Clinical trial NCT05307978
Conditions: Healthy
Keywords: ALXN1910 Safety Pharmacokinetics Pharmacodynamics Japanese Descent
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2022-04-12; Completion date: 2023-02-07
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1, randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of single ascending doses (SADs) of ALXN1910 subcutaneous (SC) and SAD of ALXN1910 intravenous (IV).

Detailed description:

Arms: arm 1: Participants will receive a single dose of 5 mg of ALXN1910 IV or Placebo IV. arm 2: Participants will receive a single dose of 15 mg of ALXN1910 SC or Placebo SC. arm 3: Participant will receive a single dose of 15 mg of ALXN1910 IV or Placebo IV. arm 4: Japanese participants will receive a single dose of 15 mg of ALXN1910 SC or Placebo SC. arm 5: Participants will receive a single dose of 45 mg of ALXN1910 SC or Placebo SC. arm 6: Participants will receive a single dose of 135 mg of ALXN1910 SC or Placebo SC.
Interventions: intervention 1: ALXN1910 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive a single dose of ALXN1910 IV or ALXN1910 SC according to their assigned cohort. intervention 2: Participants will receive Placebo IV or Placebo SC according to their assigned cohort.

Protocol documents:
Prot_000.pdf: 




Protocol Amendment 3 
ALXN1910-HV-101 
27 Jul 2022 
Page 3 of 85 
Alexion Confidential 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 3 (27 Jul 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 and 
any applicable local regulations. 
Overall Rationale for the Amendment 
The main reason for this amendment is to have all participants return on Day 75 for the EOS visit 
(instead of Day 43), regardless of ADA results, to maintain blinding of Alexion staff, the 
Investigator, and site staff. Changes implemented in Administrative Change Letter No.2 (14 Jun 
2022), as well as some clarifications to wording and minor administrative changes, have also 
been made. 
Changes to the protocol are detailed below: 
Section Number and Name 
Description of Change 
Brief Rationale and/or 
Clarification 
1.1 Synopsis 
Text in the “Study Cohort and 
Duration” subsection was updated 
to reflect the Dosing and Follow-up 
Period as a total of 74 days for all 
participants. 
To ensure consistency with the 
changes made to Schedule of 
Activities for EOS visit. 
1.2 Schema, Figure 1 
Number of days for Follow-up 
period was updated from 42 days to 
74 days. 
Number of days for the Follow-up 
period was updated to align with 
the EOS visit. 
1.3 Schedule of Activities 
Text was updated to reflect the 
change in Schedule of Activities 
from “Day 6 through Day 43” to 
“Day 6 through Day 75”. 
To ensure consistency with Table 3 
in Schedule of Activities. 
1.3 Schedule of Activities, Table 3 
Footnote b 
Title of Table 3 was changed from 
“Schedule of Activities – Single 
Ascending Dose Cohorts (Day 6 
through Day 43 [or Day 75 if 
Positive for ADAs])” to “Schedule 
of Activities – Single Ascending 
Dose Cohorts (Day 6 through Day 
75)”  
Footnote b text changed to reflect 
End of Study procedures will be 
performed on Day 75. 
To maintain blinding of Alexion 
staff, the Investigator, and site staff, 
all participants are required to 
return on Day 75 for the EOS visit 
(instead of Day 43), regardless of 
ADA results. 
2.4.1.1 Coronavirus Disease 2019 
Removed text saying that Day 75 is 
only necessary for positive ADAs. 
To ensure consistency with study 
timeline specified in Schedule of 
Activities. 
4.5 Duration of Treatment and End 
of Study Duration 
Text updated to specify that End of 
Study activities will occur on Day 
75. 
To clarify End of Study timeline for 
all participants. 
4.5 Duration of Treatment and End 
of Study Duration, Figure 2 
Figure 2 was updated to reflect Day 
75 as the EOS, and text regarding 
EOS for ADA positive participants 
was removed.  
To indicate Day 75 as EOS visit for 
all participants, regardless of ADA 
results. 


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Section Number and Name 
Description of Change 
Brief Rationale and/or 
Clarification 
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
Text related to ALP data blinding 
was added. 
To maintain blinding of Alexion 
staff, the Investigator, and site staff. 
8.3.1 Time Period and Frequency 
for Collecting AE and SAE 
Information 
Edited text to specify AEs and 
SAEs will be collected until Day 
75. 
To ensure AE and SAE collection 
procedures reflect the Schedule of 
Activities including Day 75 for all 
participants 
8.9.1 ADA Variables 
Added text that includes 
“Treatment-boosted ADA 
Responses” as part of ADA positive 
categorizations. 
This ADA response category was 
missing in the previous version of 
the protocol. 
10.1.1 Regulatory and Ethical 
Considerations 
Removed repeated mention of 
European regulation 536/2014. 
This regulation was erroneously 
mentioned twice in a sentence. 
10.2 Clinical Laboratory Tests, 
Table 10 
Removed repeated mention of 
“urea” as a parameter of “clinical 
chemistry” assessments. 
 
Added “Serum or urine pregnancy 
test” as a parameter of “other 
screening tests” laboratory 
assessments. 
This parameter was erroneously 
mentioned twice. 
 
 
To ensure consistency with the 
Schedule of Activities. 
Overall 
Minor administrative changes. 
For clarity. 
Abbreviations: ADA = antidrug antibodies; AE = adverse event; ALP = alkaline phosphatase; SAE = serious 
adverse event 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................3 
LIST OF TABLES ...........................................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Schema ........................................................................................................................13 
1.3. 
Schedule of Activities .................................................................................................13 
2. 
INTRODUCTION ......................................................................................................19 
2.1. 
Study Rationale ...........................................................................................................19 
2.2. 
Background .................................................................................................................19 
2.3. 
Target Indications .......................................................................................................20 
2.3.1. 
Hypophosphatasia .......................................................................................................20 
2.3.2. 
Atypical Femoral Fracture ..........................................................................................20 
2.3.3. 
Neurofibromatosis Type 1 ..........................................................................................21 
2.4. 
Benefit/Risk Assessment ............................................................................................22 
2.4.1. 
Risk Assessment .........................................................................................................22 
2.4.1.1. 
Coronavirus Disease 2019 ..........................................................................................23 
2.4.2. 
Benefit Assessment .....................................................................................................23 
2.4.3. 
Overall Benefit: Risk Conclusion ...............................................................................23 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................25 
4. 
STUDY DESIGN .......................................................................................................26 
4.1. 
Overall Design ............................................................................................................26 
4.2. 
Scientific Rationale for Study Design ........................................................................27 
4.3. 
Dose Escalation ..........................................................................................................27 
4.4. 
Justification for Dose ..................................................................................................27 
4.5. 
Duration of Treatment and End of Study Definition ..................................................28 
5. 
STUDY POPULATION .............................................................................................30 
5.1. 
Inclusion Criteria ........................................................................................................30 
5.2. 
Exclusion Criteria .......................................................................................................31 
5.3. 
Justification for Study Population ..............................................................................33 


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5.4. 
Lifestyle Considerations .............................................................................................33 
5.4.1. 
Meals and Dietary Restrictions ...................................................................................33 
5.4.2. 
Activity .......................................................................................................................33 
5.4.3. 
Caffeine, Alcohol, and Tobacco .................................................................................33 
5.5. 
Screen Failures ............................................................................................................34 
6. 
STUDY INTERVENTION ........................................................................................35 
6.1. 
Study Interventions Administered ..............................................................................35 
6.1.1. 
Study Intervention Packaging and Labeling ...............................................................35 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................35 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................36 
6.4. 
Study Intervention Compliance ..................................................................................37 
6.5. 
Concomitant Therapy .................................................................................................37 
6.5.1. 
Allowed Medicine and Therapy .................................................................................37 
6.5.2. 
Disallowed Medicine and Therapy .............................................................................38 
6.6. 
Dose Modification ......................................................................................................38 
6.7. 
Intervention After the End of the Study .....................................................................39 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................40 
7.1. 
Discontinuation of Study Intervention ........................................................................40 
7.2. 
Cohort Stopping Rules ................................................................................................40 
7.3. 
Participant Discontinuation/Withdrawal from the Study ...........................................40 
7.4. 
Lost to Follow-up .......................................................................................................41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................42 
8.1. 
Efficacy Assessments .................................................................................................42 
8.2. 
Safety Assessments .....................................................................................................42 
8.2.1. 
Physical Examinations ................................................................................................42 
8.2.2. 
Vital Signs ..................................................................................................................42 
8.2.3. 
Electrocardiograms .....................................................................................................43 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................43 
8.2.5. 
Pregnancy ...................................................................................................................44 
8.3. 
Adverse Events and Serious Adverse Events Considerations ....................................44 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................44 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................45 


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8.3.3. 
Follow-up of AEs and SAEs .......................................................................................45 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................45 
8.3.5. 
Special Warnings and Precautions for Use .................................................................45 
8.4. 
Treatment of Overdose ...............................................................................................45 
8.5. 
Pharmacokinetics ........................................................................................................46 
8.6. 
Pharmacodynamics .....................................................................................................46 
8.7. 
Genetics ......................................................................................................................47 
8.8. 
Biomarkers ..................................................................................................................47 
8.9. 
Immunogenicity Assessments ....................................................................................47 
8.9.1. 
ADA Variables ...........................................................................................................47 
8.10. 
Health Economics Data and/or Medical Resource Utilization ...................................48 
9. 
STATISTICAL CONSIDERATIONS .......................................................................49 
9.1. 
Statistical Hypotheses .................................................................................................49 
9.2. 
Sample Size Determination ........................................................................................49 
9.3. 
Populations for Analyses ............................................................................................49 
9.4. 
Statistical Analyses .....................................................................................................49 
9.4.1. 
Safety Analyses ..........................................................................................................50 
9.4.2. 
Other Analyses ............................................................................................................51 
9.4.2.1. 
Pharmacokinetic Analysis ..........................................................................................51 
9.4.2.2. 
Pharmacodynamic Analysis ........................................................................................51 
9.4.2.3. 
Immunogenicity Analysis ...........................................................................................52 
9.5. 
Interim Analyses .........................................................................................................52 
9.6. 
Safety Review Committee ..........................................................................................52 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................54 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................54 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................54 
10.1.2. 
Financial Disclosure ...................................................................................................55 
10.1.3. 
Informed Consent Process ..........................................................................................55 
10.1.4. 
Data Protection ...........................................................................................................55 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................56 
10.1.6. 
Data Quality Assurance ..............................................................................................56 
10.1.7. 
Source Documents ......................................................................................................57 


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10.1.8. 
Study and Site Start and Closure ................................................................................57 
10.1.9. 
Publication Policy .......................................................................................................58 
10.1.10. 
Good Clinical Practice Compliance ............................................................................59 
10.2. 
Clinical Laboratory Tests ...........................................................................................60 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................62 
10.3.1. 
Definition of AE .........................................................................................................62 
10.3.2. 
Definition of SAE .......................................................................................................62 
10.3.3. 
Recording and Follow-up of AE and/or SAE .............................................................63 
10.3.4. 
Reporting of SAEs ......................................................................................................65 
10.4. 
Management of Potential Adverse Events During Study Intervention 
Administration ............................................................................................................68 
10.5. 
Acute Infusion Reaction Algorithm ............................................................................69 
10.6. 
Country-specific Requirements: United Kingdom Resuscitation Council 
Anaphylaxis Algorithm - Guidelines 2021 .................................................................70 
10.7. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................71 
10.7.1. 
Definitions ..................................................................................................................71 
10.7.2. 
Contraception Guidance .............................................................................................71 
10.7.2.1. 
Guidance for Female Participants ...............................................................................71 
10.7.2.2. 
Guidance for Male Participants ..................................................................................72 
10.7.3. 
Collection of Pregnancy Information .........................................................................73 
10.8. 
Biomarkers ..................................................................................................................74 
10.9. 
Resuscitation Procedures, Equipment, Medicines, and Training ...............................75 
10.9.1. 
General Procedures .....................................................................................................75 
10.9.2. 
Resuscitation Equipment and Medicines/Antidote .....................................................75 
10.9.3. 
Resuscitation Training ................................................................................................76 
10.10. 
COVID-19 Risk Assessment ......................................................................................77 
10.11. 
COVID-19 Vaccine Risk Assessment ........................................................................78 
10.12. 
Abbreviations ..............................................................................................................79 
10.13. 
Protocol Amendment History .....................................................................................81 
11. 
REFERENCES ...........................................................................................................84 
 


Protocol Amendment 3 
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LIST OF TABLES 
Table 1: 
Planned ALXN1910-HV-101 Dosing Cohorts ...........................................................12 
Table 2: 
Schedule of Activities – Single Ascending Dose Cohorts (Screening through 
Day 5) .........................................................................................................................14 
Table 3: 
Schedule of Activities – Single Ascending Dose Cohorts (Day 6 through 
Day 75) .......................................................................................................................17 
Table 4: 
Risk Assessment for ALXN1910 ...............................................................................22 
Table 5: 
Planned ALXN1910-HV-101 Dosing Cohorts ...........................................................26 
Table 6: 
Simulated ALXN1910 PK Exposure and Safety Exposure Margins in 
Humans .......................................................................................................................28 
Table 7: 
Dose Reference Chart for Study ALXN1910-HV-101 ..............................................35 
Table 8: 
Detailed Dose Escalation Criteria for Each Cohort ....................................................39 
Table 9: 
Populations for Analyses ............................................................................................49 
Table 10: Protocol-required Laboratory Assessments ................................................................60 
Table 11: Cohort and Study Stopping Rules ...............................................................................66 
Table 12: Potential Risks and Mitigation Measures due to COVID-19 .....................................77 
Table 13: Potential Risks and Mitigation Measures due to COVID-19 Vaccine .......................78 
Table 14: Abbreviations and Specialist Terms ...........................................................................79 
 


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LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................13 
Figure 2: 
Overview of Study Visits ............................................................................................29 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, Randomized, Double-blind, Placebo-controlled, Single Ascending 
Dose Study of Subcutaneously and Intravenously Administered ALXN1910 in Healthy Adult 
Participants 
Short Title: Safety and Tolerability, Pharmacokinetic, and Pharmacodynamic Study of 
ALXN1910 in Healthy Participants 
Rationale: 
To gain an understanding of the safety, tolerability, PK, PD, and immunogenicity of ALXN1910, 
an FIH SAD study in healthy adult participants is proposed. Cohorts of Japanese and 
non-Japanese participants will also be evaluated to enable comparison between these 
2 populations. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and tolerability of 
ALXN1910 
• 
Incidence of TEAEs and TESAEs 
Secondary 
• 
To assess the PK of single ascending doses of 
ALXN1910 
• 
Serum ALXN1910 PK (activity) and PK 
parameters 
• 
To explore the PD effects of single ascending 
doses of ALXN1910 
• 
Plasma concentrations of PPi, PLP, PL, and 
PA versus time profiles 
• 
To assess the immunogenicity of ALXN1910 
• 
Incidence and titers of treatment-emergent 
ADAs 
• 
To assess the absolute bioavailability of 
ALXN1910 SC 
• 
GMR of AUC values of SC versus IV from 
serum concentrations of ALXN1910 
• 
To compare the safety, tolerability, PK, and 
PD of ALXN1910 SC between Japanese and 
non-Japanese healthy participants 
• 
Quantitative assessment of safety/tolerability 
and PK/PD parameters between Japanese and 
non-Japanese participants 
Abbreviations: ADA = antidrug antibody; AUC = area under the serum concentration-time curve; GMR = geometric 
mean ratio; IV = intravenous; PA = pyridoxic acid; PD = pharmacodynamics(s); PK = pharmacokinetic(s); 
PL = pyridoxal; PLP = pyridoxal-5′-phosphate; PPi = inorganic pyrophosphate; SC = subcutaneous; 
TEAE = treatment emergent adverse event; TESAE = treatment emergent serious adverse event 
Overall Design 
This is a Phase 1, randomized, double-blind, placebo-controlled study designed to evaluate the 
safety, tolerability, PK, PD, and immunogenicity of SADs of ALXN1910 SC and a SAD of 
ALXN1910 IV in up to approximately 48 healthy adult participants across treatment cohorts (up 
to approximately 36 participants to receive ALXN1910 and up to approximately 12 participants 
to receive placebo). Of the 48 participants, 8 will be of Japanese descent, defined as those 
participants whose parents and grandparents are both Japanese and who have spent less than 
10 years outside of Japan. 
For this FIH study, 8 participants will be randomly assigned in a 3:1 ratio to treatment and 
placebo in each of the 6 cohorts with escalating doses of 5 mg IV (Cohort 1), 15 mg SC 


Protocol Amendment 3 
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Alexion Confidential 
(Cohort 2), 15 mg IV (Cohort 3) in parallel with 15 mg SC in Japanese participants (Cohort 4) 
and 45 mg SC (Cohort 5), followed by 135 mg SC (Cohort 6). The first 2 participants 
randomized to each cohort will be dosed as a sentinel pair, with 1 participant on active treatment 
and 1 participant on placebo. This dosing strategy is justified given the large exposure margins 
(approximately 15-fold at the highest planned single dose of 135 mg SC). At the discretion of the 
Investigator, up to 3 more participants will be dosed at least 48 hours (as anticipated tmax occurs 
prior to 48 hours postdose) after the dosing of the sentinel pair, followed by dosing of the 
remaining participants in the cohort no earlier than 72 hours after sentinel pair dosing, as long as 
no suspension/stopping criteria have been met. At no time will more than 4 participants per 
cohort be dosed in a given day.  
Participants who meet the qualifications for the study based on screening will be admitted to the 
CRU the day prior to dosing (Day -1) to undergo Check-in assessments per the applicable SoA. 
Final determination of eligibility will be determined based on Check-in and predose procedures, 
and eligible participants will be randomized to ALXN1910 or placebo on Day 1 prior to dosing. 
There will be extensive PK/PD sampling during the first 24 hours after dosing. Safety 
assessments will be performed per the SoA. 
Safety Review Committee: The blinded SRC, consisting of the Investigator, Medical Monitor, 
Drug Safety Physician, Study Statistician, and Clinical Pharmacologist will evaluate the 
available study data at prespecified time points for participant safety and make recommendations 
on dose escalation, dose modification, or termination of the study. Decisions to continue, modify 
(explore the dose cohort further), or escalate dosing will be made by the Investigator and/or 
SRC. 
Number of Participants: 
Up to approximately 48 participants will be randomized according to a randomization schedule 
generated prior to the start of the study. 
Study Cohort and Duration: 
The participants in each dose cohort will be randomized in a 3:1 ratio to receive ALXN1910 or 
placebo. Following a Screening Period of up to 28 days, there will be a Dosing and Follow up 
Period (single dose on Day 1 through the EOS Visit) of approximately 74 days. 
Table 1: 
Planned ALXN1910-HV-101 Dosing Cohorts 
Cohorta 
Number of Participants 
(ALXN1910:Placebo) 
Route of 
Administration 
Dose 
Number of 
Doses/Dose Interval 
1 
8 (3:1) 
IVb 
5 mg 
Single dose 
2 
8 (3:1) 
SC 
15 mg 
Single dose 
3 
8 (3:1) 
IVb 
15 mg 
Single dose 
4 
8 (3:1) (Japanese participants) 
SC 
15 mg 
Single dose 
5 
8 (3:1) 
SC 
45 mg 
Single dose 
6 
8 (3:1) 
SC 
135 mg 
Single dose  
a Cohort 3, Cohort 4, and Cohort 5 can be initiated in parallel after dose escalation decision following SRC review 
of Cohort 2 safety and PK data. 
b Slow IV infusions (rate of infusion = 6 mL/h) using a controllable infusion pump. The pharmacy manual will 
include details regarding infusion rate and duration. 
Abbreviations: IV = intravenous; PK =pharmacokinetic; SC = subcutaneous; SRC = Safety Review Committee 


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1.2. 
Schema 
Figure 1: 
Study Design Schematic 
 
1.3. 
Schedule of Activities 
The SoAs for all cohorts from Screening through Day 5 and from Day 6 through Day 75 are 
presented in Table 2 and Table 3, respectively. 
 


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Table 2: 
Schedule of Activities – Single Ascending Dose Cohorts (Screening through Day 5) 
Study Daya 
Screen
-ing 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 
5 
Assessments 
D -29 
to D-2 
Admit 
Pre-
dose 
0 h 
I/ 
SOI 
30 min 
post 
I/SOI 
2 h 
post 
I/SOI 
4 h 
post 
I/SOI 
8 h 
post 
I/SOI 
12 h 
post 
I/SOI 
24 h 
post 
I/ 
SOI 
36 h 
post 
I/ 
SOI 
48 h 
post 
I/ 
SOI 
60 h 
post 
I/ 
SOI 
72 h 
post 
I/ 
SOI 
84 h 
post 
I/ 
SOI 
96 h 
post 
I/SOI 
Status (OP or CRU) 
OP 
CRU 
Admission 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusiond 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight, and 
BMIf 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV (Types 1 and 2) 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle-stimulating 
hormoneg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine alcohol test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
testh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
testh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationi 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
administration 
(ALXN1910 or 
placebo) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Injection/infusion 
site evaluationj 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2: 
Schedule of Activities – Single Ascending Dose Cohorts (Screening through Day 5) 
Study Daya 
Screen
-ing 
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 
5 
Assessments 
D -29 
to D-2 
Admit 
Pre-
dose 
0 h 
I/ 
SOI 
30 min 
post 
I/SOI 
2 h 
post 
I/SOI 
4 h 
post 
I/SOI 
8 h 
post 
I/SOI 
12 h 
post 
I/SOI 
24 h 
post 
I/ 
SOI 
36 h 
post 
I/ 
SOI 
48 h 
post 
I/ 
SOI 
60 h 
post 
I/ 
SOI 
72 h 
post 
I/ 
SOI 
84 h 
post 
I/ 
SOI 
96 h 
post 
I/SOI 
Status (OP or CRU) 
OP 
CRU 
Brief physical 
examinationk 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Vital sign 
measurementsl 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
ECGm 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Chemistryn 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Hematologyn 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Coagulationn 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urinalysisn 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
PKo 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
PD (PPi, PLP, PL, 
and PA) 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Urine for calcium, 
phosphorus, and 
creatininep 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Immunogenicity 
samplesq 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypersensitivity 
reactionsr  
 
 
 
←Monitor continuously after dose→ 
Hypersensitivity 
reaction laboratory 
tests (tryptase & 
complement C5b-9)s 
 
 
X 
←See footnoter→ 
Concomitant 
medications 
←Monitor continuously (after ICF is signed at Screening)→ 
Adverse events 
review and 
evaluation 
←Monitor continuously (after ICF is signed at Screening)→ 
Note: When scheduled at the same timepoint, the triplicate ECG should be performed first, followed by vital sign measurements, and then PK/PD sampling.  


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a Permissible windows for study assessments are described in the Windows Allowance Document. 
b Participants will be discharged from the CRU after completing all Day 5 assessments. Due to the time needed for turnaround of laboratory test results, discharge 
will actually occur on Day 6. 
c A signed and dated IEC-approved ICF must be obtained before any study-specific screening procedures are performed. 
d Recheck clinical status before randomization and/or dose of study intervention. 
e Including substance usage (drugs, alcohol, tobacco, and caffeine) and past/current medical conditions. 
f Height and BMI only at Screening. 
g Only female participants claiming postmenopausal status will have a follicle-stimulating hormone test to confirm postmenopausal status. 
h All female participants will have a pregnancy test (serum at Screening and urine on Day -1) to confirm the participant is not pregnant. Any female participant 
who becomes pregnant while participating in the study will be withdrawn. 
i Randomization will occur predose on Day 1. 
j Injection/infusion site evaluations will be performed within 15 minutes after I/SOI and ± 15 minutes at 4 and 24 hours post I/SOI. See Section 10.5 for 
additional details. 
k Brief physical examination to be conducted on Day 5 prior to discharge from the CRU.  
l At Screening, supine and standing (orthostatic) blood pressures will be performed according to the CRU’s typical procedure to exclude participants who are 
prone to orthostatic hypotension. 
m Each ECG timepoint during the study will be 12-lead and performed in triplicate sequentially within 5 minutes, at least 1 minute apart after 10 minutes of 
bedrest in supine position (note, no bedrest is required post ECG), at Screening and 90, 75, and 60 minutes before dosing. ECGs should not be performed within 
1 hour after any major meal or major meals should be withheld until after ECG assessments.  
n Investigators should review Day 5 laboratory results to ensure each participant is suitable for discharge. 
o The IV dose cohorts will also have an end-of-infusion PK time point. 
p Spot urine collection. 
q Sample for ADA assessments will be collected prior to administration of the drug. In the event of suspected SAE like hypersensitivity or anaphylaxis, 
additional samples may be collected for ADA assessments at or near the event. 
r See Section 10.4 for details. 
s Collect 3 lab samples after a suspected hypersensitivity reaction: as soon as possible and at 2 and 8 hours after the suspected reaction (+ 1 hour window for 
each sample). If the suspected hypersensitivity reaction persists beyond 8 hours, the CRU should contact the Medical Monitor for guidance. Predose samples 
will only be analyzed for participants with a reported suspected hypersensitivity reaction. 
Abbreviations: ADA = antidrug antibody; BMI = body mass index; C5b-9 = terminal complement complex; CRU = clinical research unit; 
ECG = electrocardiogram; h = hours; HIV = human immune deficiency virus; I = injection; ICF = informed consent form; IEC = Independent Ethics Committee; 
OP = outpatient; min = minutes; PA = pyridoxic acid; PD = pharmacodynamic; PK = pharmacokinetic; PL = pyridoxal; PLP = pyridoxal 5′‑phosphate; 
PPi = inorganic pyrophosphate; SOI = start of infusion; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event 


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Table 3: Schedule of Activities – Single Ascending Dose Cohorts (Day 6 through Day 75) 
Study Daya 
Day 6 
post 
I/SOI 
Day 7 
post 
I/SOI 
Day 8 
post 
I/SOI 
Day 15 
post 
I/SOI 
Day 22 
post 
I/SOI 
Day 29 
post 
I/SOI 
Day 36 
post 
I/SOI 
Day 43  
post  
I/SOI 
Day 75 post 
I/SOI 
(EOS/EDb) 
Status (OP or CRU) 
OP 
Full physical examination 
 
 
 
 
 
 
 
X 
 
Brief physical examination 
 
 
X 
X 
 
X 
 
 
 
Vital sign measurementsc 
 
 
X 
X 
 
X 
 
X 
 
12-lead ECG (triplicate)d 
X 
X 
X 
X 
X 
 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (via dipstick) 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy teste 
 
 
 
 
 
X 
 
 
 
Serum pregnancy teste 
X 
X 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD (PPi, PLP, PL, and PA) 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity samplesf 
X 
X 
X 
Urine for calcium, phosphorus, and creatinineg 
X 
X 
X 
X 
X 
Hypersensitivity reactionsh 
←Monitor continuously after dose→ 
Hypersensitivity reaction laboratory tests (tryptase and 
complement C5b-9)i 
←See footnoteh→ 
Concomitant medications 
←Monitor continuously (after ICF is signed at Screening)→ 
Adverse event review and evaluation 
←Monitor continuously (after ICF is signed at Screening)→ 
Note: When scheduled at the same timepoint, the triplicate ECG should be performed first, followed by vital sign measurements, and then PK/PD sampling.  
a Permitted windows for study assessments are described in the Windows Allowance Document. 
b EoS procedures will be performed on Day 75. If possible, participants who withdraw/are withdrawn from the study should have an ED visit conducted at the 
time of discontinuation that includes the EoS assessments. All efforts will be made to contact participants who discontinued early from the study via phone for 
a safety follow-up call approximately 30 days (4.5 half-lives) after their last dose to assess AEs.  
c Vital signs taken postdose will be performed before the coinciding blood collection, whenever possible. 
d Each ECG will be 12-lead and performed in triplicate sequentially within 5 minutes, at least 1 minute apart after 10 minutes of bedrest in supine position (note, 
no bedrest is required post ECG). ECGs should not be assessed within 1 hour after any major meal or major meals should be withheld until after ECG 
assessments.  
e Only female participants of childbearing potential will have a pregnancy testing to confirm the participant is not pregnant. 
f Sample for ADA assessments will be collected prior to administration of the drug. In the event of suspected SAE like hypersensitivity or anaphylaxis, 
additional samples may be collected for ADA assessments at or near the event. 
g Spot urine collection. 


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h See Section 10.4 for details. 
i If the participant is in the clinic, collect the first sample as soon as possible (preferred) or within 1 hour of the suspected hypersensitivity reaction, and 2 
additional samples at 2 and 8 hours after the suspected hypersensitivity reaction (+ 1 hour window for each sample). If the participant is not in the clinic, these 
samples do not need to be collected and suspected hypersensitivity reactions will be reported as TEAEs/TESAEs only. If the suspected hypersensitivity 
reaction persists beyond 8 hours, the CRU should contact the Medical Monitor for guidance. 
Abbreviations: ADA = anti-drug antibody; C5b-9 = terminal complement complex; CRU = clinical research unit; ECG = electrocardiogram; ED = early 
discontinuation; EOS = end of study; h = hours; I = injection; ICF = informed consent form; OP = outpatient; PA = pyridoxic acid; PD = pharmacodynamic; 
PK = pharmacokinetic; PL = pyridoxal; PLP = pyridoxal 5′‑phosphate; PPi = inorganic pyrophosphate; SOI = start of infusion; TEAE = treatment-emergent 
adverse event; TESAE = treatment-emergent serious adverse event 


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2. 
INTRODUCTION  
Similar to asfotase alfa (STRENSIQ®, Alexion Pharmaceuticals, Inc.), ALXN1910 is intended to 
replace or enhance TNSALP activity in deficient tissues, resulting in improved mineralization of 
the skeleton that is important for normal bone development, homeostasis, and repair. This 
mechanism of action is anticipated to be useful in conditions associated with poor bone 
mineralization due to elevated PPi and/or impaired TNSALP activity, such as HPP where 
supplementation with a bone-directed TNSALP ERT may result in conditions more favorable for 
proper bone mineralization. ERT may also be beneficial in conditions of poor bone healing (eg, 
after fractures or surgical interventions), including AFFs and NF1.  
2.1. 
Study Rationale 
To gain an understanding of the safety, tolerability, PK, PD, and immunogenicity of ALXN1910, 
an FIH SAD study in healthy adult participants is proposed.  
This study is also being conducted to meet regulatory requirements of the ICH Guidance E5(R1), 
which provides a general framework for evaluating the potential impact of ethnic factors on the 
acceptability of foreign clinical data. Therefore, cohorts of Japanese and non-Japanese 
participants will also be evaluated to enable comparison between these 2 populations. 
2.2. 
Background 
ALXN1910 is a fusion protein comprised of a human TNSALP catalytic domain, a human Ig Fc 
domain, and a C-terminal poly-aspartate (n = 7) peptide. 
In humans, there are 4 ALP isoenzymes, each encoded by a separate gene. Three of these 
isoenzymes are primarily expressed in specific tissues: intestine, placenta, and germ cells. The 
fourth isoenzyme is expressed throughout the body, but primarily in the liver, kidney, and bone; 
and hence, it is referred to as TNSALP and is encoded by the ALPL gene.  
The physiological role of TNSALP has not been fully elucidated, but its function in bone is best 
understood. In bone, TNSALP enables mineralization by locally cleaving PPi, thereby removing 
this inhibitor of mineralization, while increasing the local concentration of Pi. Pi then 
precipitates with calcium to form calcium phosphate, which is transformed into the 
hydroxyapatite crystal that gives bone its strength and rigidity. ALXN1910 has been rationally 
engineered to confer greater enzymatic activity than asfotase alfa, with the intention to improve 
mineralization of the skeleton in conditions associated with poor bone mineralization due to 
elevated PPi and/or impaired TNSALP activity. 
Compared with asfotase alfa, the human TNSALP catalytic domain in ALXN1910 has been 
rationally altered in a single position to confer greater enzymatic activity, remaining 99.8% 
identical to the catalytic domain in asfotase alfa. Additionally, the IgG Fc domain isotype in 
ALXN1910 is IgG2/4 instead of the IgG1 Fc domain present in asfotase alfa. This alteration was 
designed to improve ALXN1910’s PK profile relative to asfotase alfa, including improved 
systemic exposure/bioavailability and terminal half-life (approximately 7 days for ALXN1910 
versus approximately 5 days for asfotase alfa). These improvements are anticipated to support 
lower doses and longer dosing intervals.  


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Moreover, unlike the C-terminal deca-aspartate of asfotase alfa, ALXN1910 utilizes an affinity 
optimized hepta-aspartate C-terminal peptide to direct the molecule to sites of bone 
mineralization. 
ALXN1910 is a next-generation ERT developed with the intent to deliver a molecule with 
equivalent potency and improved activity compared with asfotase alfa, providing higher 
exposure, longer half-life, and better bioavailability. These improvements may support lower 
doses and longer dosing intervals, which may mitigate the risk of injection site reactions. 
A detailed description of the chemistry, pharmacology, and toxicology data available for 
ALXN1910 is provided in the IB. 
Alexion is planning to initiate a Phase 1, randomized, double-blind, placebo-controlled, SAD 
study of SC and IV administered ALXN1910 in healthy adult participants (Study ALXN1910-
HV-101). The proposed study is designed to evaluate the safety and tolerability, PK, 
immunogenicity, and absolute and relative bioavailability of SADs of ALXN1910 administered 
SC and compared with a single dose of IV ALXN1910.  
2.3. 
Target Indications 
Similar to asfotase alfa (STRENSIQ®), ALXN1910 is intended to replace TNSALP activity in 
deficient tissues, resulting in improved mineralization of the skeleton that is important for normal 
bone development, homeostasis, and repair. This mechanism of action is anticipated to be useful 
in conditions associated with poor bone mineralization due to elevated PPi and/or impaired 
TNSALP activity, such as HPP where supplementation with a bone-directed TNSALP ERT may 
result in conditions more favorable for proper bone mineralization. ERT may also be beneficial 
in conditions of poor bone healing (eg, after fractures or surgical interventions), including AFFs 
and NF1. 
2.3.1. 
Hypophosphatasia 
HPP is a rare, serious, genetic disorder caused by loss of function mutation(s) in the ALPL gene, 
which encodes TNSALP. 
As a direct result of deficient TNSALP, progressive damage to vital organs along with other 
clinical sequelae may occur, including deformity and softness of bones (rickets-like bone 
deformities and osteomalacia), fractures and pseudofractures, pain, profound muscle weakness, 
respiratory failure (primarily in infants), seizures (mainly in infants), impaired renal function, 
impaired mobility, and dental abnormalities. HPP is associated with a high fracture and 
orthopedic/dental surgical burden, pain, need for assistive walking devices (due to impaired 
mobility), and impairments in activities of daily living in children and adults. Rachitic changes in 
the chest often lead to diminished respiratory function (due to lack of rib cage support) and risk 
of ventilator dependence and premature death (mainly in infants). The deficiency of PLP, 
(vitamin B6) in the central nervous system in patients with HPP can result in seizures 
(Whyte, 1994; Baumgartner-Sigl, 2007). 
2.3.2. 
Atypical Femoral Fracture 
TNSALP plays a significant role in fracture healing and mineralization. Significant elevation of 
serum ALP is a normal physiological response in the first few weeks after bone fracture 


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(Hosking, 1978). A normal response to femoral fracture is a 2- to 3-fold elevation of serum ALP 
within the first 5 weeks of the fracture. A lack of this response has been shown to lead to greater 
rates of delayed fracture healing or non-union after 9 months (Singh, 2013). Delayed healing and 
non-union occur in many fractures, but certain fracture types, such as AFFs, are particularly 
prone to complications. 
AFFs are transverse fractures in the shaft of the femur associated with minimal or no trauma, 
such as a fall from a standing height. AFFs can be complete, breaking through both femoral 
cortices, or incomplete. AFFs are a common complication of HPP, but are also seen in other 
subpopulations, including patients taking long-term bisphosphonate treatment. Chronic 
bisphosphonate treatment for osteoporosis is a known risk factor for development of AFF 
(and has been implicated in chronic lowering of serum ALP activity in some patients; 
Bhattacharyya, 2016). 
As the effect of bisphosphonates is to cause a reduction of bone turnover, long-term 
bisphosphonate use is associated with an altered bone structure and biomechanics that can 
predispose some patients to the occurrence of an AFF. AFFs can be slow to heal and have 
relatively high rates of delayed union and non-union, even after surgery and intermedullary 
nailing. Clinical studies have shown that a significant number of patients suffering from an AFF 
have low serum ALP, which is a risk factor for delayed fracture healing or nonunion 
(Nakagawa, 2006; Singh, 2013; Sipani, 2020). 
2.3.3. 
Neurofibromatosis Type 1 
NF1 is caused by pathogenic variants in the NF1 gene resulting in the loss of production or 
reduced function of the protein neurofibromin, which belongs to a family of GTPase-activating 
proteins and is an inhibitor of the Ras-MAPK signaling pathway. Therefore, in patients with 
NF1, the MAPK/extracellular signal-regulated kinase signaling pathway is constitutively 
activated. NF1 occurs in approximately 1:3000 people worldwide and is inherited in an 
autosomal dominant fashion (Lammert, 2005; Evans, 2010). Almost half of all affected 
individuals have the disorder as the result of de novo mutation. The mutation rate for NF1 
(approximately 1:10000) is among the highest known for any gene in humans. The cause of the 
unusually high mutation rate is unknown (Friedman, 1999). 
NF1 is a multisystemic disease, affecting the skin, nervous system, eyes, and bones. Typical 
symptoms include neurofibromas, café-au-lait macules, Lisch nodules, and optic gliomas among 
others. Approximately 30% to 70% of patients with NF1 have significant musculoskeletal 
manifestations that can be generalized (eg, low bone mineral density that affects about 50% of 
patients) or focal (eg, tibial dysplasia/pseudoarthrosis or dystrophic scoliosis that affects up to 
10% of patients) (Stevenson, 2007; Lodish, 2012). Bone mineral density deficits are more 
pronounced in children with localized skeletal abnormalities. The presence of these bone 
abnormalities is usually coupled with poor bone mineralization, which compromises their 
strength and makes them prone to fracture. Patients with NF1 with known long bone dysplasia 
have a very high rate of fracture of the dysplastic bone (70%) and a higher rate of multiple 
fractures compared with controls (George-Abraham, 2013). Surgery is often required to repair 
these fractures, which, due to low bone TNSALP activity and/or high PPi concentrations, may be 
very slow to heal and require repeated surgical interventions, including lower limb amputation 
(Kolanczyk, 2007; Brunetti-Pierri, 2008; Stevenson, 2009; Seitz, 2010). 


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ALXN1910 treatment increases the TNSALP activity on the bone tissue and is anticipated to 
improve the defective bone mineralization in patients with NF1. In agreement with this 
hypothesis, a preclinical study evaluated the efficacy of asfotase alfa using a mouse model of 
postnatal osteoprogenitor cell NF1 ablation. Mice treated with asfotase alfa, using a dose and 
dose frequency that had demonstrated efficacy in the Akp2-/- mouse model of HPP, showed a 
73% reduction in osteoid volume per bone volume, indicating substantial improvement of bone 
mineralization in NF1 ablated mice compared with untreated control mice (de la Croix 
Ndong, 2014). 
In 2020, a case study was published in which a patient with NF1 suffering from severe 
dystrophic lumbar scoliosis and 3 prior surgical interventions was treated with STRENSIQ® after 
corrective spinal surgery. In this case, the patient received recombinant human bone 
morphogenetic protein-2 intraoperatively, followed by a bisphosphonate at 3 months after 
surgery, then STRENSIQ® starting at 7 months after surgery to achieve solid arthrodesis after 
spinal surgery, a successful outcome for the patient. The authors of this study suggest that the 
inclusion of asfotase alfa in the treatment regimen of the NF1 patient after surgery likely 
improved bone mineralization and healing of bone fractures after surgery in this patient 
(Harindhanavudhi, 2020). 
2.4. 
Benefit/Risk Assessment 
Identified potential risks are described below. More detailed information may be found in the IB.  
2.4.1. 
Risk Assessment 
This study is the first human exposure to ALXN1910, and as there is no clinical experience to 
date. 
A detailed assessment of potential risks is provided in Table 4. 
Table 4: 
Risk Assessment for ALXN1910 
Potential Risk of 
Clinical Significance 
Summary of 
Data/Rationale for Risk 
Mitigation Strategy 
ISRs and IARs 
(including 
hypersensitivity) 
ISRs are a potential risk 
with any agent 
administered SC or IV. 
Monitoring for ISRs and IARs will be conducted as part of 
routine safety assessments for this study, including signs and 
symptoms of anaphylaxis for the FIH study. ALXN1910 
treatment will be discontinued in case a severe 
hypersensitivity reaction occurs. 
See Section 10.4 for the management of potential AEs, 
including injection/infusion-related reactions, during study 
intervention administration. 
Immunogenicity 
Treatment with any 
therapeutic protein may 
induce an immune 
response, so ALXN1910 
has the potential to elicit 
an ADA response. 
Immunogenicity monitoring for ALXN1910 is in place for 
this study, as specified in the SoA (Section 1.3) and 
Section 10.4, including ADA and PK/PD monitoring, an 
algorithm for hypersensitivity reaction management, 
stopping rules, and staggered dosing. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; FIH = first-in-human; 
IAR = injection/infusion-associated reaction; ISR = injection/infusion site reaction; IV = intravenous; 
PD = pharmacodynamic; PK =pharmacokinetic; SC = subcutaneous; SoA = schedule of activities 


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2.4.1.1. 
Coronavirus Disease 2019 
Alexion is carefully considering the potential impact of COVID-19 on the proposed FIH study, 
including Investigators, other site staff, and study participants. The protocol will include 
provisions to mitigate risks so that participant/site personnel safety and study integrity are 
ensured considering the COVID-19 pandemic status at time of Clinical Trial Applications 
submission. At this time, provisions are being considered, including housing participants in the 
CRU facility during the study observation period (i.e., Day -1 to Day 75), as well as testing for 
COVID-19 infection at Screening and prior to admission to the CRU. The mitigations will be 
finalized based on the conditions in the future and conditions in the local area of the CRU. 
Alexion notes that, based on its mechanism of action, ALXN1910 is not expected to act as an 
immunosuppressant. Further, safety data collected in the clinical studies for the related ERT, 
asfotase alfa, indicate that it did not reduce the immune response in study participants or increase 
the risk of viral infections. 
See Section 10.10 and Section 10.11 for more detailed information on COVID-19 and 
COVID-19 vaccine risk assessments, respectively. 
2.4.2. 
Benefit Assessment 
This is a healthy participant study, and there is no direct benefit to participants.  
Data obtained from this clinical study may inform future clinical studies in participants with 
HPP, NF1, and/or AFFs. 
2.4.3. 
Overall Benefit: Risk Conclusion 
This is the first time that ALXN1910 will be administered to humans. Healthy participants are 
the appropriate population for this study as they will enable PK and PD assessments without the 
potential of confounding effects due to other disease activity, comorbidities, or concomitant 
medications. 
ALXN1910 is a next-generation ERT of asfotase alfa. In 2015, a healthy participant study has 
been completed for asfotase alfa (Study AA-HV-104), which tested a single 2 mg/kg dose by SC 
injection. Asfotase alfa was generally well tolerated with an acceptable safety profile. No NAb 
response to asfotase alfa was observed in any of the treated healthy participants at 42 days post 
dose, suggesting a very low risk to healthy participants with short term dosing of asfotase alfa. 
As the catalytic domains of ALXN1910 and asfotase alfa are structurally 99.8% identical, it is 
anticipated that ALXN1910 and asfotase alfa will possess pharmacologic and immunological 
similarities and share the same safety profile. Additional results for this study are provided in the 
ALXN1910 IB. 
This study has been designed to minimize the identified potential risks to participants; there are 
strict inclusion/exclusion criteria with a robust safety monitoring and risk mitigation plan in 
place. 
As described in Section 4.1, a sentinel group will be implemented for each cohort. The first 
2 participants randomized to each cohort will be dosed as a sentinel pair with 1 participant on 
active treatment and 1 participant on placebo. This dosing strategy is justified given the large 
safety margin (approximately 15-fold [based on predicted AUC0-168h value] at the highest 


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planned single dose of 135 mg SC). A sentinel safety report will be produced and reviewed 
before dosing the remaining participants in each cohort. 
At the discretion of the Investigator, up to 3 more participants will be dosed at least 48 hours 
after dosing of the sentinel pair, followed by dosing of the remaining participants in the cohort 
no earlier than 72 hours after sentinel pair dosing, as long as no suspension/stopping criteria have 
been met. At no time will more than 4 participants per cohort be dosed in a given day.  
A blinded SRC, consisting of the Investigator, Medical Monitor, Drug Safety Physician, Study 
Statistician, and Clinical Pharmacologist will evaluate the available study data at prespecified 
time points for participant safety and make recommendations on dose escalation, dose 
modification, or termination of the study. Decisions to continue, modify (explore the dose cohort 
further), or escalate dosing will be made by the Investigator and/or SRC as described in 
Section 4.1 and Section 7. 
The SC and IV doses to be studied in healthy participants in this study are predicted to be within 
the PK/safety exposure margins established from a 28-day toxicology study in monkeys. 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To assess the safety and tolerability of 
ALXN1910 
• 
Incidence of TEAEs and TESAEs 
Secondary 
• 
To assess the PK of single ascending doses of 
ALXN1910 
• 
Serum ALXN1910 PK (activity) and PK 
parameters 
• 
To explore the PD effects of single ascending 
doses of ALXN1910 
• 
Plasma concentrations of PPi, PLP, PL, and 
PA versus time profiles 
• 
To assess the immunogenicity of ALXN1910 
• 
Incidence and titers of treatment-emergent 
ADAs 
• 
To assess the absolute bioavailability of 
ALXN1910 SC 
• 
GMR of AUC values of SC versus IV from 
serum concentrations of ALXN1910 
• 
To compare the safety, tolerability, PK, and 
PD of ALXN1910 SC between Japanese and 
non-Japanese healthy participants 
• 
Quantitative assessment of safety/tolerability 
and PK/PD parameters between Japanese and 
non-Japanese participants 
Abbreviations: ADA = antidrug antibody; AUC = area under the serum concentration-time curve; GMR = geometric 
mean ratio; IV = intravenous; PA = pyridoxic acid; PD = pharmacodynamics(s); PK = pharmacokinetic(s); 
PL = pyridoxal; PLP = pyridoxal-5′-phosphate; PPi = inorganic pyrophosphate; SC = subcutaneous; 
TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 1, randomized, double-blind, placebo-controlled study designed to evaluate the 
safety, tolerability, PK, PD, and immunogenicity of SADs of ALXN1910 SC and a SAD of 
ALXN1910 IV in up to approximately 48 healthy adult participants across treatment cohorts (up 
to approximately 36 participants to receive ALXN1910 and up to approximately 12 participants 
to receive placebo) (Table 5).  
Of the 48 participants, 8 will be of Japanese descent, defined as those participants whose parents 
and grandparents are both Japanese and who have spent less than 10 years outside of Japan. The 
inclusion of Japanese participants aims to meet the regulatory requirements of the ICH Guidance 
E5(R1), which provides a general framework for evaluating the potential impact of ethnic factors 
on the acceptability of foreign clinical data.  
For this FIH study, 8 participants will be randomly assigned in a 3:1 ratio to treatment and 
placebo in each of the 6 cohorts with escalating doses of 5 mg IV (Cohort 1), 15 mg SC 
(Cohort 2), 15 mg IV (Cohort 3) in parallel with 15 mg SC in Japanese participants (Cohort 4) 
and 45 mg SC (Cohort 5), followed by 135 mg SC (Cohort 6). The first 2 participants 
randomized to each cohort will be dosed as a sentinel pair, with 1 participant on active treatment 
and 1 participant on placebo. This dosing strategy is justified given the large exposure margins 
(approximately 15-fold at the highest planned single dose of 135 mg SC). 
At the discretion of the Investigator, up to 3 more participants will be dosed at least 48 hours (as 
anticipated tmax occurs prior to 48 hours postdose) after the dosing of the sentinel pair, followed 
by dosing of the remaining participants in the cohort no earlier than 72 hours after sentinel pair 
dosing, as long as no suspension/stopping criteria have been met. At no time will more than 
4 participants per cohort be dosed in a given day. 
Participants who meet the qualifications for the study based on screening will be admitted to the 
CRU the day prior to dosing (Day -1) to undergo Check-in assessments per the applicable SoA 
(Section 1.3).  
Final determination of eligibility will be determined based on Check-in and predose procedures, 
and eligible participants will be randomized to ALXN1910 or placebo on Day 1 prior to dosing. 
There will be extensive PK/PD sampling during the first 24 hours after dosing. Safety 
assessments will be performed per the SoA. The study schematic is presented in Figure 1. 
Table 5: 
Planned ALXN1910-HV-101 Dosing Cohorts 
Cohorta 
Number of Participants 
(ALXN1910:placebo) 
Route of 
Administration 
Dose 
Number of 
Doses/Dose Interval 
1 
8 (3:1) 
IVb 
5 mg 
Single dose 
2 
8 (3:1) 
SC 
15 mg 
Single dose 
3 
8 (3:1) 
IVb 
15 mg 
Single dose 
4 
8 (3:1) (Japanese Participants) 
SC 
15 mg 
Single dose 
5 
8 (3:1) 
SC 
45 mg 
Single dose 
6 
8 (3:1) 
SC 
135 mg 
Single dose  
a Cohort 3, Cohort 4, and Cohort 5 can be initiated in parallel after dose escalation decision following SRC review 
of Cohort 2 safety and PK data. 


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b Slow IV infusions (rate of infusion = 6 mL/h) using a controllable infusion pump. The pharmacy manual will 
include details regarding infusion rate and duration. 
Abbreviations: IV = intravenous; PK =pharmacokinetic; SC = subcutaneous; SRC = Safety Review Committee 
4.2. 
Scientific Rationale for Study Design 
To gain an understanding of the safety, tolerability, PK, PD, and immunogenicity of ALXN1910, 
an FIH SAD study in healthy adult participants is proposed. Cohorts of Japanese and 
non-Japanese participants will also be evaluated to enable comparison between these 
2 populations. 
4.3. 
Dose Escalation 
Prior to initiating the next higher dose cohort, safety from the preceding dose cohort will be 
reviewed. After dosing 8 participants in Cohort 1, Cohort 2, and Cohort 5, the SRC will review 
14-day safety data (equivalent to 2 half-lives), including TEAEs, safety laboratory results, 
12-lead ECG findings, and vital sign measurements. PK data will be reviewed by SRC prior to 
dose escalation decision from Cohort 2 to Cohort 5, and from Cohort 5 to Cohort 6. For detailed 
cohort dose escalation requirements, please refer to Table 8. 
4.4. 
Justification for Dose 
The FIH dose selection is based on PK data collected from rat and monkey dose-range finding 
studies, 28-day GLP toxicology studies in rats and monkeys, and efficacy data from 2 Akp2GW 
(-/-) mouse efficacy studies.  
Two methods have been evaluated to determine a starting dose, with the first method based on 
the NOAEL and a second method based on the MABEL (EMA, 2017b). After comparing 
expected safety and feasibility factors for each method’s proposed starting dose, a 
NOAEL-based approach was selected to determine the final starting dose. The NOAEL-based 
starting dose at 5 mg is considered as the maximum recommended starting dose and is justified 
by the FIH starting dose decision tree, low concern of the risk factors (not an agonist, not a novel 
target, relevant, and translatable model) (Leach, 2021) and experience from asfotase alfa study 
AA-HV-104. In addition, this approach can avoid logistical challenges with dosing small 
volumes associated with the MABEL approach. The starting dose was selected based on NOAEL 
from the 28-day GLP toxicology study in monkeys dosed SC once weekly, which was 
determined to be 50 mg/kg. Monkey was selected because it has relevant biology with humans. 
Assumptions of 1) no allometric scaling for a molecule with molecule weight > 100 kDa 
(FDA, 2005), 2) applying safety factor of 750, 3) SC bioavailability (90%), and 4) adult body 
weight of 70 kg were factored into the calculation of the starting dose. Based on Pop-PK 
simulation results, the observed exposure of the NOAEL at 50 mg/kg/dose from the GLP 
toxicology study in monkeys is approximately 230-fold of projected human exposure from the 
5 mg IV starting dose (Table 6). Moreover, a single dose of 5 mg is not expected to be 
pharmacologically active with respect to bone mineralization. 
Single dose will be escalated by 3-fold from 5 mg IV (Cohort 1) to 15 mg SC (Cohort 2), by 
3-fold from 15 mg SC (Cohort 2) to 45 mg SC (Cohort 5), and by 3-fold from 45 mg SC 
(Cohort 5) to 135 mg SC (Cohort 6). A single dose of 15 mg IV (Cohort 3) and a single dose of 


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15 mg SC in Japanese participants (Cohort 4) will be administered after dose escalation decision 
following SRC review of Cohort 2 safety and PK data.  
At 15 mg SC, ALXN1910 is predicted to achieve clinical meaningful response in 85% of a 
treated population at steady state and is considered as the target effective dose. Based on the 
established extrapolation of asfotase alfa dose-response relationship with respect to 
improvements of bone mineralization in Akp2GW (-/-) mouse model of HPP, the dose producing 
normal bone mineralization in ED85 is considered as the target effective dose. Mouse ED85 was 
calculated using a dose response model developed using ALXN1910 preclinical efficacy studies 
in Akp2GW (-/-) mouse model of HPP and allometrically scaled to a weekly flat dose of 
15 mg/week in humans. A 135 mg SC dose is projected to achieve normalized bone 
mineralization in 98% of a treated population at steady state and is expected to cover the 
therapeutic range in humans. Predicted human exposure at 135 mg SC is around 1/15 of the 
28-day monkey NOAEL exposure with the NOAEL dose at the highest dose of 50 mg/kg. 
Three-fold dose escalation is supported by results of a single dose range finding study in 
monkeys and rats where the high dose was well tolerated, and there were no ALXN1910 
treatment-related mortalities and noteworthy biologically meaningful veterinary observations. 
The Pop-PK model uses standard body weight-based allometric principles and approach to 
account for body weight differences between species to simulate human exposure. Safety 
(including PK) exposure margins were estimated using simulated human exposure based on the 
Pop-PK model and observed 28-day monkey NOAEL exposure. Table 6 shows the FIH SAD 
study design and a summary of the predicted exposure and safety exposure margin for 
ALXN1910. The forecasted human exposure for the single SC and IV doses to be studied in 
healthy participants are predicted not to exceed exposure of the NOAEL dose (50 mg/kg) of the 
28-day monkey GLP toxicology study. The proposed maximum SC single dose (135 mg) is 
expected to maintain a large safety exposure margin of at least 15-fold in human. 
Table 6: 
Simulated ALXN1910 PK Exposure and Safety Exposure Margins in 
Humans 
Cohort 
Dose 
Predicted 
AUC168h 
(hour × µg /mL) 
Predicted 
Cmax 
(µg/mL) 
Expected Safety 
Exposure Margin 
for AUC0-168h 
Expected Safety 
Exposure 
Margin for Cmax  
1 
5 mg IV 
78.2 
1.2 
230 
232 
2 
15 mg SC 
136.0 
1.2 
132 
231 
3 
15 mg IV 
225.1 
3.4 
80 
79 
4 
15 mg SC 
(Japanese participants) 
153.6 
1.3 
117 
205 
5 
45 mg SC 
398.2 
3.3 
45 
81 
6 
135 mg SC 
1208.8 
10.2 
15 
26 
Abbreviations: AUC168h = area under the serum concentration-time curve from time 0 to 168 hours; 
Cmax = maximum observed serum concentration; IV = intravenous; PK = pharmacokinetics; SC = subcutaneous 
4.5. 
Duration of Treatment and End of Study Definition 
Following a Screening Period of up to 28 days, there will be a Dosing and Follow up Period 
(single dose on Day 1 through the EOS Visit) of approximately 74 days.  


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Based on data from preclinical models, the half-life of ALXN1910 is expected to be 
approximately 7 days in healthy adult participants; therefore, the end of study visit is planned on 
Day 75, representing approximately 10 half-lives after initial study intervention administration. 
The total study duration per participant is approximately 103 days. An overview of the study 
visits is present in Figure 2. 
A participant is considered to have completed the study if they complete all visits of the study 
including the last scheduled visit specified in the SoA (Section 1.3). 
The end of the study is defined as the date the last participant completes the last visit (as 
specified in the SoA [Section 1.3]). 
Figure 2: 
Overview of Study Visits 
 
Abbreviation: D = day 


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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 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants must be between 18 and 55 years of age (Japanese participants must be 
between 20 and 55 years of age), inclusive, at the time of signing the ICF. 
Sex 
2. Male or female, and willing to follow protocol-specified contraception guidance as 
specified in Section 10.7. 
Type of Participant 
3. Participants who are healthy as determined by satisfactory medical assessment with no 
clinically significant or relevant abnormalities as determined by medical history, physical 
examination, vital signs, 12-lead ECG, and clinical laboratory evaluation (hematology, 
chemistry, coagulation, and urinalysis) that is reasonably likely to interfere with the 
participant’s participation in or ability to complete the study, or to potentially confound 
interpretation of study results, as assessed by the Investigator. 
4. Female participants must have a negative serum pregnancy test at Screening and negative 
urine pregnancy test on Day -1. 
5. Participants of Japanese descent are defined as: 
• First generation (born to 2 Japanese parents and 4 Japanese grandparents). 
• Participant must have been born in Japan, and not have lived outside Japan for more 
than 10 years. 
• Lifestyle, including diet, must not have significantly changed since leaving Japan. 
Weight 
6. Body weight within 50 to 100 kg, inclusive, and body mass index within the range 18 to 
29.9 kg/m2, inclusive. 
Informed Consent 
7. Capable of giving signed informed consent as described in Section 10.1.3, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.  


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Current or recurrent disease (eg, cardiovascular, hematological, neurological, endocrine, 
immunological, rheumatological, renal, hepatic or gastrointestinal, or other conditions).  
2. Current or relevant history of physical or psychiatric illness, use of prohibited therapies 
during the study, or make the participant unlikely to fully comply with the requirements 
of the study or complete the study, or any condition that presents undue risk from the 
study intervention or study procedures. 
3. Any other significant disease or disorder that, in the opinion of the Investigator, may put 
the participant at risk. 
4. Clinically significant abnormal vital signs at Screening or predose on Day 1. If vital signs 
are significantly abnormal, up to 2 additional readings will be taken. If neither of the 2 
replicates are normal or non-significantly abnormal, the participant will be excluded from 
study participation. Blood pressure should be taken after a minimum of 5 minutes in 
supine position. Standing (orthostatic) blood pressure will also be performed at Screening 
only to exclude participants who are prone to orthostatic hypotension. 
5. Clinically significant abnormal ECG at Screening or 12-lead ECG (triplicate) predose on 
Day 1. If ECG values are significantly abnormal, up to 2 additional triplicate ECGs will 
be performed. If neither of the 2 replicates are normal or non-significantly abnormal, the 
participant will be excluded from study participation.  
6. History of malignancy, apart from nonmelanoma skin cancer or carcinoma in situ of the 
cervix, that has been treated with no evidence of recurrence within 5 years. 
7. HIV infection (evidenced by HIV-1 or HIV-2 antibody titer). 
8. Acute or chronic hepatitis B virus infection (evidenced by positive hepatitis B surface 
antigen [HBsAg] or positive core antibody [HBcAb] with negative surface antibody 
[HBsAb]) at Screening will not be enrolled. 
9. Acute or chronic hepatitis C virus infection (evidenced by antibody titer). 
10. History of significant allergic reaction (eg, anaphylaxis or angioedema) to any product 
(eg, food, pharmaceutical). 
Prior/Concomitant Therapy 
11. Use or intended use of prescription medications (excluding oral contraceptives and 
paracetamol/acetaminophen at doses ≤ 3000 mg per day) within 14 days or 5 half-lives of 
the drug (whichever is longer) prior to Day -7, and/or intended use at any point over the 
duration of the study except with prior approval of Alexion. 
12. Use of nonprescription/over-the-counter medications (excluding 
paracetamol/acetaminophen at doses ≤ 3000 mg per day), including herbal remedies and 
supplements, within 7 days to dosing Day 1, except with prior approval of Alexion. 


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13. Use of vitamin B6 (including vitamin supplements that contain vitamin B6) for at least 
2 weeks prior to Screening. 
Prior/Concurrent Clinical Study Experience 
14. Current enrollment or past participation, within the last 90 days, before signing of 
consent in this or any other clinical study involving an investigational study intervention. 
Participants, involved in intervention studies using investigation or non-investigational 
drug with prolonged half-lives, are not eligible unless the time since last treatment has 
exceeded 90 days or 5 half-lives of the study intervention, whichever is longer. 
Diagnostic Assessments 
15. Presence of fever (confirmed body temperature > 37.6°C) (eg, a fever associated with a 
symptomatic viral or bacterial infection) within 14 days prior to dosing on Day 1. 
16. Alkaline phosphatase greater than the ULN or lower than the lower limit of normal of the 
reference range of the testing laboratory at Screening or on Day -1. 
17. Serum creatinine greater than the ULN of the laboratory reference range at Screening or 
on Day -1; estimated glomerular filtration rate < 90 mL/min/1.73 m2. 
18. ALT or aspartate aminotransferase > ULN of the reference range of the testing laboratory 
at Screening or on Day -1. 
19. Any clinically significant abnormal hematological parameters (per the Investigator’s 
discretion). 
20. Positive urine drug toxicology screen at Screening or on Day -1. 
21. Positive urine alcohol test at Screening or Day -1 
22. Donation of plasma within 7 days prior to dosing; donation or loss of blood (excluding 
volume drawn at Screening) of more than 50 mL within 30 days of dosing on Day 1, or 
more than 499 mL of blood within 56 days of dosing on Day 1. 
Other Exclusions 
23. Female participants who are pregnant or breastfeeding. 
24. Major surgery or hospitalization within 90 days prior to dosing on Day 1. 
25. History of exposure to asfotase alfa. 
26. History of allergy or hypersensitivity to excipients of asfotase alfa or ALXN1910 
(eg, sodium phosphate, sodium chloride). 
27. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing 
products in any form (eg, gum, patch, electronic cigarettes) from 2 hours before 
admission through discharge from the CRU, for both inpatient and outpatient visits. 
(Former smokers may be permitted to enroll at the Investigator’s discretion).  
28. History of illicit drug abuse, history of alcohol abuse within 1 year prior to Screening, or 
clinical evidence of substance and/or alcohol abuse within the 2 years before Screening. 
Alcohol abuse is defined as regular weekly intake of more than 14 units for both men and 
women (https://www.nhs.uk/conditions/alcohol-misuse/). 


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5.3. 
Justification for Study Population 
This is the first time that ALXN1910 will be administered to humans. Alexion considers that 
healthy participants are the appropriate population for this study, as they will enable PK and 
safety assessments without the potential of confounding effects due to other disease activity, 
comorbidities, or medications. Based on the available nonclinical data with ALXN1910, the 
sequential cohort study design with SAD administration of ALXN1910 IV or SC are expected to 
adequately assess safety, tolerability, and PK, and allow flexibility to change the injected dose as 
clinical data are generated. 
The inclusion of a cohort of Japanese participants will meet regulatory requirements of the ICH 
Guidance E5(R1) and Japan Ministry of Health, Labour and Welfare guidance on Basic 
Principles on Global Clinical Trials. The ICH E5 guideline provides a general framework for 
evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with 
the underlying objective of minimizing duplication of clinical data, and it also describes the 
requirement of bridging studies for extrapolation of foreign clinical data to a new region 
(ie, Japan). 
5.4. 
Lifestyle Considerations 
5.4.1. 
Meals and Dietary Restrictions 
• Participants are required to abstain from ingesting food containing poppy seeds 
within 24 hours prior to admission to the CRU. 
• No outside food or drink is permitted at the CRU. All meals and snacks will be 
provided. Participants will receive standard meals and snacks at scheduled times 
during confinement. 
5.4.2. 
Activity 
Participants will be required to remain in supine position for dosing and for approximately 
15 minutes after study intervention administration. Vigorous activity will be prohibited at all 
times throughout confinement at the CRU. 
5.4.3. 
Caffeine, Alcohol, and Tobacco 
Participants will be required to abstain from the following: 
• Ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and 
chocolate) 24 hours before admission through discharge from the CRU and 24 hours 
before each outpatient visit. 
• Ingesting alcohol 24 hours before admission through discharge from the CRU and 
24 hours before each outpatient visit. 
• Smoking nicotine or use of tobacco products from 2 hours before admission through 
discharge from the CRU. 


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5.5. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. 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. 
Individuals who do not meet the criteria for participation in this study (screen failure) 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. Rescreened participants are 
required to sign a new ICF. 


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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.  
6.1. 
Study Interventions Administered 
The study intervention composition and doses to be administered in this study are presented in 
Table 7.  
Table 7: 
Dose Reference Chart for Study ALXN1910-HV-101 
Study Intervention 
Name 
ALXN1910 IV  
ALXN1910 SC 
Placebo 
Type  
Biologic  
Biologic 
Placebo 
Dose Formulation 
ALXN1910 is formulated 
at pH 7.3 and each vial 
contains 100 mg of 
ALXN1910 in 10 mM 
sodium phosphate, 70 mM 
glycine, 210 mM sucrose, 
and 0.05% PS80. 
ALXN1910 is formulated 
at pH 7.3 and each vial 
contains 100 mg of 
ALXN1910 in 10 mM 
sodium phosphate, 70 mM 
glycine, 210 mM sucrose, 
and 0.05% PS80 
0.9% normal saline 
Unit Dose 
Strength(s)/Dosage 
Level(s) 
5 and 15 mg, single-dose 
15, 45, and 135 mg, 
single-dose 
0 mg, single-dose 
Route of Administration 
IV infusion 
SC injection 
IV infusion or SC 
injection 
Use 
Experimental 
Experimental 
Placebo 
IMP and NIMP 
IMP 
IMP 
IMP 
Abbreviations: IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal 
product; PS80 = polysorbate 80; SC = subcutaneous 
6.1.1. 
Study Intervention Packaging and Labeling 
At minimum, bulk ALXN1910 vials supplied by Alexion will be labeled with: 
A. Protocol number 
B. Lot number/expiry date 
C. Alexion name and address 
D. Instructions for use and storage 
ALXN1910 will be labeled according to the country’s regulatory requirements. All packaging 
and labeling operations will be performed according to GMP and relevant regulatory 
requirements. Participant doses prepared by the site will be QP certified and released by the 
CRU. 
6.2. 
Preparation/Handling/Storage/Accountability 
Details regarding preparation, handling, storage, accountability, and administration of the study 
intervention are discussed below. 


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• The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and that any discrepancies 
are reported and resolved before use of the study intervention. 
• Only participants enrolled in the study may receive the study intervention and only 
authorized site staff may supply or administer the study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
• The Investigator (or designee), institution, or the head of the medical institution 
(where applicable) is responsible for study intervention accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records). 
• This responsibility includes the reporting of any temperature excursions and product 
complaints to AlexionIMPTE@alexion.com and productcomplaints@alexion.com 
within 1 business day of awareness. A product complaint is defined as any written, 
electronic, or oral communication that alleges deficiencies related to the identity, 
quality, durability, reliability, usability, safety, effectiveness, or performance of a 
product or clinical study material and/or its packaging components after it is has been 
released for distribution to an end customer that affects the performance of such 
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 
Up to approximately 48 participants will be randomized according to a randomization schedule 
generated prior to the start of the study. The participants in each dose cohort will be randomized 
in a 3:1 ratio to receive ALXN1910 or placebo. 
The randomization codes will be maintained in a location with access restricted to pharmacy 
personnel only. Once a randomization number has been assigned to a participant, it may not be 
assigned to another participant.  
This is a double-blind study. Participants and on-site medical/nursing staff at the study site will 
be blinded to study intervention/dose assignment. The pharmacy staff preparing the 
investigational products will not be blinded to study intervention/dose assignment, but all other 
site staff, including the Investigator, will be blinded.  
As the treatment with ALXN1910 can cause increases in serum ALP, knowledge of the ALP 
results could jeopardize the double-blind design of the study. Therefore, ALP results for the 
post-dose time points will not be available to review by the Investigator; however, the ALP 
results will be available in a blinded manner for each cohort at the time of SRC meeting. 
Alexion staff will be unblinded only when necessary (eg, to monitor that SC/IV dosing are being 
prepared appropriately, to determine reportability of SAEs for dose escalation decisions) and will 
refrain from sharing any information on study intervention assignment with the study center staff 
or others at Alexion, especially with regard to assessment and reporting of safety.  


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The study intervention assignment to each participant will be provided to the Investigator. This 
information will be retained by the Investigator (or representative) in a secured manner. In case 
of an emergency, the Investigator has the sole responsibility for determining if unblinding of a 
participants’ intervention assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should contact Alexion prior to unblinding a participant’s 
intervention assignment unless this could delay emergency treatment for that participant. If a 
participant’s intervention assignment is unblinded, Alexion must be notified within 24 hours 
after breaking the blind.  
Additional details regarding the blinding/unblinding process (including masking techniques) will 
be included in the pharmacy manual. 
As emerging PK and safety data from each cohort of this study will be needed for timely 
decisions about adjustments of doses or escalate dosing in subsequent cohorts, the emerging data 
will be unblinded for analysis. An independent unblinded team that is limited to key stakeholders 
will perform unblinded PK analyses and prepare preliminary summaries of PK and safety data as 
needed before data are more generally unblinded. These summaries will not reveal individual 
participant’s treatment assignments. Except as noted above, other members of the study team 
will remain blinded. 
6.4. 
Study Intervention Compliance 
Participants will receive study intervention directly from the Investigator or designee, under 
medical supervision. Dosing date and time will be recorded in the source documents and 
recorded in the eCRFs. The dose of study intervention and study participant identification will be 
confirmed at the time of dosing by a study site personnel other than the person administering the 
study intervention.  
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 
from 14 days prior to the dose of study intervention until the EOS Visit 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 
• Paracetamol/acetaminophen at doses of a maximum 3000 mg per day is permitted for 
use as an exception with the approval of the Investigator. 


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• Concomitant procedures are not allowed unless medically indicated and/or permitted 
by Alexion or the Investigator or designee. 
• Concomitant medications may be used during the study if deemed medically 
indicated by the Investigator. The Investigator or designee will notify Alexion of any 
AEs requiring administration of prescription medication(s) while on study. 
6.5.2. 
Disallowed Medicine and Therapy 
• Participants must abstain from taking prescription or non-prescription drugs 
(including vitamins and dietary or herbal supplements) within 7 days (or 14 days if 
the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before 
the start of study intervention until completion of the EOS Visit, unless, in the 
opinion of the Investigator and Alexion, the medication will not interfere with the 
study. 
• Participants must abstain from taking prescription medications within 21 days or 
5 half-lives (whichever is longer) of Day -1 or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days or 5 half-lives (whichever 
is longer) before Day -1 and until completion of the EOS Visit. 
6.6. 
Dose Modification 
Decisions to continue or modify dosing will be made by the Investigator and/or SRC after review 
of the blinded data as described in Table 8. The SRC may also make recommendations regarding 
safety issues, study conduct, or study suspension. 
Predicted ALXN1910 human PK exposure (Table 6) indicates Cohort 5 or Cohort 6 mean 
projected PK exposure should not exceed 50% of the NOAEL exposure established in the 28-day 
GLP toxicology study in monkeys. In the event that mean PK exposure in Cohort 5 or Cohort 6 
is predicted to exceed 50% of the NOAEL exposure, a lower dose will be selected so the above 
criteria can be met. PK data will not be used for dose escalation from Cohort 1 to Cohort 2 as 
greater than 150-fold PK (safety) exposure margin is expected for Cohort 2. 
Dose escalation requires agreement between the Investigator and Alexion; Alexion may not 
supersede the Investigator if there are concerns that dosing should be stopped. 


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Table 8: 
Detailed Dose Escalation Criteria for Each Cohort 
Dosing Decision 
Responsible 
Party 
Data to be Reviewed 
Documentation/ 
Communication Methods 
Dose escalation from 
Cohort 1 to Cohort 2 
SRC 
• 
At minimum, 14 days of postdose 
safety and tolerability data from at 
least 7 participants in Cohort 1. 
The SRC will document the 
decision on the 
escalation/progression 
approval form. 
Dose escalation from 
Cohort 2 to Cohort 5 
(in parallel with 
Cohort 3 and Cohort 4) 
SRC 
• 
At minimum, 14 days of postdose 
safety and tolerability data from at 
least 7 participants in Cohort 2. 
• 
Seven days of PK data from at 
least 7 participants in Cohort 1 
and at least 7 participants in 
Cohort 2. 
The SRC will document the 
decision on the 
escalation/progression 
approval form. 
Dose escalation from 
Cohort 5 to Cohort 6 
SRC 
• 
At minimum, 14 days of postdose 
safety and tolerability data from at 
least 7 participants in Cohort 5. 
• 
Seven days of PK data from at 
least 7 participants in Cohort 5. 
• 
The cumulative PK data from 
Cohort 1 and Cohort 2. 
The SRC will document the 
decision on the 
escalation/progression 
approval form. 
Abbreviations: PK = pharmacokinetic; SRC = Safety Review Committee 
6.7. 
Intervention After the End of the Study 
This is a healthy participant study. No follow-up ALXN1910 administration is planned. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Although not anticipated for this study, if an acute infusion reaction occurs during IV infusion 
dosing, the research clinic should follow the steps outlined in the Acute Infusion Reaction 
Algorithm (Section 10.5). Participants who are unable to complete their IV dose on Day 1 should 
complete the scheduled safety assessments, if possible, but another participant must be enrolled.  
7.2. 
Cohort Stopping Rules 
In the event an acute safety event occurs in any cohort, dosing should be stopped until a causality 
assessment has taken place and an appropriate risk mitigation strategy is put into place before 
dosing the remainder of the cohort. 
Assessment of AE intensity/severity should be performed by the Investigator using clinical 
judgment and according to criteria from NCI CTCAE version 5.0, published 27 Nov 2017 (see 
Section 10.3.3). As CTCAE grading is intended for oncology patients, study-specific 
modifications related to the liver, hematology, and QT interval prolongation have been made to 
ensure clear guidance and appropriate grading of AEs for this study in healthy participants 
(Table 11). 
If a cohort stopping rule (Table 11) is met, no further dosing at the dose level or higher will 
proceed. Continuation of the cohort and/or study will require a substantial protocol amendment. 
Unless a cohort stopping rule is met, dose continuation or escalation will proceed as scheduled 
and the study will continue as planned provided no prespecified toxicity events occur (as 
determined by the SRC). 
7.3. 
Participant Discontinuation/Withdrawal from the Study 
• All efforts should be made to ensure participants are willing to comply with study 
participation prior to conducting the screening procedures.  
• The study staff should notify Alexion and their site monitor of all study withdrawals 
as soon as possible. The reason for participant discontinuation must be recorded in the 
source documents and eCRF. 
• A participant may withdraw from the study at any time at their own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This activity is expected to be uncommon. 
• At the time of discontinuing from the study, an early discontinuation visit should be 
conducted that includes the EOS assessments shown in the SoA, if possible 
(Section 1.3).  
• All efforts will be made to contact participants who withdraw/are withdrawn from the 
study via phone for a safety follow-up call approximately 30 days (4.5 half-lives) 
after their dose to assess AEs. 


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• The first participant in each cohort to withdraw/be withdrawn from the study prior to 
completion of the EOS assessments may not be replaced; subsequent participants in 
that cohort to withdraw/be withdrawn before EOS completion will be replaced. 
• 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, the participant may request destruction of 
any samples taken and not tested, and the Investigator must document this in the site 
study records. 
7.4. 
Lost to Follow-up 
A participant will be considered lost to follow-up if the participant 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 to reschedule the missed visit as soon 
as possible, 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, 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, they will be considered lost to 
follow-up. 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.8. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. 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 (Section 1.3). 
• See Section 10.2 for the list of clinical laboratory tests. 
8.1. 
Efficacy Assessments 
No efficacy assessments will be performed during the study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3).  
8.2.1. 
Physical Examinations 
• Complete or brief physical examinations will be performed according to the 
timepoints indicated in the SoA (Section 1.3). Investigators should pay special 
attention to clinical signs related to previous serious illnesses. 
• Complete physical examinations will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.  
• Brief physical examinations will include assessments at the Investigator’s discretion. 
• Height and BMI will be recorded only at Screening.  
• Weight will be recorded at Screening and Day -1. 
8.2.2. 
Vital Signs 
• Oral temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure 
(mm Hg) will be assessed. 
• Blood pressure and pulse measurements will be assessed using a completely 
automated device after the participant has been resting in the supine position for at 


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least 5 minutes. At Screening, supine and standing (orthostatic) blood pressures will 
be performed according to the CRU’s typical procedure to exclude participants who 
are prone to orthostatic hypotension. Manual techniques will be used only if an 
automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell 
phones). Ideally, the same arm for each participant should be used for measurements. 
• Vital signs taken postdose will be performed before the coinciding blood collection, 
whenever possible. 
8.2.3. 
Electrocardiograms 
• At each timepoint indicated in the SoA (Section 1.3), 12-lead ECGs will be 
performed in triplicate sequentially within 5 minutes, at least 1 minute apart to obtain 
heart rate, PR, QRS, QT, and QTc intervals. 
• ECGs should not be performed within 1 hour after any major meal or major meals 
should be withheld until after ECG assessments.  
• Participants should rest in supine position for at least 10 minutes before each ECG 
timepoint.  
• Predose ECGs (Baseline) should be performed at least 1 minute apart after 
10 minutes of bedrest in supine position (note, no bedrest is required post ECG), at 
90, 75, and 60 minutes before dosing. 
• Postdose ECGs will be performed before the coinciding blood collection, whenever 
possible. 
8.2.4. 
Clinical Safety 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. 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents.  
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator 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 
collected in accordance with the Laboratory Manual and the SoA (Section 1.3). 


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− Laboratory assessments performed at the institution’s local laboratory that require 
a change in participant management or are considered clinically significant by the 
Investigator (eg, AE or SAE) must be recorded in the eCRF.  
• The maximum total blood volume collected from participants in this study will not 
exceed 500 mL. The National Health Service blood donation policy at the time of 
completion of this protocol (http://www.blood.co.uk/who-can-give-blood/) states that 
women can give 470 mL of blood every 16 weeks. Therefore, the ≤ 500 mL of blood 
collected during this study of less than 16 weeks is permitted/consistent with current 
clinical practice. 
8.2.5. 
Pregnancy 
Pregnancy data from female participants and female spouses/partners of male participants will be 
collected from the time points specified in the SoA (Section 1.3). Any female participant who 
becomes pregnant during the study will be withdrawn from the study. If a pregnancy is reported, 
the Investigator must immediately inform Alexion within 24 hours of awareness of the 
pregnancy and follow the procedures outlined in Section 10.7.3. 
8.3. 
Adverse Events and Serious Adverse Events Considerations 
• The definitions of AEs and SAEs and specific reporting requirements 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 EOS visit on 
Day 75 as specified in the SoA (Section 1.3). 
• All SAEs will be recorded and reported to Alexion immediately and under no 
circumstance should this exceed 24 hours of the Investigator's awareness, 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 they 


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consider the event to be reasonably related to the study intervention or study 
participation, the Investigator must promptly notify Alexion. 
8.3.2. 
Method of Detecting AEs and SAEs 
• The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
• Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-
ended and non-leading verbal questioning of the participant is the preferred method to 
inquire about AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each 
participant at subsequent visits/contacts. All SAEs will be followed up until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.4). Further information on follow-up procedures is provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs  
• Prompt notification of an SAE by the Investigator to Alexion is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
• Alexion has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. Alexion will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and Investigators. 
• Alexion is required to submit individual suspected unexpected serious adverse 
reaction (SUSAR) reports (defined in Section 10.3.2) in the format of CIOMS I Form 
to health authorities and Investigators as required. Forms submitted to Investigators 
will be blinded to treatment assignment. In limited circumstances, the blind may be 
broken in the case of urgent safety issues that could compromise participant safety.  
• 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. 
8.3.5. 
Special Warnings and Precautions for Use 
Please refer to the current ALXN1910 Investigator’s Brochure for special warnings and 
precautions for use. 
8.4. 
Treatment of Overdose 
• For this study, any blinded dose of study intervention greater than that specified in the 
protocol will be considered a suspected overdose. 


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• Alexion does not recommend specific treatment for a suspected overdose and no 
antidote is currently available for ALXN1910. 
• Overdoses are medication errors that are not considered AEs unless there is an 
untoward medical occurrence resulting from the overdose. 
• In the event of a suspected overdose, the Investigator/Treating Physician should: 
− Contact the Medical Monitor immediately. 
− Closely monitor the participant for any AE/SAE.  
− Obtain a serum sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).  
− 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 will be collected for measurement of serum concentrations of 
ALXN1910 as specified in the SoA (Section 1.3). Samples collected within ± 10% in 
minutes or 30 minutes of the scheduled time, whichever is less, will not be considered 
a protocol deviation. Additional samples may be collected at additional time points 
during the study if warranted and agreed upon between the Investigator and Alexion. 
The IV dose cohorts (1 and 3) will also have an end-of-infusion PK time point. The 
total blood volume will not exceed the volume limit for healthy participants 
(Section 8.2.4). To ensure appropriate monitoring, 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 or to extend the study duration to 
capture sufficient PK elimination phase). 
• 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 collection will 
be recorded. 
• Samples will be used to evaluate the PK of ALXN1910. Samples collected for 
analyses of ALXN1910 serum concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study. 
8.6. 
Pharmacodynamics 
• Whole blood will be collected for measurement of plasma concentrations of PPi, PLP, 
PL, and PA as specified in the SoA (Section 1.3). Samples collected within ± 10% in 
minutes or 30 minutes of the scheduled time, whichever is less, will not be considered 
a protocol deviation. Additional samples may be collected at additional time points 
during the study if warranted and agreed upon between the Investigator and Alexion. 


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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 PD of ALXN1910. Samples collected for 
analyses of plasma concentrations of PPi, PLP, PL, and PA may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the 
study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarker assays may be conducted as exploratory analyses on collected whole blood samples 
(details provided in Section 10.8). 
8.9. 
Immunogenicity Assessments 
Serum samples for ADA analysis will be collected at time points according to the SoAs 
(Section 1.3). All efforts will be made to obtain the immunogenicity samples at the exact 
nominal time relative to dosing. Out-of-window protocol deviation capture for immunogenicity 
samples follows that specified for PK sample collection (Section 8.5). 
8.9.1. 
ADA Variables 
ADA variables include ADA response category incidence and titer over the duration of the study 
as follows. ADA response category definitions and titer thresholds will be provided in the SAP.  
ADA response categories 
• ADA Negative 
• ADA Positive 
Participants that are ADA positive will be categorized as follows: 
• Pre-existing Immunoreactivity 
• Treatment-emergent ADA Responses 
• 
Treatment-boosted ADA Responses 
ADA Maximum Titer Value Categories: 
• Lower Titer 
• Moderate Titer 
• High Titer 


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8.10. 
Health Economics Data and/or Medical Resource Utilization 
Health economics data and/or medical resource utilization parameters are not collected or 
evaluated in this study. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No statistical hypotheses will be tested for this study. 
9.2. 
Sample Size Determination 
The sample size of up to approximately 48 participants is empirical and was selected to support 
the initial characterization of safety, tolerability, PK, PD, and immunogenicity for ALXN1910. 
Although the selected sample size was not based on statistical power considerations, the 
following table provides the probability of observing AEs under various underlying event 
incidence. 
Incidence of AE in the Population 
Probability to Observe at least 1 AE Occurrence 
in 6 Participants from Each Cohort 
10% 
46.9% 
15% 
62.3% 
20% 
73.8% 
25% 
82.2% 
30% 
88.2% 
35% 
92.5% 
40% 
95.3% 
Abbreviation: AE = adverse event 
9.3. 
Populations for Analyses 
The population sets used for analysis are defined in Table 9. 
Table 9: 
Populations for Analyses 
Population 
Description 
Safety Set 
All participants who receive any amount of study intervention will be included in the 
Safety Set. Participants will be analyzed according to the study intervention received. 
PK Set 
All treated participants for whom the PK profile of ALXN1910 can be adequately 
characterized will be included in the PK Set. PK analyses will be based upon the 
study intervention received. 
PD Set 
All treated participants for whom the PD profile of ALXN1910 can be adequately 
characterized will be included in the PD Set. 
ADA Analysis Set 
All randomized/enrolled participants who receive at least 1 dose of the study 
intervention and who after the dose have at least 1 reportable ADA result. 
Participants will be analyzed according to the study intervention they actually 
received. 
Abbreviations: ADA = antidrug antibody; PD = pharmacodynamic; PK = pharmacokinetic 
9.4. 
Statistical Analyses 
Statistical methods described in this section will be further elaborated in the SAP. This SAP will 
be developed and finalized before first data cutoff if interim analysis is conducted or database 
lock. Summary statistics will be computed and displayed by treatment group and by visit, where 
applicable. Participants in the placebo group of each cohort will be pooled in the analysis. 


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Descriptive statistics for continuous variables will minimally include the number of participants, 
mean, standard deviation, minimum, median, and maximum. For categorical variables, 
frequencies, and percentages will be presented. Graphical displays will be provided as 
appropriate. 
9.4.1. 
Safety Analyses 
All safety analyses will be based on the Safety Set.  
The primary objective of the study is to assess the safety and tolerability of ALXN1910. The 
endpoints to support the primary objective include incidence of TEAEs and TESAEs.  
The incidence of TEAEs and TESAEs will be summarized by SOC and PT for each dose cohort 
overall, by intensity/severity, and by relationship to study intervention. Treatment-emergent AEs 
and TESAEs resulting in withdrawal from the study will be listed. Participants having multiple 
AEs within a category (eg, overall, SOC, PT) will be counted once in that category. For 
intensity/severity tables, a participant’s most severe event within a category will be counted. 
Adverse events of special interest (such as ISRs and IARs) will be analyzed similarly.  
Changes from baseline in vital signs and laboratory assessments (as displayed in Table 10) will 
be summarized by visit for each dose cohort and pooled placebo group. Laboratory parameter 
values will be assessed by the Investigator for intensity/severity grade by taking into 
consideration clinical judgment and using CTCAE version 5.0 (for grading see Section 10.3.3).  
Shift tables by treatment group will be produced for these laboratory parameters. These tables 
will summarize the number of participants with each baseline intensity/severity grade relative to 
the normal ranges, and changes to the worst highest grade assessed postdose during the study 
ECG parameters will be measured at the specified time points, including heart rate, PR, RR, 
QRS, QT, and QTcF intervals. Each 12-lead ECG will be performed in triplicate (sequentially 
within 5 minutes, at least 1 minute apart) and should not be assessed within 1 hour after any 
major meal or, major meals should be withheld until after ECG assessments. The average of the 
triplicate ECG readings at the time points collected will be calculated, and changes from baseline 
values will be assessed. Intensive cardiac assessments will be performed in the Safety Set using 
food effects on ECG to establish assay sensitivity. Analysis of drug related QT/QTc interval 
changes relative to serum 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). The ECG utilized for this analysis requires adjudication by qualified cardiologists in 
accordance with principles set out in the ICH E14 guideline and subsequent Q&A documents. 
All ECG recordings will be in triplicate and compliant with the correct recording and manual 
adjudication of ECG in thorough QT/QTc studies. The ECG analyses will be based on 
adjudicated selected triplicates from each time point. 
An outlier analysis will be performed that will summarize the frequency and percentage of 
participants who meet any of the following outlier criteria at each visit by cohort: 
• QT, QTcF interval ≤ 450 msec 
• 450 msec < QT, QTcF interval ≤ 480 msec  
• 480 msec < QT, QTcF interval ≤ 500 msec  


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• QT, QTcF interval > 500 msec 
• QT, QTcF interval increases from baseline ≤ 30 msec 
• 30 msec < QT, QTcF interval increases from baseline ≤ 60 msec  
• QT, QTcF interval increases from baseline > 60 msec 
9.4.2. 
Other Analyses  
9.4.2.1. 
Pharmacokinetic Analysis 
All PK analyses will be performed on the PK Set and will be reported by each cohort. The 
individual serum concentration data from participants who receive ALXN1910 with actual 
sampling dates and times will be used to derive the PK parameters by non-compartmental 
analyses methods using Phoenix WinNonlin version 6.3 or higher. 
The following PK parameters will be derived: 
Parameter 
Definition 
Cmax 
Maximum observed serum concentration 
tmax 
Time to maximum observed serum concentration 
AUCt 
Area under the serum concentration-time curve from time 0 (dosing) to the last 
quantifiable concentration 
AUC∞ 
Area under the serum concentration-time curve from time 0 (dosing) to infinity 
t½ 
Terminal elimination half-life 
λz 
Terminal-phase elimination rate constant 
CL or CL/F 
Total body clearance or apparent clearance 
Vd or Vd/F 
Volume of distribution or apparent volume of distribution 
F 
Absolute bioavailability 
The F for the ALXN1910 SC cohorts will be defined by the ratio of the geometric means for the 
area under the serum concentration-time curve from time 0 (dosing) to infinity parameter for the 
ALXN1910 SC cohort over the ALXN1910 IV cohort. For the F estimates, a 95% CI for each of 
the ratios of the geometric means will be provided. 
The PK parameters for ALXN1910 will be evaluated for Japanese and non-Japanese participants 
(Cohort 2 versus Cohort 4) on active treatment, using an analysis of variance statistical model 
with cohort as the fixed effects on the natural logarithms of the data. In addition, the Japanese 
versus non-Japanese cohorts will be evaluated using descriptive statistics; for each cohort, the 
geometric means and the associated 95% CIs of difference of PK parameters will be reported. 
Dose-proportionality will be assessed and additional ALXN1910 PK parameters may be 
calculated if deemed appropriate with details to be provided in the SAP. 
9.4.2.2. 
Pharmacodynamic Analysis 
All PD analyses will be performed on the PD Set and will be reported by each cohort. Observed 
values and changes from baseline in plasma concentrations of PPi, PLP, PL, and PA versus time 
will be presented graphically by treatment over time compared with placebo-treated participants. 
The PD parameters for ALXN1910 will be evaluated over time for Japanese and non-Japanese 
participants (Cohort 2 versus Cohort 4) on active treatment by using MMRM model with cohort, 


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visit, and cohort by visit interaction as fixed effects, subject as a random effect, and baseline 
value as a covariate. The unstructured covariance structure will be employed; however, if the 
model fails to converge, Toeplitz, heterogeneous compound symmetry, and compound symmetry 
covariance structure will be applied in the order listed until the model converges. 
In the case that all covariance structures fail to converge, the analysis of variance statistical 
model with baseline and cohort as the fixed effects will be used. In addition, the Japanese versus 
non-Japanese cohorts will be evaluated using descriptive statistics; for each cohort, the geometric 
means and the associated 95% CIs of difference of PD parameters in observed value and CFB 
value will be reported. Figures of absolute values and change from baseline over time may be 
produced if needed. 
Biomarker assays may be conducted as exploratory analyses on collected samples (Section 10.8). 
9.4.2.3. 
Immunogenicity Analysis 
All ADA analyses will be performed on the ADA Analysis Set Population using the ADA 
variables included in Section 8.9.1.  
The incidence of ADA response categories will be summarized as absolute occurrence (n) and 
percent of all participants (%) by cohort. Participants in the placebo group will be pooled from 
each cohort for the summary analysis. Maximum ADA titer levels will be listed and summarized 
for ADA-positive participants as absolute occurrence (n) and percent of all participants (%). 
Additional details will be provided in the SAP. 
Associations between ADA response categories and systemic exposure to study intervention may 
be explored for ALXN1910-treated participants by cohort, for analyzing the potential impact of 
immunogenicity on PK profiles. Additional details will be provided in the SAP. 
Associations between ADA response categories and SAEs and severe adverse events may be 
explored, including SAEs such as systemic hypersensitivity, anaphylaxis, ISRs lasting more than 
24 hours, and other immune-related SAEs. 
Additional analysis may be performed with details to be provided in the SAP. 
9.5. 
Interim Analyses  
Interim analyses may be performed as needed. In particular, an interim analysis may be 
conducted after Cohort 5 completes Day 15. This analysis for further evaluation of the doses and 
for planning subsequent dosing will be included in the SAP finalized prior to analysis 
ALXN1910. 
9.6. 
Safety Review Committee 
The blinded SRC, consisting of the Investigator, Medical Monitor, Drug Safety Physician, Study 
Statistician, and Clinical Pharmacologist will evaluate the available study data at prespecified 
time points for participant safety and make recommendations on dose escalation, dose 
modification, or termination of the study. Decisions to continue, modify (explore the dose cohort 
further), or escalate dosing will be made by the Investigator and/or SRC. 


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The SRC will meet at minimum to support each cohort dose escalation after review of blinded 
data. Where review of unblinded data may be necessary in the event of emerging safety signals, 
additional ad hoc meetings will be scheduled without the Investigator/site staff in attendance. If 
dosing is stopped because of a safety event, continuation of the cohort and/or study will require a 
substantial amendment. 


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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 the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
− Applicable ICH GCP Guidelines 
− Applicable laws and regulations 
• The protocol, substantial protocol amendments, ICF, IB, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the 
Investigator/Alexion 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 substantial amendments to the protocol will require IRB/IEC and 
regulatory/health authority approval before implementation of changes made to the 
study design, except for changes necessary to eliminate an immediate hazard to study 
participants. 
• For studies to be approved by the Medicines and Healthcare products Regulatory 
Agency: The Investigator will notify the IRB/IEC of deviations from the study 
protocol or GCP as defined by UK legislation as a serious breach or as required by 
IRB/IEC procedures. 
• 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 the 
requirements of ICH guidelines and the IRB/IEC, all regional and national 
regulations as applicable (eg, CFR Title 21, Regulation [EU] No 536/2014 on 
clinical trials on medicinal products for human use, Directive 2001/20/EC), and all 
other applicable local regulations. 


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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. 
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 prior to performing 
any study-related procedures including screening assessments. 
• The Investigator or designee 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 their 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, ICH GCP 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
• The participant’s medical record must reflect/indicate a statement that signed (written 
or electronic) informed consent was obtained before any screening procedures were 
performed with a participant, and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF(s). 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study, as applicable. 
• 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. Original signed (written or electronic) consent forms must remain in each 
participant’s study file and must be available for verification at any time. 
• Rescreened participants are required to sign a new ICF (Section 5.5). 
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. 


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• 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 
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. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on the eCRF. The 
Investigator is responsible for verifying that data entries are accurate and correct by 
signing the eCRF. 
• 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 after study completion per local regulations 
or institutional policies. No records may be destroyed without the written approval of 
Alexion. No records may be transferred to another location or party without written 
notification to Alexion. 
• QTLs will be predefined in the study-specific risk register to identify systematic 
issues that can impact participant safety and/or reliability of study results. These 
predefined parameters will be monitored during the study, and important deviations 
from the QTLs and remedial actions taken will be summarized in the CSR. 
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The Investigator or designee will prepare and maintain adequate 
and accurate source documents (eg, medical records, ECGs, AE and concomitant medication 
reporting, raw data collection forms) designed to record all observations and other pertinent data 
for each participant. 
Data reported on the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. eCRFs must be completed by the 
Investigator or designee as indicated in the site delegation log. 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 investigational 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. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented. 
Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at 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 end of study 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. 


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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 
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. 
10.1.9. 
Publication Policy 
• Where possible, primary manuscripts reporting results of the primary efficacy 
endpoint or the final results will be submitted for publication within 12 to 18 months 
of the primary evaluation date or end of study, whichever is earlier. 
• Investigators who participate as authors in manuscripts derived from 
Alexion-sponsored studies will agree to the prerequisites as outlined in the Alexion 
author engagement agreement prior to engaging in manuscript development. 
• The Investigator agrees to submit proposals for new manuscripts (whether or not the 
proposed analyses are derived from protocol-specified endpoints) to Alexion for 
review and consideration. All manuscripts or abstracts emanating from approved 
proposals are to be submitted to Alexion for review before submission to the 
journal/society. This allows Alexion to protect proprietary information and 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. 


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− 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 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 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 Patient Lay Summaries and include participants and/or 
caregivers as reviewers for readability and understanding of lay person language. 
10.1.10. 
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), 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 ALXN1910 for shipment to the 
site. 


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10.2. 
Clinical Laboratory Tests 
Except ADAs, which will be analyzed via the central laboratory, the tests detailed in Table 10 
will be performed by local laboratories. 
If local laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be available in the participant’s source documents. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Pregnancy testing: WOCBP should only be enrolled after a negative serum pregnancy test result 
at Screening. Additional pregnancy testing (urine or serum) will be performed per the time points 
specified in the SoA (Section 1.3). Any female participant who becomes pregnant while 
participating in the study will be withdrawn from the study and the Investigator must 
immediately notify the Alexion Medical Monitor and follow the procedures outlined in 
Section 10.7.3.  
Table 10: 
Protocol-required Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
White blood cell count 
Red blood cell count 
Hematocrit 
Hemoglobin 
Red blood cell indices: 
Mean corpuscular volume  
Mean corpuscular 
hemoglobin 
Mean corpuscular 
hemoglobin concentration 
Reticulocytes 
Monocytes 
Eosinophils 
Basophils 
Neutrophils 
Lymphocytes 
Platelet count  
Mean platelet volume 
Clinical 
chemistry 
Blood urea nitrogen/urea 
Potassium  
Creatinine 
Sodium 
Chloride  
HbA1ca 
Creatine kinase 
eGFRb 
AST/SGOT 
ALT/SGPT 
Gamma-glutamyltransferase 
Alkaline phosphatasec 
Total and direct bilirubin 
Indirect bilirubin 
Total protein  
Albumin 
Calcium including ionized 
calcium 
Phosphate 
Magnesium 
Bicarbonate 
Coagulation 
Prothrombin time 
Partial thromboplastin time 
International normalized ratio 
Other safety 
laboratory tests 
• Antidrug antibodies 
(Alexion) 
The following tests are to be conducted in case of an acute 
injection/infusion-associated reaction: 
• Tryptase (Alexion) 
• C5b-9 (Alexion) 
• Hematology, chemistry, and urinalysis panels 
Routine 
urinalysis (by 
dipstick) 
• Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and 
leukocyte esterase 
• Microscopic examination (if any leukocytes, trace protein, nitrites, and blood [if not 
menstruating] are abnormal) 
Urine 
electrolyte  
Urine for calcium, phosphorus, and creatinine 


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Laboratory 
Assessments 
Parameters 
Other screening 
tests 
• Urine drug and alcohol tests 
• FSH (confirmation of postmenopausal state) 
• HIV-1 and HIV-2 antibodies, HBsAg, HBcAb, HBsAb and anti-HCV 
• Serum human chorionic gonadotropin pregnancy test 
• Serum or urine pregnancy test 
a HbA1c will be assessed only at Screening. 
b eGFR will be assessed only at Screening and admission. 
c The results for ALP assessments for the post‑dose time points will only be available in a blinded manner. 
 
Abbreviations: ALT = alanine aminotransferase; anti-HCV = hepatitis C virus antibody; AST = aspartate 
aminotransferase; C5b-9 = terminal complement complex; eGFR = estimated glomerular filtration rate; 
FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; 
HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase 


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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, temporally associated with the use of study 
intervention, whether or not considered related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital sign measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity/severity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
 
Events Not Meeting the AE Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): The condition that leads to the procedure is 
the AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for elective 
surgery if planned before the signing the ICF, admissions for social reasons or for convenience).  
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not worsen.  
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what 
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result 
of a medication error.  
• 
Cases of pregnancy that occur during maternal or paternal exposure to study intervention are to be reported 
within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be collected for 
regulatory reporting and safety evaluation.  
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 


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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. 
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/Severity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to 1 of the following categories from National Cancer Institute CTCAE version 5.0, published 27 Nov 2017: 


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• 
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 
Changes in the severity of an AE should be documented to allow an assessment of the AE duration at each level 
of intensity to be evaluated. AEs characterized as intermittent require documentation of onset and duration of 
each episode, if the severity of the intermittent event changes. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in the definition 
of an SAE, NOT when it is rated as severe. 
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. 
o 
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. 
o 
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. 
o 
The AE has a temporal relationship to the administration of the study intervention. 
o 
The event does not have a likely alternative etiology. 
o 
The event corresponds with the known pharmaceutical profile of the study 
intervention. 
o 
There is improvement on discontinuation and/or reappearance on rechallenge. 
o 
AEs/SAEs assessed as “Probably Related” or “Possibly Related” will be grouped with 
“Related” AEs/SAEs. 
• 
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 in their 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 or designee. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the SAE data to 
Alexion or designee. 
• 
The Investigator may change their 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 or designee to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide Alexion or designee with a copy of any postmortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 


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• 
The Investigator will submit any updated SAE data to Alexion or designee within 24 hours of receipt of the 
information. 
10.3.4. 
Reporting of SAEs  
SAE Reporting to Alexion or Delegate via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours awareness. 
• 
SAEs will be reported using the Safety Reporting Form and submitted to Alexion 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) 
− 
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. 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
eCRF = electronic case report form; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; GDS = Global Drug Safety; Hb = hemoglobin; SAE = serious adverse event; 
ULN = upper limit of normal. 


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Table 11: 
Cohort and Study Stopping Rules 
Adverse Events Related to Study 
Intervention 
Showing Signs 
of Reversibility  
Number of 
Participants 
Action 
Moderate (CTCAE Grade 2)  
Yes  
≥ 3 in 1 SOC  
≥ 4 total in 
different SOCs  
Cohort: Dosing of the 
remainder of the 
cohort suspended  
Study: Dosing of 
equal or higher doses 
suspended  
 
Dosing of lower dose 
levels can continue  
Continuation of 
dosing of equal or 
higher doses requires 
a substantial 
amendmentd 
No 
≥ 2 total in 
different SOCs 
Injection/infusion site reactions: 
Moderate (CTCAE Grade 2) 
Noa 
≥ 3 
Injection/infusion related reactions (including 
hypersensitivity): 
Moderate (CTCAE Grade 2) 
Noa 
≥ 3 
QT interval prolongation: 
A prolongation of the uncorrected QT interval 
of greater than 500 msec, using consistent, 
technically valid triplicate ECG (CTCAE 
Grade 2) 
NA 
≥ 2 
Hematology (CTCAE Grade 2): 
Hb drop to absolute values of < 10g/dL (100 
g/L) 
Platelet count drop to absolute values of < 
75,000/mm3  
NA 
≥ 2 
Severe (CTCAE Grade 3) 
Or 
Serious AE (not fatal or life-threatening)  
Or 
Hy’s law: 
ALT or AST value > 3 × ULN together with 
bilirubin increase > 2 × ULN, without other 
evidence of cholestasis (CTCAE Grade 3) 
Or 
ALT or AST value > 8 × ULN.  
ALT or AST value > 3 × ULN, and 
symptomatic (CTCAE Grade 3) 
Or 
Injection/infusion site reactions: 
Severe (CTCAE Grade 3) 
Or 
Injection/infusion related reactions (including 
hypersensitivity): 
Severe (CTCAE Grade 3) 
Or 
Hematology (CTCAE Grade 3): 
Hb drop to absolute values of < 8 g/dL  
NA 
2 
Study suspended (all 
dosing [lower, equal, 
or higher doses] 
suspended)  
 
Continuation of the 
cohort or study 
requires a substantial 
amendmentb 
Serious (fatal or life-threatening, CTCAE 
Grades 4 and 5) 
NA 
1 
a For injection/infusion site reactions, a cohort and/or the study will be suspended when ≥ 3 participants are 
observed. If all but 1 affected participant show signs of recovery (at least to Grade 1), cohort and study 
continuation can then proceed. If ≥ 2 participants remain at Grade 2 after the minimum data review period, the 
period of observation should be extended for up to 168 hours. If all but 1 affected participant show sign of 


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recovery (at least to Grade 1), cohort and study continuation can then proceed. If ≥ 2 affected participants remain 
at Grade 2 after the first 168-hour extension period, the SRC will make the decision to either prolong further the 
observation period up to a maximum of another 168 hours or suspend the remainder of the cohort and study. At the 
end of the second extension period, if all but 1 participant show sign of recovery (at least to Grade 1), cohort and 
study continuation can then proceed. If, however, ≥ 2 affected participants remain at Grade 2, cohort and study 
will be suspended.  
b A substantial amendment may include an amendment to the protocol, the ICF, or other study-related documents as 
appropriate. 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; Hb = hemoglobin; ICF 
= informed consent form; NA = not applicable; QT = interval between the start of the Q wave and the end of the T 
wave in an ECG; SOC = System Organ Class; SRC = Safety Review Committee; ULN = upper limit of normal 


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10.4. 
Management of Potential Adverse Events During Study Intervention 
Administration 
Participants will be closely monitored during and after study intervention administration for any 
symptoms of anaphylaxis and other hypersensitivity reactions, including circulatory and/or 
respiratory changes or arrest, or urticaria, arthralgias, myalgias, or other signs of related 
reactions. Adequate treatment will be immediately available. Injection/infusion-associated AEs 
may occur, and depending on their type and intensity/severity, discontinuation of infusion may 
be required. Participants will be informed of early symptoms and signs of hypersensitivity 
reactions including hives, swollen face, eyelids, lips, or tongue, or trouble with breathing. An 
acute infusion reaction algorithm will be used to manage IARs (Section 10.5 [Acute Infusion 
Reaction Algorithm]). In this study, regular assessments to monitor IARs and ISRs will be done. 
To ensure that reactions can be dealt with promptly, there will be at least 30 minutes between the 
end of IV/SC infusion in 1 participant and the start of IV/SC infusion in the next participant. If 
anaphylactic reactions occur, the current “UK Treatment Guideline for Anaphylactic Reactions” 
of the UK Resuscitation Council will be followed (Section 10.6 [United Kingdom Resuscitation 
Council Anaphylaxis Algorithm]). 
Decisions to continue or modify dosing will be made by the Investigator and SRC after review of 
the blinded data as described in Table 8. The SRC may also make recommendations regarding 
safety issues, study conduct, or study suspension. 
Participants who experience a severe reaction during administration of study intervention that 
results in discontinuation of study intervention should undergo all scheduled safety, 
immunogenicity, PK, and PD evaluations required by the protocol. Participants will therefore be 
instructed to attend all scheduled visits and undergo all procedures per protocol. 


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10.5. 
Acute Infusion Reaction Algorithm 
 
Abbreviations: AE = adverse event; O2 = oxygen; SpO2 = oxygen saturation 


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10.6. 
Country-specific Requirements: United Kingdom Resuscitation 
Council Anaphylaxis Algorithm - Guidelines 2021 
 
Source: https://www resus.org.uk/library/additional-guidance/guidance-anaphylaxis/emergency-treatment 
Abbreviations: ECG = electrocardiogram; IM = intramuscular; IV = intravenous; SpO2 = oxygen saturation 


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10.7. 
Contraceptive Guidance and Collection of Pregnancy Information 
10.7.1. 
Definitions 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the Following Categories Are Not Considered WOCBP 
• Premenopausal female with one of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months prior to Day 1 
without an alternative medical cause. A high FSH level in the postmenopausal 
range, as per local laboratory reference ranges, may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement may be required. 
o Female participants on HRT and whose menopausal status is in doubt will be 
required to use one of the non-estrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
• 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. 
10.7.2. 
Contraception Guidance 
10.7.2.1. Guidance for Female Participants 
Female participants of non-childbearing potential are exempt from contraception requirements. 
Female participants of childbearing potential, if heterosexually active, must use highly effective 
contraception as defined below. Antibiotic prophylaxis may be administered during this study, 
which can compromise the efficacy of hormonal contraception. Therefore, participants using 
hormonal contraception must also use barrier contraception (eg, condom or diaphragm with 
spermicide) for the duration of antibiotic prophylaxis. 


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Highly effective contraceptive methods for females are as follows: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation as follows: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation as 
follows: 
o Oral 
o Injectable 
o Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized male partner (with documented evidence of azoospermia if possible) 
• Sexual abstinence (in line with the preferred and usual lifestyle of the participant) 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. 
Calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal do NOT meet the 
definition of abstinence. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant. 
Participants must use an appropriate form of highly effective contraception as stated for females 
of childbearing potential who are sexually active, from 1 complete menstrual cycle prior to the 
first intercourse with a male and continue until for at least 3 months after the dose. 
10.7.2.2. Guidance for Male Participants  
To prevent transfer of study intervention to a male or female partner or fetus/baby, all male 
participants including those who have had a vasectomy (even with documented evidence of 
azoospermia) must agree to use a barrier method (male condom) during intercourse with a male 
or female partner from the time of screening for up to 3 months after the dose. 
Male participants, if sexually active and with a female spouse or partner of childbearing potential 
or a pregnant or breastfeeding spouse or partner, must agree to use barrier contraception (male 
condom). Barrier contraception is required even with documented medical assessment of surgical 
success of a vasectomy. Female spouses or partners of male participants who are of childbearing 
potential must use highly effective contraception as defined above. 
Contraception for all cohorts must start during Screening and continue for up to 3 months after 
the dose. 


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Male participants must not donate sperm and female participants must not donate ova for up to 
3 months after dose administration. 
10.7.3. 
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 
intervention, the Investigator must submit the “Pregnancy/Breastfeeding Reporting 
and Outcome Form” to Alexion GDS 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 Global Drug Safety or designee. If 
additional follow-up is required, the Investigator will be requested to provide the 
information. 
• Exposure of an infant to an Alexion product during breastfeeding must also be 
reported (via the “Pregnancy/Breastfeeding Reporting and Outcome Form”) and any 
AEs experienced by the infant must be reported to Alexion Global Drug Safety or 
designee via facsimile or email. 
• A pregnancy in and of itself is not regarded as an AE unless there is a suspicion that 
the study intervention 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 10.3).  
• Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
 


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10.8. 
Biomarkers 
• Biomarker assays may be conducted as exploratory analyses on collected whole 
blood samples and the data used for research (eg, exploratory) related to ALXN1910. 
The samples may also be used to develop tests/assays including diagnostic tests 
related to ALXN1910 and/or others of this study intervention class. 
• The samples may be analyzed as part of a multistudy assessment of biomarkers in the 
response to ALXN1910 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 CSR 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. 
• Samples will be retained no longer than 5 years from the end of the study (or another 
time period consistent with local requirements) while research on ALXN1910 
continues. 
 


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10.9. 
Resuscitation Procedures, Equipment, Medicines, and Training 
There must be procedures, equipment, medicines, and trained staff to deal with any medical 
emergency that might arise during the study (https://www.abpi.org.uk/media/4992/guidelines-
for-phase-i-clinical-trials-2018-edition-20180626.pdf). 
10.9.1. 
General Procedures  
Study participants must: 
• Have a call button by their bed and in places such as social areas, toilets, and showers 
to call study staff. 
• Be given the names and telephone numbers of the study physicians, so that the 
participant (or another doctor who might see the participant) can call the ‘on-call’ 
physician or a study physician at any time. 
Study staff must have access to and must be trained in the following: 
• Medical cover throughout the study. 
• An ‘on-call’ doctor who they can contact by telephone at any time. 
• Alexion Medical Monitor or defined delegates whom they can contact by telephone at 
any time. A cascade of contactable personnel on the side of Alexion should be 
available to the Investigator site; this can be added to the study protocol or be detailed 
in a separate document. 
• A procedure to report SAEs. 
• A procedure to break the blind should a participant have an SAE 
• An alarm system to call for assistance in case of a medical emergency. 
• Continuous monitoring of vital signs such as ECG and pulse oximetry. 
• Procedures for dealing with the most likely medical emergencies such as profound 
syncope, hypotension, anaphylaxis, and cardiopulmonary arrest. 
• A procedure to transfer a participant to a hospital (see below) 
10.9.2. 
Resuscitation Equipment and Medicines/Antidote 
In each of the main clinical areas of the premises, there must be a resuscitation trolley with 
equipment and medicines that can be moved quickly to where they are needed in a medical 
emergency. Each trolley should have the same equipment and medicines, which must be checked 
at least weekly and after use, and records of the checks must be kept. The main items on each 
trolley should be as those recommended by the Resuscitation Council 
(https://www.resus.org.uk/library/additional-guidance/guidance-anaphylaxis/emergency-
treatment), for example: 
• Defibrillator with an ECG monitor (both mains and battery operated)  
• Suction apparatus  


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• Oxygen cylinder and flowmeter  
• Oropharyngeal airways and face masks  
• Self-inflating bag  
• Laryngoscope and endotracheal tubes or laryngeal mask/alternative supraglottic 
airway device  
• Consumables such as IV cannula and fluid infusion sets 
• Emergency medicines, including IV fluids  
• Transcutaneous cardiac pacer (one should be enough for the whole premises)  
• Waveform capnograph with appropriate tubing and connector 
10.9.3. 
Resuscitation Training  
Physicians, nurses, and other staff who help to care for participants must all be trained and hold a 
valid certificate in basic life support, ILS, or ALS procedures, as appropriate. For example, all 
physicians must be trained and hold a valid certificate in ALS or ILS. The medical director or 
another doctor with clinical expertise in resuscitation should set and maintain standards of 
training and assessment of the unit’s staff and ensure that competence is maintained by regular 
refresher training. Appropriately trained people, such as doctors and resuscitation training 
officers, should carry out the training and assessment.  


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10.10. 
COVID-19 Risk Assessment 
Based on the mechanism of action of ALXN1910, it is expected that participants will have the 
same risk to contract severe acute respiratory syndrome coronavirus 2 infection and develop 
COVID-19 of the same intensity/severity as the general population. Mitigation measures 
implemented to reduce the risk of transmission as per national and institutional guidances are to 
be followed. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 12. 
Table 12: 
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 pandemic 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 the sites 
have the resourcing and capabilities 
to implement the study 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, participants 
eligibility as well as 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 safety 
monitoring. 
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 for missing data 
(eg, missed study visits or 
participant study discontinuations 
due to COVID-19). 
Abbreviations: COVID-19 = coronavirus disease 2019; eCRF = electronic case report form 


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10.11. 
COVID-19 Vaccine Risk Assessment 
Following a review of the available COVID-19 vaccine data (eg, Pfizer/BioNTech, Moderna, 
AstraZeneca, and 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 
ALXN1910 administration, based on ALXN1910’s mechanism of action. There is currently no 
information available evaluating the safety and efficacy of COVID-19 vaccines in participants 
treated with ALXN1910.  
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 13. 
Table 13: 
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 
 


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10.12. 
Abbreviations 
The following abbreviations and terms are used in this study protocol. 
Table 14: 
Abbreviations and Specialist Terms 
Abbreviation or 
Term  
Explanation 
ADA 
antidrug antibody 
AE 
adverse event 
AFF 
atypical femoral fracture 
ALP 
alkaline phosphatase 
ALS 
advanced life support 
ALT 
alanine aminotransferase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COVID-19 
coronavirus disease 2019 
CRU 
clinical research unit 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ED85 
effective dose in 85% of the treated population 
EMA 
European Medicines Agency 
EOS 
end of study 
ERT 
enzyme replacement therapy 
EU 
European Union 
F 
absolute bioavailability 
Fc 
fragment crystallizable 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GDS 
Global Drug Safety 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GTP 
Guanosine triphosphate 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
HPP 
hypophosphatasia 
HRT 
hormonal replacement therapy 
HV 
healthy volunteer 
IAR 
injection/infusion-associated reaction 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IgG 
immunoglobulin G 
ILS 
immediate life support 


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Abbreviation or 
Term  
Explanation 
IRB 
institutional review board 
ISR 
injection/infusion site reaction 
IV 
intravenous(ly) 
MABEL 
minimum anticipated biological effect 
MAPK 
mitogen-activated protein kinase 
NAb 
neutralizing antibody 
NCI 
National Cancer Institute 
NF1 
neurofibromatosis type-1 
NOAEL 
no-observed-adverse-effect level 
PA 
pyridoxic acid 
PD 
pharmacodynamic(s) 
Pi 
inorganic phosphate 
PK 
pharmacokinetic(s) 
PL 
pyridoxal 
PLP 
pyridoxal-5′-phosphate 
Pop-PK 
population pharmacokinetic(s) 
PPi 
inorganic pyrophosphate 
PT 
Preferred Term 
QT 
interval between the start of the Q wave and the end of the T wave in an ECG 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
quality tolerance limit 
Ras 
rat sarcoma virus family of related proteins 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SoA 
schedule of activities 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
tmax 
time to maximum observed serum concentration 
TNSALP 
tissue nonspecific alkaline phosphatase 
ULN 
upper limit of normal 
UK 
United Kingdom 
WOCBP 
woman of childbearing potential 


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10.13. 
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 
Date 
Protocol Amendment 3 
27 Jul 2022 
Protocol Amendment 2 
20 Apr 2022 
Protocol Amendment 1 
27 Jan 2022 
Original protocol 
06 Dec 2021 
Amendment 2 (20 Apr 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 and 
any applicable local regulations. 
Overall Rationale for the Amendment 
The main reasons for this amendment were to include an ECG assessment on the day of 
Screening, to add assessments to the clinical laboratory tests, and to clarify the timing of other 
assessments (brief physical examination, COVID-19 testing, hepatitis B testing). Changes 
implemented in Administrative Change Letter No.1 (15 Feb 2022), as well as some clarifications 
to wording and minor administrative changes, were also made. 
Changes to the protocol are detailed below. 
Section 
Description of Change 
Brief Rationale and/or 
Clarification 
1.1 Synopsis 
A paragraph on SRC Review 
Committee was deleted. 
To eliminate redundancy. 
1.3 Schedule of Activities, Table 2 
Addition of ECG assessment on the 
day of screening. 
Correction of Table 2 to align with 
Section 5.1 Inclusion Criteria. 
1.3 Schedule of Activities, Table 2, 
Footnote k 
Addition of text to stating that a 
brief physical examination will be 
conducted on Day 5 prior to 
discharge from the CRU. 
To clarify when the brief physical 
examination will be performed on 
Day 5. 
1.3 Schedule of Activities, Table 2, 
Footnote m 
1.3 Schedule of Activities, Table 3, 
footnote d 
8.2.3 Electrocardiograms 
9.4.1 Safety Analyses 
Addition of text stating the ECG 
should not be performed within 
1 hour after any major meal. 
To clarify the time period within 
which an ECG must not be 
measured after a major meal. 
2.4.1.1 Coronavirus Disease 
Correction to state that COVID-19 
testing will be performed at 
Screening and “prior to admission”. 
To clarify that COVID-19 testing 
will also be done prior to admission 
to the CRU. 
5.2 Exclusion Criteria  
Addition of text stating hepatitis B 
testing (evidenced by HBsAg, 
HBcAb and HBsAb) will be done at 
Screening. Removal of testing 
algorithm if HBsAg is negative. 
To clarify and streamline how 
hepatitis B testing will be 
performed. 
 


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Section 
Description of Change 
Brief Rationale and/or 
Clarification 
 
Revised text in Exclusion Criteria 
# 27. 
 
 
To clarify smoking is not allowed 
from 2 hours before admission 
through discharge from the CRU 
for both inpatient and outpatient 
visits. 
5.5 Screening Failures 
10.1.3 Informed Consent Process 
Modified to state rescreened 
participants are required to sign a 
new ICF. 
To clarify all participants who are 
rescreened are required to sign a 
new ICF. 
6.3 Measure to Minimize Bias: 
Randomization and Blinding 
Removal of text indicating files and 
envelopes containing study 
intervention assignment to each 
participant will be used. 
 
Deleted text stating SRC may be 
unblinded at summary level. 
To clarify that study intervention 
assignment will be provided in a 
secured manner to the Investigator, 
without stating the format, because 
it may not be within envelopes. 
Corrections. SRC will not be 
unblinded. 
6.6 Dose Modification 
Revised text to indicate “mean” 
projected PK exposure should not 
exceed 50% of NOAEL exposure. 
Revised for clarity. 
6.6 Dose Modification, Table 8  
Removal of text stating that at least 
6 of each cohort will have received 
active treatment. 
To ensure maintaining blind during 
dose escalation meeting. 
8.2.3 Electrocardiograms 
Removal of text stating that 
participants should rest for 5 
minutes after each ECG 
measurement. 
To clarify that no resting is required 
post ECG. 
10.1.1 Regulatory and Ethical 
Considerations and 10.1.10 Good 
Clinical Practice Compliance 
Modified text to remove specific 
reference to regional guidance and 
listed as examples only. Inclusion 
of Regulation (EU) No 536/2014 on 
clinical trials on medicinal products 
for human use as example. 
To include a more general 
statement as not all regional 
guidances previously included are 
applicable. 
10.2 Clinical Laboratory Tests, 
Table 10 
Added the following parameters: 
white blood cell count, hemoglobin, 
mean corpuscular hemoglobin 
concentration, neutrophils, 
lymphocytes, eGFR. 
Added footnotes regarding HbA1c 
and eGFR and deleted glycated 
hemoglobin from the table. 
Removed erythrocytes and % of 
reticulocytes. 
To further ensure participant safety. 
Overall 
Minor administrative changes. 
For clarity. 
Abbreviations: COVID-19 = coronavirus disease 2019; CRU = clinical research unit; ECG = electrocardiogram; 
eGFR = estimated glomerular filtration rate; EU-CTR = European Union Clinical Trial Register; HbcAb = hepatitis 
B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; ICF = informed 
consent form; NOAEL = no-observed-adverse-effect level 
 
 


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Amendment 1 (27 Jan 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 and 
any applicable local regulations. 
Overall Rationale for the Amendment 
This protocol has been amended in response to queries raised by the UK MHRA regarding the 
inclusion of Japanese participants, wording on stopping rules, and the definition of abnormal 
laboratory findings. 
In addition, a correction was made to the time that participants are required to be in the supine 
position prior to ECG timepoints, to align within the protocol. 
Changes to the protocol are detailed below. 
Section 
Description of Change 
Brief Rationale and/or Clarification 
2.1 Study 
Rationale 
4.1 Overall Design 
Rationale included for the inclusion of 
Japanese participants in the study. 
To clarify that Japanese participants have 
been included in the study to meet 
regulatory requirements of the ICH 
Guidance E5(R1), which provides a general 
framework for evaluating the potential 
impact of ethnic factors on the acceptability 
of foreign clinical data, with the underlying 
objective of minimizing duplication of 
clinical data, and it also describes the 
requirement of bridging studies for 
extrapolation of foreign clinical data to a 
new region. 
7.1 
Discontinuation of 
Study Intervention 
Removal of “Individual Stopping Rules” 
from the section title, which previously read 
“Discontinuation of Study 
Intervention/Individual Stopping Rules”. 
The following text has also been removed 
from the section: 
As each participant will receive 1 SC or IV 
dose in this study, discontinuation of study 
intervention/individual stopping rules apply 
only to participants who receive the IV dose. 
To clarify that as this is a single dose study, 
individual stopping rules do not apply.  
8.2.3 
Electrocardiograms 
The time that participants should be in the 
supine position before each ECG timepoint 
has been changed from 15 to 10 minutes. 
To align with footnote m of Table 2, 
Schedule of Activities, which states 10 
minutes before the ECG time point 
8.2.4 Clinical 
Safety Laboratory 
Assessments 
Removal of text stating that 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. 
Removed because the study is conducted in 
healthy participants, not participants with a 
disease. All abnormal laboratory results 
will be considered clinically significant. 
 


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11. 
REFERENCES 
Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first 
symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, 
p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 
2007;40(6):1655-1661. 
Bhattacharyya T, Jha S, Wang H, Kastner DL, Remmers EF. Hypophosphatasia and the risk of 
atypical femur fractures: a case–control study. BMC Musculoskelet Disord. 2016;17(1). 
Brunetti-Pierri DS, Doty SB, Hicks J, et al. Generalized metabolic bone disease in 
Neurofibromatosis type I. Mol Genet Metab. 2008;94(1):105-111. 
de la Croix Ndong J, Makowski AJ, MA, Uppuganti S, et al. Asfotase-α improves bone growth, 
mineralization and strength in mouse models of neurofibromatosis type-1. Nat Med. 
2014;20(8):904-910. 
Evans DG, Howard E, Giblin C, et al. Birth incidence and prevalence of tumor-prone syndromes: 
estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A(2):327-332. 
EMA. Guideline on immunogenicity assessment of therapeutic proteins. 
EMEA/CHMP/BMWP/14327/2006 Rev 1. 18 May 2017. 
EMA. Strategies to identify and mitigate risks for FIH and early clinical trials with investigational 
medicinal products. EMEA/CHMP/SWP/28367/07 Rev.1. 20 July 2017. 
FDA. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials 
for therapeutics in adult healthy volunteers. 2005. 
Friedman DS, Katz J, Bressler NM, Rahmani B, Tielsch JM. Racial differences in the prevalence 
of age-related macular degeneration: the Baltimore Eye Survey. Ophthalmology. 
1999;106(6):1049-1055. 
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modelling. 
J Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
George-Abraham JK, Martin LJ, Kalkwarf HJ, et al. Fractures in children with neurofibromatosis 
type 1 from two NF clinics. Am J Med Genet A. 2013;161A(5):921-926. 
Harindhanavudhi T, Takahashi T, Petryk A, Polly DW. An adjunctive use of asfotase alfa and 
zoledronic acid after spinal surgery in neurofibromatosis type 1 related dystrophic scoliosis. 
AACE Clin Case Rep. 2020;6(6):e305-e310. 
Hosking DJ. Changes in serum alkaline phosphatase after femoral fractures. J Bone Joint Surg 
Br. 1978;60(1):61-65. 
Kolanczyk M, Kossler N, Kühnisch J, et al. Multiple roles for neurofibromin in skeletal 
development and growth. Hum Mol Genet. 2007;16(8):874-876. 
Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German 
children at elementary school enrollment. Arch Dermatol. 2005;141(1):71-74. 
Leach MW, Clarke DO, Dudal S, et al. Strategies and recommendations for using a data-driven 
and risk-based approach in the selection of first-in-human starting dose: an International 


Protocol Amendment 3 
ALXN1910-HV-101 
27 Jul 2022 
Page 85 of 85 
Alexion Confidential 
 
Consortium for Innovation and Quality in Pharmaceutical Development (IQ) assessment. Clin 
Pharmacol Ther. 2021;109(6):1395-1415. Epub 2020 Nov 3. 
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. J 
Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
Lodish MB, Dagalakis U, Sinaii N, et al. Bone mineral density in children and young adults with 
neurofibromatosis type 1. Endocr Relat Cancer. 2012;19(6):827-825. 
Nakagawa H, Kamimura M, Takahara K, et al. Changes in total alkaline phosphatase level after 
hip fracture: comparison between femoral neck and trochanter fractures. J Orthop Sci. 
2006;11:135-139. 
Seitz SC, Schnabel C, Busse B, et al. High bone turnover and accumulation of osteoid in patients 
with neurofibromatosis 1. Osteoporos Int. 2010;21(1):119-127. 
Singh A, Sabir A, Mahdi AA, Srivastava RN. Evaluation of serum alkaline phosphatase as a 
biomarker of healing process progression of simple diaphyseal fractures in adult patients. Int Res 
J Biological Sci. 2013;2(2):40-43. 
Sipani AK, Dhar A, Sungte N. Serum alkaline phosphatase: a prospective biomarker for 
assessment of progress of fracture healing in diaphyseal fractures of long bones in adult patients. 
Int J Orthop Sci. 2020;6(2):248-251. 
Stevenson DA, Moyer-Mileur LJ, Murray M, et al. Bone mineral density in children and 
adolescents with neurofibromatosis type 1. J Pediatr. 2007;150(1):83-88. 
Stevenson DA, Viskochil DH, Carey JC, et al. Tibial geometry in individuals with 
neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral 
quantitative computed tomography. Bone. 2009;44(4):585-589. 
Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. 
Endocr Rev. 1994;15(4):439-461. 

SAP_001.pdf: 
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ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 1 of 48 
 
 
 
 
 
 
Parexel International 
 
 
Alexion Pharmaceuticals, Inc.  
 
 
ALXN1910-HV-101 
 
A Phase 1, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study of 
Subcutaneously and Intravenously Administered ALXN1910 in Healthy Adult Participants  
 
 
 
 
Statistical Analysis Plan 
 
 
Version: 3.0 
 
 
Parexel Project Number: PXL268911 
 
 


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ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 2 of 48 
SPONSOR SIGNATURE PAGE 
 
 
Approved by:  
_________________________ 
 
_______________ 
 
  
 
 
 
Date 
 
 
 
 
Alexion Pharmaceuticals 
 
  
Approved by:  
_________________________ 
 
_______________ 
 
 
 
 
 
Date 
 
 
 
 
Alexion Pharmaceuticals 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD




Parexel International 
Alexion Pharmaceuticals, Inc.  
 
ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 4 of 48 
TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................... 11 
2 
STUDY OBJECTIVES ............................................................................................................ 11 
2.1 
Primary Objective ............................................................................................................ 11 
2.2 
Secondary Objective ........................................................................................................ 11 
2.3 
Exploratory Objective(s) ................................................................................................. 12 
3 
INVESTIGATIONAL PLAN................................................................................................... 12 
3.1 
Overall Study Design and Plan ........................................................................................ 12 
3.2 
Determination of Sample Size ......................................................................................... 13 
3.3 
Endpoints and Associated Variables ............................................................................... 13 
3.3.1 
Safety Variables .......................................................................................................... 14 
3.3.2 
Pharmacokinetic Variables ......................................................................................... 14 
3.3.3 
Pharmacodynamic Variables ...................................................................................... 15 
3.3.4 
Immunogenicity Variables .......................................................................................... 15 
3.3.5 
Exploratory Variables ................................................................................................. 15 
4 
STATISTICAL METHODS..................................................................................................... 16 
4.1 
Data Quality Assurance ................................................................................................... 16 
4.2 
General Presentation Considerations ............................................................................... 16 
4.2.1 
Treatment .................................................................................................................... 16 
4.2.2 
Study Day ................................................................................................................... 16 
4.2.3 
End of Study ............................................................................................................... 16 
4.2.4 
Baseline ....................................................................................................................... 16 
4.2.5 
Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment ....................... 16 
4.2.6 
Summary and Representation of Data ........................................................................ 17 
4.3 
Software 17 
4.4 
Study Participants ............................................................................................................ 17 
4.4.1 
Analysis Sets ............................................................................................................... 17 
4.4.2 
Disposition of Participants .......................................................................................... 18 
4.4.3 
Protocol Deviations ..................................................................................................... 18 
4.4.3.2 Protocol Deviations with PK Implications ................................................................. 18 
4.5 
Demographics and Baseline Characteristics .................................................................... 19 
4.6 
Medical and Surgical History .......................................................................................... 19 
4.7 
Prior and Concomitant Medications ................................................................................ 19 
4.8 
Treatment Exposure and Compliance .............................................................................. 19 
4.8.1 
Treatment Exposure .................................................................................................... 19 
4.9 
Analysis Supporting Primary Objective(s) ...................................................................... 20 
4.10 Analysis Supporting Secondary Objective(s) .................................................................. 20 
4.11 Efficacy Evaluation ......................................................................................................... 20 
4.12 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis of 
Pharmacokinetic Parameters for Final Analysis .............................................................. 20 
4.12.1 
Pharmacokinetic Concentrations ................................................................................ 20 
4.12.2 
Pharmacokinetic Parameters ....................................................................................... 22 
4.12.3 
Interim Pharmacokinetic Analysis to Support SRC Dose Escalation Decisions ........ 25 
4.12.4 
Statistical Analysis of Pharmacokinetic Parameters ................................................... 26 


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ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
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Related to:  SOP-GDO-WW-019 
Page 5 of 48 
4.12.5 
Pharmacodynamic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacodynamic Parameters ................................................................... 27 
4.12.5.1 Pharmacodynamics Analysis and Tables, Figures, and Listings ................................ 27 
4.13 Safety Evaluation ............................................................................................................. 28 
4.13.1 
Adverse Events ........................................................................................................... 28 
4.13.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 29 
4.13.3 
Clinical Laboratory Evaluation ................................................................................... 29 
4.13.4 
Vital Signs ................................................................................................................... 30 
4.13.5 
ECG 
30 
4.13.6 
12-Lead Holter ECG ................................................................................................... 31 
4.13.7 
Physical Examination ................................................................................................. 31 
4.13.8 
Daylight Saving Time (DST): ..................................................................................... 32 
4.13.9 
Safety Monitoring (Safety Review Committee) ......................................................... 32 
4.14 Immunogenicity Analysis ................................................................................................ 32 
4.15 Biomarkers....................................................................................................................... 32 
4.16 Handling of Dropouts or Missing Data ........................................................................... 32 
4.17 Subgroup Analysis ........................................................................................................... 32 
4.18 Planned Interim Analyses ................................................................................................ 32 
4.19 Changes in the Conduct of the Study or Planned Analysis ............................................. 32 
5 
REFERENCES ......................................................................................................................... 32 
6 
APPENDICES .......................................................................................................................... 33 
6.1 
Schedule of Assessments ................................................................................................. 33 
6.2 
Imputation Rules for Partial Dates .................................................................................. 40 
6.3 
Laboratory Test Parameters ............................................................................................. 43 
6.4 
ECG Notable Criteria ...................................................................................................... 44 
6.5 
Sample SAS Code for statistical analysis ........................................................................ 44 
 
List of Tables 
Table 1  Planned ALXN1910-HV-101 Dosing Cohorts .................................................................... 12 
Table 2 Serum Pharmacokinetic Parameters After Single Dose Administration .............................. 14 
Table 3 Pharmacokinetic Parameter and Estimation ......................................................................... 22 
Table 4 TEMA/PCS Criteria for Vital Signs ..................................................................................... 30 
Table 5  Schedule of Assessments ..................................................................................................... 34 
Table 6  Algorithm for Treatment-Emergent Adverse Events:.......................................................... 40 
Table 7   Algorithm for Prior/Concomitant Medications Categorization: ......................................... 42 
 
 


Parexel International 
Alexion Pharmaceuticals, Inc.  
 
ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 6 of 48 
REVISION HISTORY 
Version No. 
Effective Date 
Summary of Change(s) 
Final 1.0 
07 Jun 2022 
 
Final 2.0 
27 Jan 2023 
Page 14, updated the sentence “nominal infusion time is 
within 5 seconds” 
Due to protocol amendment 3, and the major changes are 
the EOS visit for all participant is at Day 75, and ADA 
titer category analysis removed.
Final 3.0 
27 Mar 2023 
In Section 4.8.1, “Exposure to IMP data will be 
summarized using descriptive statistics for each 
treatment cohort” removed  
 
 










Parexel International 
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ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 11 of 48 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes all planned analyses for the Clinical Study Report (CSR) 
of Study ALXN1910-HV-101, A Phase 1, Randomized, Double-blind, Placebo-controlled, Single 
Ascending Dose Study of Subcutaneously and Intravenously Administered ALXN1910 in Healthy 
Adult Participants. It describes the data to be analysed, including details of the statistical analyses to 
be performed. 
The content of this SAP is based on the following study documents:  
 Study ALXN1910-HV-101 protocol Amendment 3 dated 27 Jul 2022. 
 Electronic Case Report Form (eCRF) Version 11. 06 May 2022.  
 Data Management Plan (DMP) Final 1.0 dated 18 Mar 2022.   
This SAP will be finalized prior to database lock. Should circumstances arise during the study 
rendering these analyses inappropriate, or if improved methods of analysis arise, updates to the 
analyses may be made. Any changes after the finalization of this SAP will be documented in Statistical 
Method Modification Form. Any deviations from the final SAP after database lock and all alternative 
or additional statistical analyses that may be performed will be discussed in the Clinical Study Report 
(CSR)(changes to planned analysis) and, if applicable, in an SAP addendum.  
2 
STUDY OBJECTIVES 
The primary and secondary objectives of the study are as mentioned below: 
2.1 
Primary Objective 
Objective
Endpoint
 To assess the safety and tolerability of 
ALXN1910
 Incidence of TEAEs and TESAEs 
2.2 
Secondary Objective 
Objective
Endpoint
 To assess the PK of single ascending 
doses of ALXN1910
 Serum ALXN1910 PK (activity) and 
PK parameters
 To explore the PD effects of single 
ascending doses of ALXN1910
 Plasma concentrations of PPi, PLP, PL, 
and PA versus time profiles
 To assess the immunogenicity of 
ALXN1910
 Incidence and titers of treatment-
emergent ADAs
 To assess the absolute bioavailability of 
ALXN1910 SC 
 GMR of AUC values of SC versus IV 
from serum concentrations of 
ALXN1910
 To compare the safety, tolerability, PK, 
and PD of ALXN1910 SC between 
Japanese and non-Japanese healthy 
participants
 Quantitative assessment of 
safety/tolerability and PK/PD 
parameters between Japanese and non-
Japanese participants
Abbreviations: ADA = antidrug antibody; AUC = area under the serum concentration-time curve; GMR = geometric 
mean ratio; IV = intravenous; PA = pyridoxic acid; PD = pharmacodynamics(s); PK = pharmacokinetic(s); PL = 
pyridoxal; PLP = pyridoxal-5′-phosphate; PPi = inorganic pyrophosphate; SC = subcutaneous; TEAE = treatment 
emergent adverse event; TESAE = treatment emergent serious adverse event 


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ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
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Page 12 of 48 
2.3 
Exploratory Objective(s) 
Not Applicable. 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 1, randomized, double-blind, placebo-controlled study designed to evaluate the safety, 
tolerability, PK, PD, and immunogenicity of SADs of ALXN1910 SC and a SAD of ALXN1910 IV 
in up to approximately 48 healthy adult participants across treatment cohorts (up to approximately 36 
participants to receive ALXN1910 and up to approximately 12 participants to receive placebo) (Table 
1). Of the 48 participants, 8 will be of Japanese descent, defined as those participants whose parents 
and grandparents are both Japanese and who have spent less than 10 years outside of Japan. 
Table 1    Planned ALXN1910-HV-101 Dosing Cohorts 
Cohorta  
Number of Participants  
(ALXN1910:Placebo)  
Route of  
Administration  
Dose  
Number of  
Doses/Dose Interval  
1  
8 (3:1)  
IVb  
5 mg  
Single dose  
2  
8 (3:1)  
SC  
15 mg  
Single dose  
3  
8 (3:1)  
IVb  
15 mg  
Single dose  
4  
8 (3:1) (Japanese participants)  
SC  
15 mg  
Single dose  
5  
8 (3:1)  
SC  
45 mg  
Single dose  
6  
8 (3:1)  
SC  
135 mg  
Single dose   
a Cohort 3, Cohort 4, and Cohort 5 can be initiated in parallel after dose escalation decision following SRC review  
of Cohort 2 safety and PK data.  
b Slow IV infusions (rate of infusion = 6 mL/h) using a controllable infusion pump. The pharmacy manual will include 
details regarding infusion rate and duration.  
Abbreviations: IV = intravenous; PK =pharmacokinetic; SC = subcutaneous; SRC = Safety Review Committee  
For this FIH study, 8 participants will be randomly assigned in a 3:1 ratio to treatment and placebo in 
each of the 6 cohorts with escalating doses of 5 mg IV (Cohort 1), 15 mg SC (Cohort 2), 15 mg IV 
(Cohort 3) in parallel with 15 mg SC in Japanese participants (Cohort 4) and 45 mg SC (Cohort 5), 
followed by 135 mg SC (Cohort 6). The first 2 participants randomized to each cohort will be dosed 
as a sentinel pair, with 1 participant on active treatment and 1 participant on placebo. This dosing 
strategy is justified given the large exposure margins (approximately 15-fold at the highest planned 
single dose of 135 mg SC). 
Participants who meet the qualifications for the study based on screening will be admitted to the CRU 
the day prior to dosing (Day -1) to undergo Check-in assessments per the applicable SoA (Section 6.1). 
 
Final determination of eligibility will be determined based on Check-in and predose procedures, and 
eligible participants will be randomized to ALXN1910 or placebo on Day 1 prior to dosing. There will 
be extensive PK/PD sampling during the first 24 hours after dosing. Safety assessments will be 
performed per the SoA. The study schematic is presented in Figure 1. 


Parexel International 
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ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
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Related to:  SOP-GDO-WW-019 
Page 13 of 48 
Figure 1 Study Design Schematic 
 
 
3.2 
Determination of Sample Size 
No formal testing of hypotheses has been planned for this study. Therefore, no formal sample size 
calculations were performed. Approximately 48 participants are considered to be adequate to support 
and analyze the initial characterization of safety, tolerability, PK, PD, and immunogenicity for 
ALXN1910. The following table provides the probability of observing AEs under various underlying 
event incidence. 
Incidence of AE in the Population  
Probability to Observe at least 1 AE Occurrence 
in 6 Participants from Each Cohort  
10%  
46.9%  
15%  
62.3%  
20%  
73.8%  
25%  
82.2%  
30%  
88.2%  
35%  
92.5%  
40%  
95.3%  
 
3.3 
Endpoints and Associated Variables 
The following endpoints will be used to investigate single ascending doses of ALXN1910 in 
participants. 


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Statistical Analysis Plan 
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3.3.1 Safety Variables 
• 
Physical examinations 
• 
Vital signs (Oral body temperature, pulse rate, respiratory rate, and supine blood pressure [BP]) 
• 
12-lead electrocardiogram (ECG): Heart rate, PR interval, QRS interval, QT interval, QTC 
interval and QT interval using Fridericia’s correction [QTcF] 
• 
Clinical laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis parameters) 
• 
Treatment Emergent Adverse Event (TEAE) assessments 
• 
Concomitant medication assessments 
3.3.2 Pharmacokinetic Variables 
Pharmacokinetic concentration data will be obtained at time point(s) described in the protocol, as 
detailed in Table 2 and Table 3 of study protocol and as follows: 
Serum PK samples will be collected at the following nominal times: 0 (pre-dose sample), 30 min and, 
2, 4, 8, 12, 24, 48, 72, 96 hours and on D6, D7, D8, D15, D22, D29, D36, D43 and D75 (after injection 
(for sc administration) or after start of infusion (for IV administration). The IV dose cohorts will also 
have an end-of-infusion PK time point (nominal infusion time is within 5 seconds  and 0.5 hours for 
Cohort 1 and Cohort 3, respectively). 
Unless otherwise stated, derivation of PK parameters will be the responsibility of Clinical 
Pharmacology, Modeling and Simulation (CPMS) group, Parexel.   
If calculable, the following PK parameters listed in Table 2 will be determined for ALXN1910 in 
Serum following single SC or IV dose administration. 
Table 2 Serum Pharmacokinetic Parameters After Single Dose Administration  
Parameter 
WNL  
Name 
CDISC 
Name 
Definition 
Cmax 
Cmax 
CMAX 
Maximum observed concentration 
DNCmax 
Cmax_D 
CMAXD 
Dose-normalized Cmax 
tmax 
Tmax 
TMAX 
Time corresponding to occurrence of 
Cmax 
t½ 
HL_Lambda_z 
LAMZHL 
Apparent terminal elimination half-life 
λz 
Lambda_z 
LAMZ 
Terminal elimination rate constant 
AUCt 
AUClast 
AUCLST 
AUC from time zero to the last 
quantifiable concentration 
DNAUCt 
AUClast_D 
AUCLSTD
Dose-normalized AUCt 
AUC0-168 
AUC0-168 
AUCINT 
AUC from time zero to time 168 h  


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Parameter 
WNL  
Name 
CDISC 
Name 
Definition 
AUC∞ 
AUCINF_obs 
AUCIFO 
AUC from time zero extrapolated to 
infinity 
DNAUC∞ 
AUCINF_D_obs 
AUCIFOD 
Dose-normalized AUC∞ 
%AUCex 
AUC_%Extrap_obs
AUCPEO 
Percentage of AUC∞ obtained by 
extrapolation beyond tlast 
CL or CL/F 
Cl_F_obs 
CLFO 
Total body clearance (IV route)or 
apparent clearance (SC route) 
Vd or Vd/F 
Vd_F_obs 
VZFO 
Volume of distribution (IV route) or 
apparent volume of distribution (SC 
route)  
Source: NCI EVS Terminology Resources website: 
http://www.cancer.gov/cancertopics/cancerlibrary/terminologyresources/cdisc.   
Additional PK parameters may be calculated if deemed appropriate. 
 
3.3.3 Pharmacodynamic Variables   
To assess the effect of ALXN1910 on pharmacodynamic (PD) variables PPi, PLP, PL, and PA versus 
time profiles, whole blood samples will be collected at the times specified in the Schedule of 
Assessments. 
3.3.4 Immunogenicity Variables  
ADA positive: Include participant with a positive response in the ADA assay at any time point will be 
categorized as follows: 
 Pre-existing Immunoreactivity: Defined as ADA positive result in the assay at baseline with all 
post first dose ADA results negative or a positive result at baseline with all post first dose ADA 
results less than 4 folds over the baseline titer levels. 
 Treatment-emergent ADA Responses: Defined as a positive result in the ADA assay post first 
dose, when baseline results are negative or missing. 
 Treatment-boosted ADA responses: Defined as a positive result in the ADA assay post first 
dose, that is greater than or equal to 4-fold over baseline titer levels, when baseline results are 
positive.  
ADA negative:  ADA negative response in the ADA assay at all time points. 
 
3.3.5 Exploratory Variables 
 Biomarker assays may be conducted as exploratory analyses on collected whole blood samples. 


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4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures, and data listings to be included in the report will be independently checked for 
consistency, integrity, and in accordance with standard Parexel procedures. 
4.2 
General Presentation Considerations 
This section is not applicable to PK data. 
4.2.1 Treatment 
During this study up to approximately 48 participants will be randomized in a 3:1 ratio to receive either 
of ALXN1910 or placebo as mentioned in Table 1. 
4.2.2 Study Day 
Study days will be numbered relative to the first day of study drug administration. 
 
If the date of event is before the study drug administration, then: 
Study day = (Date of measurement – Date of study drug administration [i.e. Day 1] in each cohort) 
 
If the date of event is on or after the study drug administration, then:  
Study day = (Date of measurement – Date of study drug administration [i.e. Day 1] in each cohort) 
+ 1 
4.2.3 End of Study 
The end of the study is defined as the date the last participant completes the last safety follow up. 
End of study visit is planned on Day 75. 
A participant is considered to have completed the study if they complete all visits of the study 
including the last scheduled visit specified in the SoA. 
4.2.4 Baseline 
Baseline is defined as the last non-missing measurement recorded before first dose of study drug 
administration. 
Measurements taken in triplicates: 
For safety parameters (e.g. ECGs), where the study requires multiple replicates (e.g. triplicates) per 
time point, the average of these measurements would be calculated (if not already available in the 
database) before determining baseline. 
Baseline is defined as average of non-missing triplicate measurement collected prior to study drug 
administration.    
No imputation will be done for missing baseline value for derivation of change from baseline or 
summary tables and shift tables. 


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4.2.5 Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment  
Repeat, retest, and unscheduled assessment will not be considered for the calculation of summary 
statistics and figures, unless assessment qualifies as baseline. 
Average of controlled and planned (scheduled) assessments will be considered for the calculation of 
summary statistics and figures, if more than one controlled/planned assessment will be performed at a 
specific time point.  
4.2.6 Summary and Representation of Data  
Continuous data will be summarized in terms of mean, standard deviation (SD), median, minimum, 
maximum, and number of observations, unless otherwise stated.  
Categorical data will be summarized in terms of the number of participants providing data at the 
relevant time point (n), frequency counts, and percentages.  
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean and median will be reported to one more decimal place than the 
raw data recorded in the database. The SD will be reported to two more decimal places than the raw 
data recorded in the database. In general, the maximum number of decimal places reported shall be 
four for any summary statistics. 
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts.  
Percentages will be calculated using N as the denominator.  If sample sizes are small, the data displays 
will show the percentages, but any textual report will describe frequencies only. Percentage will be 
presented as whole number if value is 100.  
If for any summary table, n is less than three then only n, mean, minimum, and maximum should be 
presented, and other summary statistics will be left blank. 
4.3 
  Software 
All report outputs will be produced using SAS® version 9.4 or later in a secure and validated 
environment.  
The PK analyses will be conducted using Phoenix® WinNonlin (WNL) version 8.0 or later in a secure 
and validated environment.  
All report outputs will be provided to the Sponsor in RTF and PDF format.   
4.4 
Study Participants 
4.4.1 Analysis Sets 
Randomized Analysis Set (RAS):  
All eligible participants who have signed informed consent and assigned a randomization number, 
regardless of whether they actually received IMP. 
Safety Analysis Set (SAF):  
All participants who receive any amount of study intervention will be included in the Safety Set. 
Participants will be analyzed according to the study intervention received. 
Pharmacokinetic Analysis Set (PKAS): 


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All treated participants for whom the PK profile of ALXN1910 can be adequately characterized will 
be included in the PK Set. PK analyses will be based upon the study intervention received. 
Pharmacodynamic Analysis Set (PDAS): 
All treated participants for whom the PD profile of ALXN1910 can be adequately characterized will 
be included in the PD Set.  
ADA Analysis Set (ADAAS): 
All randomized/enrolled participants who receive at least 1 dose of the study intervention and who 
after the dose have at least 1 reportable ADA result. Participants will be analyzed according to the 
study intervention they actually received. 
A summary table with the number of participants in each of the analysis set will be provided and this 
table will be displayed by dose cohort, including pooled placebo, pooled active treatment across 
cohorts, pooled IV cohorts, pooled SC cohorts and overall. A listing of participants excluded from 
analysis sets will also be provided including reason of exclusion for RAS. 
4.4.2 Disposition of Participants 
A clear accounting of the disposition of all participants who enter the study will be provided, from 
screening to study completion. 
A summary of participant study completion status and reason for study withdrawal will be provided 
for the RAS. This display will show the number and percentage of participants who withdrew from the 
study, including primary reasons for study withdrawal. 
A summary of study treatment status will be provided for the RAS by dose cohort, including pooled 
placebo, pooled active treatment across cohorts, pooled IV cohorts, pooled SC cohorts and overall. 
This display will show the number and percentage of participants who have completed the study.  
A by-participant listing of study discontinuation will be presented for the RAS. The listing will include 
dose date and reasons for study discontinuation, when applicable.  
4.4.3 Protocol Deviations 
All protocol deviations are predefined in the separate document, Protocol Deviation Specification. 
4.4.3.1 Protocol Deviations with Non-PK Implications 
The defined protocol deviations will be collected during the study period by site monitor/clinical team 
and programming team. All deviations related to study inclusion or exclusion criteria, conduct of the 
study, participant management or participant assessment, and handling of the participant’s rights will 
be described.  
4.4.3.2 Protocol Deviations with PK Implications 
Protocol deviations that may potentially impact PK parameter derivations include, but are not limited 
to: 
 IV administration deviations – interruption of administration, etc. 
 Missed PK samples that impact estimation of PK parameter(s) 
 Concomitant medications not authorized by protocol 


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 PK samples obtained out of allowance window that may impact the estimation of PK 
parameter(s) 
Protocol deviations (mentioned in Sections 4.4.3.1 and 4.4.3.2) and analysis sets will be reviewed in 
the (blinded) data review meeting to decide inclusion or exclusion of participant(s) from analyses sets. 
Decisions regarding the exclusion of participants and/or participant data from analyses will be made 
prior to database lock and will be documented and approved.  
A by-participant listing of major and minor protocol deviations will be provided including participant 
identifier, protocol deviation classification, and protocol deviation description and exclusion from 
specific analysis sets. 
4.5 
Demographics and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, height, body weight, body mass index 
[BMI]) will be summarized by dose cohort, including pooled placebo, pooled active treatment across 
cohorts, pooled IV cohorts, pooled SC cohorts and overall and listed by participant for the SAF.  
Age, height, BMI, and weight will be summarized using the mean, SD, minimum, median, and 
maximum. The count and percentage will be computed for sex, race, and ethnicity. The summary table 
will be displayed by cohort and overall, for the SAF. 
4.6 
Medical and Surgical History 
Medical and surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®), Version 24.1(or higher) and assigned to a System Organ Class (SOC) and Preferred Term 
(PT). 
A by-participant listing for medical and surgical history will be provided for the SAF. 
A by-participant listing for substance use (drugs, alcohol, tobacco and caffeine) will be provided for 
the SAF. 
4.7 
Prior and Concomitant Medications 
Medications will be considered as prior if the start date of the medication is before the date of  
administration of the first dose study drug.  
Medications will be considered as concomitant if they are taken at least once in the treatment period 
starting from the first dose of study administration and up to the end of the study.  
Medications starting prior to first administration of study drug and continuing during the study visit 
will be considered both prior and concomitant medication. 
Prior and concomitant medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD Version Sept 2022) and will be classified by Anatomical Therapeutic Chemical (ATC) 
categories. 
 
The number (percentage) of participants who take prior and concomitant medications will be 
summarized by dose cohort, including pooled placebo, pooled active treatment across cohorts, pooled 
IV cohorts, pooled SC cohorts and overall for the SAF by treatment, Anatomical Therapeutic Chemical 
(ATC) Classification, and WHO-DD PT. 
  
By-participant listings of prior and concomitant medications will be provided for the SAF. 


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4.8 
Treatment Exposure and Compliance 
4.8.1 Treatment Exposure  
A by-participant listing of participant exposure to study drug will be generated. The listing will include 
dose, volume, date and time, unit, formulation, and route. 
4.9 
Analysis Supporting Primary Objective(s) 
Analysis for supporting primary objectives provided in Section 4.13.  
4.10 Analysis Supporting Secondary Objective(s) 
Analysis for supporting primary objectives provided in Section 4.12 and Section 4.14.  
4.11 Efficacy Evaluation 
Not applicable. 
4.12 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacokinetic Parameters for Final Analysis 
4.12.1 Pharmacokinetic Concentrations 
Concentration Listings:  
Pharmacokinetic concentration data for ALXN1910, will be listed by cohort, dose, day, route of 
administration (SC/IV), ethnicity category (Japanese/Non-Japanese), sex, age, weight, and participant 
for the SAF. Concentration listings will include nominal PK sampling time relative to dose 
administration or to start of infusion, actual sampling times relative to dose administration or actual 
sampling time relative to start of infusion, infusion duration, deviation from nominal time, and percent 
deviation from nominal time, and concentrations. Serum concentrations below the lower limit of 
quantification (LLOQ) will be presented as below the limit of quantification (BLQ) in the listings and 
the LLOQ value presented as a footnote. Missing PK samples will be reported as no sample (NS) or 
not reportable (NR) as appropriate and considered excluded from PK analysis.  
Concentration Summary Tables: 
Source data as reported from the laboratory will be used for calculation of concentration summary 
statistics. Tabular summaries for concentration-time data will report N (The number of Participants 
included in the pharmacokinetic analysis set for each treatment), n (number of participants with non-
missing values), and n(BLQ) (the number of participants with BLQ samples). 
Concentration for ALXN1910 will be summarized by cohort, dose and route of administration 
(SC/IV), and nominal timepoint for the PK set.  The following descriptive statistics will be presented 
for Serum concentrations obtained at each nominal time point: N, n, n(BLQ), arithmetic mean, SD, 
coefficient of variation (CV%), geometric mean, geometric CV% (calculated as: gCV% =SQRT(es²-
1)*100; where s is the SD of the log-transformed values), median, minimum, and maximum values. 


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For summary tables, all BLQs will be considered zero, and the number of BLQs at each scheduled 
time point will be reported. Summary statistics will not be calculated if non-BLQ concentrations at a 
scheduled time point is <3 and will be reported as NC (not calculated). 
The rules followed for calculation and presentation of concentration data with regards to the number 
of decimal places/significant digits for the listings of participant level concentrations and summary 
tables of concentration are as follows:  
 
Concentration Listings and Tables 
Rounding 
Individual concentrations
n s f. as supplied by bioanalytical laboratory 
Minimum and Maximum
n s.f. capped at 4 
Mean/SD/Median/Geomean
n+1 s.f. capped at 4 
CV%/gCV%
1 d.p. 
N/n
Whole number 
s.f = significant figures, d.p. = decimal place 
 
Concentration Figures: 
For arithmetic mean linear/linear graphs, all BLQ values will be substituted with zero for calculation 
of arithmetic mean and for log/linear graphs the log transformed arithmetic mean will be displayed 
(this should not include zero). 
For individual linear/linear and log/linear graphs all BLQ values will be substituted as follows: 
 BLQs at the beginning of a participant profile (i.e., before the first incidence of a measurable 
concentration) will be assigned to zero (except for intravenous administration when these 
BLQs should not be displayed). When using log/linear scale, these timepoints will be 
considered missing. 
 BLQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing. 
 Single BLQs which fall between two measurable concentrations will be set to missing.  
 Consecutive BLQs which fall between measurable concentrations will be set to missing. 
Measurable concentrations after consecutive BLQs will be set to missing. 
To visualize participant-level concentrations and the comparison between dose cohorts,  
Japanese/Non-Japanese or routes of administration (SC/IV) groups for each treatment, the descriptive 
PK graphs listed below will be generated. Include LLOQ line in individual and summary plots. 
 
Figure x.x.x: Individual participant profiles for ALXN1910 Serum Concentration versus Actual 
Time – (Linear Scale and Semi-Logarithmic Scale) (SAF) (show dose cohort, route of 
administration (SC or IV), Japanese/Non- Japanese and ADA response categories i.e. ADA 
negative, ADA positive- Pre-existing Immunoreactivity, ADA positive- Treatment-emergent, 
ADA responses and ADA positive- Treatment-boosted  ADA responses for each profile) 


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 
Figure x.x.x : Overlaid individual participant profiles for ALXN1910  Serum Concentration versus 
Actual Time – (Linear Scale and Semi-Logarithmic Scale) (SAF) by cohort (show cohort, dose, 
route of administration (SC or IV) or Japanese/Non- Japanese for each plot  
 
Figure x.x.x : Overlaid individual participant profiles for ALXN1910  Serum Concentration 
Actual Time Data by cohort with lines color coded by ADA response category i.e. ADA negative, 
ADA positive- Pre-existing Immunoreactivity, ADA positive- Treatment-emergent/Treatment-
boosted ADA responses (show cohort, dose, route of administration (SC or IV) or Japanese/Non- 
Japanese for each plot)– (Linear Scale and Semi-Logarithmic Scale) (SAF) 
 Figure x.x.x: Mean (± SD) ALXN1910 Serum Concentration versus Nominal Time grouped by 
dose cohort -Linear Scale and Semi-Logarithmic Scale) (PK set) (Different doses and formulations 
(i.v. and s.c.) will be plotted on the same graph, Non- Japanese only, but with differing colors/lines 
to distinguish the different treatment regimens).  
 Figure x.x.x: Mean (± SD) ALXN1910 Serum Concentration Time Data grouped by Japanese /non-
Japanese for the common SC dose (cohort 2 and cohort 4) -Linear Scale and Semi-Logarithmic 
Scale) (PK set) (show Japanese/Non-Japanese dose cohorts at the matching SC dose on the same 
plot but in different colors) 
When presenting the mean semi-logarithmic plot, ± SD will be omitted.  
Figures will be generated in color using unique line style and marker for each plot in the graph. For all 
PK concentration-time plots, linear scale will be used for x-axis (e.g., do not use an ordinal scale).  
4.12.2 Pharmacokinetic Parameters 
PK parameters will be provided by CPMS group. PK parameters will be calculated by NCA methods 
from the concentration-time data using Phoenix® WinNonlin® Version 8.0 or higher following these 
guidelines: 
 
Actual time from dose (SC administration) or from start of infusion (for IV administration) will 
be used in the calculation of all derived pharmacokinetic parameters, except when parameters are 
calculated for safety/dose escalation meetings when nominal times may be used to calculate PK 
parameters.   
 
There will be no imputation of missing data.  
 
Handling of BLQ samples for derivation of serum PK parameters after single dose administration 
o BLQs at the beginning of a participant profile (i.e., before the first incidence of a 
measurable concentration) will be assigned to zero. 
o BLQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing. 
o Single BLQs which fall between two measurable concentrations will be set to missing. 
o Consecutive BLQs which fall between measurable concentrations will be set to missing. 
Measurable concentrations after consecutive BLQs will also be set to missing. 
Pharmacokinetic parameters will be estimated according to the guidelines presented in Table 3. 
Table 3 Pharmacokinetic Parameter and Estimation 


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Parameter 
Guideline for Derivation 
Cmax, tmax, 
Obtained directly from the observed concentration-time data 
AUCt 
The AUC from zero time (pre-dose) to the time of last quantifiable concentration will be 
calculated by a combination of linear and logarithmic trapezoidal methods. Unless 
specifically requested and justified, the linear up/log down trapezoidal method will be 
employed. 
The AUCt is the sum of areas up to the time of the last quantifiable sample: 
 
AUCt=∫𝐶last ∗𝑑𝑡
t
0
 
AUC0-168 
The AUC from zero time to the specific time x is the sum of areas up to the specific time x 
sample: 
AUC0-168 =𝐴𝑈𝐶0−𝑥= ∫𝐶𝑥∗𝑑𝑥
x
0
 
AUC∞ 
The area from zero time extrapolated to infinite time will be calculated as follows:  
AUC∞ = AUCt+
𝐶last
𝜆𝑧 
where Clast is the last observed quantifiable concentration. 
%AUCex 
   
The percentage of AUC0-inf obtained by extrapolation will be calculated as follows:  
%AUCex =
AUC∞  ꟷ 𝐴𝑈𝐶0-t 
AUC∞
x100 . Unless otherwise determined by PK Scientist’s best 
knowledge and judgment, if the %AUCex is greater than 30%, the value, %AUCex, will 
be flagged and all dependent parameters (ie, AUC∞,Vd/F and CL/F (SC) or Vd and CL 
(IV) will be flagged in listings and excluded from summary tables and statistical 
analysis of PK parameters, unless instructed otherwise by the Sponsor. In the case that 
20% ≤ %AUCex, ≤ 30%, the parameter together with all derived parameters will be 
flagged in listings. The reason for flagging/exclusion will be listed/footnoted in 
parameter listings.  
λz and t½ 
1. 
The apparent terminal phase rate-constant (λz) will be estimated by linear 
regression of concentration versus time data presented in a log-linear scale. 
2. 
Data are primarily monotonically decreasing in magnitude and are 
representative of the actual decline in the log concentration-time curve. 
3. 
Only those data points that are judged to describe the terminal log-linear 
decline will be used in the regression.  
4. A minimum number of three data points in the terminal phase will be used in 
calculating λz with the line of regression starting at any post-Cmax data point (Cmax 
should not be part of the regression slope). Unless otherwise determined by PK 
Scientist’s best knowledge and judgment or if instructed by the Sponsor, if the 
adjusted correlation coefficient (R2 adjusted) is <0.8, then λz and all the λz dependent 
parameters (i.e. t½, AUC∞, CL/F and Vd/F (SC admin.) or CL and Vd (IV admin) will 
be flagged in listings and excluded accordingly from summary tables and statistical 
analysis of PK parameters. %AUCex will be flagged, but not excluded. In the case of 
0.8 ≤ R 2 < 0.9, λz and all the λz dependent parameters will be flagged. The reason for 
flagging/exclusion will be listed/footnoted in parameter listings.  
5. 
Unless otherwise determined by PK Scientist’s best knowledge and judgment, 
the interval used to determine λz should be equal or greater than 1.5-fold the estimated 
t½, and if less than 1.5-fold, λz will be flagged in listings and might be excluded (based 


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Parameter 
Guideline for Derivation 
on sponsor specific requirements) from summary tables and statistical analysis of PK 
parameters. All the derived parameters (i.e. t½,, AUC∞, CL/F and Vd/F (SC) or CL 
and Vd (IV)) may also be flagged in listings and excluded from statistical analysis of 
PK parameters. %AUCex may also be flagged in listings, but not excluded. The reason 
for flagging/exclusion will be listed/footnoted in parameter listings.  
 
6. 
The t½ will be calculated as follows:  
 
 
 
t½ =  ln2/λz = 0.693/ λz 
7. 
Data points may be dropped from the linear regression if the PK Scientist 
considers the reported values to be anomalous.  Any data points so designated should 
remain in the listings with a footnote and be identified in the study report with a 
rationale for exclusion.
CL or CL/F 
Following IV or SC administration, systemic clearance of parent drug will be 
calculated from:  
CL or CL/F = 
Dose
AUC∞ 
CL for IV cohorts and CL/F for SC cohorts 
Vd or Vd/F 
Volume of distribution at terminal phase following either intravascular or 
subcutaneous dosing may be calculated from: 
 
 
Vd or Vd/F = 
Dose
λz×AUC∞ = CL / z or (CL/F)/ z 
Vd for IV cohorts and Vd/F for SC cohorts 
DNCmax, DNAUCt 
and DNAUC∞ 
Parameter value divided by dose 
 
 
PK Parameters Listings:  
PK parameters will be listed by participant, cohort, dose, administration route and Japanese/non-
Japanese for the SAF. PK parameters that will be flagged and/or excluded from summary tables and 
statistical analyses of PK parameters will be flagged and footnoted with the reason for 
flagging/exclusion.  
PK Parameter Summary Tables: 
Biostatistics group will consider the derived PK parameters as source data and will use this data 
without rounding for calculation of PK parameters summary statistics tables.   
PK parameters will be summarized by cohort, dose and route of administration (SC /IV), as appropriate 
for the PK set. Tabular summaries for PK parameters will report N (The number of Participants 
included in the pharmacokinetic analysis set for each treatment) and n (number of subjects with a 
specific parameter). 
Descriptive statistics for calculated PK parameters will include N, n, arithmetic mean, SD, CV%, 
geometric mean,  gCV%, median, minimum, and maximum values. For tmax, only N, n, median, 


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minimum, and maximum values will be presented. No descriptive statistics will be determined when 
fewer than three individual PK parameters are available. 
The rules followed for presentation of PK parameters data with regards to the number of decimal 
places/significant digits for the listings of participant level PK parameters and summary tables of PK 
parameters are as follows:  
PK Parameter Listings and Tables 
Rounding  
Derived Individual parameters
3 s f. 
Directly Derived Individual parameters (Cmax, 
C12, C24)
n s.f. as supplied by the analytical laboratory but not 
more than 3 s f. 
Minimum and Maximum
3 s f. 
Mean/SD/Median/Geomean
4 s f. 
CV%/gCV%
1 d.p. 
Comparative estimates (e.g. ratios)
3 d.p. 
CI and other percentages
2 d.p. 
p-values
4 d.p. 
N/n
Whole number 
Exceptions for PK Tables 
  
tmax individuals and min/max
2 d.p 
tmax median only
2 d.p 
s.f = significant figures, d.p. = decimal place 
PK Parameter Figures: 
Scatter plots of individual PK parameters (Cmax, AUC∞, AUCt) versus treatment cohort (x axis) with 
symbols for mean and median and box plots of dose-adjusted Cmax, AUC∞, AUCt versus  treatment 
cohort will be generated for : 
 Different doses and formulations (i.v. and s.c.) plotted on the same graph, non-Japanese only, 
(cohorts 1, 2, 3, 5 and 6; show on the x axis cohort, dose, route of administration). 
 Japanese and Non-Japanese SC cohorts at the matching dose (cohort 2 and Cohort 4; show on 
the x axis cohort, dose, route of administration and Japanese /Non-Japanese). 
Scatter plots of Cmax, AUC∞, AUCt versus ADA response categories (ADA- negative, ADA positive -Pre-
existing Immunoreactivity, ADA positive- Treatment-emergent ADA responses and ADA positive- Treatment-
boosted ADA responses) will be also generated by cohort, if there is sufficient number of participants in multiple 
ADA response categories (i.e. not all/almost all participants with the same ADA response category).  
4.12.3 Interim Pharmacokinetic Analysis to Support SRC Dose Escalation Decisions 
Cohort PK analysis is the responsibility of the CPMS group. The SRC will review blinded PK data 
(only for dose escalation from Cohort 2 to Cohort 5 and from Cohort 5 to Cohort 6) before dose 
escalation. Concentration data will be obtained directly from the bioanalytical laboratory Charles River 
Lab as per data transfer agreement in a unblinded manner. Phoenix® WinNonlin® version 8.0 or higher 
will be used to create an analysis ready dataset to conduct non-compartmental analysis (NCA) and to 
generate plots and tables for the blinded cohort PK analysis report to be discussed in the dose 
escalation/safety meeting. QCed (not QAed) concentration data from the bioanalytical laboratory, as 
agreed upon in data receipt agreement (DRA), will be used for PK analysis. All concentrations prior 


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to the first measurable concentration will be set to 0 and all concentrations within the individual profile, 
and after the last measurable concentration in a profile will be set to missing to create an analysis-
dataset for non-compartmental analysis, as well as for creating tables and figures. Nominal time from 
dose or from start of infusion (not actual time) will be used to calculate PK parameters. PK parameters 
described in the SAP will be calculated as data permit. Linear-log trapezoidal rule will be used to 
calculate PK parameters. Individual linear and semi-log participant plots by dose group, and linear and 
semi-log arithmetic mean concentration (+/- SD) versus time plots will be created by dose group. 
Individual and summary concentration and parameters will be tabulated. Box plots of Cmax and AUC 
or of dose normalized Cmax and AUC may be plotted to visualize dose linearity and proportionality. 
No exclusions may be made to create descriptive summary tables. The blinded interim PK report will 
not reveal individual participant’s treatment assignments. Anonymized individual and summary data 
will be reported in the interim PK report to maintain blinding.   Alias numbers will be used in place of 
actual subject numbers to present individual PK data. Placebo data will not be included in the blinded 
interim PK report. 
In the event of one or more missing samples (from the subjects on active treatment only), to keep the 
blind, these will be replaced with the mean value or mean and median values, respectively, of the 
available data at that sampling time point and summary statistics will be computed and reported in 
tables including these imputed samples. In case of one missing subject’s profile (e.g. incomplete cohort 
of at least 7 subjects or in case of incomplete PK set of a subject (active or placebo) due to 
discontinuation), only data for a maximum of 5 subjects on active treatment will be provided to avoid 
unblinding. Parexel team will ensure the subject with the highest concentrations will not be removed.  
4.12.4  Statistical Analysis of Pharmacokinetic Parameters 
 Assessment of Absolute Bioavailability  
The absolute bioavailability (F) for the ALXN1910 SC cohorts will be defined by the ratio of the 
geometric means for the area under the serum concentration-time curve from time 0 (dosing) to infinity 
parameter for the ALXN1910 SC cohort (cohort 2, 15 mg) over the ALXN1910 IV cohort (cohort 3, 
15 mg). 
A mixed effect model will be performed to the ln-transformed AUC∞ and the independent variables 
will include fixed effects for treatment and participant as a random effect. Geometric least-squares 
means for each treatment (SC or IV), point estimates and associated 95% CIs for the ratios for AUC∞ 
will be produced in tabular format. This will be anti-log transformed to obtain the point estimates and 
the 95% CI for the geometric mean ratio on the original scale. Estimates of between -participant 
variability (%CV) will also be provided. 
SAS code for this analysis is mentioned in Section 6.5.  
 Assessment of Dose Proportionality 
Power model using linear regression method: 
Dose proportionality will be assessed for sc cohorts, Non-Japanese only,  for Cmax and AUC (AUCt, 
AUC∞) using the PKAS who received single dose of ALXN1910 SC (Cohort 2, 5, and 6). PK 
parameters will be used to perform a LS linear regression analysis, using the formula ln_PK parameter 
=A ln_dose + B, where ‘ln PK Parameter’ represents the natural log transformed Cmax and AUC 
parameters and ‘ln_dose’ represents the natural log-transformed dose, A is the slope of the regression 
line and B is the intercept of the lines. The estimate obtained for A is a measure of dose proportionality. 


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An estimate of the slope and intercept of the regression line and corresponding 95% CI will be obtained 
for each PK parameter (Cmax, AUCt, and AUC∞).  
SAS code for this analysis is mentioned in Section 6.5.  
Dose-proportionality based on the power model will be accepted (“not rejected”, in terms of statistical 
inference) if the 95% CIs of the slope does not include 0 for each PK parameter. 
Figure for Dose-Proportionality with 95% CI will be presented.    
 Assessment of Ethnicity Comparison  
The PK parameters for ALXN1910 will be evaluated for Japanese and non-Japanese participants 
(Cohort 2 versus Cohort 4) on active treatment, using an analysis of variance statistical model with 
cohort as the fixed effects on the natural logarithms of the data. In addition, the Japanese versus non-
Japanese cohorts will be evaluated using descriptive statistics; for each cohort, the geometric means 
and the associated 95% CIs of difference of PK parameters will be reported. 
PK parameters will be separately analyzed using a mixed effects model. The dependent variable will 
be the log-transformed PK parameters of interest (AUC∞, AUCt and Cmax) and the independent 
variables will include a fixed effect for ethnicity (Japanese vs non-Japanese) and participant as a 
random effect.  
The estimated difference and CI obtained on the log scale will be exponentiated to provide an estimate 
of the Japanese to non-Japanese ratio and its associated 95% CI. Estimates of between -participant 
variability (%CV) will also be provided. 
Plots of adjusted GMR of Japanese to non-Japanese together with 95% CIs will be produced. 
SAS code for this analysis is mentioned in Section 6.5.  
4.12.5 Pharmacodynamic Analysis, Concentration, and Parameter TFLs, and Statistical 
Analysis of Pharmacodynamic Parameters 
Individual participant PPi versus time profiles values, both observed and change from baseline, will 
be calculated by Charles River Lab and Individual participant PLP, PL, PA versus time profiles values, 
both observed and change from baseline, will be calculated by PPD Laboratories respectively. Baseline 
observed, observed, change from baseline, and percent change from Baseline PPi, PLP, PL, PA versus 
time profiles values will be listed by treatment, sampling time and participant. Listings will include 
actual sampling times relative to dose administration, observed PPi, PLP, PL, PA versus time profiles 
value, change from baseline value, and percentage change from baseline. Baseline will be taken as the 
last measurement prior to dosing, see Section 6.1 Descriptive statistics (number, mean, SD, CV%, 
minimum, median, and maximum) will be presented by dose cohort, including pooled placebo, pooled 
active treatment across cohorts, pooled IV cohorts, pooled SC cohorts and overall  for absolute, and 
percentage change from baseline PD assessment, time of minimum and time of maximum will only 
have minimum, maximum, and median time.  
To visualize the comparison between participants and treatments the following descriptive PD graphs 
will be generated. 
 
Figure x.x.x: Overlaid Participant Profiles for PPi, PLP, PL, and PA Time Profile Data (Observed, 
Change from Baseline, and percent change from Baseline) 
 
Figure x.x.x: Mean (± SD) PPi, PLP, PL, and PA Time Profile Data (Observed, Change from  
Baseline, and percent change from Baseline) 


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For each figure, participants belonging to each category will be shown on the same plot with separate 
figures for each level of dose. Participant level figures will use actual time, while mean plots will use 
planned time, except for predose time point(s), where time 0 will be used rather than actual time. 
4.12.5.1 Pharmacodynamics Analysis and Tables, Figures, and Listings 
All PD analyses will be performed on the PD Analysis Set and will be reported by each cohort. 
Observed values and changes from baseline in plasma concentrations of PPi, PLP, PL, and PA versus 
time will be presented graphically by treatment over time compared with placebo-treated participants.  
The PD parameters for ALXN1910 will be evaluated over time for Japanese and non-Japanese 
participants (Cohort 2 versus Cohort 4) on active treatment by using MMRM model with cohort, visit, 
and cohort by visit interaction as fixed effects, participant as a random effect, and baseline value as a 
covariate. The unstructured covariance structure will be employed; however, if the model fails to 
converge, Toeplitz, heterogeneous compound symmetry, and compound symmetry covariance 
structure will be applied in the order listed until the model converges.  
In the case that all covariance structures fail to converge, the analysis of variance statistical model with 
baseline and cohort as the fixed effects will be used. In addition, the Japanese versus non-Japanese 
cohorts will be evaluated using descriptive statistics; for each cohort, the geometric means and the 
associated 95% CIs of difference of PD parameters in observed value and CFB value will be reported. 
Figures of absolute values and change from baseline over time may be produced if needed. 
4.13 Safety Evaluation 
All safety summaries and analyses will be based upon the SAF as defined in Section 4.4.1 unless 
otherwise specified in specific section. 
All summaries will be provided by cohort and placebo across cohorts will be pooled. 
In addition, the summary tables will be presented for by dose cohort, including pooled placebo, pooled 
active treatment across cohorts, pooled IV cohorts, pooled SC cohorts and overall.  
4.13.1 Adverse Events 
All outputs for AEs/treatment-emergent adverse events (TEAEs) will be based on the SAF unless 
specified separately in TLF shells. AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®), version 24.1 or latest.  
All AE summaries should provide the number and percentages of participants reporting at least one 
AE and the total number of events reported.  
Summaries of AEs will include the following: 
 Incidence of TEAEs (by dose and by cohort and overall, SOC, and PT) 
 Incidence of TEAEs by highest relationship (by cohort and overall, SOC, and PT) 
 Incidence of TEAEs by worst severity (mild/moderate/severe/life threatening/fatal, by cohort 
and overall, SOC, and PT) 
Summary tables will contain counts of participants, percentages of participants in parentheses, and the 
number of events where applicable. A participant who has multiple events in the same SOC and PT 
will be counted only once in the participant counts, but all events will be included. 


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All Adverse Events (AEs) 
All AEs will be listed including pretreatment AEs. 
 
Treatment-emergent Adverse Event (TEAE) 
 
A TEAE will be defined as any AE that emerges during treatment (i.e., an AE that started after study 
drug administration or pre-existed that worsened in severity after study drug administration) and will 
be analyzed for the purpose of safety analysis. 
TEAEs will be summarized by SOC and PT, including the number and percentage of participants 
experiencing events, separately. 
A by-participant listing of all TEAEs leading to withdrawal from the study will be provided. 
Severity 
TEAEs will be summarized by SOC, PT, and severity, including the number and percentage of 
participants experiencing events. If a participant reports the same TEAE more than once within that 
SOC and PT, the TEAE with the highest severity will be used in the corresponding severity summaries. 
In summaries including severity, the following intensity categories will be summarized as per CTCAE 
version 5.0 published 27 Nov 2017: ‘Mild’, ‘Moderate’, ‘Severe’ ,’Life-threatening’, ‘Fatal’. 
Participants who experience the same event multiple times will be included in the most severe 
category. Events with missing intensity will be considered as ‘Severe’ events for summary purposes 
but recorded as missing in the listings. 
If severity is reported by Common Terminology Criteria for Adverse Events (CTCAE) grade, then 
summary of severity will be presented using CTCAE grade. 
Relationship (Causality) 
TEAEs will be summarized by SOC, PT, and causality, including the number and percentage of 
participants experiencing events. Relationship to study drug will be tabulated respectively. If a 
participant reports the same TEAE more than once within that SOC and PT, the TEAE with the 
strongest relationship to study drug will be counted. In summaries including relationship to study 
treatment, the following relationships will be summarized: ‘Not related’, ‘Related’. Participants who 
experience the same event multiple times will be included in the most related category. Events with 
missing relationship will be considered as ‘Related’ to the last given study drug for summary purposes 
but recorded as missing in the listings. 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) will be summarized by SOC and PT, including the number 
and percentage of participants experiencing events. Listing of AESI will be provided. 
4.13.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
A by-participant listing of all serious adverse events will be created. These may include the following 
listings: 
 A by-participant listing of all TESAEs leading to withdrawal from the study 
Listings should follow the format described for AEs in Section 4.13.1 if appropriate. 


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4.13.3 Clinical Laboratory Evaluation 
Clinical laboratory test results of hematology, clinical chemistry, coagulation, urinalysis, urinary drug 
screening will be provided by participant. A list of laboratory assessments is included in Section 6.3. 
Individual data listings of all the laboratory results will be presented for each participant. 
All TLFs will display only the standard international (SI) units after conversion by means of standard 
conversion factors.  
Quantitative clinical laboratory variables, i.e., hematology, biochemistry, and urinalysis will be 
summarized using descriptive statistics (n, mean, SD, minimum, maximum and median) by dose cohort, 
including pooled placebo, pooled active treatment across cohorts, pooled IV cohorts, pooled SC cohorts and  
overall , by visit. Additionally, a within-participant change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized in the same way.  
Any quantitative laboratory parameters that are given as '<xx' or '>xx' in the database will be imputed 
with the absolute value of the number without the sign (e.g., <2.2 will be imputed as 2.2) for the 
calculation of the changes from baseline and for the descriptive statistics. In the listings, no imputations 
will be performed, and all data will be displayed as recorded in the database. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each time point according 
to the laboratory supplied reference ranges. For hematology and biochemistry, shift tables will be 
presented showing the number and percentage of participants with shifts from baseline to each 
postdose time point. Tabulations will be presented by treatment cohort.  
Measurements obtained at Screening and EOS will not be included in the shift tables.  
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be presented by 
treatment cohort and time-point. 
All laboratory data will be displayed in listings. 
Laboratory abnormalities that are considered clinically significant (CS) are recorded in the database as 
AEs.  
Results of pregnancy tests (females only), serology, drugs of abuse and alcohol tests will be listed only. 
4.13.4 Vital Signs 
A by-participant listing of all vital sign measurements (including weight) and change from baseline 
will be presented. 
 
This listing will include a flag for measurements identified as treatment-emergent markedly abnormal 
(TEMA)/potentially clinically significant (PCS) as calculated by the criteria outlined in Table 4. 
 
Measured (observed) values including changes from baseline will be summarized by cohort and time 
point and by vital sign parameter (Oral temperature, pulse rate, respiratory rate, and systolic and 
diastolic blood pressure (mm Hg)). 
Measurements obtained at Screening will not be included in the shift tables or in the tabulations of 
descriptive statistics.  




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 QT, QTcF interval ≤ 450 msec  
 450 msec < QT, QTcF interval ≤ 480 msec   
 480 msec < QT, QTcF interval ≤ 500 msec   
 QT, QTcF interval > 500 msec  
 QT, QTcF interval increases from baseline ≤ 30 msec  
 30 msec < QT, QTcF interval increases from baseline ≤ 60 msec   
 QT, QTcF interval increases from baseline > 60 msec  
The listing of ECG abnormality will be presented separately. 
Mean of the triplicates for ECG measurements will also be presented in the listing and used for deriving 
baseline and change from baseline. 
4.13.6 12-Lead Holter ECG 
Not applicable. 
4.13.7 Physical Examination 
Physical examinations will be performed as shown in the Section  6.1. 
The full physical examination includes an assessment of general appearance and a review of systems 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic systems). 
The brief physical examination includes an assessment of the general appearance, skin, abdomen, 
cardiovascular system and lungs. 
Clinically significant physical examination findings will be listed.  
4.13.8 Daylight Saving Time (DST): 
   DST is not implemented at clinbase level, hence not applicable. 
4.13.9  Safety Monitoring (Safety Review Committee)  
The blinded SRC, consisting of the Investigator, Medical Monitor, Drug Safety Physician, Study 
Statistician, and Clinical Pharmacologist will evaluate the available study data at prespecified time 
points for participant safety and make recommendations on dose escalation, dose modification, or 
termination of the study. Decisions to continue, modify (explore the dose cohort further), or escalate 
dosing will be made by the Investigator and/or SRC. 
The SRC will meet at minimum to support each cohort dose escalation after review of blinded data. 
Where review of unblinded data may be necessary in the event of emerging safety signals, additional 
ad hoc meetings will be scheduled without the Investigator/site staff in attendance. If dosing is stopped 
because of a safety event, continuation of the cohort and/or study will require a substantial amendment.    
4.14 Immunogenicity Analysis  
All ADA analyses will be performed on the Immunogenicity Analysis Set Population . 
Participants in the placebo group will be pooled from each cohort for the summary analysis. ADA titer 
values will be summarized descriptively by dose cohort, including pooled placebo, pooled active 
treatment across cohorts, pooled IV cohorts, pooled SC cohorts and overall , by visit. Summary of 
ADA response to investigation product by visit and dose cohort, including pooled placebo, pooled 


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Statistical Analysis Plan 
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active treatment across cohorts, pooled IV cohorts, pooled SC cohorts and overall ADA response will 
be provided. A listing for immunogenicity analysis which including sampling date, time, day, ADA 
response category, ADA titer level and ADA maximum titer level will be presented. 
4.15 Biomarkers 
Biomarker assays may be conducted as exploratory analyses on collected whole blood samples and the 
data used for research (eg, exploratory) related to ALXN1910. The results of biomarker analyses may 
be reported in the CSR or in a separate study summary.   
4.16 Handling of Dropouts or Missing Data 
No imputation of missing data will be performed except for partial dates imputation mention in Section 
6.2. 
4.17 Subgroup Analysis 
No subgroup analysis is planned for the study.  
4.18 Planned Interim Analyses 
Interim analyses will not be conducted for this study.  
4.19 Changes in the Conduct of the Study or Planned Analysis 
The ADA titer categories analysis is removed as categories based on quartiles is not informative due 
to the small number of study participants.  
5 
REFERENCES 
Software: 
[4] SAS® Version 9.4 of the SAS System for Personal Computers. Copyright © 2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered trademarks 
or trademarks of SAS Institute Inc., Cary, NC, USA. 
[5] Phoenix®WinNonlin®  Software Version 8.0 or higher. https://www.certara.com 
6 
APPENDICES 
6.1 
Schedule of Assessments 


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Table 5 Schedule of Assessments-Single Ascending Dose Cohorts (Screening through Day 5) 
Study Daya 
Screen
-ing  
Day -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5
Assessments 
D -29 to 
D-2  
Admit 
Predose 
0 h 
I/  
SOI  
30 min 
post  
I/SOI  
2 h 
post  
I/SOI  
4 h 
post  
I/SOI  
8 h 
post  
I/SOI  
12 h 
post  
I/SOI  
24 h 
post 
I/  
SOI  
36 h 
post 
I/  
SOI  
48 h 
post 
I/  
SOI  
60 h 
post 
I/  
SOI  
72 h 
post 
I/  
SOI  
84 h 
post 
I/  
SOI  
96 h 
post  
I/SOI  
Status (OP or CRU) 
OP 
CRU 
Admission 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Discharge 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xb 
Informed consentc 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusiond 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical historye 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Height, weight, and 
BMIf  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hepatitis B and C screen 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HIV (Types 1 and 2) 
screen  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Follicle-stimulating 
hormoneg  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine alcohol test 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine drug screen 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum pregnancy 
testh  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urine pregnancy 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Statistical Analysis Plan 
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CONFIDENTIAL 
 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21                                                                                                                                             Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                                                                                                        Page 35 of 48 
testh 
Study Daya 
Screen
-ing  
Day -1 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5
Assessments 
D -29 
to D-2 
Admit 
Predose 
0 h 
I/  
SOI  
30 min 
post  
I/SOI  
2 h 
post  
I/SOI  
4 h 
post  
I/SOI  
8 h 
post  
I/SOI  
12 h 
post  
I/SOI  
24 h 
post 
I/SOI 
36 h 
post 
I/SOI 
48 h 
post 
I/SOI 
60 h 
post 
I/SOI 
72 h 
post 
I/SOI 
84 h 
post 
I/SOI 
96 h 
post  
I/SOI  
Status (OP or CRU) 
OP 
 
 
 
CRU 
 
 
Randomizationi  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
Study intervention 
administration 
(ALXN1910 or placebo) 
  
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
Injection/infusion site 
evaluationj  
  
  
  
X  
  
  
X  
  
  
X  
  
X  
  
X  
  
X  
Physical examination  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brief physical 
examinationk  
  
  
  
  
  
  
  
  
  
X  
  
X  
  
  
  
X  
Vital sign measurementsl 
X  
  
X  
  
X  
X  
X  
X  
X  
X  
  
X  
  
X  
  
X  
ECGm 
X
  
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
Chemistryn 
X 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
Hematologyn 
X 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
Coagulationn 
X 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
Urinalysisn 
X 
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
PKo 
  
  
X 
  
X 
X 
X 
X 
X 
X 
  
X 
  
X 
  
X 


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Statistical Analysis Plan 
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Related to:  SOP-GDO-WW-019                                                                                                                                                                                                        Page 36 of 48 
PD (PPi, PLP, PL, and 
PA)  
  
  
X  
  
  
  
  
  
  
X  
  
X  
  
  
  
X  
 
Study Daya  
Screen
-ing  
Day -1 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Assessments  
D -29 
to D-2 
Admit 
Predose 
0 h 
I/  
SOI  
30 min 
post  
I/SOI  
2 h 
post  
I/SOI 
4 h 
post  
I/SOI 
8 h 
post  
I/SOI 
12 h 
post  
I/SOI 
24 h 
post 
I/SOI 
36 h 
post 
I/SOI 
48 h 
post 
I/SOI 
60 h 
post 
I/SOI 
72 h 
post 
I/SOI 
84 h 
post 
I/SOI 
96 h 
post  
I/SOI 
Status (OP or CRU)  
OP  
 
 
 
CRU  
 
 
 
 
 
 
 
 
 
 
 
Urine for calcium, 
phosphorus, 
and 
creatininep  
  
  
X  
  
  
  
  
  
  
X  
  
X  
  
  
  
X  
Immunogenicity samplesq 
  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hypersensitivity 
reactionsr   
  
  
  
 
←Monitor continuously after dose→  
 
 
Hypersensitivity reaction 
laboratory  
tests 
(tryptase 
& 
complement C5b-9)s  
  
  
X  
 
←See footnoter→  
 
 
Concomitant medications  
 
 
 
←Monitor continuously (after ICF is signed at Screening)→  
 
 
Adverse events review 
and evaluation  
 
 
 
 
←Monitor continuously (after ICF is signed at Screening)→  
 
 
 
Note: When scheduled at the same timepoint, the triplicate ECG should be performed first, followed by vital signs assessments, and then PK/PD sampling.   


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a Permissible window for study assessments are described in the Windows Allowance Document.  
b Participants will be discharged from the CRU after completing all Day 5 assessments. Due to the time needed for turnaround of laboratory test results, discharge will actually occur 
on Day 6.  
c A signed and dated IEC-approved ICF must be obtained before any study-specific screening procedures are performed.  
d Recheck clinical status before randomization and/or dose of study intervention.  
e Including substance usage (drugs, alcohol, tobacco, and caffeine) and past/current medical conditions.  
f Height and BMI only at Screening.  
g Only female participants claiming postmenopausal status will have a follicle-stimulating hormone test to confirm postmenopausal status.  
h All female participants will have a pregnancy test (serum at Screening and urine on Day -1) to confirm the participant is not pregnant. Any female participant who becomes 
pregnant while participating in the study will be withdrawn.  
i Randomization will occur predose on Day 1.  
j Injection/infusion site evaluations will be performed within 15 minutes after I/SOI and ± 15 minutes at 4 and 24 hours post I/SOI. See Protocol Section 10.5 for additional 
details.  
k Brief physical examination to be conducted at discharge from the CRU.  
l At Screening, supine and standing (orthostatic) blood pressures will be performed according to the CRU’s typical procedure to exclude participants who are prone to 
orthostatic hypotension.  
m Each ECG timepoint during the study will be 12-lead and performed in triplicate sequentially within 5 minutes, at least 1 minute apart after 10 minutes of bedrest in supine 
position (note, no bedrest is required post ECG), at 90, 75, and 60 minutes before dosing. ECGs should not be performed after any major meal (i.e., major meals should be withheld 
until after ECG assessments).   
n Investigators should review Day 5 laboratory results to ensure each participant is suitable for discharge.  
o The IV dose cohorts will also have an end-of-infusion PK time point.  
p Spot urine collection.  
q Sample for ADA assessments will be collected prior to administration of the drug. In the event of suspected SAE like hypersensitivity or anaphylaxis, additional samples 
may be collected for ADA assessments at or near the event.  
r See Protocol Section 10.4 for details.  
s Collect 3 lab samples after a suspected hypersensitivity reaction: as soon as possible and at 2 and 8 hours after the suspected reaction (+ 1 hour window for each sample). If the 
suspected hypersensitivity reaction persists beyond 8 hours, the CRU should contact the Medical Monitor for guidance. Predose samples will only be analyzed for participants with a 
reported suspected hypersensitivity reaction.  
Abbreviations: ADA = antidrug antibody; BMI = body mass index; C5b-9 = terminal complement complex; CRU = clinical research unit;  
ECG = electrocardiogram; h = hours; HIV = human immune deficiency virus; I = injection; ICF = informed consent form; IEC = Independent Ethics Committee;  
OP = outpatient; min = minutes; PA = pyridoxic acid; PD = pharmacodynamic; PK = pharmacokinetic; PL = pyridoxal; PLP = pyridoxal 5′‑phosphate;  
PPi = inorganic pyrophosphate; SOI = start of infusion; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event 


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Statistical Analysis Plan 
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CONFIDENTIAL 
 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21                                                                                                                                             Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                                                                                                        Page 38 of 48 
 
 


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CONFIDENTIAL 
 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21                                                                                                                                             Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                                                                                                        Page 39 of 48 
Schedule of Activities – Single Ascending Dose Cohorts (Day 6 through Day 75)   
Study Daya
Day 
6 
post  
I/SOI  
Day 7 
post  
I/SOI 
Day 8 
post  
I/SOI 
Day 15 
post  
I/SOI  
Day 22 
post  
I/SOI  
Day 29 
post  
I/SOI  
Day 36 
post  
I/SOI  
Day 43 post 
I/SOI  
(EOS/EDb) 
Day 75 post 
I/SOI  
(EOS/EDb) 
Status (OP or CRU) 
 
 
OP 
 
Full physical examination 
  
  
  
  
  
  
  
X 
X 
Brief physical examination 
  
  
X 
X 
  
X 
  
  
  
Vital sign measurementsc 
  
  
X 
X 
  
X 
  
X 
X 
12-lead ECG (triplicate)d 
X 
X 
X 
X 
  
  
  
X 
X 
Chemistry 
  
  
X 
X 
X 
X 
X 
X 
X 
Hematology 
  
  
X 
X 
X 
X 
X 
X 
X 
Coagulation 
  
  
X 
X 
X 
X 
X 
X 
X 
Urinalysis (via dipstick) 
  
  
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy teste 
  
  
  
  
  
X 
  
  
  
Serum pregnancy teste 
  
  
  
  
  
  
  
X 
X 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD (PPi, PLP, PL, and PA) 
  
  
X 
X 
X 
X 
X 
X 
X 
Immunogenicity samplesf 
  
  
  
  
  
X 
  
X 
X 
Urine for calcium, phosphorus, and creatinineg 
  
  
X 
X 
  
X 
  
X 
X 
Hypersensitivity reactionsh 
 
 
←Monitor continuously after dose→ 
 
Hypersensitivity reaction laboratory tests (tryptase and 
complement C5b-9)i  
 
 
←See footnoteh→ 
 
Concomitant medications 
 
 
←Monitor continuously (after ICF is signed at Screening)→ 
 
Adverse event review and evaluation 
 
 
←Monitor continuously (after ICF is signed at Screening)→ 
 


Parexel International 
Alexion Pharmaceuticals, Inc.  
 
ALXN1910-HV-101   
 
 
 
 
Statistical Analysis Plan 
TP-GDO-WW-133-03 
 
CONFIDENTIAL 
 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21                                                                                                                                             Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                                                                                                                        Page 40 of 48 
Note: When scheduled at the same timepoint, the triplicate ECG should be performed first, followed by vital signs assessments, and then PK/PD sampling.   
a Permitted windows for study assessments are described in the Windows Allowance Document.  
b EoS procedures will be performed on Day 75.. If possible, participants who withdraw/are withdrawn from the study should have an ED visit conducted at the time of discontinuation 
that includes the EoS assessments. All efforts will be made to contact participants who ED from the study via phone for a safety follow-up call approximately 30 days (4.5 half-lives) 
after their dose to assess AEs.   
c Vital signs taken postdose will be performed before the coinciding blood collection, whenever possible.  
d Each ECG will be 12-lead and performed in triplicate sequentially within 5 minutes, at least 1 minute apart after 10 minutes of bedrest in supine position (note, no bedrest is required 
post ECG). ECGs should not be assessed after any major meal (i.e., major meals should be withheld until after ECG assessments).   
e Only female participants of childbearing potential will have a pregnancy testing to confirm the participant is not pregnant.  
f Sample for ADA assessments will be collected prior to administration of the drug. In the event of suspected SAE like hypersensitivity or anaphylaxis, additional samples may be 
collected for ADA assessments at or near the event.  
g Spot urine collection. 
h See Protocol Section 10.4 for details.  
i If the participant is in the clinic, collect the first sample as soon as possible (preferred) or within 1 hour of the suspected hypersensitivity reaction, and 2 additional samples at 2 and 
8 hours after the suspected hypersensitivity reaction (+ 1 hour window for each sample). If the participant is not in the clinic, these samples do not need to be collected and suspected 
hypersensitivity reactions will be reported as TEAEs/TESAEs only. If the suspected hypersensitivity reaction persists beyond 8 hours, the CRU should contact the Medical Monitor 
for guidance.  
Abbreviations: ADA = anti-drug antibody; C5b-9 = terminal complement complex; CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; EOS = end 
of study; h = hours; I = injection; ICF = informed consent form; OP = outpatient; PA = pyridoxic acid; PD = pharmacodynamic; PK = pharmacokinetic; PL = pyridoxal; PLP = 
pyridoxal 5′‑phosphate; PPi = inorganic pyrophosphate; SOI = start of infusion; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event 








Parexel International 
Alexion Pharmaceuticals, Inc.  
 
ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 44 of 48 
6.3 
Laboratory Test Parameters 




Parexel International 
Alexion Pharmaceuticals, Inc.  
 
ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 46 of 48 
Abbreviations: ALT = alanine aminotransferase; anti-HBC = hepatitis B core antibody; anti-HCV = hepatitis C virus 
antibody; AST = aspartate aminotransferase; C5b-9 = terminal complement complex; FSH = follicle-stimulating 
hormone; HbsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic 
transaminase 
 
6.4 
ECG Notable Criteria  
ECG Parameters
Definition/threshold
QT, QTcF
 
QTcF interval ≤ 450 msec
450 msec < QT, QTcF interval ≤ 480 msec
480 msec < QT, QTcF interval ≤ 500 msec
QT, QTcF interval > 500 msec
QT, QTcF interval increases from baseline ≤ 30 msec
30 msec < QT, QTcF interval increases from baseline ≤ 60 msec
QT, QTcF interval increases from baseline > 60 msec
ECG = electrocardiogram; bpm = beats per minute; QTcF = QT corrected using Fridericia’s formula 
6.5 
Sample SAS Code for statistical analysis 
Dose proportionality analysis 
ODS OUTPUT parameterestimates=est FitStatistics=fit; 
PROC REG DATA = PP ALPHA=0.05 PLOTS=ALL; 
BY PARAMCD PARAM; 
MODEL LNAVAL=LNDOS/CLB; 
RUN; 
where: 
LNAVAL: natural log-transformed PK parameter  
LNDOS: natural log-transformed dose level of ALXN1910  
PARAM: PK parameter  
SUBJECT: participant 
 
 
 
 
Microscopic examination (if any leukocytes, trace protein, nitrites, and blood [if not
menstruating] are abnormal) 
Urine electrolyte 
Urine for calcium, phosphorus, and creatinine 
Other screening tests 
Urine drug and alcohol tests 
 
FSH (confirmation of postmenopausal state) 
 
HIV-1 and HIV-2 antibodies, HbsAg, anti-HBC IgG + IgM (if IgG positive), and anti-HCV
 
Serum human chorionic gonadotropin pregnancy test 
Serum or urine pregnancy tests  


Parexel International 
Alexion Pharmaceuticals, Inc.  
 
ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 47 of 48 
Absolute Bioavailability analysis 
 
ODS SELECT NOPRINT(NOWARN); 
                ODS OUTPUT CovParms= Cv1 lsmeans=lsm estimates=est Diffs=diff1; 
                PROC MIXED DATA=DATA1 NOITPRINT; 
                BY COMPOUND PPSPEC PARAMN PARAMCD PARAM; 
                CLASS SUBJID TRTA; 
                MODEL LN_PK = TRTA/DDFM=KR; 
                RANDOM SUBJID ; 
                LSMEANS TRTA/PDIFF ALPHA=0.05 CL; 
                ESTIMATE “SC vs IV” TRTA 1 -1 /CL ALPHA=0.05; 
                RUN; 
where: 
COMPOUND: compound used in the study 
PPSPEC : Specification (Serum) 
PARAMN : numerical order of PK parameter 
PARAMCD :short name of PK parameter 
PARAM: PK parameter  
LN_PK; natural log transformed value of PK parameter 
SUBJID: Participant 
TRTA: actual treatment 
Ethnicity Comparison 
Sample SAS Code: 
ODS SELECT NOPRINT(NOWARN); 
ODS OUTPUT CovParms= Cv1 lsmeans=lsm estimates=est Diffs=diff1; 
PROC MIXED DATA=DATA1 NOITPRINT; 
BY COMPOUND ANALYTE PPSPEC PARAMN PARAMCD PARAM; 
CLASS SUBJID ETHNICITY; 
MODEL LN_PK = ETHNICITY/DDFM=KR; 
RANDOM INT SUBJID ; 
LSMEANS ETHNICITY/PDIFF ALPHA=0.05 CL; 
ESTIMATE “JAPANESE vs NON-JAPANESE” ETHNICITY 1 -1 /CL ALPHA=0.05; 
RUN; 
where: 


Parexel International 
Alexion Pharmaceuticals, Inc.  
 
ALXN1910-HV-101   
Statistical Analysis Plan 
TP-GDO-WW-133-03 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  22 Dec 21 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 48 of 48 
COMPOUND: compound used in the study 
ANALYTE : analyte of the drug (can be parent or metabolite) 
PPSPEC : Specification (serum) 
PARAMN : numerical order of PK parameter 
PARAMCD :short name of PK parameter 
PARAM: PK parameter  
LN_PK; natural log transformed value of PK parameter 
SUBJID: Participant