCD, and in 
particular the role of complement activation in the pathophysiology of SCD (Tampaki, 2021; 
Varelas, 2021). In Investigator-initiated studies, eculizumab has demonstrated clinical effect in 
SCD patients with delayed hemolytic transfusion reaction, VOC, and drug-induced immune 
hemolytic anemia (Chonat, 2020). Compared to C5 inhibitors, CAP inhibitors have potential 
advantages in treatment of SCD. An increasing number of publications supports the hypothesis 
that sickle RBCs are the focal point of CAP activation, which triggers C3 opsonization on the 
cell surface as well as complement-mediated RBC hemolysis. Intravascular hemolysis is one of 
the main causes of anemia and also contributes to further amplification of CAP activation by 
releasing free heme from RBCs. C3 opsonization of sickle RBCs also promotes anemia through 
extravascular hemolysis via the reticuloendothelial system. Furthermore, C3 opsonization has 
been shown to be a key contributor to VOC. It has also been demonstrated that C3 opsonization 
can be precipitated by exposure of phosphatidyl serine on sickle RBCs and contributes to VOC 
by enhancing its interaction with adhesion molecules such as P-selectin and complement receptor 
3 on activated endothelial cells (Lombardi, 2019). Thus, SCD nonclinical literature collectively 
underscores the role of CAP activation in SCD pathophysiology. 
ALXN1820 binds with high affinity to human properdin, which is a component of the CAP, 
preventing it from stabilizing the CAP C3 and C5 convertases that cleave C3 and C5 into their 
activation products. By binding properdin, ALXN1820 prevents activation of the alternative 
complement system and thereby has the potential to treat SCD. In support of this, studies carried 
out at Alexion in a mouse model of SCD demonstrated that pretreatment of animals with an 
mouse anti-properdin antibody significantly ameliorated signs of hemolysis and vaso-occlusion, 
which are 2 main clinical features of SCD. 
The current nonclinical data and data from the first in human study ALXN1820-HV-101 support 
further investigation of ALXN1820 as a potential for treatment of patients with SCD. This study 
is designed to allow preliminary evaluation of changes in SCD disease-related biomarkers and 
will guide the design of further clinical studies in patients with SCD. 
4.3. 
Justification for Dose 
The dose and the frequency of dosing will be based on all available data including the overall 
safety, tolerability, PK/PD modeling from the ongoing cohorts in Study ALXN1820-HV-101; 
available nonclinical data including PK, PD, and efficacy in SCD mouse models, and toxicology 
data from the GLP 6-week and 6-month studies in cynomolgus monkeys.  
A preliminary PK/PD model has been established based on data from Study ALXN1820-HV-101 
in healthy participants. This semi-mechanistic model assumed monovalent ALXN1820 binding 
to trimeric properdin with 3 binding sites. The relationship between free properdin and CAP 
activity was characterized by a sigmoidal Emax model. The model provided good fits to the 
observed data (ALXN1820, total and free properdin, and CAP activity) judged by the model 
diagnostics. To estimate the therapeutic dose in SCD patients, the following assumptions have 
been made: 
•
Complete suppression of CAP activity (<1% of baseline activity) is needed for
clinical efficacy based on data from mouse SCD model (described in detail in the
ALXN1820 IB)
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•
The baseline properdin concentration is about 20% higher in sickle cell patients than
in healthy subjects (Strauss, 1977)
In addition, ALXN1820 clearance in sickle cell patients was set as similar to or 40% higher (seen 
in other antibody treatments for SCD (Crizanlizumab, 2019)) than that of the healthy participants 
to evaluate the impact of increased clearance on exposure and CAP inhibition. Based on these 
assumptions and analysis, it is predicted that a dose of 300 mg QW could inhibit the CAP 
activity to < 1% of the baseline values (upper limit of the 90% prediction interval) and maintain 
this effect during the Treatment Period. A dose of 600 mg Q4W or 300 mg Q2W was also shown 
to inhibit the CAP activity < 1% during majority of the dosing interval. The CAP activity will 
slowly recover and return to baseline after terminating dosing of ALXN1820. The safety margin 
at 300 mg QW is approximately 30-fold based on the NOAEL exposure established in the 
6-month (or 26-week) monkey toxicology study. The safety margin at 600 mg Q4W or 300 mg
Q2W is approximately 60-fold, based on the NOAEL exposure.
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 (EOS) 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 
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. Confirmed diagnosis of SCD (HbSS, or HbSβ0-thalassemia).
Weight 
3. Body weight ≥ 40 kg (inclusive) at Screening.
Sex 
4. 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 6 months after last dose of study drug
(described in Section 10.4).
Other Inclusion Criteria 
5. Hemoglobin between 5.5 and 10 g/dL at Screening.
6. Have had 1 to 10 VOCs in the past 12 months.
7. Patients receiving hydroxyurea must have been on a stable dose for ≥ 3months prior to
providing informed consent, with no anticipated need for dose adjustment during the
study. For patients who previously used hydroxyurea but are not currently on
hydroxyurea treatment (due to non-responsiveness, intolerance, or unwillingness to take
hydroxyurea), hydroxyurea treatment must have been discontinued at least 30 days prior
to providing informed consent.
8. Patients will be vaccinated with MCV4 and serogroup B meningococcal vaccinations at
least 14 days before dosing, if not already vaccinated within 3 years before the first dose
(or per national/local guidelines). Participants who initiate study intervention treatment
less than 14 days after receiving a meningococcal vaccine must receive treatment with
appropriate prophylactic antibiotics until at least 2 weeks after vaccination.
9. Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae vaccination are up
to date according to current national/local vaccination guidelines for patients with SCD.
10. Must be willing to abide by all study requirements and restrictions.
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Informed Consent 
11. Capable of giving signed informed consent (or assent, as applicable) as described in
Section 10.1.3, which includes compliance with the requirements and restrictions listed in
the ICF and in this protocol.
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Planned initiation, termination, or dose alteration of hydroxyurea during the study.
2. Receiving Voxelotor (OXBRYTA) or crizanlizumab (ADAKVEO) within 60 days of
providing informed consent.
3. Receiving treatment with recombinant human erythropoetins (eg, epoetin alfa).
4. Treated with complement inhibitors within 6 months prior to the first dose.
5. Patients who are on chronic transfusion or receive a transfusion within 60 days of first
dose.
6. Any significant disease or disorder which, in the opinion of the Investigator, may put the
participant at risk.
7. History of complement deficiency.
8. History of N meningitidis, S pneumoniae, or H influenzae infection.
9. 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.
10. Evidence of hepatitis B (positive hepatitis surface antigen [HBsAg] or positive core
antibody (anti-HBc) with negative surface antibody [anti-HBs]) or hepatitis C viral
infection (hepatitis C virus [HCV] antibody positive, except for patients with documented
successful treatment and documented sustained virologic response) at Screening.
11. Active systemic bacterial, viral, or fungal infection within 14 days prior to dosing.
Prior/Concurrent Clinical Study Experience 
12. 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.
13. Participation in more than 1 clinical study of a monoclonal antibody (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 
14. Severe renal impairment (estimated glomerular filtration rate [eGFR]
< 30 mL/min/1.73 m2) or on chronic dialysis.
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Other Exclusions 
15. Female participants who are pregnant or breastfeeding.
16. History of allergy or hypersensitivity to excipients of ALXN1820 (eg, polysorbate 80).
5.3. 
Lifestyle Considerations 
Not applicable, Study ALXN1820-SCD-201 does not include any specific lifestyle 
considerations. 
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 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) due to 
a reason that is expected to resolve or has resolved may be rescreened based on discussion and 
agreement between the Investigator and the Medical Monitor. 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), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. For Study ALXN1820-SCD-201 the study intervention is ALXN1820 and also 
referred to as study drug throughout this study protocol. 
6.1. 
Study Intervention Administered 
The ALXN1820 study drug composition and doses to be administered (open-label, SC) in this 
study are presented in Table 12.  
Table 12: 
Dose Reference Chart for Study ALXN1820-SCD-201 
Characteristics 
ALXN1820 SC 
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. 
Unit dose 
strength(s)/dosage 
level(s) 
300 mg, 600 mg 
Route of 
administration 
SC 
Dosing instructions 
ALXN1820 SC will be administered as a single manual push for the 300 mg 
dose and as 2 manual pushes for the 600 mg dose. 
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. 
Manufacturer 
Alexion 
Abbreviation: SC = subcutaneous. 
In the event of missed doses, unscheduled dosing may be required to ensure therapeutic 
coverage. The unscheduled dose will be determined by the study Clinical Pharmacologist on an 
individual basis. 
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 drugs must be stored in a secure,
environmentally controlled, and monitored (manual or automated) area in accordance
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with the labeled storage conditions with access limited to the Investigator and authorized 
site staff. 
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. Further guidance regarding preparation, handling, storage, and
accountability and information for the final disposition of unused study intervention is
provided in the Pharmacy Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All eligible participants who meet all inclusion and no exclusion criteria in Cohorts 1, 2, and 
optional Cohort 3 will receive open-label ALXN1820. 
6.4. 
Study Intervention Compliance 
The administration of study intervention to participants will be under the supervision of the 
Investigator or their designee to ensure that participants receive the appropriate dose at the 
appropriate time points during the study. 
The date and time of each dose administered in the clinic will be recorded in the source 
documents and case report form (CRF). 
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 (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements), vaccine, 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.  
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See Section 8.2.9 for details on administration and duration of treatment with prophylactic 
antibiotics as 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. 
Medication and therapy for SCD are allowed except for those presented in Section 6.5.2. 
6.5.2. 
Disallowed Medicine and Therapy 
During the Screening and Treatment Period, if patients are not currently treated with 
hydroxyurea, hydroxyurea should not be initiated. If patients are on stable dose of hydroxyurea, 
the dose of hydroxyurea should not be altered or terminated. The use of voxelotor, 
crizanlizumab, erythropoetins, other complement inhibitors, and transfusion are not allowed. If 
any of the above medication/therapy is used, the patient will be discontinued as per Section 7.1. 
The above medications/therapy are allowed during the safety Follow-Up period.  
6.6. 
Dose Modification 
Decisions to continue or modify dosing will be made by the Investigator and/or DMC after review of 
the safety data. The DMC may also make recommendations regarding safety issues, study conduct, 
or study suspension.  
6.7. 
Intervention After the End of the Study 
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 (Section 1.3). 
7.2. 
Stopping Criteria 
7.2.1. 
Individual Stopping Rules 
Participants should be considered for discontinuation from intervention if any of the following 
occur during the study: 
•
Serious hypersensitivity reaction;
•
Grade 3 or higher injection site reactions;
•
Severe uncontrolled infection;
•
Serious N meningitidis, S pneumoniae, or H influenzae infections;
•
Use of disallowed medication as defined in Section 6.5.2;
•
Pregnancy or planned pregnancy; or
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the
Investigator or Alexion, presents a substantial clinical risk to the patient with
continued study drug dosing.
7.2.2. 
Study Stopping Rules
The study may be terminated at the recommendation of the DMC, if the following occur and are 
deemed to be related to the study drug:  
•
Two or more meningococcal infections;
•
Two or more serious (≥ Grade 3) pneumococcal infections;
•
Two or more serious (≥ Grade 3) H influenzae infections;
•
One meningococcal, pneumococcal, or H influenzae infection resulting in a fatal
outcome.
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 electronic case report form (eCRF). 
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A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an Early Discontinuation Visit should be 
conducted, as shown in the SoA (Section 1.3). Refer to the SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to be 
completed.  
The participant will be permanently discontinued both from the study drug and from the study at 
that time. 
If the participant withdraws consent for disclosure of future information, Alexion may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
Participants who discontinue during the Screening or Dosing Period for reasons other than 
drug-related AEs may be replaced. 
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 lost to
follow up.
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.9. 
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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 ALXN1820. 
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 standard operating procedures. 
8.1. 
Efficacy Assessments 
Timing for collection of assessments for Cohort 1 is detailed in Section 1.3, Table 3, and 
Table 6. Timing for intensive collection of PK and PD samples for Cohorts 1 and 2 is detailed in 
Section 1.3, Table 5. Timing for collection of assessments for Cohort 2 are detailed in 
Section 1.3, Table 4 and Table 6. If conducted, timing for collection of assessments for optional 
Cohort 3 are detailed in Table 7 and Table 8. 
8.1.1. 
Change in Complement Biomarkers 
The following complement markers (absolute and percentage change from baseline) will be 
measured during the study: 
•
complement component Ba (Ba)
•
complement component C3a (C3a)
•
soluble complement component C5B-9 (sC5B9)
Other complement markers may be evaluated, if feasible. 
8.1.2. 
Change in Biomarkers Related to VOC 
The following markers of VOC (absolute and percentage change from baseline) may be 
measured during the study: 
•
Hemopexin
•
Nitric oxide
•
Inflammatory markers (eg, interleukin-1)
•
Cell adhesion markers (eg, soluble P-selectin)
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Other markers may be evaluated, if feasible. 
8.1.3. 
Change in Hemoglobin 
Blood samples will be collected for assessment of hemoglobin changes from baseline. 
8.1.4. 
Markers of Hemolysis 
The following markers of hemolysis will be measured during the study: 
•
Serum LDH levels
•
Absolute reticulocyte count
•
Serum indirect bilirubin
•
Serum haptoglobin and hemopexin
8.1.5. 
Assessment of VOC
Sickle cell disease–related pain crises (VOC) will be collected throughout the study per detailed 
in the SoA (Section 1.3). 
Patients will be issued a paper diary to record symptoms of VOC after signing the informed 
consent.  The diary will be collected by the Investigator or designee at every visit to the site and 
a new diary will be provided.  
8.2. 
Safety Assessments 
Planned time points for all safety assessments for all cohorts 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.  
An abbreviated physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
Height, weight and BMI will be recorded per Section 1.3, SoA. 
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. Ideally, the same arm for each participant 
should be used for BP and pulse measurements.  Orthostatic (standing) blood pressure will only 
be measured at Screening. 
The timing of vital sign measurements is described in the SoA (Section 1.3). 
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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. 
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 may be made, and the abnormality will be 
followed to resolution. 
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 laboratory assessments will be performed by 
a central laboratory unless otherwise specified.  
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. 
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, HBc antibody 
(anti-HBc IgG + IgM, if IgG positive), and HCV antibody titers. 
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8.2.6. 
Pregnancy 
Pregnancy testing must be performed on all women of childbearing potential (WOCBP) at the 
time points specified in the SoA (Section 1.3). Pregnancy tests (local urine testing will be 
standard unless serum testing is required by local regulation or ethic committees) may also be 
performed at any time during the study at the Investigator’s discretion. 
WOCBP must have a negative pregnancy test (serum if required per country regulations) before 
study intervention administration. 
•
Details of all pregnancies in female participants and, if indicated, female partners of
male participants will be collected after the start of study intervention and until
termination of the pregnancy.
•
If a pregnancy is reported, the Investigator should inform Alexion within 24 hours of
learning of the pregnancy and should follow the procedure outlined in Section 10.4.3.
•
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAEs. Pregnancy alone is
not considered an AE.
•
If a participant becomes pregnant, the study intervention must be immediately
discontinued, and Alexion must be notified as per Section 10.4.3. Each pregnancy
will be followed to term and Alexion should be notified regarding the outcome
(Section 10.4.3).
8.2.7. 
Injection Site Evaluation
Subcutaneous injection site evaluations will be performed at the time points specified in the SoA 
(Section 1.3). Injection site reactions will not be recorded as AEs unless deemed clinically 
significant.  
8.2.8. 
Injection-associated Reactions 
Injection-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 SC injection 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, 
participants will be administered the following: 
1. Patients will be vaccinated with MCV4 and serogroup B meningococcal vaccinations, if
available at least 14 days before dosing, if not already vaccinated within 3 years before
the first dose (or per national/local guidelines).
2. Patients will be treated with prophylactic antibiotics at the Investigator’s discretion.
Patients must be vaccinated against other pathogens (e.g. Haemophiles influenzae, Streptococcus 
pneumoniae) according to current national/local guidelines. 
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8.2.10. 
Participant Safety Card 
Participants will 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. 
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. The Investigator will 
submit any updated SAE data to Alexion within 24 hours of the date the investigational site 
became aware of the event. 
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, 
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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 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. 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.
2. Closely monitor the participant for any AE/SAE.
3. Obtain a sample for PK/PD analysis if requested by the Medical Monitor (determined on
a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdose in the
eCRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5. 
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 participants per national/local guidelines. 
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 serum concentrations) to ensure appropriate 
monitoring. 
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•
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.
8.6. 
Pharmacodynamics
Whole blood samples will be collected for measurement of serum total and free properdin 
concentrations, CAP 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, and upon 
receipt of consent from the study participant. The total blood volume will not exceed the blood 
volume limit for participants per national/local guidelines. 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 
25 years to perform additional assessments as necessary. 
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 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, inflammation, and endothelial activation/damage. 
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8.9. 
Immunogenicity Assessments 
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 Alexion. Samples may 
be further characterized to determine the titer and the presence of neutralizing antibodies (as an 
exploratory analysis) if deemed necessary.  
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 25 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. 
Health Economics Data and/or Medical Resource Utilization 
Medical resource utilization and health economics data will not be evaluated in this study. 
8.11. 
Other Assessments and Procedures 
Not applicable. 
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9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses
Not applicable. 
9.2. 
Sample Size Determination 
Twelve participants will be enrolled in each of Cohorts 1 and 2. In patients with stable SCD, 
hemoglobin level is unlikely to change. The sample size is determined based on a targeted 
hemoglobin change from baseline to exclude 0 g/dL with a lower 2-sided 95% confidence 
bound. Assuming a standard deviation of 1 g/dL, a sample size of 12 participants will provide 
88% power to detect a change from baseline of 1 g/dL with a 2-sided significance level of 0.05. 
In the optional Cohort 3, 6 participants will be enrolled to define the exposure/response 
relationship of ALXN1820 by combining Cohort 1, Cohort 2 and Cohort 3 data using a PK/PD 
modeling approach. The Cohort 3 sample size is not determined for power purposes. 
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. 
Enrolled Set 
All subjects who sign the ICF and passed inclusion/exclusion criteria. 
Full Analysis Set (FAS)  
All subjects in the Enrolled Set who have been randomized and 
received at least 1 dose of study drug. 
Per Protocol Set (PPS) 
All subjects in the Enrolled Set without any major protocol deviation. 
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; ICF = informed consent form; PK = pharmacokinetic(s). 
9.4. 
Statistical Analyses 
In general, descriptive statistics for continuous variables will include number of non-missing 
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. 
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A 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 
9.4.1.1. 
Change in Complement Biomarkers 
Absolute and percentage of change from baseline in complement biomarkers (eg, Ba, C3a and 
sC5B9) will be evaluated at the end of treatment (12 weeks) for Cohorts 1 and 2. Additional 
details will be described in the SAP. 
9.4.1.2. 
Change in Hemoglobin 
Absolute and percentage change from baseline in hemoglobin will be evaluated at the end of 
treatment (12 weeks) for Cohorts 1 and 2. Additional details will be described in the SAP. 
9.4.1.3. 
Time to Hemoglobin Response 
Hemoglobin response is defined as an increase in hemoglobin levels of > 1g/dL from baseline. 
Hemoglobin response will be evaluated at the end of treatment (12 weeks) for Cohorts 1 and 2. 
Additional details will be described in the SAP. 
9.4.1.4. 
Markers of Hemolysis 
Absolute and percentage change from baseline of the markers of hemolysis (serum LDH levels, 
absolute reticulocyte count, serum indirect bilirubin, serum haptoglobin and hemopexin) will be 
evaluated at the end of treatment (12 weeks) for Cohorts 1 and 2. Additional details will be 
described in the SAP. 
9.4.1.5. 
Exploratory Analysis of Change in Biomarkers Related to VOC 
Biomarkers related to VOC may be evaluated after end of treatment (12 week for Cohorts 1 
and 2). Additional details will be described in the SAP. 
9.4.2. 
Exploratory Assessment of VOC 
Sickle cell disease–related pain crises (VOC) are defined as acute episodes of pain, with no 
medically determined cause other than a VOC event that result in a medical facility visit and 
treatment with either oral or parenteral narcotic agents, or with a parenteral nonsteroidal 
anti-inflammatory drug. Uncomplicated VOCs are defined as no occurrence of any other SCD 
complication during the VOC episode. Complicated VOCs are defined as the presence of a 
diagnosis of other SCD complications during the VOC episode. Acute chest syndrome, hepatic 
sequestration, splenic sequestration, and priapism are considered as VOC events in this study. 
Complicated VOCs are also to be reported as AEs. 
The following may also be assessed if available: 
•
Number of VOCs leading to a healthcare visit
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•
Number of uncomplicated VOCs, acute chest syndrome, hepatic sequestration,
splenic sequestration, and priapism
•
Time to first VOC after first dose of study drug
9.4.3. 
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. 
Safety analyses will include an analysis of all TEAEs, 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. AEs will also be summarized by 
cohort and treatment arm, and overall, within each treatment arm, and by severity. SAEs 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, clinical 
chemistry, cell blood count with differential, and urinalysis) will be summarized by each cohort 
and overall. 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. 
9.4.3.1. 
ECG Analysis 
Cardiac assessments will be performed in the Safety Population. 
The ECG parameters will be measured at the specified time points, including heart rate, PR, RR, 
QRS, QT, and 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
Analysis of drug-related QT/QTc interval changes relative to plasma PK concentrations may be 
conducted on all dose regimens. The principles of this analysis follow the statistical methods 
described by Garnett et al. (Garnett, 2018).  
Detailed analysis will be specified in the SAP or a separate ECG analysis plan. 
9.4.4. 
Other Analyses 
9.4.4.1. 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Population and will be reported by cohort. 
The individual serum concentration data from patients who receive ALXN1820 SC with actual 
sampling dates and times will be used to characterize PK using a population PK analysis 
approach.  The details will be provided in the SAP. 
9.4.4.2. 
Pharmacodynamic Analyses 
All PD analyses will be performed on the PD Population and will be reported by cohort. 
The PD effects of all ALXN1820 SC 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 other measures of properdin activity over time may be 
considered as deemed appropriate. 
9.4.4.3. 
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). 
9.4.4.4. 
Exploratory Analysis 
Additional exploratory analysis on biomarker assays and clinical efficacy endpoint may be 
conducted. Details of these analyses will be presented in the SAP. 
9.5. 
Interim Analyses 
An interim analysis may be performed after at least 12 patients from Cohorts 1 and 2 (6 from 
each cohort) have enrolled and completed the Treatment Period to inform later phase trials. The 
interim analysis will include safety, efficacy, PK/PD and immunogenicity data. Details of this 
analysis will be presented in the SAP.  
9.6. 
Data Monitoring Committee 
An independent DMC, comprising experts in relevant fields with no direct relationship to the 
study, will be appointed by Alexion. The specific responsibilities of the DMC and a schedule of 
meetings will be described in the DMC Charter. 
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9.7. 
Safety Review Committee 
Not applicable. 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1. 
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 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.
−
If any of these documents require regulatory/health authority approval per local
regulations, Alexion will also obtain such approval 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 or designee to obtain signed (written or
electronic signature) informed consent from all study participants or the participant’s
legally authorized representative 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, initials, 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 in 
accordance with applicable data protection law, and participants must also be 
informed of any individuals rights they may have with regard to their personal data. 
Participants will be informed about how their personal study-related data will be 
disclosed, and will be required to agree to the information contained in the informed 
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consent and provide consent to the processing of their personal data, if required by 
applicable data protection law. 
Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Alexion, 
appropriate IRB/IEC members, and inspectors from regulatory authorities. 
Alexion as a data controller has implemented privacy and security controls designed 
to help protect participant personal data; including information security controls, 
firewalls, incident detection, and secure transfer measures. 
In the event of any accidental or unlawful destruction, loss, alteration, unauthorized 
disclosure of, or access to, personal data (“breach”), the controller has implemented 
procedures and measures to promptly address and mitigate any risk to the data 
participant. In the event of a breach, the controller will notify the appropriate 
regulatory authorities and/or the data participant in accordance with applicable data 
protection law. 
10.1.5. 
Committees Structure 
See Section 9.6.  
10.1.6. 
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. 
10.1.7. 
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.
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−
Remote source data verification may be employed where permitted by local
regulations.
−
The scope of the source data verification will be described in detail in the Clinical
Monitoring Plan.
•
Records and documents, including signed ICFs, pertaining to the conduct of this
study must be retained by the Investigator per local regulations or institutional
policies. 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.
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The Investigator or designee will prepare and maintain adequate 
and accurate source documents (eg, medical records, ECGs, AE and concomitant medication 
reporting, raw data collection forms) designed to record all observations and other pertinent data 
for each participant. 
Data reported on the 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 to Alexion, Alexion delegates, and health authorities, as 
requested. Source documents are filed at the Investigator’s site. 
Per ICH E6 (R2) guidelines and good documentation practice requirements, source documents 
and study records in all media (eg, paper, electronic) must be Attributable, Legible, 
Contemporaneous, Original, Accurate, and Complete. 
10.1.9. 
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 its sole discretion. 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 last study visit or Early Discontinuation Visit, all data have been collected 
and entered into the electronic data capture system, all required documents and study supplies 
have been collected and reconciled, 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 ICH GCP guidelines 
Inadequate recruitment of participants by the Investigator 
Discontinuation of further study intervention development 
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Alexion or health authority may terminate the study for reasonable cause. Conditions that may 
warrant termination of the study include, but are not limited to: 
Discovery of an unexpected, serious, or unacceptable risk of the study intervention to 
participants enrolled or continuing in the study  
Alexion decision to suspend or discontinue testing, evaluation, or development of the 
study intervention  
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, IRBs/IECs, 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. 
10.1.10. 
Publication Policy 
•
Where possible, primary manuscripts reporting results of the primary efficacy
endpoint or the final results will be submitted for publication to peer-reviewed,
indexed (eg, PubMed, Scopus, Embase) journals within 12 to 18 months of the
primary evaluation date or EOS, 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 Letter of 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 provide
comments.
−
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.
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 as defined 
by the Pharmaceutical Research and Manufacturers of America and the International 
Committee of Medical Journal Editors recommendations and per the Alexion 
Publication Policy. In accordance with standard editorial and ethical practice, Alexion 
will generally support publication of multicenter studies only in their entirety and not 
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as individual site data. In this case, a Co-ordinating 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. 
Alexion will publish Plain Language Summaries and include participants and/or 
caregivers as reviewers for readability and understanding of lay person language. 
•
No compensation shall be provided to external Authors for authorship of publication,
including drafting or revising a publication. Alexion may reimburse the presenting
Author of an Alexion-supported publication for travel, lodging, and registration to
present a poster or oral presentation at scientific meeting, consistent with the Alexion
Global Procurement and Sourcing Procedure, the Alexion Antibribery Anticorruption
Policy and the Alexion Global Travel and Expense Policy.
•
Authors must disclose financial or personal affiliations that could be considered a
conflict of interest in the publication.
10.1.11. 
Good Clinical Practice Compliance 
Alexion and any third party to whom aspects of the study management or monitoring have been 
delegated will undertake their assigned roles for this study in compliance with all applicable 
industry regulations, ICH GCP Guideline E6 R2, EU Directive 2001/20/EC, as well as all 
applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of Alexion and/or the company 
organizing/managing the research on behalf of Alexion to inspect study data, participants’ 
medical records, and eCRFs in accordance with current GCP and respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
Alexion ensures that local regulatory authority requirements are met before the start of the study. 
Alexion (or designee) is responsible for the preparation, submission, and confirmation of receipt 
of any regulatory authority approvals required prior to release of study drug for shipment to the 
site. 
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10.2. 
Clinical Laboratory Tests 
•
The protocol-required clinical laboratory tests detailed in Table 13 will be performed
by a central laboratory unless otherwise specified.
•
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 local 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 13: 
Protocol-required Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
Red blood cell (RBC) count 
Hemoglobin  
Free Hemoglobin 
Hemoglobinopathy test (eg, hemoglobin electrophoresis, screening only) 
Hematocrit 
Haptoglobin 
Hemopexin 
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 
Fructosamine 
LDH 
Potassium 
Sodium 
Serum albumin 
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Table 13: 
Protocol-required Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Total and direct bilirubin 
Indirect 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 blood or protein is abnormal 
Spot urine 
studies 
Protein, albumin, creatinine, and protein-to-creatinine and albumin/creatinine ratio 
Complement 
activity 
Change in CAP activity using the Wieslab AP assay 
Biomarkers 
Complement biomarkers 
Biomarkers related to VOC 
Other biomarkers may be considered if feasible 
Other 
screening 
tests 
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) a  
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) 
a Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC. 
Abbreviations: AP = alternative pathway; CAP = complement alternative pathway; CCP = complement 
classical pathway; HBc = hepatitis B core; IEC = Independent Ethics Committee; IgG = 
immunoglobulin G; IgM = immunoglobulin M; IRB = Institutional Review Board; LDH = lactate 
dehydrogenase; LP = lectin pathway; MCH = mean corpuscular hemoglobin; MCV = mean 
corpuscular volume; SAE = serious adverse event; VOC = vaso-occlusive crisis. 
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10.3. 
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 or clinical investigation participant
administered a pharmaceutical product and which does not necessarily have to have a causal
relationship with this treatment (ICH E2A).
•
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 the study intervention, whether or not considered related to the 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 (ie, not related to progression of underlying disease).
• 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.
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Events Not Meeting the AE Definition 
•
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
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.
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Protocol Amendment 1.0 
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A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
An event that is assessed as serious by the Investigator and/or Alexion that is not listed in the 
appropriate Reference Safety Information (IB) and has been assessed that there is at least a reasonable 
possibility that the event is related to the investigational medicinal product by the Investigator and/or 
Alexion. 
Alexion has procedures that will be followed for the recording, medical assessment, and expedited 
reporting of SUSARs that are consistent with global regulations, legislation, and guidance documents. 
Suspected unexpected serious adverse reactions will undergo expedited reporting to the national 
regulatory authorities, IRBs/IECs, and Investigators following local regulatory reporting requirements 
where applicable. 
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 Alexion 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
An event is defined as “serious” when it meets at least one of the predefined outcomes as described in 
the definition of an SAE, not when it is rated as severe. 
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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 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 they have
reviewed the AE/SAE and has provided an assessment of causality.
• There may be situations in which an SAE has occurred, and the Investigator has minimal
information to include in the initial report to Alexion. However, it is very important that the
Investigator always make an assessment of causality for every event before the initial
transmission of the SAE data to Alexion.
• 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 Alexion to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include
additional laboratory tests or investigations, histopathological examinations, or consultation
with other health care professionals.
• 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.
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Protocol Amendment 1.0 
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Follow-up of AEs and SAEs 
• The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of
the information.
10.3.4. 
Reporting of SAEs 
SAE Reporting to Alexion via an Electronic Data Collection Tool 
• All SAEs will be recorded and reported to Alexion immediately and within 24 hours of
awareness.
• The primary mechanism for reporting an SAE to Alexion will be the electronic data capture
(EDC) system.
• If the electronic system is unavailable or site staff is unable to process the SAE via the EDC
system at the time that the Investigator or site becomes aware of an SAE, the site will use the
paper Contingency Form for SAE Reporting via facsimile or email. Facsimile transmission or
email may also be used in the event of electronic submission failure.
−
Email: clinicalsae@alexion.com or Fax: + 1.203.439.9347
• The site will enter the SAE data into the EDC system as soon as it becomes available.
• When further information becomes available, the EDC should be updated immediately with
the new information and an updated SAE report should be submitted to Alexion Global Drug
Safety (GDS) within 24 hours of Investigator/site awareness.
• After the participant has completed the study, no new data or changes to existing data are
expected to be entered in the EDC system.
−
If a site receives a report of a new SAE from a study participant which the Investigator
considers to be related to the study intervention, or the site receives updated data on a
previously reported SAE after the EDC system has been taken offline, then the site can
report this information on a paper Contingency Form for SAE Reporting via facsimile
or email.
SAE Reporting to Alexion via Paper Safety Reporting Form <to be used if EDC is not available> 
• All SAEs will be recorded and reported to Alexion immediately and within 24 hours of
awareness.
• SAEs will be reported using the Safety Reporting Form and submitted to Alexion GDS. The
Investigator must complete, sign, and date the SAE pages, verify the accuracy of the
information recorded on the SAE pages with the corresponding source documents, and send a
copy via email or facsimile to the contact information provided below:
−
Email: clinicalsae@alexion.com or Fax: + 1.203.439.9347
• 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)
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SAE Reporting to Alexion via Paper Safety Reporting Form <to be used if EDC is not available> 
−
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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Protocol Amendment 1.0 
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10.4. 
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the Following Categories Are Not Considered WOCBP 
1. Premenarchal
2. Premenopausal female with one of the following:
•
Documented hysterectomy
•
Documented bilateral tubal ligation or bilateral salpingectomy
•
Documented bilateral oophorectomy
•
For individuals with permanent infertility due to an alternate medical cause other than the
above, (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion should be
applied to determining study entry.
•
Note: Documentation can come from the site personnel’s review of the participant’s
medical records, medical examination, or medical history interview.
3. Postmenopausal female
•
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause prior to the Day 1 Visit.
−
A high follicle-stimulating hormone (FSH) level in the postmenopausal range
may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy (HRT). However, in the absence
of 12 months of amenorrhea, confirmation with a single FSH measurement is
insufficient. In the absence of 12 months of amenorrhea the reason for not
obtaining FSH levels should be documented by the Investigator at the time of
Screening.
•
Females on HRT and whose menopausal status is in doubt will be required to use one
of the non-estrogen hormonal highly effective contraception methods if they wish to
continue their HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status before study enrollment.
4. Permanent sterilization at least 6 weeks prior to the Day 1 Visit.
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Protocol Amendment 1.0 
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22 August 2022 
10.4.2. 
Contraception Guidance 
Contraceptive use by male or female participants should be consistent with local regulations 
regarding the methods of contraception utilized for those participating in clinical studies. If 
teratogenic effects are suspected to be transferred to a fetus/embryo from a female spouse/partner 
of a male participant, pregnancy follow-up information will be obtained for the partner who 
becomes pregnant (refer to Section 10.4.3.1 ). In these cases, follow-up will be conducted on the 
pregnant partner in the same manner as a female participant who becomes pregnant during the 
study. 
10.4.2.1. Guidance for Female Participants 
Female participants of childbearing potential must have a negative pregnancy test ([urine or 
serum]) as required by local regulations before the first dose of ALXN1820. Additional 
requirements for pregnancy testing during and after dosing with ALXN1820 are indicated in the 
SoA (Section 1.3). 
The Investigator is responsible for the review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
The Investigator should evaluate the potential for contraceptive method in relationship to the first 
dose of ALXN1820. 
Female participants must not donate ova from the Day 1 Visit at least until 6 months after their 
final dose of ALXN1820. 
A highly effective method of contraception, including at least 1 of the following must be used 
until 6 months after the final dose of ALXN1820. 
1. Intrauterine device in place for at least 6 weeks prior to first dose of ALXN1820.
2. Intrauterine progestogen releasing system for at least 6 weeks prior to first dose of
ALXN1820.
3. Bilateral tubal occlusion for at least 6 weeks prior to first dose of ALXN1820.
4. Progestogen-only hormonal contraception associated with inhibition of ovulation
(implantable only) for at least 6 weeks prior to first dose of ALXN1820.
5. Surgical sterilization of the male partner (medical assessment of azoospermia is required
if vasectomy was performed within 6 months prior to first dose of ALXN1820). Male
partner is still required to use condom during heterosexual intercourse.
Female participants must not donate ova from the Day 1 Visit at least until 6 months after their 
final dose of ALXN1820. 
Female participants of childbearing potential must use a highly effective method of 
contraception, including at least 1 of the following until 6 months after the final dose of 
ALXN1820. 
1. Intrauterine device in place for at least 6 weeks prior to first dose of ALXN1820.
2. Progestogen-only hormonal contraception associated with inhibition of ovulation (either
oral, injectable, or implantable) for at least 6 weeks prior to first dose of ALXN1820.
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Protocol Amendment 1.0 
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22 August 2022 
3. Intrauterine progestogen releasing system for at least 6 weeks prior to first dose of
ALXN1820.
4. Bilateral tubal occlusion for at least 6 weeks prior to first dose of ALXN1820.
5. Combined (estrogen- and progestogen-containing) hormonal contraception (either oral,
intravaginal, or transdermal) for at least 6 weeks prior to first dose of ALXN1820.
6. Surgical sterilization of the male partner (medical assessment of azoospermia is required
if vasectomy was performed within 6 months prior to first dose of ALXN1820). Male
partner is still required to use condom during sexual intercourse.
7. Sexual abstinence for female participants:
a.
Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse. In this study, abstinence is only acceptable
if consistent with the participant’s preferred and usual lifestyle. Abstinent female
participants must refrain from heterosexual intercourse for at least 6 months after the
final dose of ALXN1820.
The following methods of contraception are considered unacceptable in this study: 
−
Periodic abstinence (calendar, symptothermal or post ovulation methods
−
Withdrawal (coitus interruptus)
−
Spermicides only
−
Lactational amenorrhea method
−
Female condom and male condom should not be used together
10.4.2.2. Guidance for Male Participants 
Contraception is the responsibility of the heterosexually active male participants in the study, 
regardless of his female partner’s method of contraception. 
Male participants who have had a vasectomy > 6 months prior to the first dose of ALXN1820 
must use a condom during heterosexual intercourse. Male participants who have had a 
vasectomy < 6 months prior to the first dose ALXN1820 and those who have not had a 
vasectomy must use a condom with or without spermicide during heterosexual intercourse for at 
least 6 months after their final dose of ALXN1820.  
Male participants must not donate sperm from the Day 1 Visit until 6 months after their final 
dose of ALXN1820.  
10.4.2.2.1. Sexual Abstinence for Male Participants 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse. In this study, abstinence is only acceptable if consistent with the 
participant’s preferred and usual lifestyle. Abstinent male participants who become 
heterosexually active must use a condom and spermicide during intercourse. 
Periodic abstinence (eg, calendar, symptothermal, or post ovulation methods for a female 
partner) is not considered a highly effective method of contraception for male participants. 
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Protocol Amendment 1.0 
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Male participants must not donate sperm from the Day 1 Visit until 6 months after their final 
dose of ALXN1820.  
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 and
submitted to Alexion within 24 hours of learning of a participant’s pregnancy 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.
10.4.3.1. Male Participants with Partners Who Become Pregnant 
•
The Investigator will attempt to collect pregnancy information on any male
participant’s female partner who becomes pregnant while the male participant is in
this study. This applies only to male participants who receive ALXN1820.
•
After obtaining the necessary signed informed consent from the pregnant female
partner directly, the Investigator will record pregnancy information on the appropriate
“Pregnancy/Breastfeeding Reporting and Outcome Form” and submit it to Alexion
within 24 hours of learning of the partner’s pregnancy. The female partner will also
be followed to determine the outcome of the pregnancy. Information on the status of
the mother and child will be forwarded to Alexion. Generally, the follow-up will be
no longer than 3 months following the delivery date. Any termination of the
pregnancy will be reported regardless of fetal status (presence or absence of
anomalies) or indication for the procedure.
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Protocol Amendment 1.0 
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10.4.3.2. Female Participants Who Become Pregnant 
•
For all Alexion products, both in development or postapproval, exposure during
pregnancy must be recorded and the pregnancy followed, until the outcome of the
pregnancy is known (ie, spontaneous miscarriage, elective termination, normal birth,
or congenital abnormality), even if the participant discontinues the study intervention
or withdraws from the study. The Investigator will collect follow-up information on
the participant and the neonate and the information will be forwarded to Alexion.
Generally, follow-up will not be required for longer than 3 months beyond the
estimated delivery date. Any termination of pregnancy will be reported, regardless of
fetal status (presence or absence of anomalies) or indication for the procedure.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy for medical reasons will be
reported as an AE or SAE. A spontaneous abortion (occurring at < 22 weeks
gestational age) or still birth (occurring at > 22 weeks gestational age) is always
considered to be an SAE and will be reported as such. Any poststudy
pregnancy-related SAE considered reasonably related to the study intervention by the
Investigator will be reported to Alexion. While the Investigator is not obligated to
actively seek this information in former study participants, he or she may learn of an
SAE through spontaneous reporting.
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Protocol Amendment 1.0 
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10.5. 
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 multi-study 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 25 years or other period as per local requirements.
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10.6. 
Management of Potential Adverse Events During Study Drug 
Administration 
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.  
All 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. Alexion must be 
notified within 24 hours of any injection site 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.  
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.  
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
10.7. 
COVID-19 Risk Assessment 
Sickle cell disease can cause irreversible morbidity and even mortality, if untreated. As such, and 
due to the limited number of available treatment options, the benefit a participant may receive 
from joining an investigational study with a therapeutic treatment is potentially significant. 
Given that SCD does involve some level of immune deficiency as part of its clinical presentation 
and evolution, there is a theoretical concern that the risk for infection may be higher than the 
general population.  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 14. 
Table 14: 
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. 
Alexion Confidential
Page 86 of 93


Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
10.8. 
COVID-19 Vaccine Risk Assessment 
Following a review of the available COVID-19 vaccine data (eg, Pfizer/BioNTech, Moderna, 
AstraZeneca, Johnson & Johnson), it is unlikely that the immune response to a COVID-19 
vaccine (and therefore the efficacy of the vaccination) would be diminished with concomitant 
ALXN1820 administration, based on ALXN1820’s mechanism of action. There is currently no 
information available evaluating the safety and efficacy of COVID-19 vaccines in participants 
treated with ALXN1820.  
Local and national guidelines should be consulted for recommendations related to COVID-19 
vaccination. Alexion suggests that participants complete vaccination series before study 
participation, if feasible. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 
vaccination rollout are provided in Table 15.  
Table 15: 
Potential Risks and Mitigation Measures due to COVID-19 Vaccine 
Risks Category 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential risks 
Data quality and 
integrity 
Missing data due to appointments for 
COVID-19 vaccination or side effects of 
COVID-19 vaccine may impact study visit 
schedules, and increase missed visits and/or 
participant study discontinuations, 
inadvertently resulting in missing data (eg, 
for protocol-specified procedures). 
Capture specific information in 
the eCRF that explains the 
reason for missing data (eg, 
missed study visits due to 
appointments for COVID-19 
vaccination or side effects of 
COVID-19 vaccine). 
Abbreviations: COVID-19 = coronavirus disease 2019; eCRF = electronic case report form. 
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
10.9. 
Abbreviations 
Table 16: 
Abbreviations and Specialist Terms 
Abbreviation or 
Term 
Explanation 
ADA 
antidrug antibody 
AE 
adverse event 
AP 
alternative pathway 
AUC0-168 
area under the concentration-time curve from time 0 to 168 hours 
Ba 
complement component Ba 
BMI 
body mass index 
C3 
complement component C3 
C3a 
complement component C3a 
C5 
complement component 5 
C9 
complement component 9 
CAP 
complement alternative pathway 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum observed serum concentration 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
% CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
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 
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Table 16: 
Abbreviations and Specialist Terms 
Abbreviation or 
Term 
Explanation 
HBc 
hepatitis B core 
HbS 
sickle hemoglobin 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HiB 
Haemophilus influenzae type b 
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 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
KD 
dissociation constant 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
MCV4 
tetravalent meningococcal conjugate vaccine 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QTcF 
QT interval corrected using the Fridericia’s formula 
Q2W 
once every 2 weeks 
Q4W 
once every four weeks 
QW 
once weekly 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
sC5b9 
soluble complement component C5b-9 
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Table 16: 
Abbreviations and Specialist Terms 
Abbreviation or 
Term 
Explanation 
SCD 
sickle cell disease 
SoA 
schedule of activities 
SOC 
System Organ Class 
TCR 
tissue cross reactivity 
TEAE 
treatment-emergent adverse event 
VHH 
single variable domain on a heavy chain antibody 
VOC 
vaso-occlusive crisis 
WOCBP 
woman of childbearing potential 
Alexion Confidential
Page 90 of 93


Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
10.10. 
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 
Amendment 1.0 Global [22 August 
2022] 
The main rationale for this amendment is to clarify 
stopping rules and inclusion/exclusion criteria  
Original protocol [13 May 2022] 
Not applicable 
Alexion Confidential
Page 91 of 93


Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
11.
REFERENCES
Aliyu ZY, Kato GJ, Taylor Jt, et al. Sickle cell disease and pulmonary hypertension in Africa: a 
global perspective and review of epidemiology, pathophysiology, and management. Am J 
Hematol. 2008;83(1):63-70. 
Chonat S, Graciaa S, Shin HS, et al. Eculizumab for complement mediated thrombotic 
microangiopathy in sickle cell disease. Haematologica. 2020;105(12):2887-2891. 
Crizanlizumab. Crizanlizumab, Drug Label Information 2019. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761128s000lbl.pdf. 
Engert A, Balduini C, Brand A, et al. The European Hematology Association Roadmap for 
European Hematology Research: a consensus document. Haematologica. 2016;101(2):115-208. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin 
Microbiol Rev. 1991;4(3):359-395. 
Gardner K, Douiri A, Drasar E, et al. Survival in adults with sickle cell disease in a high-income 
setting. Blood. 2016;128(10):1436-1438. 
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. J 
Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38(4 
Suppl):S512-521. 
Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010. 
Lombardi E, Matte A, Risitano AM, et al. Factor H interferes with the adhesion of sickle red 
cells to vascular endothelium: a novel disease-modulating molecule. Haematologica. 
2019;104(5):919-928. 
Lubeck D, Agodoa I, Bhakta N, et al. Estimated Life Expectancy and Income of Patients With 
Sickle Cell Disease Compared With Those Without Sickle Cell Disease. JAMA Netw Open. 
2019;2(11):e1915374. 
Payne AB, Mehal JM, Chapman C, et al. Trends in Sickle Cell Disease-Related Mortality in the 
United States, 1979 to 2017. Ann Emerg Med. 2020;76(3S):S28-S36. 
Pecker LH, Lanzkron S. Sickle Cell Disease. Ann Intern Med. 2021;174(1):ITC1-ITC16. 
Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017;377(3):305. 
Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and 
risk factors for early death. N Engl J Med. 1994;330(23):1639-1644. 
Alexion Confidential
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Protocol Amendment 1.0 
ALXN1820-SCD-201 
22 August 2022 
Strauss RG, Asbrock T, Forristal J, West CD. Alternative pathway of complement in sickle cell 
disease. Pediatr Res. 1977;11(4):285-289. 
Tampaki A, Gavriilaki E, Varelas C, Anagnostopoulos A, Vlachaki E. Complement in sickle cell 
disease and targeted therapy: I know one thing, that I know nothing. Blood Rev. 
2021;48:100805. 
Varelas C, Tampaki A, Sakellari I, Anagnostopoulos A, Gavriilaki E, Vlachaki E. Complement 
in Sickle Cell Disease: Are We Ready for Prime Time? J Blood Med. 2021;12:177-187. 
Alexion Confidential
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Administrative Change Letter #2 
Date of Letter: 12 April 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Page 1 of 2 
Alexion Confidential 
Alexion Pharmaceuticals, Inc. 
       12 April 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Protocol Title: A Phase 2a, Randomized, Open-Label Study to Evaluate Multiple Dosing 
Regimens of Subcutaneous ALXN1820 in Adult Patients with Sickle Cell Disease 
Protocol Administrative Change Letter #2 
Reason for Letter:  Clarify guidelines on determining whether a hospitalization or prolongation 
of a hospitalization are considered an AE/SAE. Clarify the timeframe between the (2) Screening 
Blood Biomarker sample collections. Clarify that randomization can be performed as early as one 
(1) business day prior to Day 1 dosing and clarify the position a patient must be in for blood
pressure assessments.
To those sites participating in the above named and numbered clinical study, this letter serves to 
inform you about the following administrative changes to the above referenced protocol version. 
Protocol Sections below should include additional text noted in bold & underlined and remove 
the text noted; highlighted in gray and in strikethrough: 
1. Protocol Section 9.4.2: Exploratory Assessment of VOC:
Complicated VOCs (uncomplicated & complicated) that are considered exacerbated 
(increased in frequency or severity) from baseline (Day 1) are also to be reported as 
AEs. 
2. Protocol Section 10.3.2: Definition of SAE:
3. Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that Inpatient hospitalization is defined as the 
participant has been detained admitted for (usually involving at least an overnight stay) 
at least 24 hours. 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. 
3. Schedule of Activities: Tables 3, 4, and 7 footnotes:
•
Blood samples for biomarkers will be collected two times prior to receiving the
first dose (collect once during Screening and then again on Day 1 pre-dose, the 2


Administrative Change Letter #2 
Date of Letter: 12 April 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Page 2 of 2 
Alexion Confidential 
collections should must be at least 2 1 weeks apart). Collection of blood (for serum, 
citrated and K2-EDTA, or P100 plasma) and urine. 
4. Schedule of Activities: Tables 3, 4, and 7 footnotes:
c Randomization will occur following confirmation of all eligibility requirements.
Randomization can be performed up to 1 business day prior to Day 1 dosing.
5. 8.2.2. Vital Signs
Vital sign measurements will be taken after the participant has been resting in the supine 
or semi-recumbent position or preferred position per site standard practice for at least 
5 minutes and will include temperature (tympanic or oral), respiratory rate, supine blood 
pressure, and pulse. Ideally, the same arm for each participant should be used for BP and 
pulse measurements. Orthostatic (standing) blood pressure will only be measured at 
Screening. 
6. Schedule of Activities: All Tables footnotes
-
At Screening, supine and standing (orthostatic) blood pressures will be performed.
At all other visits blood pressure can be performed supine or preferred position per
site standard practice.
7. Schedule of Activities: All Tables footnotes
-
If a VOC occurs, samples will be collected as per unscheduled visit, when
feasible.
Please file this letter and any IRB/EC correspondence with all copies of the protocol in the 
Investigator Site File and in all pertinent repositories in which the protocol is maintained.
If there are any questions concerning these changes, please contact us. These changes will also be 
captured in any future protocol amendment. 
_________________
  
, Clinical Development Sciences 
Alexion Pharmaceuticals  
Phone: 
 
Email: 
  
Cc: eTMF 
, Clinical Project Lead 
XLExI• N 


Administrative Change Letter #3
Date of Letter: 14 July 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Page 1 of 1 
Alexion Confidential 
Alexion Pharmaceuticals, Inc. 
       14 July 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Protocol Title: A Phase 2a, Randomized, Open-Label Study to Evaluate Multiple Dosing Regimens 
of Subcutaneous ALXN1820 in Adult Patients with Sickle Cell Disease 
Protocol Administrative Change Letter #3 
Reason for Letter:  Clarify the Safety Follow-up period and intended visit sequence upon a 
participant meeting criteria (or deciding to) discontinue study drug intervention.   
To those sites participating in the above named and numbered clinical study, this letter serves to 
inform you about the following administrative changes to the above referenced protocol version. 
Protocol Sections below should include additional text noted in bold & underlined: 
1. Section 7.1.  
Discontinuation of Study Drug 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. The safety 
follow-up period should follow the periodicity and assessments defined in the SOA Table 
6 from Day 99 through Day 211 and includes any subsequent Complement Activity 
Follow-up visits. (Cohorts 1 & 2). The safety follow-up period for the optional cohort 
(Cohort 3) should follow the periodicity and assessments defined in the SOA Table 8 
from Day 57 through Day 169 and includes any subsequent Complement Activity 
Follow-up visits. The first safety follow-up visit, Day 99 for Cohorts 1 & 2 and Day 57 
for Cohort 3, must occur 14 days (+/- 3 days) after the patient receives their last dose of 
ALXN1820. 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 (Section 
1.3). 
Please file this letter and any IRB/EC correspondence with all copies of the protocol in the 
Investigator Site File and in all pertinent repositories in which the protocol is maintained. 
If there are any questions concerning these changes, please contact us. These changes will also be 
captured in any future protocol amendment. 
 
  
, Clinical Development Sciences 
Alexion Pharmaceuticals  
Phone: 
 
Email: 
  
Cc: eTMF 
, Clinical Project Lead 
P<LExI• N 


Administrative Change Letter #4 
Date of Letter: 14 August 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Page 1 of 2 
Alexion Confidential 
Alexion Pharmaceuticals, Inc. 
       14 August 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Protocol Title: A Phase 2a, Randomized, Open-Label Study to Evaluate Multiple Dosing Regimens 
of Subcutaneous ALXN1820 in Adult Patients with Sickle Cell Disease 
Protocol Administrative Change Letter #4 
Reason for Letter:  Clarify the allowed use of medicines and therapy permitted during the study and 
provide clarification regarding bilateral tubal ligation as a method of highly effective contraception 
but not a permanent sterilization method (ie, women who have undergone tubal ligation will be 
considered of childbearing potential) and remove duplicative text for clarification. 
To those sites participating in the above named and numbered clinical study, this letter serves to 
inform you about the following administrative changes to the above referenced protocol version. 
The Protocol Sections below should include additional text noted in bold & underlined and remove 
the text noted; highlighted in gray and in strikethrough: 
1.
Section 6.5.1  Allowed Medicine and Therapy
Multivitamins, contraceptives, and paracetamol
 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.
2.
Section 10.4.1 Women in the Following Categories Are Not Considered WOCBP
1. Premenarchal
2. Premenopausal female with one of the following:
Documented hysterectomy 
Documented bilateral tubal ligation or bilateral salpingectomy 
Documented bilateral oophorectomy 
3.
Section 10.4.2.1 Guidance for Female Participants
A highly effective method of contraception, including at least 1 of the following must be used 
until 6 months after the final dose of ALXN1820. 
1.
Intrauterine device in place for at least 6 weeks prior to first dose of ALXN1820.
2.
Intrauterine progestogen releasing system for at least 6 weeks prior to first dose of
ALXN1820. 
3.
Bilateral tubal occlusion for at least 6 weeks prior to first dose of ALXN1820.
4.
Progestogen-only hormonal contraception associated with inhibition of ovulation
(implantable only) for at least 6 weeks prior to first dose of ALXN1820. 
5.
Surgical sterilization of the male partner (medical assessment of azoospermia is required
if vasectomy was performed within 6 months prior to first dose of ALXN1820). Male 
partner is still required to use condom during heterosexual intercourse. 
Female participants must not donate ova from the Day 1 Visit at least until 6 months after 
their final dose of ALXN1820 


Administrative Change Letter #4 
Date of Letter: 14 August 2023 
Protocol: ALXN1820-SCD-201 Protocol Amendment 1 (22 August 2022) 
Page 2 of 2 
Alexion Confidential 
4.
Schedule of Activities: All Tables footnotes
-
If a VOC occurs, samples will be collected as per unscheduled visit, within 7
days of VOC resolution when feasible.
correspondence with all copies of the protocol in the 
Investigator Site File and in all pertinent repositories in which the protocol is maintained. 
If there are any questions concerning these changes, please contact us. These changes will also be 
captured in any future protocol amendment. 
__________________________________________ 
  
, Clinical Development Sciences 
Alexion Pharmaceuticals  
Phone: 
 
Email: 
  
Cc: eTMF 
, Clinical Project Lead 
XLExI• N 
Please file this letter and any IRB/EC 

SAP_001.pdf: 
Statistical Analysis Plan{Version Number} 
ALXN1820-SCD-201 Protocol Amendment 1.0 {Date 24 Oct 2023} 
Page 1 of 21 
Alexion Confidential 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
Version Number: 1.0 
Protocol Title: A Phase 2a, Randomized, Open-Label Study to Evaluate Multiple Dosing 
Regimens of Subcutaneous ALXN1820 in Adult Patients With Sickle Cell Disease 
Protocol Number: ALXN1820-SCD-201 
Protocol Amendment Number: 1.0 
Compound: ALXN1820 
Brief Title: Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Study of ALXN1820 in 
Adult Patients With Sickle Cell Disease  
Sponsor Name: Alexion Pharmaceuticals, Inc.  
Legal Registered Address: 121 Seaport Boulevard, Boston, MA 02210 
Regulatory Agency Identifier Number(s): 
NCT: 
NCT05565092 
EudraCT: 
2022-001615-74 
Author: 
 
Version Date: 24 Oct 2023 


Statistical Analysis Plan{Version Number} 
ALXN1820-SCD-201 Protocol Amendment 1.0 {Date 24 Oct 2023} 
Page 2 of 21 
Alexion Confidential 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................3 
VERSION HISTORY ......................................................................................................................4 
APPROVAL SIGNATURES...........................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Objectives, Endpoints, and Estimands..........................................................................7 
1.2. 
Study Design .................................................................................................................8 
2. 
STATISTICAL HYPOTHESES ................................................................................10 
3. 
ANALYSIS SETS ......................................................................................................11 
4. 
STATISTICAL ANALYSES .....................................................................................12 
4.1. 
General Considerations ...............................................................................................12 
4.2. 
Primary Endpoints Analysis .......................................................................................12 
4.2.1. 
Analysis of AEs ..........................................................................................................12 
4.2.2. 
Analysis of Laboratory Assessments ..........................................................................13 
4.2.3. 
Analysis of Vital Signs ...............................................................................................13 
4.2.4. 
Analysis of Physical Examination ..............................................................................13 
4.2.5. 
Analysis of ECG Results ............................................................................................13 
4.3. 
Secondary Endpoints Analysis ...................................................................................14 
4.3.1. 
Analysis of PK/PD ......................................................................................................14 
4.3.2. 
Analysis of SCD Biomarkers......................................................................................14 
4.3.3. 
Analysis of Immunogenicity .......................................................................................14 
4.4. 
Exploratory Endpoints Analysis .................................................................................15 
4.5. 
Changes to Protocol-Planned Analyses ......................................................................15 
5. 
SAMPLE SIZE DETERMINATION .........................................................................17 
6. 
SUPPORTING DOCUMENTATION ........................................................................18 
6.1. 
Technical Specifications for Derived Variables .........................................................18 
6.2. 
Study and Participant Characteristics .........................................................................18 
6.2.1. 
Participant Disposition ................................................................................................18 
6.2.2. 
Baseline Characteristics and Demographics ...............................................................18 


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6.2.3. 
Medical History ..........................................................................................................19 
6.2.4. 
Prior and Concomitant Medications ...........................................................................19 
6.2.5. 
Protocol Deviations ....................................................................................................19 
6.3. 
Instrument Scoring Details .........................................................................................19 
6.4. 
Additional Details on Statistical Methods ..................................................................20 
7. 
REFERENCES ...........................................................................................................21 
 
LIST OF TABLES 
 
Table 1: 
Objectives and Endpoints .............................................................................................7 
Table 2: 
ALXN1820-SCD-201 Dosing Cohorts .........................................................................8 
 


Statistical Analysis Plan{Version Number} 
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Alexion Confidential 
VERSION HISTORY 
This statistical analysis plan (SAP) for Study ALXN1820-SCD-201 is based on Protocol 
Amendment 1.0, dated 22 Aug 2022.  
SAP Version Version Date 
Change 
Rationale 
1.0 
 24 OCT 2023 
Not applicable 
Original version 


Statistical Analysis Plan{Version Number} 
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Alexion Confidential 
APPROVAL SIGNATURES 
 
 
 
 
, Biostatistics 
 
Date dd Mmm yyyy 
 
 
 
, Biostatistics 
 
Date dd Mmm yyyy 
 
 
 
 
 
 Clinical 
Development Sciences   
 
Date dd Mmm yyyy 
 
27-Oct-2023
27-Oct-2023
27-Oct-2023


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Alexion Confidential 
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
CAP 
complement alternative pathway 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
HR 
heart rate 
ICF 
informed consent form 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
QTcF 
corrected QT interval by Fridericia’s formula 
RR 
respiratory rate 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SCD 
sickle cell disease 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
VOC 
vaso-occlusive crisis 
WHO-Drug 
World Health Organization Drug Dictionary 


Statistical Analysis Plan{Version Number} 
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1. 
INTRODUCTION 
This statistical analysis plan describes the plan for presenting the data for final analysis for 
Protocol ALXN1820-SCD-201. Due to the early termination of the study, data will only be 
listed.  
Safety, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, biomarker, 
demographics and baseline characteristics, medical history, prior and concomitant medications 
and efficacy data are included. Standard data presentation instructions and listing specifications 
are contained in the Data Presentation Plan in a separate document. 
Changes to the protocol-planned analyses are described in Section 4.5. 
Due to the early termination of the study, Cohort 3 will not be initiated, the planned interim 
analysis will not be conducted, and the output of all participants will be listed without inclusion 
of tables and figures.  
1.1. 
Objectives, Endpoints, and Estimands 
The objectives and endpoints of ALXN 1820-SCD-201 are summarized in Table 1 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the safety and tolerability of ALXN1820 
SC in participants with SCD 
Safety assessed by incidence of TEAEs and 
SAEs, physical examination, vital sign 
measurements, clinical laboratory, and 
electrocardiogram results through Day 211 
(Cohorts 1 and 2)  
Secondary 
To assess the multiple-dose PK of ALXN1820 SC 
Serum ALXN1820 multiple-dose PK profiles 
through Day 211 (Cohorts 1 and 2)  
To assess the PD effects of ALXN1820 SC 
Change in serum concentrations of total and free 
properdin over time through Day 211 (Cohorts 1 
and 2)  
Change in CAP activity using the Wieslab AP 
assay through Day 211 (Cohorts 1 and 2)  
To assess the effect of ALXN1820 on complement 
biomarkers 
Change from Baseline in complement 
biomarkers through Week 12 (Cohorts 1 and 2)  
To assess the effect of ALXN1820 on hemolysis 
biomarkers 
Change from Baseline in hemoglobin levels at 
Week 12 (Cohorts 1 and 2)  
Change from Baseline in hemolysis markers 
(e.g., lactate dehydrogenase, reticulocytes, and 
bilirubin and hemopexin) at Week 12 (Cohorts 1 
and 2)  
To assess the immunogenicity of ALXN1820 SC 
Incidence of ADAs to ALXN1820 through 
Day 211 (Cohorts 1 and 2)  
Exploratory 
To explore the effect of ALXN1820 on VOC 
markers 
Change from Baseline in VOC-related 
biomarkers through Week 12 (Cohorts 1 and 2)  


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Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
To explore the clinical efficacy of ALXN1820 SC 
in SCD 
VOC events (rate of VOC, time to first VOC) 
through Week 12 (Cohorts 1 and 2)  
Abbreviations: ADA = antidrug antibody; AP = alternative pathway; CAP = complement alternative pathway; 
PD = pharmacodynamic; PK = pharmacokinetic(s); SAE = serious adverse event; SC = subcutaneous; 
SCD = sickle cell disease; TEAE = treatment-emergent adverse event; VOC = vaso-occlusive crisis. 
Note: Estimand is not applicable. 
1.2. 
Study Design 
This is a Phase 2a study, with up to 3 multiple-dose cohorts of open-label ALXN1820 
subcutaneous (SC) in adult participants with sickle cell disease (SCD; HbSS and HbSß0-
thalassemia). 
The study is planned to be conducted in up to 30 adults participants with SCD enrolled in up to 3 
open-label cohorts (Cohorts 1, 2, and 3 [optional]) to receive multiple SC doses of open-label 
ALXN1820. At the time of the early termination of the study, 2 participants are enrolled in the 
study. ALXN1820 is administered as described in Table 2. 
Table 2: 
ALXN1820-SCD-201 Dosing Cohorts 
Cohort 
N 
Study 
Intervention 
Route of 
Administration 
Planned 
Dose 
Number of 
Doses/Dose 
Interval 
1 
Up to 12 
Maximum 
of 6 on a 
stable dose 
of 
hydroxyurea 
ALXN1820 
SC 
300 mg 
QW × 13 
2 
Up to 12 
Maximum 
of 6 on a 
stable dose 
of 
hydroxyurea 
ALXN1820 
SC 
600 mg 
Q4W × 4 
Abbreviations: N = number of participants; QW = once weekly; Q4W = once every 4 weeks; SC = subcutaneous; 
SCD = sickle cell disease 
The dose and dosing intervals for Cohorts 1 and 2 were determined using cumulative safety data, 
an interim PK/PD analysis from participants enrolled in Study ALXN1820-HV-101, and data 
from the 6-month Good Laboratory Practice toxicology study in monkeys.  
Cohorts 1 and 2 run in parallel, and participants are randomized 1:1 to either of the cohorts upon 
determining eligibility. Each cohort is to be stratified to ensure participants with SCD who are 
treated with a stable dose of hydroxyurea and participants with SCD who are not currently 
treated with hydroxyurea are included. The Treatment Period is 12 weeks for Cohorts 1 and 2. 


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For participants who were previously treated with hydroxyurea but are not currently on 
hydroxyurea, treatment is to be stopped at least 30 days prior to providing informed consent.  
This study uses an independent Data Monitoring Committee to monitor safety and to perform the 
planned interim analyses of the study. At Alexion’s discretion and after consultation with the 
Data Monitoring Committee, additional participants with SCD may be enrolled as replacement 
participants if a participant discontinues during the Dosing Period for reasons other than drug-
related adverse events (AEs).


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2. 
STATISTICAL HYPOTHESES 
Not applicable. 


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3. 
ANALYSIS SETS 
Due to the early termination of the study, no analysis set will be defined except Enrolled Set, 
which includes all participants who signed the informed consent form, excluding screen failures. 
All the listing outputs will be based on the Enrolled Set. 
 


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4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations  
All analyses will be performed using Statistical Analysis Software® (SAS®) Version 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. 
Baseline is defined as the last nonmissing observation before the first dose of the study 
intervention. 
Treatment Period is 12 weeks for Cohorts 1 and 2. Follow-up Period is 18 weeks after the last 
dose or may be longer if CAP activity is below the normal range or 80% of the baseline value, as 
defined in the protocol.  
Study and participant characteristics (e.g., disposition, demographics and baseline characteristics, 
medical history, and protocol deviations) are described in Section 6.2. 
4.2. 
Primary Endpoints Analysis 
The primary endpoint for the study is safety, which will be assessed by the following parameters: 
• AEs 
• Clinical laboratory assessments 
• Vital signs 
• Physical examination  
• Electrocardiogram (ECG) parameters, including heart rate (HR), PR, RR, QRS, and 
QT intervals and corrected QT interval by Fridericia’s formula (QTcF) 
4.2.1. 
Analysis of AEs 
All the AEs will be listed for each participant. 
The adverse event will be presented using primary Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Classes (SOCs) and Preferred Terms (PTs) according to the version of 
the MedDRA coding in effect dictionary at the time of database lock. The SOCs will be 
presented in alphabetical order, and the PTs will be presented in descending order of frequency 
overall within each SOC.  
Treatment-emergent adverse events (TEAEs) (refer to Section 6.1 for the definition of TEAE) 
will be indicated. The following information of AEs will also be listed:  
• Relationship as assessed by the investigator 
• Severity by severity grades according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE, v5.0) (Grade 1, Grade 2, Grade 3, 
Grade 4, Grade 5) 
• Seriousness criteria 
• VOC exacerbated 
• Leading to discontinuation from study intervention 


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• Leading to study withdrawal 
• Leading to death 
• Injection site reaction (ISR) according to the Investigator. 
Clinically significant ISR will be reported as AE and will be indicated on the AE listing. 
4.2.2. 
Analysis of Laboratory Assessments 
Laboratory results based on standardized units will be used.  
Absolute values and changes from Baseline in clinical chemistry, hematology, coagulation, and 
urinalysis will be listed at each visit.  
Clinical chemistry, hematology, coagulation, and urinalysis values will be graded according to 
NCI CTCAE, v5.0, where applicable, and will be listed.   
4.2.3. 
 Analysis of Vital Signs 
Vital sign measurements include body weight, systolic blood pressure (SBP), diastolic blood 
pressure (DBP), HR, temperature and respiratory rate (RR). Actual values and change from 
Baseline in vital sign measurements will be listed at each visit for each participant. 
Abnormal vital signs will be listed for each participant, criteria for abnormal vital signs are 
defined as follows: 
• Body weight ≥ 7% decrease from Baseline; Body weight ≥ 7% increase from 
Baseline 
• SBP < 90 mmHg; SBP > 140 mmHg; SBP > 160 mmHg 
• DBP < 50 mmHg; DBP > 90 mmHg; DBP > 100 mmHg 
• HR < 60 beats per minute; HR > 100 beats per minute 
• Temperature < 36 degrees Celsius; temperature > 38 degrees Celsius  
• RR < 12 breaths per minute; RR > 20 breaths per minute 
4.2.4. 
 Analysis of Physical Examination 
All physical examination data will be provided in data listings. Abnormal physical examination 
finding during the study will be listed. 
4.2.5. 
Analysis of ECG Results 
The ECG parameters include HR, PR, RR, QRS, and QT intervals and QTcF. The mean of the 
triplicate ECG readings at the timepoints collected will be calculated. Absolute value and change 
from Baseline values will be listed at each visit for each participant. Change from Baseline 
values will be based on the calculated mean at each timepoint. 
Outlier ECG results will be listed for each reading per visit, criteria for outlier ECG results are 
defined as follows: 
• QT interval and QTcF > 450 msec 


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• QT interval and QTcF > 480 msec 
• QT interval and QTcF > 500 msec 
• QT interval and QTcF increases from Baseline > 30 msec 
• QT interval and QTcF increases from Baseline > 60 msec 
All ECG individual measurements as well as the calculated mean of triplicate ECG readings, will 
be provided in data listings. 
4.3. 
Secondary Endpoints Analysis  
4.3.1. 
Analysis of PK/PD 
Serum concentration will be listed over time for each participant. All serum concentrations 
below the lowest quantifiable sample concentration of the assay (BQL) or missing data will be 
labeled as such in the concentration data listings.  
Due to the early termination of the study and the limited sample size of enrolled participants, 
there will be no PK parameters outputs. 
Absolute values, changes from Baseline, and percent change from Baseline of PD parameters 
(serum total and free properdin concentrations and CAP activity) will be listed over time for each 
participant.  
4.3.2. 
Analysis of SCD Biomarkers 
Absolute value, change from Baseline, and percent change from Baseline in biomarkers, 
including Ba, C3a, C4a, C5a, sC5B9, LDH, bilirubin (total, direct and indirect), reticulocytes 
(absolute and percent), haptoglobin and hemopexin will be listed over time for each participant.  
4.3.3. 
Analysis of Immunogenicity 
Baseline is defined as the last nonmissing antidrug antibody (ADA) signal obtained on or before 
the first study intervention administration. 
For assessment of immunogenicity, the signal of ADAs will be categorized as positive or 
negative. Additionally, following confirmation of positive ADAs, samples will be further 
categorized into ADA response categories and will be assessed for ADA titer over time. ADA 
categories are defined as follows:  
• ADA negative: An ADA-negative signal in the ADA assay at all timepoints collected 
for ADA analysis 
• ADA positive: An ADA-positive signal in the ADA assay at any timepoint collected 
for ADA analysis 
Participants who are ADA positive may be further categorized into ADA response categories as 
follows: 
• Pre-existing immunoreactivity: An ADA-positive response with either of the 
following 2 conditions met: 


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− ADA-positive response at Baseline with all post-first-dose ADA results negative  
OR 
− ADA-positive response at Baseline with all post-first-dose ADA responses 
< 4-fold over the baseline titer level 
• Treatment-emergent ADA responses: An ADA-positive response post-first dose 
when baseline results are negative or missing 
• Treatment-boosted ADA responses: An ADA-positive response post-first dose that 
is ≥ 4-fold over the baseline titer level when the baseline result is positive 
4.4. 
Exploratory Endpoints Analysis  
Absolute value, change from Baseline, and percent change from Baseline in the markers of 
VOC, including hemopexin and nitric oxide, will be listed over time for each participant. 
SCD-related pain crises (VOC) are defined as acute episodes of pain with no medically 
determined cause other than a VOC event that results in a medical facility visit and treatment 
with either oral or parenteral narcotic agents or with a parenteral nonsteroidal anti-inflammatory 
drug. Uncomplicated VOCs are defined as no occurrence of any other SCD complication during 
the VOC episode. Complicated VOCs are defined as the presence of a diagnosis of other SCD 
complications during the VOC episode. Acute chest syndrome, hepatic sequestration, splenic 
sequestration, and priapism are considered VOC events in this study.  
The following information of VOC assessments will be listed:  
• VOCs leading to a healthcare visit 
• Start and end date of VOC 
• Complicated VOC or uncomplicated VOC 
• If complicated VOC, the complicated VOC categories will be listed (acute chest 
syndrome, hepatic sequestration, splenic sequestration, priapsim or other) 
• Location of pain 
• Tiredness during pain crisis 
• Intensity of pain 
• Medication Taken 
• VOC exacerbate (if yes, reporting to AE) 
 
4.5. 
Changes to Protocol-Planned Analyses 
Due to the early termination of the study and limited enrolled participants, data will only be 
listed. Applicable changes from Protocol Amendment 1.0 are as follows: 
• The interim analyses have been removed 


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• The Cohort 3 will not be initiated and have been removed 
• Analysis sets have been removed except for Enrolled Set, all analyses will be based on 
the Enrolled Set 
• Analyses of PK parameters have been removed 
• Summary descriptive statistics will not be provided  
• Outlier analyses of ECG have been removed 
• Inflammatory biomarkers and cell adhesion biomarkers have been removed from the 
analysis of VOC-related biomarkers 
• Visit windows have been removed 


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5. 
SAMPLE SIZE DETERMINATION 
Twelve participants were planned to be enrolled in each of Cohorts 1 and 2. In participants with 
stable SCD, hemoglobin level is unlikely to change. The sample size was determined based on a 
targeted hemoglobin change from Baseline to exclude 0 g/dL with a lower 2-sided 95% 
confidence bound. Assuming a standard deviation of 1 g/dL, a sample size of 12 participants can 
provide 88% power to detect a change from Baseline of 1 g/dL with a 2-sided significance level 
of 0.05. In Optional Cohort 3, 6 participants were planned to be enrolled to define the 
exposure/response relationship of ALXN1820 by combining Cohorts 1, 2, and 3 data using a 
PK/PD modeling approach. The Optional Cohort 3 sample size was not determined for power 
purposes. 
After the decision of the study early termination, the Cohort 3 will not be enrolled. 
   


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6. 
SUPPORTING DOCUMENTATION  
6.1. 
Technical Specifications for Derived Variables 
Adverse Events 
The analysis of AE is described in detail in Section Error! Reference source not found.. 
TEAEs are events with start dates and start times on or after the date and time of the first dose of 
study intervention and up to 100 days after the last dose of the study intervention. If the start date 
of an AE is partially or completely missing and the end (stop) date and time of the AE do not 
indicate that it occurred prior to the first dose, then the determination of treatment-emergent 
status will be based on the following: 
• If the start year is after the year of the first study intervention dose, then the AE is 
treatment emergent; else, 
• If the start year is the same as the year of the first study intervention dose and  
− the start month is missing, then the AE is treatment emergent; else if 
− the start month is present and is the same or after the month of the first study 
intervention dose, then the AE is treatment emergent; else, 
• If the start date is completely missing, then the AE is treatment emergent. 
All other AEs are considered pretreatment AEs.  
If the relationship to study intervention is missing for TEAEs, then the relationship will be 
counted as related to study intervention for the listing tables. Missing severity for TEAEs will be 
counted as Grade 3. 
 
6.2. 
Study and Participant Characteristics 
6.2.1. 
Participant Disposition 
Listings of the screen failures and reasons for screen failure will be generated. 
Listings of participants’ disposition will be based on the Enrolled Set, including treatment 
disposition, study duration, completion, or discontinuation of the study with a reason for study 
discontinuation (including COVID-19-related reasons), and completion or discontinuation of the 
treatment with a reason for treatment discontinuation (including COVID-19-related 
reasons)Baseline Characteristics and Demographics 
Baseline characteristics and demographics will be listed for each participant using the Enrolled 
Set. The following variables will be listed: 
• Age (years) 
• Sex (female, male, undifferentiated or unknown) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, nor reported or unknown) 


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• Race (White, Black or African American, American Indian or Alaska Native, Asian, 
Native Hawaiian or other Pacific Islander, not reported, unknown, multiple or other) 
• Baseline body weight (kilogram) 
• Baseline height (centimeter) 
• Baseline body mass index (kilogram/meters2) 
• Geographical region (European Union, North America or Rest of world) 
• Number of VOC in the past 12 months  
• Number of VOC in the past 3 months  
• VOC categories in the past 12 months (< 3 crisis or ≥ 3 crisis) 
• Genotype (HbSS, HbSC, HbSß+ thalassemia, HbSß0-thalassemia or Other) 
• Baseline hemoglobin (g/dL)   
• Stable dose of hydroxyurea (yes or no) 
• Prior opioid use (yes or no) 
6.2.3. 
Medical History 
Medical history will be coded using MedDRA version 23.1 or above and listed for the Enrolled 
Set, presenting the start and end date within each PT grouped by the SOC.  
6.2.4. 
Prior and Concomitant Medications 
Prior and concomitant medications/nonpharmacologic therapies and procedures will be listed 
using the Enrolled Set.  
Prior medications or procedures are defined as medications or procedure taken prior to the first 
dose of study intervention. Concomitant medications or procedures are defined as medications or 
procedures taken on or after the first dose of study intervention, including those started before 
the first dose of study intervention and continued after the first dose of the study intervention. 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary version 
in use by Alexion at the time of the analysis, while nonpharmacologic therapies and procedures 
will be coded using MedDRA. 
Medications will be coded and listed by WHO-Drug Anatomical Therapeutic Chemical Level 3 
or the next lower level if level 3 is unavailable and by WHO-Drug generic name. 
Nonpharmacologic therapies and procedures will be coded and listed by MedDRA SOC and PT. 
The medications for Meningococcal Vaccination will be listed for each participant.  
6.2.5. 
Protocol Deviations 
The protocol deviations will be listed for each participant in the Enrolled Set. 
6.3. 
Instrument Scoring Details 
Not applicable. 


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6.4. 
Additional Details on Statistical Methods 
Not applicable. 


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7. 
REFERENCES 
Not applicable. 


ALXN1820-SCD-201 SAP
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