A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of a Single Dose of ALXN1210 Administered Subcutaneously Compared to Intravenously in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Alexion Pharmaceuticals, Inc.

A Phase 1 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Immunogenicity 
of a Single Dose of ALXN1210 Administered Subcutaneously 
Compared to Intravenously in Healthy Subjects 
Unique Protocol ID: 
NCT Number: 
EudraCT Number: 
Date of Protocol: 
ALXN1210-SC-101 
NCT05288829 
2016-001617-24 
28 July 2016 

1. 
TITLE PAGE 
ALXN1210 
ALXN1210-SC-101 
A PHASE 1 STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PHARMACODYNAMICS, AND 
IMMUNOGENICITY OF A SINGLE DOSE OF ALXN1210 
ADMINISTERED SUBCUTANEOUSLY COMPARED TO 
INTRAVENOUSLY IN HEALTHY SUBJECTS 
 
Sponsor 
Alexion Pharmaceuticals, Inc. 
100 College Street 
New Haven, CT 06510 USA 
Sponsor Contact: 
 
Associate Director, Clinical Project Lead, Global Clinical 
Operations  
Alexion Pharmaceuticals, Inc. 
33 Hayden Avenue  
Lexington, MA 02421 USA 
Telephone: 
 
Email: 
  
Medical Monitor: 
 
Senior Medical Director, Research  
Alexion Pharmaceuticals, Inc. 
33 Hayden Avenue 
Lexington, MA 02421 USA 
Telephone: 
  
Email: 
  
Date of Original Protocol: 
17 May 2016 
Date of Amendment 1: 
13 Jun 2016 
Date of Amendment 2: 
28 Jul 2016 
IND Number: 
118481 
EudraCT Number: 
2016-001617-24  
Proprietary Notice 
This confidential information is provided for the exclusive use of investigators of this agent and is subject to recall at 
any time. The information in this document may not be disclosed unless such disclosure is required by federal or state 
law or regulations subject to the foregoing. This information may be disclosed only to those persons involved in the 
study who have a need to know with the obligation not to further disseminate this information. These restrictions on 
disclosure will apply equally to all future oral or written information supplied to you by Alexion, which is designated 
as “privileged” or “confidential.” 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Project Lead 
 
Associate Director, Clinical Project Lead, 
Global Clinical Operations 
Alexion Pharmaceuticals, Inc. 
33 Hayden Avenue  
Lexington, MA 02421 USA 
Telephone: 
 
Mobile: 
 
Email: 
  
Responsible Physician 
 
Senior Medical Director, Research 
Alexion Pharmaceuticals, Inc. 
33 Hayden Avenue  
Lexington, MA 02421 USA 
Telephone: 
 
Mobile: 
 
Email: 
 
24-Hour Emergency Contact 
 
Senior Medical Director, Research 
Alexion Pharmaceuticals, Inc. 
33 Hayden Avenue  
Lexington, MA 02421 USA 
Telephone: 
 
Mobile: 
 
Email: 
  
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
2. 
SYNOPSIS 
Name of Sponsor: 
Alexion Pharmaceuticals, Inc. 
Name of Investigational Product: 
ALXN1210 
Name of Active Ingredient: 
ALXN1210 
Title of Study: A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and 
Immunogenicity of a Single Dose of ALXN1210 Administered Subcutaneously Compared to Intravenously in 
Healthy Subjects (Protocol ALXN1210-SC-101) 
EudraCT Number: 2016-001617-24 
Study Center: 
This study will be conducted by Richmond Pharmacology Ltd. at the following facility: 
 
Croydon University Hospital (Woodcroft Wing) 
530 London Road 
Croydon, Surrey 
CR7 7YE 
United Kingdom 
 
Telephone: 
 
Length of Study:  
Estimated date first subject enrolled: September 2016 
Estimated date last subject completed: February 2017 
Phase of Development: 1 
 
Study Rationale: 
The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), 
and immunogenicity of a single dose of ALXN1210 administered subcutaneously (SC) compared to a single dose 
of ALXN1210 administered intravenously (IV) in healthy subjects. Data from this study will be used to determine 
the absolute bioavailability of ALXN1210 SC in healthy subjects. 
 
ALXN1210 is a humanized monoclonal antibody (mAb) that inhibits terminal complement. It specifically binds 
the human complement protein C5 thereby inhibiting its cleavage to C5a and C5b during complement activation. 
This inhibition not only prevents the release of the proinflammatory mediator C5a, but also inhibits the formation 
of the cytolytic pore-forming membrane attack complex (MAC) terminal complement complex (C5b-9). The 
mechanism of action described here provides a rationale for the potential therapeutic use of ALXN1210 in diseases 
where complement activation is involved (eg, paroxysmal nocturnal hemoglobinuria [PNH] or atypical hemolytic 
uremic syndrome [aHUS]).  
 
ALXN1210 has been administered safely to healthy subjects in 200-mg and 400-mg IV doses in a single ascending 
dose (SAD) study (Study ALXN1210-HV-101; N = 10). Healthy subjects have also been administered multiple 
400-mg and 800-mg IV doses on an every 4 week (Q4W) regimen in an ongoing multiple ascending dose (MAD) 
study (Study ALXN1210-HV-102; N = 12). The starting doses of ALXN1210 IV in the 2 healthy volunteer studies 
were selected to assess safety and tolerability in healthy volunteers and to have measurable pharmacologic activity 
(eg, inhibition of complement activation). In addition, administration of multiple doses of ALXN1210 IV to 
25 patients with PNH has been safe and tolerated, to date, at single doses up to 2000 mg. 
 
Objectives: 
The primary objectives of this study are as follows:  
• 
To evaluate the safety and tolerability of a single dose of ALXN1210 SC compared to ALXN1210 IV in 
healthy subjects, as assessed by physical examination findings, vital sign measurements, immunogenicity, 
laboratory analysis, and assessments of adverse events (AEs).  
• 
To determine the absolute bioavailability of ALXN1210 SC. 
 
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Amendment 2, 28 Jul 2016  
The secondary objective of the study is as follows: 
• 
To evaluate the PD effects of ALXN1210 SC compared to ALXN1210 IV, as assessed by the level of free 
C5 and chicken red blood cell (cRBC) hemolysis. 
Study Design and Methodology:  
This is a Phase 1 study designed to evaluate the safety, tolerability, PK, PD, and immunogenicity of a single 
400-mg dose of ALXN1210 SC compared to a single 400-mg dose of ALXN1210 IV or placebo SC in 42 healthy 
subjects. All subjects will be screened for eligibility in the study after providing signed and dated institutional 
ethics committee-approved written informed consent to participate and before any study-specific screening 
procedures are performed. 
 
Six subjects will initially be randomly assigned in a 2:1 ratio to Cohort 1a, in a blinded fashion, to receive either a 
single 400-mg dose of ALXN1210 SC or single dose of placebo SC. The Safety Review Committee (SRC) will 
evaluate the first 48 hours of post-dose clinical safety data for subjects in Cohort 1a before enrollment into 
Cohorts 1b or 2 may begin. Thirty-six subjects will then be randomly assigned, in a 2:1 ratio, to either Cohort 1b 
(N=24) or Cohort 2 (N=12). Within Cohort 1b, the 24 subjects will further be randomly assigned, in a 5:1 ratio and 
blinded fashion, to receive either a single 400-mg dose of ALXN1210 SC or a single dose of placebo SC, 
respectively. The 12 subjects in Cohort 2 will receive a single 400-mg dose of ALXN1210 IV in an open-label 
fashion. 
 
 
 
At the sponsor’s discretion, up to 8 additional subjects (2 subjects each in Cohorts 1a and 1b and 4 subjects in 
Cohort 2) may be enrolled into the study if 2 or more subjects discontinue within 3 months for reasons other than 
drug-related AEs, and after consultation with the SRC. All enrolled subjects will be included in analyses as 
appropriate. Subjects in Cohorts 1a and 1b will be combined for analyses. Subjects who withdraw from the study 
subsequent to dosing will be followed for safety assessments through the last scheduled study visit, if possible. 
 
Subjects will participate in the study for up to 39 weeks, including a screening period of up to 70 days, followed by 
a 200day follow-up period for safety, PK, PD, and immunogenicity assessments after study drug administration. 
Screening
Up to 70 days
Dosing & Follow-up
200 days
Day 1
Dose
Cohort 1b
400 mg SC
N = 24 (20A/4P)
SRC
Day 1
Dose
Cohort 1a
400 mg SC
N = 6 (4A/2P)
Cohort 2
400 mg IV
N = 12
Day 1
Dose
Abbreviations: A = active drug; IV = intravenous; P = placebo; SC = subcutaneous; SRC = Safety Review Committee
Note:  The SRC will review the first 48 hours of post-dose safety data from Cohort 1a before enrollment into 
Cohorts 1b or 2 may begin.
 
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Number of subjects (planned):  
Forty-two subjects are planned for evaluation of the primary and secondary objectives in this study: 
6 (4 ALXN1210 SC, 2 placebo SC) subjects in Cohort 1a; 24 (20 ALXN1210 SC, 4 placebo SC) subjects in 
Cohort 1b, and 12 (ALXN1210 IV) subjects in Cohort 2. See the synopsis section “Study Design and 
Methodology” regarding addition of subjects who withdraw or are withdrawn from the study after dosing. 
Diagnosis and main criteria for inclusion:  
All subjects must meet the following inclusion and exclusion criteria. Subjects who fail to meet eligibility criteria 
may not be rescreened for participation in the study, unless the condition that led to eligibility failure is transient, 
self-limited, and easily treatable, and is expected to be resolved at the time of dosing, as agreed by the investigator 
and medical monitor.  
 
Inclusion: 
1. Healthy subjects, aged 25 through 55 years, inclusive, at the time of dosing. 
2. Body mass index (BMI) from 18 through 29.9 kg/m2, inclusive, and weight between 50 and 100 kg, 
inclusive.  
3. QT interval corrected using the Fridericia’s formula (QTcF) ≤ 450 msec for males and ≤ 470 msec for 
females at screening and prior to dosing on Day 1. 
4. Willing and able to give written informed consent and comply with the study visit schedule.  
5. Documented vaccination with a tetravalent meningococcal conjugate vaccine (MCV4) at least 56 days 
and not more than 3 years prior to dosing. Documentation must include a positive serum bactericidal 
antibody (SBA) titer to confirm an immune response before study drug administration. 
6. Vaccination with serogroup B meningococcal vaccine at least 56 days prior to dosing on Day 1, with a 
booster administered at least 28 days prior to dosing on Day 1, with at least 28 days between the first and 
second injections. 
7. Female subjects of childbearing potential, if heterosexually active, must use highly effective or acceptable 
contraception as defined below, starting at screening and continuing until at least 6 months after study 
drug administration. Antibiotic prophylaxis is required during this study, which can compromise the 
efficacy of hormonal contraception. Therefore, it is recommended that subjects using hormonal 
contraception also use barrier contraception (eg, condom or diaphragm with spermicide) for the duration 
of antibiotic prophylaxis. 
 
Highly effective contraceptive methods for females are as follows: 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation as follows: 
− 
Oral 
− 
Intravaginal 
− 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation as follows: 
− 
Oral 
− 
Injectable 
− 
Implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
 
Male subjects, if heterosexually 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) for the 
treatment period and for at least 6 months after study drug administration. Barrier contraception is 
required even with documented medical assessment of surgical success of a vasectomy. Female spouses 
or partners of male subjects who are of childbearing potential must use highly effective contraception as 
defined above, or acceptable contraception as defined below, starting at screening and continuing until at 
least 6 months after study drug administration. Male subjects must not donate sperm during the screening 
and treatment periods and for at least 6 months after study drug administration. 
 
 
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Acceptable contraceptive methods are as follows: 
• 
Simultaneous use of male condom and, for the female partner, occlusive cap (diaphragm or 
cervical/vault caps) with intravaginally applied spermicide 
Exclusion: 
1. Subjects who are in intimate and prolonged contact with (defined as living under the same roof or 
providing personal care to) people younger than 2 years of age or older than 65 years of age, or who are 
either immunocompromised or have one of the following underlying medical conditions: anatomic or 
functional asplenia (including sickle cell disease); congenital complement, properdin, factor D, or primary 
antibody deficiencies; acquired complement deficiencies (eg, those receiving eculizumab); or human 
immunodeficiency virus (HIV). 
2. Subjects who are one of the following: 
• 
Professionals who are exposed to environments of greater risk for meningococcal disease  
• 
Research, industrial, and clinical laboratory personnel who are routinely exposed to 
N meningitidis 
• 
Military personnel during recruit training (military personnel may be at increased risk of 
meningococcal infection when accommodated in close quarters)  
• 
Daycare center workers  
• 
Those living on a college or university campus  
• 
Those who plan to travel during the course of the study to or have travelled to endemic areas for 
meningococcal meningitis (eg, India, Sub-Saharan Africa, pilgrimage to Saudi Arabia for Hajj) 
within 6 months prior to dosing 
3. History of any Neisseria infection. 
4. History of unexplained, recurrent infection, or infection requiring treatment with systemic antibiotics 
within 90 days prior to dosing.  
5. HIV infection (evidenced by HIV-1 or HIV-2 antibody titer). 
6. Acute or chronic hepatitis B virus (HBV) infection. Hepatitis B surface antigen (HBsAg) testing is 
required for all subjects prior to enrollment. Subjects with positive HBsAg will not be enrolled.  
For subjects with negative HBsAg, the following testing algorithm will be required:  
• 
If hepatitis B core antibody (HBcAb) is negative, the subject is eligible to enroll;  
• 
If HBcAb is positive, the hepatitis B surface antibody (HBsAb) will be tested.  
− 
If both HBcAb and HBsAb are positive, the subject is eligible to enroll.  
− 
If HBcAb is positive and HBsAb is negative, the subject will not be enrolled. 
7. Acute or chronic hepatitis C virus (HCV) infection (evidenced by antibody titer). 
8. Active systemic viral or fungal infection within 14 days prior to dosing. 
9. Positive or indeterminate QuantiFERON®-TB test indicating possible tuberculosis (TB) infection. 
10. History of latent or active TB or exposure to endemic areas within 8 weeks prior to the screening visit. 
11. Female subjects who are breastfeeding or are heterosexually active and unwilling to practice 
contraception and are not postmenopausal. Postmenopausal is defined as amenorrhea ≥ 12 consecutive 
months without another cause and a documented serum follicle-stimulating hormone level ≥ 40 mIU/mL 
and estradiol concentration ≤ 110 pmol/L within the 6 months prior to study drug administration. 
12. Positive serum pregnancy test at screening or on Day –1. 
13. Serum creatinine greater than the upper limit of normal (ULN) of the reference range of the testing 
laboratory at screening or on Day –1. 
14. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN of the reference range of the 
testing laboratory at screening or > 1.5 × ULN of the reference range of the testing laboratory on Day –1. 
15. Any of the following hematology results: hemoglobin < 130 g/L for males and < 115 g/L for females, 
hematocrit < 0.37 L/L for males and < 0.33 L/L for females, white blood cell (WBC) count < 3.0 × 
103/μL, absolute neutrophil count < 2.0 × 103/μL, and platelet count < 150 or > 400 × 103/μL at screening 
or on Day –1. Complete blood count (CBC) clinical laboratory results that are considered clinically 
relevant and unacceptable by the investigator on Day –1. 
16. History of complement deficiency or complement activity below normal reference range as evaluated by 
complement alternative pathway (CAP) ELISA at screening. 
17. History of malignancy with the exception of a nonmelanoma skin cancer or carcinoma in situ of the cervix 
that has been treated with no evidence of recurrence. 
18. Participation in a clinical study within 30 days before initiation of dosing on Day 1 or use of any 
 
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experimental small-molecule therapy within 30 days prior to dosing on Day 1. 
19. Participation in more than one clinical study of an mAb, or participation in a clinical study of an mAb 
within the 12 months prior to screening, during which the subject was exposed to the active study drug. 
Subjects who have participated in only one study of an mAb may be considered for enrollment if they 
completed that study more than 12 months prior to screening. 
20. Prior exposure to ALXN1210. 
21. Major surgery or hospitalization within 90 days prior to dosing. 
22. History of allergy to excipients of ALXN1210 (eg, polysorbate 80).  
23. Documented history of allergy to penicillin or cephalosporin.  
24. History of significant allergic reaction (eg, anaphylaxis or angioedema) to any product (food, 
pharmaceutical, etc).  
25. Currently smokes > 10 cigarettes daily (former smokers may be permitted to enroll at the investigator’s 
discretion). 
26. History of illicit drug abuse, history of significant alcohol abuse within 1 year prior to the screening visit, 
or regular use of alcohol within 6 months prior to the screening visit (more than 14 units of alcohol per 
week [1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]).  
27. Positive urine drug toxicology screen at screening or on Day –1. 
28. Alcohol consumption within 48 hours prior to study drug administration or positive alcohol breath test on 
Day –1. 
29. Donation of plasma within 7 days prior to dosing. Donation or loss (excluding volume drawn at 
screening) of more than 50 mL of blood within 30 days prior to dosing or more than 499 mL of blood 
within 56 days prior to dosing. 
30. History of continuous topical, inhaled, or systemic steroid use > 28 days or history of any inhaled or 
topical immunosuppressive therapy within 90 days prior to study drug administration.  
31. Use of prescription medications (excluding oral contraceptives) within 14 days prior to study drug 
administration, except with prior approval of the sponsor. 
32. Regular use of nonprescription, over-the-counter medications, including herbal remedies and 
supplements, within 14 days prior to study drug administration. Multivitamins, acetaminophen ≤ 2 g per 
day, and topical skin products without significant systemic absorption are allowed. 
33. Clinical diagnosis of any autoimmune or rheumatologic disease (eg, systemic lupus erythematosus, 
rheumatoid arthritis). 
34. Immunization with a live-attenuated vaccine 28 days prior to dosing or planned vaccination during the 
course of the study (except for the vaccination planned by the study protocol). Immunization with 
inactivated or recombinant influenza vaccine is permitted. 
35. 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. 
36. Subjects with any medical history, conditions, or risks that, in the opinion of the investigator, may 
interfere with the subject's full participation in the study or compliance with the protocol, or may pose any 
additional risk for the subject or confound the assessment of the subject or outcome of the study. 
Investigational product, dosage, and mode of administration:   
ALXN1210 SC:  ALXN1210 SC is formulated at pH 7.4 and each vial contains 100 mg of ALXN1210 in 50 mM 
sodium phosphate, 25 mM arginine, 5% sucrose, and 0.05% polysorbate 80. ALXN1210 SC is provided as a fully 
formulated, sterile, preservative-free, 100-mg/mL aqueous solution of ALXN1210 for SC administration and is 
supplied in 2-mL single-use vials. Each vial of ALXN1210 SC drug product includes a nominal overfill to ensure 
that 1 mL (100 mg of ALXN1210) can be withdrawn for administration. ALXN1210 SC will be administered SC 
as four 1-mL injections.  
 
ALXN1210 IV:  ALXN1210 IV is formulated at pH 7.0 and each vial contains 150 mg of ALXN1210 in 10 mM 
sodium phosphate, 150 mM sodium chloride, 0.02% polysorbate 80, and water for injection. ALXN1210 IV is 
provided as a fully formulated, sterile, preservative-free, 10-mg/mL aqueous solution of ALXN1210 and is 
supplied in 20-mL single-use vials. ALXN1210 IV will be administered by IV infusion at a maximum rate of 333 
mL/hr, excluding interruption for safety or technical reasons. 
Reference therapy, dosage, and mode of administration:  
Placebo SC:  Each dose of placebo SC contains 0.9% sodium chloride for injection, European Pharmacopoeia 
(Ph Eur) or British Pharmacopeia (BP), to the same volume as specified for Cohorts 1a and 1b.  
 
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Planned duration of treatment:  
Screening period: up to 70 days  
Dosing and observation periods: For Cohorts 1a and 1b, a single 400-mg dose of ALXN1210 SC or placebo SC 
(administered as four 100-mg SC injections) on Day 1, followed by an observation period of 200 days. For Cohort 
2, a single 400-mg dose of ALXN1210 IV on Day 1, followed by an observation period of 200 days. Subjects will 
be followed for safety, PK, PD, and immunogenicity assessments. 
Endpoints: 
Safety: 
Safety assessments will include physical examination findings, vital sign measurements, immunogenicity (antidrug 
antibody [ADA]) testing, laboratory evaluations, electrocardiogram (ECG) results, infusion site and injection site 
evaluations, and monitoring of AEs. Adverse events will be graded according to criteria from the National Cancer 
Institute Common Terminology Criteria for Adverse Events v4.03, published 14 Jun 2010. Laboratory evaluations 
will include hematology, chemistry, and coagulation panels; CBC with differential; urinalysis; and pregnancy 
testing for female subjects. 
 
Pharmacokinetics and Pharmacodynamics: 
• 
Serum concentrations of ALXN1210 will be assayed and serum samples for PD assays will be collected 
from the following sampling time points: pre-dose (within 15 minutes prior to start-of-infusion/injection 
[SOI]); Day 1 at end of infusion/injection (EOI), 30 minutes post EOI, and the following time points 
following SOI: 2 h, 4 h, and 8 h; Day 2 (24 h); Day 3 (48 h); Day 5 (96 h); Day 8 (168 h); Day 15 (336 h); 
Day 22 (504 h); Day 29 (672 h); Day 36 (840 h); Day 43 (1008 h); Day 50 (1176 h); Day 57 (1344 h); 
Day 71 (1680 h); Day 90 (2136 h); Day 120 (2856 h); Day 150 (3576 h); and Day 200 (4776 h). 
• 
Using noncompartmental analysis methods, the serum concentrations data will be used to derive the 
following PK parameters: maximum observed serum concentration (Cmax), time to maximum observed 
serum concentration (Tmax), area under the serum concentration versus time curve from time zero to the 
last quantifiable concentration (AUCt), AUC from time zero to infinity (AUC∞), terminal elimination rate 
constant (λz), terminal elimination half-life (T½), total clearance (CL or CL/F), and volume of distribution 
(Vd or Vd/F). 
Immunogenicity: 
• 
Serum samples will be collected at the following time points: pre-dose (within 15 minutes prior to SOI), 
and on Days 15 (336 h), 29 (672 h), 57 (1344 h), 90 (2136 h), 120 (2856 h), 150 (3576 h), and 200 (4776 
h) and analyzed for ADA to ALXN1210.  
The total anticipated volume of serum collected per subject for clinical laboratory, PK, PD, and immunogenicity 
assessments will not exceed 500 mL. 
Statistical methods: 
General:  
A total evaluable sample size of 36 subjects, 24 ALXN1210 SC subjects from Cohort 1 and 12 ALXN1210 IV 
subjects from Cohort 2, will provide >80% power to infer that the lower bound of a 90% confidence interval for 
the ratio of the bioavailability of ALXN1210 SC to IV is > 0.4 assuming an absolute bioavailability of 0.6 and a 
coefficient of variation of 0.35. Additionally, 6 subjects will receive placebo SC, 2 in Cohort 1a and 4 in 
Cohort  1b.  Randomization to Cohort 1a will be conducted in a 2:1 ratio, and Cohort 1b in a 5:1 ratio, to receive 
either ALXN1210 SC or placebo SC. This brings the total planned number of subjects to N=42. 
 
In general, descriptive statistics for continuous variables will include number of nonmissing values, arithmetic 
mean, standard deviation, median, minimum, and maximum. Descriptive statistics for PK parameters will include 
number of observations, arithmetic mean, standard deviation, arithmetic coefficient of variation (%CV), median, 
minimum, maximum, geometric mean and geometric %CV. Categorical variables will be summarized using 
percentages and frequency counts, by cohort and time point. 
 
Safety: 
All subjects who received at least 1 dose of study drug will be included in the safety analysis. Safety data will be 
assessed using descriptive statistics. No inferential statistical analyses are planned on the safety parameters of this 
 
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study. Safety analysis will include an analysis of all AEs, laboratory values, ECGs, and vital sign measurements. 
 
Shift tables will be produced for selected laboratory parameters. These tables will summarize the number of 
subjects with each baseline grade relative to the normal ranges and changes to the worst highest grade assessed 
post-dose during the study. 
 
Pharmacokinetics/Pharmacodynamics:  
Individual PK parameters (including descriptive statistics as follows: number of observations, arithmetic mean, 
standard deviation, arithmetic coefficient of variation [CV], median, minimum, maximum, geometric mean, and 
geometric CV) will be determined for the ALXN1210-treated subjects. 
 
The PD effects of ALXN1210 SC and IV will be evaluated by assessing changes in serum total and free C5 
concentrations, cRBC hemolysis, and other measures of C5 activation over time, using descriptive statistics. 
 
Immunogenicity: 
Immunogenicity, as measured by ADA, will be summarized in tabular form by cohort and by-subject listings. 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Background .................................................................................................................19 
5.1.1. 
Clinical Studies ...........................................................................................................19 
5.1.2. 
Nonclinical Studies .....................................................................................................20 
5.1.3. 
General Considerations for This Study.......................................................................21 
5.1.4. 
Potential Risks ............................................................................................................21 
5.1.4.1. 
Infections (Neisseria meningitidis and Other Encapsulated Organisms) ...................21 
5.1.4.2. 
Immunogenicity and Hypersensitivity ........................................................................22 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................23 
6.1. 
Primary Objectives .....................................................................................................23 
6.2. 
Secondary Objectives .................................................................................................23 
7. 
ENDPOINTS ..............................................................................................................24 
7.1. 
Safety Endpoints .........................................................................................................24 
7.2. 
Pharmacokinetic Endpoints ........................................................................................24 
7.3. 
Pharmacodynamic Endpoints .....................................................................................24 
8. 
INVESTIGATIONAL PLAN .....................................................................................25 
8.1. 
Overall Study Design ..................................................................................................25 
8.2. 
Number of Subjects ....................................................................................................26 
8.3. 
Dose Rationale ............................................................................................................27 
8.3.1. 
ALXN1210 IV Dose ...................................................................................................27 
8.3.2. 
ALXN1210 SC Dose ..................................................................................................27 
8.4. 
Dose Continuation and Suspension/Stopping Rules...................................................27 
8.5. 
Safety Review Committee ..........................................................................................29 
8.6. 
Criteria for Study Termination ...................................................................................29 
 
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9. 
SCHEDULE OF ASSESSMENTS.............................................................................30 
10. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................34 
10.1. 
Subject Inclusion Criteria ...........................................................................................34 
10.2. 
Subject Exclusion Criteria ..........................................................................................35 
10.3. 
Subject Withdrawal Criteria .......................................................................................38 
11. 
TREATMENT OF SUBJECTS ..................................................................................39 
11.1. 
Description of Study Drug ..........................................................................................39 
11.2. 
Infection ......................................................................................................................39 
11.2.1. 
Vaccine and Antibiotic Prophylaxis ...........................................................................39 
11.2.2. 
Risk of Infection Reminders .......................................................................................40 
11.3. 
Prior and Concomitant Medications and Procedures ..................................................40 
11.4. 
Permitted Medications ................................................................................................41 
11.5. 
Restrictions .................................................................................................................41 
11.6. 
Treatment Compliance ................................................................................................41 
11.7. 
Randomization and Blinding ......................................................................................42 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................44 
12.1. 
Study Drugs ................................................................................................................44 
12.1.1. 
ALXN1210 SC ...........................................................................................................44 
12.1.2. 
Placebo SC ..................................................................................................................44 
12.1.3. 
ALXN1210 IV ............................................................................................................44 
12.2. 
Study Drug Packaging and Labeling ..........................................................................44 
12.3. 
Study Drug Storage .....................................................................................................44 
12.4. 
Study Drug Preparation ..............................................................................................45 
12.4.1. 
Preparation of ALXN1210 SC and Placebo SC .........................................................45 
12.4.2. 
Preparation of ALXN1210 IV ....................................................................................45 
12.4.3. 
In-Use Shelf Life ........................................................................................................45 
12.5. 
Administration ............................................................................................................45 
12.5.1. 
Administration of ALXN1210 SC and Placebo SC ...................................................45 
12.5.2. 
Administration of ALXN1210 IV ..............................................................................46 
12.6. 
Management of Potential Adverse Events During Study Drug 
Administration ............................................................................................................46 
12.7. 
Study Drug Accountability .........................................................................................47 
12.8. 
Study Drug Handling and Disposal ............................................................................47 
 
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13. 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............48 
13.1. 
Serum Sample Collection ...........................................................................................48 
13.2. 
Criteria for Evaluation ................................................................................................48 
13.3. 
Sample Analysis .........................................................................................................48 
14. 
IMMUNOGENICITY ASSESSMENTS....................................................................49 
14.1. 
Serum Sample Collection ...........................................................................................49 
14.2. 
Criteria for Evaluation ................................................................................................49 
14.3. 
Sample Analysis .........................................................................................................49 
15. 
ASSESSMENT OF SAFETY .....................................................................................50 
15.1. 
Safety Parameters .......................................................................................................50 
15.1.1. 
Demographic/Medical History ...................................................................................50 
15.1.2. 
Vital Sign Measurements ............................................................................................50 
15.1.3. 
Weight, Height, and BMI ...........................................................................................50 
15.1.4. 
Physical Examination .................................................................................................50 
15.1.5. 
Electrocardiogram .......................................................................................................50 
15.1.6. 
Laboratory Assessments .............................................................................................51 
15.1.6.1. 
Hematology .................................................................................................................51 
15.1.6.2. 
Blood Chemistry .........................................................................................................51 
15.1.6.3. 
Coagulation .................................................................................................................51 
15.1.6.4. 
Urinalysis and Urine Chemistry .................................................................................51 
15.1.6.5. 
Virus Serology ............................................................................................................52 
15.1.6.6. 
Drug and Alcohol Screen ............................................................................................52 
15.1.6.7. 
Pregnancy Testing ......................................................................................................52 
15.1.6.8. 
Tuberculosis ................................................................................................................52 
15.1.6.9. 
Complement Activity ..................................................................................................52 
15.1.6.10. Serum Bactericidal Antibody .....................................................................................53 
15.1.6.11. Injection or Infusion Site Evaluation ..........................................................................53 
15.1.6.12. Immunogenicity Evaluation ........................................................................................53 
16. 
ADVERSE EVENT MANAGEMENT ......................................................................54 
16.1. 
Definition of an Adverse Event ..................................................................................54 
16.2. 
Definition of a Serious Adverse Event .......................................................................55 
16.3. 
Severity Assessment ...................................................................................................56 
16.4. 
Causality Assessment .................................................................................................56 
 
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16.5. 
Outcome ......................................................................................................................57 
16.6. 
Recording Adverse Events .........................................................................................57 
16.7. 
Reporting of Serious Adverse Event(s) to the Sponsor ..............................................58 
16.8. 
Exposure During Pregnancy and Lactation ................................................................58 
16.9. 
Reporting Requirements .............................................................................................59 
16.9.1. 
Sponsor .......................................................................................................................59 
16.9.2. 
Investigator .................................................................................................................59 
17. 
DATA COLLECTION ...............................................................................................60 
18. 
STATISTICS ..............................................................................................................61 
18.1. 
Statistical Analysis Plan Summary .............................................................................61 
18.2. 
Analysis Populations ..................................................................................................61 
18.3. 
Sample Size and Power ..............................................................................................61 
18.4. 
Descriptive Statistics ..................................................................................................61 
18.5. 
Demographics, Baseline Characteristics, and Subject Disposition ............................62 
18.6. 
Safety Analysis ...........................................................................................................62 
18.7. 
Pharmacokinetic Analysis ..........................................................................................63 
18.8. 
Pharmacodynamic and Immunogenicity Analyses .....................................................63 
18.9. 
Interim Analysis ..........................................................................................................63 
19. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................64 
19.1. 
Study Monitoring ........................................................................................................64 
19.2. 
Audits and Inspections ................................................................................................64 
19.3. 
Institutional Review Board/Independent Ethics Committee ......................................65 
19.4. 
Safety Review Committee ..........................................................................................65 
19.5. 
Regulatory Agency .....................................................................................................65 
20. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................66 
21. 
ETHICS ......................................................................................................................67 
21.1. 
Ethics Review .............................................................................................................67 
21.2. 
Ethical Conduct of the Study ......................................................................................67 
21.3. 
Written Informed Consent ..........................................................................................67 
21.4. 
Urgent Safety Measures ..............................................................................................67 
22. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
22.1. 
Inspection of Records .................................................................................................68 
22.2. 
Retention of Records ..................................................................................................68 
 
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23. 
PUBLICATION POLICY ..........................................................................................69 
24. 
LIST OF REFERENCES ............................................................................................70 
25. 
APPENDICES ............................................................................................................71 
APPENDIX 1. ACUTE INFUSION REACTIONS ALGORITHM ...........................................72 
APPENDIX 2. UNITED KINGDOM RESUSCITATION COUNCIL 
ANAPHYLAXIS ALGORITHM ...............................................................................73 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Terms ............................................................................................17 
Table 3: 
Toxicity Rules .............................................................................................................28 
Table 4: 
Schedule of Assessments: Screening through Visit 1 .................................................31 
Table 5: 
Schedule of Assessments: Visit 2 through Visit 14 ....................................................33 
Table 6: 
Investigational Product ...............................................................................................39 
Table 7: 
Dosing Reference Chart for ALXN1210 SC and Placebo SC Preparation ................46 
Table 8: 
Dosing Reference Chart for ALXN1210 IV Preparation ...........................................46 
 
LIST OF FIGURES 
Figure 1: 
Study Diagram ............................................................................................................26 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and terms are used in this study protocol. 
Table 2: 
Abbreviations and Terms 
Abbreviation or 
Term  
 
Explanation  
λz  
apparent terminal-phase elimination rate constant  
ADA 
antidrug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE  
adverse event  
ALT  
alanine aminotransferase  
AST  
aspartate aminotransferase 
aHUS  
atypical hemolytic uremic syndrome  
AUC∞ 
area under the serum concentration versus time curve from zero to infinity 
AUCt  
area under the serum concentration versus time curve from time zero to the last quantifiable 
concentration 
BMI  
body mass index  
BP  
British Pharmacopoeia 
C5b-9  
terminal complement complex  
CAP  
complement alternative pathway  
CBC 
complete blood count 
CDC 
complement-dependent cytotoxicity 
CH50 
50% hemolytic complement activity (screening test for deficiency of classical complement 
pathway in which hemolysis of liposomes sensitized by specific antibodies is measured; one 
CH50 unit is the volume or dilution of serum that lyses 50% of liposomes) 
CL  
total body clearance of drug from the serum  
Cmax  
maximum observed serum concentration  
cRBC  
chicken red blood cell 
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG  
electrocardiogram  
eCRF 
electronic case report form 
EOI  
end of infusion  
GCP  
Good Clinical Practice  
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV  
hepatitis B virus  
HCV  
hepatitis C virus  
HIV  
human immunodeficiency virus  
IB 
Investigator’s Brochure 
ICF  
informed consent form  
ICH  
International Council for Harmonisation  
IEC 
independent ethics committee 
IRB 
institutional review board 
IV  
intravenous(ly)  
mAb  
monoclonal antibody  
MAD 
multiple ascending dose 
MCV4  
tetravalent meningococcal conjugate vaccine  
OP 
outpatient 
PD  
pharmacodynamic(s)  
 
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Ph Eur 
European Pharmacopoeia 
PK  
pharmacokinetic(s)  
PNH  
paroxysmal nocturnal hemoglobinuria  
Q4W 
every 4 week 
QTcF  
QT interval corrected using the Fridericia’s formula  
RBC  
red blood cell(s)  
SAD  
single ascending dose  
SAE  
serious adverse event  
SBA 
serum bactericidal antibody 
SC 
subcutaneous(ly) 
SOI  
start of infusion/injection  
SOM 
study operations manual 
SRC  
Safety Review Committee  
t½ 
terminal elimination half-life  
TB 
tuberculosis 
Tmax  
time to maximum observed serum concentration  
ULN  
upper limit of normal  
Vd  
volume of distribution  
WBC  
white blood cell(s)  
 
 
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5. 
INTRODUCTION 
ALXN1210 is a humanized monoclonal antibody (mAb) that is structurally related to eculizumab 
(Soliris®) and is being developed by Alexion Pharmaceuticals, Inc. (Alexion). It specifically 
binds to the human complement protein C5, inhibiting its cleavage to C5a and C5b during 
complement activation. This inhibition prevents the release of the proinflammatory mediator C5a 
and inhibits the formation of the cytolytic pore-forming membrane attack complex (MAC) 
terminal complement complex (C5b-9) while preserving the proximal or early components of 
complement activation (eg, C3 and C3b) essential for the opsonization of microorganisms and 
clearance of immune complexes. The mechanism of action provides a rationale for the potential 
therapeutic use of ALXN1210 in diseases where complement activation is involved (eg, 
paroxysmal nocturnal hemoglobinuria [PNH], atypical hemolytic uremic syndrome [aHUS]). 
These disorders of uncontrolled complement activation (PNH and aHUS) are chronic and 
progressive with severe morbidities and significant premature mortality  (Hillmen, 1995; 
Kavanagh, 2006). 
5.1. 
Background 
Detailed information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of ALXN1210 may be found in the current edition of the Investigator’s 
Brochure (IB).  
5.1.1. 
Clinical Studies 
ALXN1210 has been administered safely to healthy subjects in 200 mg and 400 mg intravenous 
(IV) doses in a single ascending dose (SAD) study (Study ALXN1210-HV-101, N = 10). 
Healthy subjects have also been administered multiple 400 mg and 800 mg IV doses on an every 
4 week (Q4W) regimen in an ongoing multiple ascending dose (MAD) study 
(Study ALXN1210-HV-102, N = 12). The starting doses of ALXN1210 IV in these 2 healthy 
volunteer studies were selected to assess safety in healthy volunteers and to have measurable 
pharmacologic activity (eg, inhibition of complement activation) based on the therapeutic 
exposure required with eculizumab. No safety concerns have been identified in either of the 
Phase 1 studies, both of which were randomized, blinded, and placebo controlled. In the 
completed Study ALXN1210-HV-101 (SAD), no serious adverse drug reactions, treatment 
discontinuations, or deaths were reported. 
Conclusions from Study ALXN1210-HV-101 are as follows: 
• ALXN1210 exhibited prolonged pharmacokinetic (PK) exposure with mean 
geometric half-life estimates of 32.4 days and 30.8 days following single doses of 200 
and 400 mg, respectively. 
• The PK parameters (area under the serum concentration versus time curve from time 
zero to the last quantifiable concentration [AUCt], area under the curve from time 
zero to infinity [AUC∞], and maximum observed serum concentration [Cmax]) 
increased in a slightly less than dose-proportional manner over the studied range of 
200 to 400 mg based on the protocol-specified statistical analysis.  
 
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• Following single 200 mg and 400 mg doses of ALXN1210 IV, all 6 
pharmacodynamic (PD) variables (total complement C5 serum concentration, free 
complement C5 serum concentration, chicken red blood cell [cRBC] hemolysis, 
classical complement pathway [CCP] activity, complement alternative pathway 
[CAP] activity, and plasma C5b-9 activity) showed dose-dependent reductions from 
baseline. The effect of ALXN1210 on these PD variables was immediately evident 
after end of infusion (EOI). At the EOI, the mean free C5 serum concentrations and 
cRBC hemolysis activity were inhibited by > 99% and > 97%, respectively.  
• The duration of the effect was longer following a 400-mg dose than a 200-mg dose.  
• All subjects were negative for antidrug antibody (ADA) through Day 150. 
In addition, multiple doses of ALXN1210 IV have been administered to patients with PNH. 
5.1.2. 
Nonclinical Studies 
The binding characteristics, potency, and effector functions of ALXN1210 have been studied in 
vitro and compared with its parent molecule, eculizumab. ALXN1210 does not bind with strong 
affinity to any FcγR subclass or to C1q, and has shown only a modest increased binding capacity 
to FcγRIIa relative to eculizumab. Based on the structure of the antibody (IgG4 FcR portion) and 
the soluble target, ALXN1210 is unlikely to be capable of initiating antibody-dependent 
cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) in vivo. In 
Study ALXN1210-HV-101, no indication of CDC or ADCC was observed.  
ALXN1210 does not exhibit pharmacologic activity or cross-reactivity with any nonhuman 
animal species (including cynomolgus monkey), prohibiting the design of a predictive 
nonclinical safety testing strategy. Because ALXN1210 is specific for human C5, nonclinical 
safety tests (safety pharmacology, general toxicity, and reproductive toxicology) will not be 
predictive of human on-target toxicity. Moreover, significant immunoreactivity (ADA) to 
ALXN1210 was observed in a non-GLP PK study in cynomolgus monkeys. In the animals with a 
positive ADA response, clearance of ALXN1210 was accelerated. This observation suggests that 
interpretation of results from nonhuman primate toxicology studies performed with ALXN1210 
(evaluating only potential off-target effects), might be further confounded by an antibody 
response, and consequent effects on test article clearance. 
To study the potential toxicity of long-term inhibition of C5 and to evaluate the influence of such 
inhibition on reproductive function, a 26-week repeat-dose toxicity study in mice and Segment I, 
II, and III reproduction studies in mice were performed using a surrogate murine anti-mouse C5 
mAb (BB5.1). Like ALXN1210, the BB5.1 surrogate antibody binds directly to and prevents the 
cleavage of C5, thereby inhibiting the generation of both C5a and C5b-9 in the mouse. These 
studies showed no meaningful adverse observations at doses that blocked C5 in a sustained 
fashion. 
In addition to the studies with a surrogate antibody, GLP tissue cross-reactivity studies were 
performed using a standard set of human and cynomolgus monkey tissues. These studies 
confirmed the lack of cross-reactivity in a nonhuman primate and demonstrated no unexpected 
binding to human tissues.  
 
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An attempt was made to study the potential local irritation in rabbits of ALXN1210, when 
administered subcutaneously (SC) with a previous formulation; however, the results were not 
interpretable due to the development of a severe immune-complex based immunologic response. 
Such immune responses in animals are not considered predictive of similar potential outcomes in 
humans. To assess the potential for immunogenicity with ALXN1210, the amino acid 
substitutions to eculizumab used to make ALXN1210 were modeled in the context of the binding 
motifs for MHC class II receptors using the Immune Epitope Database Analysis Resource 
(IEDB, 2016; http://tools.iedb.org/main/). None of the peptide fragments in ALXN1210 that are 
novel relative to eculizumab were predicted to confer high affinity binding to MHC class II 
receptors. 
5.1.3. 
General Considerations for This Study 
This Phase 1 study will be performed in healthy subjects. Data from this study will be used to 
evaluate the safety, immunogenicity, PK, and PD investigations obtained in subjects receiving a 
single dose of ALXN1210 SC compared to results obtained in subjects receiving a single dose of 
ALXN1210 IV.  
5.1.4. 
Potential Risks 
5.1.4.1. 
Infections (Neisseria meningitidis and Other Encapsulated Organisms) 
A risk associated with complete terminal complement inhibition, such as that anticipated with 
ALXN1210, is infection with encapsulated organisms, particularly N meningitidis. Clinically, 
this risk is mitigated in patients receiving complement inhibitors such as eculizumab by 
vaccinating all patients against N meningitidis with a tetravalent meningococcal conjugate 
vaccine (MCV4) before dosing.  
In the current setting, ie, normal healthy subjects with an induced transient state of complement 
deficiency, subjects will receive the MCV4 vaccination at least 56 days prior to dosing with 
ALXN1210 (if not vaccinated with MCV4 within the last 3 years, or if adequate documentation 
to verify previous vaccination is unavailable). The serum bactericidal antibody (SBA) titer to the 
tetravalent vaccine will be established prior to enrollment. Subjects who are not already 
vaccinated will also receive vaccination for serotype B meningococcal infections at least 56 days 
prior to Day 1 dosing with a booster administered at least 28 days prior to dosing on Day 1. 
In addition to vaccination against N meningitidis with MCV4 and the serogroup B vaccine, all 
subjects will be treated with prophylactic antibiotics (oral penicillin V 500 mg twice daily) for 
the duration of reduced complement activity, ie, until complement activity is predicted to be 
restored to normal based on an exposure-response analysis of data from clinical study 
ALXN1210-HV-101. Unless the investigator and sponsor agree to an alternative regimen, all 
subjects will take prophylactic antibiotics (oral penicillin V 500 mg twice daily) until 
complement activity has normalized (anticipated at Day 56).  
Analysis of serum samples to establish actual complement activity will be performed using a 
CH50 in vitro liposome immunoassay (LIA). The analysis will take place approximately when 
complement activity is expected to normalize. Results will be used to confirm that complement 
activity has returned to normal and, once confirmed prophylactic antibiotic treatment can be 
stopped. All subjects will be closely monitored for signs of infection throughout the study.  
 
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5.1.4.2. 
Immunogenicity and Hypersensitivity 
Treatment with any therapeutic protein (human, humanized, chimeric) may induce an immune 
response. Occasionally, this immune response is clinically significant. The consequences of an 
immune reaction to a therapeutic protein range from transient appearance of antibodies without 
any clinical consequence, to severe, life-threatening conditions. Potential clinical consequences 
also may include the following: severe hypersensitivity-type reactions; decrease in efficacy; and 
induction of autoimmunity, including antibodies to the endogenous form of the protein 
(Casadevall, 2002; Li, 2001). 
Some patients treated with IV infusions of mAbs have experienced concurrent infusion-related 
reactions with signs or symptoms that can be classified as acute allergic/hypersensitivity 
reactions or cytokine release syndrome (Bugelski, 2009; Castells, 2015). The signs and 
symptoms include headache, fever, facial flushing, pruritus, myalgia, nausea, chest tightness, 
dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, chills, hypertension, 
lightheadedness, hypotension, palpitations, and somnolence. Anaphylaxis might occur at any 
time during an infusion. In addition, readministration of some mAbs has been associated with 
serum sickness-like reactions, manifesting 1 to 14 days after study drug administration. 
 
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6. 
STUDY OBJECTIVES AND PURPOSE 
The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), and immunogenicity of a single dose of ALXN1210 administered 
subcutaneously (SC) compared to a single dose of ALXN1210 administered intravenously (IV) 
in healthy subjects. Data from this study will be used to determine the absolute bioavailability of 
ALXN1210 SC in healthy subjects. 
6.1. 
Primary Objectives 
The primary objectives of this study are as follows: 
• To evaluate the safety and tolerability of a single dose of ALXN1210 SC compared to 
ALXN1210 IV in healthy subjects, as assessed by physical examination findings, 
vital sign measurements, immunogenicity, laboratory analysis, and assessments of 
AEs. 
• To determine the absolute bioavailability of ALXN1210 SC. 
6.2. 
Secondary Objectives 
The secondary objective of the study is as follows: 
• To evaluate the PD effects of ALXN1210 SC compared to ALXN1210 IV, as 
assessed by the level of free C5 and chicken red blood cell (cRBC) hemolysis. 
 
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7. 
ENDPOINTS 
The safety, immunogenicity, PK, and PD endpoints are described in the sections to follow. The 
timing of assessments is displayed in the Schedule of Assessments (Section 9). 
7.1. 
Safety Endpoints 
Safety endpoints include the following: 
• Change from baseline in physical examination findings 
• Change from baseline in vital sign measurements 
• Incidence of ADA measured via immunogenicity testing 
• Change from baseline in electrocardiogram (ECG) parameters 
• Change from baseline in laboratory measurements 
• Incidence of AEs and serious AEs (SAEs) 
7.2. 
Pharmacokinetic Endpoints 
The following PK parameters will be evaluated: 
• Maximum observed serum concentration (Cmax) 
• Time to maximum observed serum concentration (Tmax) 
• Area under the serum concentration versus time curve from time zero to the last 
quantifiable concentration (AUCt)  
• Area under the serum concentration versus time curve from time zero to infinity 
(AUC∞)  
• Terminal elimination rate constant (λz) 
• Terminal elimination half-life (T½) 
• Total body clearance of drug from the serum (CL) 
• Volume of distribution (Vd) 
7.3. 
Pharmacodynamic Endpoints 
The following PD effects will be evaluated: 
• Change in serum total and free C5 concentrations over time  
• Change in cRBC hemolysis over time 
 
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8. 
 
INVESTIGATIONAL PLAN 
8.1. 
Overall Study Design 
This is a Phase 1 study designed to evaluate the safety, tolerability, PK, PD, and immunogenicity 
of a single 400 mg dose of ALXN1210 SC compared to a single 400-mg dose of ALXN1210 IV 
or placebo SC in 42 healthy subjects. All subjects will be screened for eligibility in the study 
after providing signed and dated institutional ethics committee-approved written informed 
consent to participate and before any study specific screening procedures are performed.  
Subjects who fail to meet eligibility criteria may not be rescreened for participation in the study, 
unless the condition that led to eligibility failure is transient, self-limited, and easily treatable, 
and is expected to be resolved at the time of dosing, as agreed by the investigator and medical 
monitor.  
Six subjects will initially be randomly assigned in a 2:1 ratio to Cohort 1a, in a blinded fashion, 
to receive either a single 400-mg dose of ALXN1210 SC or single dose of placebo SC 
(Figure 1). The Safety Review Committee (SRC) will evaluate the first 48 hours of post-dose 
clinical safety data for subjects in Cohort 1a before enrollment into Cohorts 1b or 2 may begin. 
Thirty-six subjects will then be randomly assigned, in a 2:1 ratio, to either Cohort 1b (N=24) or 
Cohort 2 (N=12). Within Cohort 1b, the 24 subjects will further be randomly assigned, in a 
5:1 ratio and blinded fashion, to receive either a single 400-mg dose of ALXN1210 SC or a 
single dose of placebo SC, respectively. The 12 subjects in Cohort 2 will receive a single 400 mg 
dose of ALXN1210 IV in an open-label fashion. 
 
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Figure 1: 
Study Diagram 
 
At the sponsor’s discretion, up to 8 additional subjects (2 subjects each in Cohorts 1a and 1b and 
4 subjects in Cohort 2) may be enrolled into the study if 2 or more subjects discontinue within 
3 months for reasons other than drug-related AEs, and after consultation with the SRC. All 
enrolled subjects will be included in analyses as appropriate. Subjects in Cohorts 1a and 1b will 
be combined for analyses. Subjects who withdraw from the study subsequent to dosing will be 
followed for safety assessments through the last scheduled study visit, if possible.  
Subjects will participate in the study for up to 39 weeks, including a screening period of up to 
70 days, followed by a 200-day follow-up period for safety, PK, PD, and immunogenicity 
assessments after study drug administration.  
8.2. 
Number of Subjects 
Forty-two subjects are planned for evaluation of the primary and secondary objectives in this 
study: 6 (4 ALXN1210 SC, 2 placebo SC) subjects in Cohort 1a; 24 (20 ALXN1210 SC, 
4 placebo SC) subjects in Cohort 1b, and 12 (ALXN1210 IV) subjects in Cohort 2. At the 
sponsor’s discretion, up to 8 additional subjects (2 subjects each in Cohorts 1a and 1b and 
4 subjects in Cohort 2) may be enrolled into the study if 2 or more subjects discontinue within 
3 months for reasons other than drug-related AEs, and after consultation with the SRC. 
Screening
Up to 70 days
Dosing & Follow-up
200 days
Day 1
Dose
Cohort 1b
400 mg SC
N = 24 (20A/4P)
SRC
Day 1
Dose
Cohort 1a
400 mg SC
N = 6 (4A/2P)
Cohort 2
400 mg IV
N = 12
Day 1
Dose
Abbreviations: A = active drug; IV = intravenous; P = placebo; SC = subcutaneous; SRC = Safety Review Committee
Note:  The SRC will review the first 48 hours of post-dose safety data from Cohort 1a before enrollment into 
Cohorts 1b or 2 may begin.
 
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8.3. 
Dose Rationale 
8.3.1. 
ALXN1210 IV Dose 
The geometric mean (coefficient of variation [CV]) ALXN1210 half-life in Study 
ALXN1210-HV-101 ranged from 30.8 (10.2%) to 32.4 (16.2%) days over the studied doses. 
Following single 200-mg and 400-mg doses of ALXN1210 IV to healthy volunteers, all studied 
PD variables showed dose-dependent changes from baseline that recovered back to baseline. The 
effect of ALXN1210 on these PD variables was immediately evident after EOI. At the EOI, the 
mean free C5 serum concentrations and cRBC hemolysis activity were inhibited by > 99% and 
> 97%, respectively. In the ongoing Study ALXN1210-HV-102, 400-mg and 800-mg (Q4W) 
doses of ALXN1210 IV are being studied to assess safety, tolerability, PK, PD, and 
immunogenicity in healthy volunteers.  
8.3.2. 
ALXN1210 SC Dose 
A single dose of 400 mg, equivalent to 4 mL, will be administered SC via 4 x 1 mL injections in 
the abdominal area. Administration of a single 400-mg dose of ALXN1210 SC is expected to 
have an acceptable safety profile. Single doses of 400 mg of ALXN1210 SC and placebo SC, 
administered as described in this protocol, are anticipated to provide data from which multiple 
dose simulations may be generated in order to project the dosing regimens necessary to achieve 
therapeutic serum concentrations (> 50 μg/mL) in patients. 
8.4. 
Dose Continuation and Suspension/Stopping Rules 
Parallel randomization of 36 subjects into Cohort 1b and Cohort 2 will occur based on review by 
the SRC of the first 48 hours of post-dose clinical safety data from the 6 subjects in Cohort 1a. 
Enrollment into Cohort 1b and Cohort 2 will proceed as described in Table 3. These rules apply 
to AEs assessed as related to study drug by the investigator. 
Group toxicity rules: 
• Toxicity refers to clinically significant drug-related adverse reaction(s).  
• ‘Cohort progression’ refers to progression to a consecutive dose/dosing regimen in line 
with the dose progression rules and minimum data requirements. 
• ‘Suspension’ refers to no further IMP being administered at the dose level/dosing regimen 
concerned and that further cohort progression will be suspended. If a dosing regimen is 
suspended, an ad hoc SRC meeting will be held. Any resumption at the same dose 
level/dosing regimen will require a substantial amendment, which has been approved by 
the competent authority and the IEC. 
 
Page 27 of 73 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
Table 3: 
Toxicity Rules  
CTCAE Grade 
Severity/  
Seriousness 
Number of 
Subjects Affected 
Action 
Effect on cohort 
progression 
I 
Mild 
N/A 
Dose regimen may continue. 
Study continues as 
per clinical study 
protocol. 
II 
Moderate 
≤ 2 subjects in 
different SOC 
2 subjects in same 
SOC 
OR 
3 subjects in 
different SOC 
Dose regimen may continue. 
Cohorts 1b and 2 
may commence, if 
they have not 
already.  
≥ 3 subjects in same 
SOC 
OR 
≥ 4 subjects in 
different SOC 
All dose regimens suspended 
UNLESS the toxicity is 
either a local tolerability 
event or and 
injection/infusion site 
reaction, in which case only 
the affected cohort is 
suspended. 
 
Study continuation 
(if both cohorts 
stopped) requires 
substantial 
amendment. 
Continuation of the 
affected cohort (for 
local tolerability or 
injection/infusion 
site reactions) 
requires substantial 
amendment. 
III 
Severe 
1 subject 
Dose regimen may continue. 
 
Cohorts 1b and 2 
may commence, if 
they have not 
already. 
≥ 2 subjects 
All dose regimens suspended 
UNLESS the toxicity is 
either a local tolerability 
event or and 
injection/infusion site 
reaction, in which case only 
the affected cohort is 
suspended. 
Study continuation 
(if both cohorts 
stopped) requires 
substantial 
amendment. 
Continuation of the 
affected cohort (for 
local tolerability or 
injection/infusion 
site reactions) 
requires substantial 
amendment. 
IV 
Life-
threatening 
≥ 1 subject 
Study suspended. 
Study continuation 
requires substantial 
amendment. 
V 
Fatal  
SAE 
Serious 
≥ 1 subject 
Study suspended. 
Study continuation 
requires substantial 
amendment. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; SAE = serious adverse event; SOC = system organ 
class. 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
8.5. 
Safety Review Committee 
The SRC is composed of the medical monitor, clinical scientist, biostatistician, 
pharmacovigilance representative, clinical pharmacologist, and investigator. The membership, 
schedule of meetings, data required for each safety review, and requirements for documenting 
meeting discussions and outcome will be outlined in the SRC charter. 
In order to perform its primary function of ensuring subject safety, the members of the SRC will 
have access to all safety and clinical data.  
The SRC will review the first 48 hours of post-dose clinical safety data for the 6 subjects 
randomly assigned into Cohort 1a before enrollment into Cohorts 1b or 2 may begin. This will 
allow for further assessment of safety and tolerability of the SC formulation before exposing 
additional subjects to ALXN1210 SC. After the SRC has reviewed the safety and clinical data of 
the last completed subject in Cohort 1a, subjects will be randomly assigned into Cohort 1b in a 
blinded fashion, to receive either a single 400-mg dose of ALXN1210 SC or a single dose of 
placebo. In parallel, subjects will be randomly assigned into Cohort 2 to receive a single 400-mg 
dose of ALXN1210 IV in an open-label fashion. 
The SRC will convene to review safety data if unexpected safety concerns arise. The SRC will 
conduct a review of the clinical and safety data of individual subjects if prespecified criteria as 
described in Table 3 are met that warrant suspension of the study. 
The SRC may make recommendations regarding safety issues, study conduct, and modifying 
(ie, exploring the dose cohort further, suspending dose cohort[s]), or stopping the study. 
8.6. 
Criteria for Study Termination 
The investigator, competent authority, or sponsor may terminate the study for reasonable cause. 
Conditions that warrant termination of the study include, but are not limited to, the following: 
• Discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the 
study 
• Decision on the part of the sponsor to suspend or discontinue testing, evaluation, or 
development of the study drug 
• Failure of the investigator to comply with the approved protocol, pertinent guidelines, 
and/or regulations 
• Submission of knowingly false information from the investigator to the sponsor 
and/or regulatory authorities 
The end of the study will be defined as the date of the last subject’s last visit. 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
9. 
SCHEDULE OF ASSESSMENTS 
The timing of study procedures is provided in the Schedule of Assessments (Table 4 and 
Table 5). 
 
 
Page 30 of 73 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
 
 Table 4: 
Schedule of Assessments: Screening through Visit 1 
 
 
Visit 1 
Study Day 
Screening 
Day –1 
 
Day 1 
Day 2 
Day 3 
Day 5 
Assessments1 
Day –70  
to Day –2 
Admit 
Day –1 
Pre-
dose 
 
0 h 
(SOI) 
EOI2 
15 min 
post 
EOI 
30 min 
post 
EOI  
2 h 
post 
SOI  
4 h 
post 
SOI  
8 h 
post 
SOI  
24 h 
 
48 h 
 
96 h 
 
Status (OP or CRU) 
OP 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU3 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MCV4 immunization (Day -56)5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal serogroup B immunization 
(Day -56 and Day -28)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum bactericidal antibody 
(meningococcal serogroups A, C, W135, 
and Y) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON®-TB test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Coagulation 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, types I and II screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complement activity6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CH507 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test8 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis and urine chemistry 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital sign measurements 
X 
X 
X9 
 
X 
 
X9 
X9 
X9 
X9 
X 
X 
X 
ECG 
X 
 
X10 
 
 
X 
 
 
 
 
X 
X 
X 
Cardiac telemetry11 
 
 
X 
X 
(X) 
(X) 
(X) 
(X) 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PK samples 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum C5, cRBC hemolysis) 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Infusion site evaluation12 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Immunogenicity (ADA) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Review potential safety risks of 
ALXN121013 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Page 31 of 73 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
 
 
 
Visit 1 
Study Day 
Screening 
Day –1 
 
Day 1 
Day 2 
Day 3 
Day 5 
Assessments1 
Day –70  
to Day –2 
Admit 
Day –1 
Pre-
dose 
 
0 h 
(SOI) 
EOI2 
15 min 
post 
EOI 
30 min 
post 
EOI  
2 h 
post 
SOI  
4 h 
post 
SOI  
8 h 
post 
SOI  
24 h 
 
48 h 
 
96 h 
 
Status (OP or CRU) 
OP 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU3 
Concomitant medications 
 
←Monitor continuously (after ICF is signed at screening)→ 
Adverse events14 
 
←Monitor continuously (after ICF is signed at screening)→ 
Antibiotic prophylactic treatment15 
 
←Antibiotic prophylaxis→ 
1 Permissible windows for study assessments are described in the study operations manual. 
2 EOI will be approximately 15 minutes after SOI. 
3 Subject will be discharged from CRU after completing all Day 5 assessments. Subjects will be provided a “Study Participant ID card” with information for 
Healthcare Provider and participant on symptoms of meningitis infection. 
4 Signed and dated EC-approved ICF must be obtained before any study-specific screening procedures are performed. 
5 For subjects who do not have adequate documentation of prior MCV4 immunization or serogroup B vaccination, MCV4 immunization will be performed at 
least 56 days prior to first dose on Day 1, and vaccination for serogroup B meningococcal infections will be administered at least 56 days prior to Day 1 dosing 
with a booster administered at least 28 days prior to dosing on Day 1. 
6 Complement activity, confirmed by a suitable assay such as complement alternative pathway (CAP) ELISA/C5 (hemolysis) inhibition, will be performed at 
screening to confirm subjects do not have a complement deficiency. 
7 The sample drawn on Day -1 will be stored for future analysis should the post-dose sample indicate that complement has not normalized. 
8 Serum pregnancy test for all female subjects to confirm a female subject is not pregnant. 
9 On Day 1, vital sign measurements will be assessed pre-dose (within 15 minutes prior to SOI) and at EOI, 30 minutes after EOI, 2 hours after SOI, 4 hours after 
SOI, and 8 hours after SOI. 
10 On Day 1, triplicate 12-lead ECGs will be performed pre-dose and approximately 15 minutes post-EOI. 
11Continuous cardiac registration predose through duration of IV infusion (Cohort 2) and until 3 hours post SC injection (Cohorts 1a and 1b). 
12 Infusion or injection site evaluations will be done within 15 minutes of the start of infusion/injection and ± 15 minutes of the other scheduled times on Day 1. 
Indurations or reactions < 1cm will not be listed as an adverse event unless it persists for more than 24 hr. Pain at site of infusion or injection will be assessed 
using a Visual Analog Scale (0-10). Pain will not be assessed pre-dose. 
13 The investigator or designee will meet with the subject at each visit to discuss the potential safety risks of ALXN1210, and to address any safety concerns on 
the part of the subject. 
14 Collection of AEs and SAEs will begin at ICF signing. 
15 Subjects will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of 
Day -1, until complement activity has normalized, as determined by CH50 assay. 
Abbreviations: ADA = antidrug antibody; BMI = body mass index; cRBC = chicken red blood cell; CRU = clinical research unit; ECG = electrocardiogram; 
EOI = end-of-infusion/injection; HIV = human immunodeficiency virus; ICF = informed consent form; MCV4 = tetravalent meningococcal conjugate vaccine; 
OP = outpatient; SOI = start-of-infusion/injection; TB = tuberculosis 
 
Page 32 of 73 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016  
 
Table 5: 
Schedule of Assessments: Visit 2 through Visit 14 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 
10
Visit 
11
Visit 12 
Visit 13 
Visit 14 
Procedures 
Day 8 
Day 15 
Day 22 
Day 29 
Day 36 
Day 43 
Day 50  Day 57  Day 71  Day 90  
Day 120  
Day 150  
Day 200 
Status (OP or CRU) 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Physical Examination 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Vital Sign Measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Chemistry 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Urinalysis and Urine Chemistry 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Serum Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
CH50 Testing 
 
 
 
 
 
X 
 
X1 
 
 
 
 
 
Pharmacokinetic Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacodynamics Panel (serum 
C5, cRBC hemolysis)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity (ADA) 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Review Potential Safety Risks of 
ALXN12102 
--- Discuss potential safety risks of ALXN1210 -- 
Concomitant Medications 
--- Monitor continuously (after ICF is signed at screening)-- 
Adverse Events3 
--- Monitor continuously (after ICF is signed at screening)--  
Antibiotic Prophylactic4 
4
--- Antibiotic prophylaxis-- 
1 Additional samples may be taken after Day 57 as per Section 5.1.4.1. 
2 The investigator or designee will meet with the subject at each visit to discuss the potential safety risks of ALXN1210, and to address any safety concerns on 
the part of the subject. 
3 Collection of adverse events will begin at ICF signing. 
4  Subjects will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units) until complement activity has 
normalized, as determined by CH50 assay. 
Abbreviations: ADA = antidrug antibody; cRBC = chicken red blood cell; CRU = clinical research unit; ECG = electrocardiogram; ICF = informed consent 
form; OP = outpatient 
 
Page 33 of 73 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016 
10. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
10.1. 
Subject Inclusion Criteria 
Subjects must meet all of the following criteria in order to be eligible for the study: 
1. Healthy subjects, aged 25 through 55 years, inclusive, at the time of dosing. 
2. Body mass index (BMI) from 18 through 29.9 kg/m2, inclusive, and weight between 
50 and 100 kg, inclusive.  
3. QT interval corrected using the Fridericia’s formula (QTcF) ≤ 450 msec for males and 
≤ 470 msec for females at screening and prior to dosing on Day 1. 
4. Willing and able to give written informed consent and comply with the study visit 
schedule.  
5. Documented vaccination with MCV4 at least 56 days and not more than 3 years prior to 
dosing. Documentation must include a positive SBA titer to confirm an immune response 
before study drug administration.  
6. Vaccination with serogroup B meningococcal vaccine at least 56 days prior to dosing on 
Day 1, with a booster administered at least 28 days prior to dosing on Day 1, with at least 
28 days between the first and second injections.  
7. Female subjects of childbearing potential, if heterosexually active, must use highly 
effective or acceptable contraception as defined below, starting at screening and 
continuing until at least 6 months after study drug administration. Antibiotic prophylaxis 
is required during this study, which can compromise the efficacy of hormonal 
contraception. Therefore, it is recommended that subjects using hormonal contraception 
also use barrier contraception (eg, condom or diaphragm with spermicide) for the 
duration of antibiotic prophylaxis. 
Highly effective contraceptive methods for females are as follows: 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation as follows: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
as follows: 
− Oral 
− Injectable 
− Implantable  
• Intrauterine device  
 
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Amendment 2, 28 Jul 2016 
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
Male subjects, if heterosexually 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) during the treatment period and for at least 6 months 
after study drug administration. Barrier contraception is required even with documented 
medical assessment of surgical success of a vasectomy. Female spouses or partners of 
male subjects who are of childbearing potential must use highly effective contraception 
as defined above, or acceptable contraception as defined below, starting at screening and 
continuing until at least 6 months after study drug administration. Male subjects must not 
donate sperm during the screening and treatment periods and for at least 6 months after 
study drug administration. 
Acceptable contraceptive methods are as follows: 
• Simultaneous use of male condom and, for the female partner, occlusive cap 
(diaphragm or cervical/vault caps) with intravaginally applied spermicide. 
10.2. 
Subject Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not eligible to participate in the 
study: 
1. Subjects who are in intimate and prolonged contact with (defined as living under the 
same roof or providing personal care to) people younger than 2 years of age or older than 
65 years of age, or who are either immunocompromised or have one of the following 
underlying medical conditions: anatomic or functional asplenia (including sickle cell 
disease); congenital complement, properdin, factor D, or primary antibody deficiencies; 
acquired complement deficiencies (eg, those receiving eculizumab); or human 
immunodeficiency virus (HIV). 
2. Subjects who are one of the following: 
• Professionals who are exposed to environments of greater risk for meningococcal 
disease  
• Research, industrial, and clinical laboratory personnel who are routinely exposed to 
N meningitidis 
• Military personnel during recruit training (military personnel may be at increased risk 
of meningococcal infection when accommodated in close quarters)  
• Daycare center workers  
• Those living on a college or university campus  
• Those who plan to travel during the course of the study to or have travelled to 
endemic areas for meningococcal meningitis (eg, India, Sub-Saharan Africa, 
pilgrimage to Saudi Arabia for Hajj) within 6 months prior to dosing 
3. History of any Neisseria infection. 
 
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Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016 
4. History of unexplained, recurrent infection, or infection requiring treatment with systemic 
antibiotics within 90 days prior to dosing.  
5. HIV infection (evidenced by HIV-1 or HIV-2 antibody titer). 
6. Acute or chronic hepatitis B virus (HBV) infection. Hepatitis B surface antigen (HBsAg) 
testing is required for all subjects prior to enrollment. Subjects with positive HBsAg will 
not be enrolled. 
For subjects with negative HBsAg, the following testing algorithm will be required: 
• If hepatitis B core antibody (HBcAb) is negative, the subject is eligible to enroll.  
• If HBcAb is positive, the hepatitis B surface antibody (HBsAb) will be tested. 
− If both HBcAb and HBsAb are positive, the subject is eligible to enroll. 
− If HBcAb is positive and HBsAb is negative, the subject will not be enrolled. 
7. Acute or chronic hepatitis C virus (HCV) infection (evidenced by antibody titer). 
8. Active systemic viral or fungal infection within 14 days prior to dosing. 
9. Positive or indeterminate QuantiFERON®-TB test indicating possible tuberculosis (TB) 
infection. 
10. History of latent or active TB or exposure to endemic areas within 8 weeks prior to the 
screening visit. 
11. Female subjects who are breastfeeding or are heterosexually active and unwilling to 
practice contraception and are not postmenopausal. Postmenopausal is defined as 
amenorrhea ≥ 12 consecutive months without another cause and a documented serum 
follicle-stimulating hormone level ≥ 40 mIU/mL and estradiol concentration ≤ 110 
pmol/L within the 6 months prior to study drug administration.  
12. Positive serum pregnancy test at screening or on Day –1. 
13. Serum creatinine greater than the upper limit of normal (ULN) of the reference range of 
the testing laboratory at screening or on Day –1. 
14. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN of the 
reference range of the testing laboratory at screening or > 1.5 × ULN of the reference 
range of the testing laboratory on Day –1. 
15. Any of the following hematology results: hemoglobin < 130 g/L for males and < 115 g/L 
for females, hematocrit < 0.37 L/L for males and < 0.33 L/L for females, white blood cell 
(WBC) count < 3.0 × 103/μL, absolute neutrophil count < 2.0 × 103/μL, and platelet count 
< 150 or > 400 × 103/μL at screening or on Day –1. Complete blood count (CBC) clinical 
laboratory results that are considered clinically relevant and unacceptable by the 
investigator at Day –1. 
16. History of complement deficiency or complement activity below the normal reference 
range as evaluated by CAP ELISA at screening. 
17. History of malignancy with the exception of a nonmelanoma skin cancer or carcinoma in 
situ of the cervix that has been treated with no evidence of recurrence. 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016 
18. Participation in a clinical study within 30 days before initiation of dosing on Day 1 or use 
of any experimental small-molecule therapy within 30 days prior to dosing on Day 1.  
19. Participation in more than one clinical study of an mAb, or participation in a clinical 
study of an mAb within the 12 months prior to screening, during which the subject was 
exposed to the active study drug. Subjects who have participated in only one study of a 
mAb may be considered for enrollment if they completed that study more than 12 months 
prior to screening. 
20. Prior exposure to ALXN1210. 
21. Major surgery or hospitalization within 90 days prior to dosing. 
22. History of allergy to excipients of ALXN1210 (eg, polysorbate 80).  
23. Documented history of allergy to penicillin or cephalosporin. 
24. History of significant allergic reaction (eg, anaphylaxis or angioedema) to any product 
(food, pharmaceutical, etc).  
25. Currently smokes > 10 cigarettes daily (former smokers may be permitted to enroll at the 
investigator’s discretion). 
26. History of illicit drug abuse, history of significant alcohol abuse within 1 year prior to the 
screening visit, or regular use of alcohol within 6 months prior to the screening visit 
(more than 14 units of alcohol per week [1 unit = 150 mL of wine, 360 mL of beer, or 
45 mL of 40% alcohol]). 
27. Positive urine drug toxicology screen at screening or on Day –1. 
28. Alcohol consumption within 48 hours prior to study drug administration or positive 
alcohol breath test on Day –1. 
29. Donation of plasma within 7 days prior to dosing. Donation or loss (excluding volume 
drawn at screening) of more than 50 mL of blood within 30 days prior to dosing or more 
than 499 mL of blood within 56 days prior to dosing. 
30. History of continuous topical, inhaled, or systemic steroid use > 28 days or history of any 
inhaled or topical immunosuppressive therapy within 90 days prior to study drug 
administration.  
31. Use of prescription medications (excluding oral contraceptives) within 14 days prior to 
study drug administration, except with prior approval of the sponsor. 
32. Regular use of nonprescription, over-the-counter medications, including herbal remedies 
and supplements, within 14 days prior to study drug administration. Multivitamins, 
acetaminophen ≤ 2 g per day, and topical skin products without significant systemic 
absorption are allowed. 
33. Clinical diagnosis of any autoimmune or rheumatologic disease (eg, systemic lupus 
erythematosus, rheumatoid arthritis). 
34. Immunization with a live-attenuated vaccine 28 days prior to dosing or planned 
vaccination during the course of the study (except for the vaccination planned by the 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016 
study protocol). Immunization with inactivated or recombinant influenza vaccine is 
permitted. 
35. 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. 
36. Subjects with any medical history, conditions, or risks that, in the opinion of the 
investigator, may interfere with the subject's full participation in the study or compliance 
with the protocol, or may pose any additional risk for the subject or confound the 
assessment of the subject or outcome of the study. 
10.3. 
Subject Withdrawal Criteria 
A subject may withdraw from the study at any time at his or her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
administrative reasons. Subjects who discontinue dosing will be instructed to return for 
follow-up visits as described in the Schedule of Assessments (Section 9).  
Unless the investigator and sponsor agree to an alternative regimen, all subjects will take 
prophylactic antibiotics (oral penicillin V 500 mg twice daily) until complement activity has 
normalized (as determined by CH50 assay). 
 
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Protocol ALXN1210-SC-101 
 
Alexion Pharmaceuticals, Inc. 
Amendment 2, 28 Jul 2016 
11. 
TREATMENT OF SUBJECTS 
11.1. 
Description of Study Drug 
The investigational product is described in Table 6. 
Table 6: 
Investigational Product 
 
Investigational Product 
Product Name 
ALXN1210 IV 
ALXN1210 SC 
Placebo SC 
Dosage Form 
Sterile solution for 
infusion 
Sterile solution for 
injection 
Sterile solution for 
injection 
Unit Dose 
150 mg/vial1  
100 mg/vial
2 
NA 
Route of Administration 
Intravenous 
Subcutaneous injection 
Subcutaneous injection 
Physical Description 
Sterile, 
preservative-free 
solution 
Sterile, 
preservative-free 
solution 
0.9% sodium chloride for 
injection, Ph Eur or BP, 
sterile, preservative-free 
solution 
Manufacturer 
Alexion 
Pharmaceuticals, Inc. 
Alexion 
Pharmaceuticals, Inc. 
Saline solution marketed 
in UK 
1 Each vial of ALXN1210 IV drug product includes a nominal overfill to ensure that 15 mL (150 mg of 
ALXN1210) can be withdrawn for administration. 
2 Each vial of ALXN1210 SC drug product includes a nominal overfill to ensure that 1 mL (100 mg of ALXN1210) 
can be withdrawn for administration. 
Abbreviations: BP = British Pharmacopoeia; IV = intravenous; NA = not applicable; Ph Eur = European Pharmacopoeia; 
SC = subcutaneous  
11.2. 
Infection 
11.2.1. 
Vaccine and Antibiotic Prophylaxis 
To mitigate the risk of infection associated with terminal complement inhibition, subjects in this 
study will be administered the following:  
1. A MCV4 vaccination at least 56 days prior to dosing of ALXN1210 on Day 1 (if not 
vaccinated with MCV4 within the last 3 years, or if subjects have been previously 
vaccinated but there is not adequate documentation to verify prior vaccination).  
2. Two injections of the serogroup B meningococcal vaccine. The first injection must be 
administered at least 56 days prior to dosing on Day 1, with a booster administered at 
least 28 days prior to dosing on Day 1, with at least 28 days between the first and 
second injections. 
 
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Amendment 2, 28 Jul 2016 
3. Prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 
1 × 106 units) until complement activity has normalized (as determined by CH50 
assay) (see Section 5.1.4.1).  
The first dose of antibiotic will be administered orally on Day –1 in the evening, prior to the 
Day 1 (dose administration) of study drug. For the outpatient portion of the study, subjects will 
be instructed to take the antibiotic approximately at the same times (twice daily) on each 
scheduled day. A suitable system (such as text messaging) will be used for daily monitoring of 
subjects’ compliance with the antibiotic prophylaxis regimen.  
The following observations support the administration of antibiotic prophylaxis in this 
single-dose study: 
1. Penicillin is the drug of choice in eradication of N meningitidis in carriers. 
2. Complement-deficient patients who received monthly injections with benzathine 
penicillin G as prophylaxis for recurrent meningococcal disease during a 2- to 4-year 
period experienced significantly fewer episodes of Neisseria infection than deficient 
individuals not receiving prophylaxis (Figueroa, 1991). 
3. High levels of resistance to penicillin caused by plasmid-encoded β-lactamases are 
rarely encountered in meningococcal strains (Yazdankhah, 2004). 
4. Antibiotic prophylaxis with orally administered penicillin V 500 mg twice daily has 
been provided in the treatment of PNH and aHUS patients with eculizumab by some 
physicians (Kelly, 2011; Leeds Teaching Hospitals NHS Trust, 2013). 
5. Uncertainty around the effectiveness of vaccines in immunocompromised patients has 
prompted several countries, such as France, to recommend continuous antibiotic 
prophylaxis for the duration of eculizumab treatment in PNH and aHUS patients 
(Zuber, 2012). 
11.2.2. 
Risk of Infection Reminders 
Risk of infection will be explained and discussed with subjects during the informed consent 
process, occurring at the screening visit. In order to increase the risk awareness and promote 
quick disclosure of any potential signs or symptoms of infection experienced by the subjects 
during the course of the study, additional discussion and explanation of the potential risks, signs, 
and symptoms, as described in the informed consent form (ICF), will take place at specific time 
points throughout the study as noted in the Schedule of Assessments (Section 9). Subjects will 
also be provided a safety card to carry with them at all times. 
11.3. 
Prior and Concomitant Medications and Procedures 
Prior medications (any drug or substance taken by the subject within 14 days prior to the time the 
subject signs the ICF until study drug administration) and concomitant medications (any drug or 
substance taken by the subject after study drug administration until completion of the last study 
visit) will be recorded on the subject’s electronic case report form (eCRF). Prior procedures (any 
therapeutic intervention [eg, surgery/biopsy, physical therapy] performed within 14 days prior to 
the time the subject signs the informed consent until study drug administration) and concomitant 
procedures (any therapeutic intervention [eg, surgery/biopsy, physical therapy] performed after 
 
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study drug administration until completion of the last study visit) will be recorded on the 
subject’s eCRF. 
A concomitant therapy is any drug or substance administered from the time the subject is 
screened for the study until completion of the last study visit. For the duration of the study, 
subjects will be instructed not to start taking any new medications, including nonprescription 
drugs and herbal preparations, unless they have received permission from the investigator. The 
occasional use of over-the-counter antipyretics or analgesics (eg, acetaminophen) may be 
allowed during the study, at the discretion of the investigator. 
A concomitant procedure is any therapeutic intervention (eg, surgery/biopsy, physical therapy) 
or nonstudy diagnostic assessment (eg, blood gas measurement, bacterial cultures) performed 
from the time the subject signs the informed consent until the last study visit. Concomitant 
procedures are not allowed unless medically indicated. 
The use of concomitant therapies defined above as well as any AEs related to administration of 
these therapies or procedures must be documented on the subject’s eCRF. 
11.4. 
Permitted Medications 
Subjects are permitted to take multivitamins, acetaminophen ≤ 2 g per day, and topical skin 
products without significant systemic absorption. Subjects are also permitted to receive a booster 
vaccine, if required.  
11.5. 
Restrictions 
Caffeine: Xanthine-containing products (eg, coffee, tea, chocolate) are prohibited for at least 
24 hours prior to admission through discharge from the study center, and for 24 hours prior to 
each follow-up visit. 
Alcohol: Alcohol use is prohibited 48 hours prior to admission until discharge from the study 
center, and for 24 hours prior to each follow-up visit. 
Meals: No outside food or drink is permitted at the study center. All meals and snacks will be 
provided. Subjects will receive standard meals and snacks at regimented times during 
confinement. 
Poppy Seeds: Subjects are required to abstain from food containing poppy seeds within 24 hours 
prior to admission. 
Tobacco: Subjects will be required to abstain from smoking from at least 2 hours prior to start of 
study drug administration until discharge from the study center. 
11.6. 
Treatment Compliance 
Subjects will be administered study drug in a controlled setting under the supervision of the 
investigator, thereby ensuring compliance with study drug administration. Study coordinators at 
the study center will ensure that all subjects are adequately informed on the specific study drug 
dosing regimen required for compliance with the study protocol. 
Alexion or its designee will periodically monitor the study center to ensure compliance with the 
protocol, and communicate with study centers on a regular basis regarding study protocol 
 
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deviations. All protocol deviations will be appropriately documented by the investigator or 
designee, and study monitors. 
Unless otherwise specified, procedures, data collection, and evaluation will be conducted as per 
the study center’s standard operating procedures. 
11.7. 
Randomization and Blinding 
Eligible subjects who meet the inclusion and exclusion criteria will be assigned unique numbers 
for enrollment and randomization. 
This is a partially blinded study such that: 
• Cohort 1a. Dosing (a single 400-mg dose of ALXN1210 SC or placebo SC) is double-
blind. Subjects in Cohort 1a will be randomly assigned in a 2:1 ratio (4 ALXN1210 SC, 
2 placebo SC; N = 6). 
• Cohort 1b. Dosing (a single 400-mg dose of ALXN1210 SC or placebo SC) is double-
blind. Subjects in Cohort 1b will be randomly assigned in an 5:1 ratio (20 ALXN1210 
SC, 4 placebo SC; N = 24). 
• Cohort 2. Dosing (a single 400-mg dose of ALXN1210 IV) is open-label (N = 12). 
During Cohort 2 dosing, both subjects and onsite medical/nursing staff will know the drug/dose 
being administered.  
During Cohorts 1a and 1b dosing, subjects and onsite medical/nursing staff at the study center 
will be blinded to study drug assignment. The pharmacy staff preparing the SC injections will 
not be blinded, nor will the study drug administrator(s), while all other study center staff 
involved in the safety evaluations will remain blinded to study drug assignment. Sponsor staff 
will be unblinded as needed (eg, to monitor that the SC injections are being prepared 
appropriately, to determine reportability of SAEs), and will refrain from sharing any information 
on study drug assignment with the study center staff. 
In the event of an emergency, an envelope for each subject containing his or her study drug 
assignment will be available from the pharmacy staff preparing the investigational products. 
There is no antidote to reverse the effects of ALXN1210; therefore, unblinding would not be 
helpful in the planning of subject treatment for a given event. 
Unblinding should only be considered for the safety of the subject. If unblinding is deemed 
necessary by the investigator, the investigator can unblind the subject’s treatment allocation 
using the envelope available from the pharmacy staff. The investigator must note the date, time, 
and reason for unblinding. The investigator should inform the medical monitor that the subject 
was unblinded; however, the investigator is not required to reveal to the medical monitor the 
subject's treatment allocation. When an AE is serious, unexpected, and related, the blind will be 
broken by the sponsor only for that specific subject. The blind will be maintained for persons 
responsible for the ongoing conduct of the study (such as the management, monitors, 
investigator, etc) and those responsible for data analysis and interpretation of results at the 
conclusion of the study, such as biometrics personnel. Unblinded information will only be 
accessible to those who need to be involved in the safety reporting to health authorities, IEC, or 
 
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persons performing ongoing safety evaluations during the study. The investigator will receive 
only blinded information unless unblinded information is judged necessary for safety reasons. 
 
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12. 
STUDY DRUG MATERIALS AND MANAGEMENT 
12.1. 
Study Drugs 
12.1.1. 
ALXN1210 SC 
Each vial of ALXN1210 SC contains 100 mg of ALXN1210 (100 mg/mL) in 50 mM sodium 
phosphate, 25 mM arginine, 5% sucrose, and 0.05% polysorbate 80. ALXN1210 SC is 
formulated at pH 7.4 and is provided as a fully-formulated, sterile, preservative-free, 100-mg/mL 
aqueous solution of ALXN1210 supplied in 2-mL single-use vials. Each vial of ALXN1210 SC 
includes a nominal overfill to ensure that 1 mL (100 mg of ALXN1210) can be withdrawn for 
administration. 
ALXN1210 SC will be provided by the sponsor and is suitable for human use and manufactured 
under current Good Manufacturing Practices. 
Further details are provided in the ALXN1210 IB and in the pharmacy manual. 
12.1.2. 
Placebo SC 
Each dose of placebo SC contains 0.9% sodium chloride injection, Ph Eur or BP, to the same 
volume as specified for Cohorts 1a and 1b.  
Placebo SC will be provided by the study center and is suitable for human use and manufactured 
under current Good Manufacturing Practices. 
Further details are provided in the pharmacy manual. 
12.1.3. 
ALXN1210 IV 
Each vial of ALXN1210 IV contains 150 mg of ALXN1210 in 10 mM sodium phosphate, 
150 mM sodium chloride, 0.02% polysorbate 80, and water for injection. ALXN1210 IV is 
formulated at pH 7.0 and is provided as a fully-formulated, sterile, preservative-free, 10-mg/mL 
aqueous solution of ALXN1210, supplied in 20-mL single-use vials. ALXN1210 IV will be 
diluted in 0.9% sodium chloride injection, Ph Eur or BP, and administered by IV infusion at a 
maximum rate of 333 mL/hr, excluding interruption for safety or technical reasons.  
ALXN1210 IV will be provided by the sponsor and is suitable for human use and manufactured 
under current Good Manufacturing Practices. 
Further details are provided in the ALXN1210 IB and in the pharmacy manual. 
12.2. 
Study Drug Packaging and Labeling 
ALXN1210 will be supplied in a one-vial-per-kit configuration. Each vial and carton will be 
labeled according to local regulatory requirements. 
12.3. 
Study Drug Storage 
ALXN1210 vials must be stored in refrigerated conditions at 2°C to 8°C (36°F to 46°F) and 
protected from light. ALXN1210 vials should not be frozen or shaken. 
 
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12.4. 
Study Drug Preparation 
Preparation of ALXN1210 and placebo SC doses must be performed in accordance with study 
center-specific local standards by qualified and study-trained pharmacy personnel. 
The handling and preparation of materials used to prepare and administer the investigational 
product must be carried out using aseptic techniques for sterile products. For each subject, doses 
will be prepared as required for the dose cohort. 
12.4.1. 
Preparation of ALXN1210 SC and Placebo SC 
ALXN1210 SC and placebo SC will be prepared in a blinded fashion in a syringe for SC 
administration. There will be no dilution of ALXN1210 SC or placebo SC. ALXN1210 SC and 
placebo SC will be placed directly into the syringe. 
The pharmacy staff preparing the SC injections for Cohort 1a and Cohort 1b will be unblinded, 
as will the study drug administrator(s). All other staff involved will be blinded (Section 11.7).  
Please refer to the pharmacy manual for additional dose preparation instructions and the SOM 
for additional information regarding blinding and study drug administration. 
12.4.2. 
Preparation of ALXN1210 IV 
ALXN1210 IV is designed for infusion by diluting into commercially available saline (0.9% 
sodium chloride injection; Ph Eur or BP) for IV infusion at a maximum rate of 333 mL/hr, 
excluding interruption for safety or technical reasons.   
The pharmacy staff preparing the infusions for Cohort 2 will be unblinded to study drug 
assignment; the subjects and all other study center staff involved in the study will also be 
unblinded (Section 11.7).  
Please refer to the pharmacy manual for additional dose preparation instructions. 
12.4.3. 
In-Use Shelf Life 
ALXN1210 IV will be diluted with 0.9% sodium chloride injection, Ph Eur or BP, before 
administration (dosing solution). The in-use shelf life of the dosing solution is 4 hours at room 
temperature 15°C to 25°C (59°F to 77°F).The expiration date and time of the dosing solution is 
calculated from breach of the first vial. The dose must be administered within the expiration date 
and time. 
Each 1-mL syringe of ALXN1210 SC or placebo SC that is drawn up (4 syringes per subject) 
should be administered within 1 hour once drawn up from vial to syringe.  
12.5. 
Administration 
12.5.1. 
Administration of ALXN1210 SC and Placebo SC 
All doses of ALXN1210 SC or placebo SC will be administered by four 100-mg SC injections of 
1 mL each (Table 7) in the abdominal area.  All four 1-mL injections should be administered 
over a 15-minute period, and there should be at least 15 minutes between the end of injection in 
one subject and the start of injection in the next subject.  
 
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Table 7: 
Dosing Reference Chart for ALXN1210 SC and Placebo SC Preparation 
Cohort 
Study drug and dose 
Number of 1-mL 
syringes prepared 
Total volume 
administered 
1a 
1 dose of 400 mg ALXN1210 SC 
or placebo SC 
4 
4 mL 
1b 
1 dose of 400 mg ALXN1210 SC 
or placebo SC 
4 
4 mL 
For further information regarding the preparation and administration of study drug, please see the 
pharmacy manual. Please refer to the SOM for additional information regarding blinding and 
study drug administration. 
12.5.2. 
Administration of ALXN1210 IV 
All doses of ALXN1210 IV will be administered by IV infusion, using IV sets with in-line 
filters, at a maximum rate of 333 mL/hr, excluding interruption for safety or technical reason. 
There should be at least 15 minutes between the end of infusion in one subject and the start of 
infusion in the next subject. For further information regarding the preparation and administration 
of study drug, please see the pharmacy manual. 
Table 8: 
Dosing Reference Chart for ALXN1210 IV Preparation 
Cohort 
Study drug and 
dose 
ALXN1210 
volume per 
dose (mL) 
Diluent 
volume per 
dose (mL) 
Infusion 
volume 
(mL) 
Maximum 
infusion 
rate 
(mL/h) 
Minimum 
infusion 
duration1 
minutes 
(hour) 
2 
1 dose of 400 mg 
ALXN1210 IV 
40 
40 
80 
333 
15 (0.25) 
1 Infusion duration is approximate. 
Please refer to the pharmacy manual for additional dose preparation instructions. 
12.6. 
Management of Potential Adverse Events During Study Drug 
Administration 
Some subjects treated with IV infusions of mAbs have experienced concurrent infusion-related 
reactions with signs or symptoms that can be classified as acute allergic reactions/ 
hypersensitivity reactions or cytokine release syndrome.  
Subjects will be closely monitored during and after study drug 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. Infusion-associated AEs may occur, and depending on 
their type and severity, discontinuation of infusion may be required. Subjects 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 infusion-related reactions (see Appendix 1: Acute Infusion Reactions Algorithm). In this 
study, regular assessments to monitor infusion reactions and infusion site reactions will be done. 
To ensure that reactions can be dealt with promptly, there will be at least 15 minutes between the 
end of infusion/injection in one subject and the start of infusion/injection in the next subject. No 
 
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more than 6 subjects will be dosed per day. Any reactions will be treated and taken into account 
in the dose continuation/escalation and toxicity rules (see Table 3). If anaphylactic reactions 
occur, the current “UK Treatment Guideline for Anaphylactic Reactions” of the UK 
Resuscitation Council will be followed (see Appendix 2: United Kingdom Resuscitation Council 
Anaphylaxis Algorithm). 
Subjects who experience a severe reaction during administration of study drug that results in 
discontinuation of study drug should undergo all scheduled safety, immunogenicity, PK, and PD 
evaluations required by the protocol. Subjects will therefore be instructed to attend all scheduled 
visits and undergo all procedures per protocol. 
Similar reactions could potentially occur with SC injections of mAbs. 
12.7. 
Study Drug Accountability 
The study center must maintain accurate records demonstrating dates and amount of study drug 
received from Alexion, to whom study drug was dispensed (a subject-by-subject accounting), 
and accounts of any study drug accidentally or deliberately destroyed. 
Unless otherwise notified, all vials, both used and unused, must be saved for study drug 
accountability. At the end of the study, a final reconciliation must be made between the amount 
of study drug supplied, dispensed, and subsequently destroyed or returned to Alexion. 
A written explanation will be provided for any discrepancies. After reconciliation, the 
investigator must destroy or return to Alexion all unused vials of study drug as instructed by 
Alexion. 
12.8. 
Study Drug Handling and Disposal 
If any study drug supplies are to be destroyed at the study center, the investigator must obtain 
prior approval by Alexion. The investigator must notify Alexion, in writing, of the method, date, 
and location of the destruction. 
At the completion of the study, in order to satisfy regulatory requirements regarding drug 
accountability, all remaining investigational product inventory will be reconciled and retained or 
destroyed according to applicable United Kingdom regulations and the policies and procedures 
applicable to the study center. 
For handling instructions, please refer to the pharmacy manual. 
 
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13. 
PHARMACOKINETIC AND PHARMACODYNAMIC 
ASSESSMENTS 
13.1. 
Serum Sample Collection 
The total anticipated volume of serum collected per subject for clinical laboratory, PK, PD, and 
immunogenicity assessments will not exceed 500 mL per subject. Please refer to the laboratory 
manual for specific details regarding serum volumes.  
After study drug administration, serum samples for the determination of serum ALXN1210 
concentrations and for analyses of total and free C5 concentrations, cRBC hemolysis, and 
potentially other measures of C5 activation will be collected at the following time points, with 
the actual serum sampling dates and times being recorded and used in the PK and PD 
calculations:  
• Serum concentrations of ALXN1210 will be assayed from the following sampling 
time points: pre-dose (within 15 minutes prior to start-of-infusion/injection [SOI]); 
Day 1 at end of infusion/injection (EOI), 30 minutes post EOI, and the following time 
points following SOI: 2 h, 4 h, and 8 h; Day 2 (24 h); Day 3 (48 h); Day 5 (96 h); Day 
8 (168 h); Day 15 (336 h); Day 22 (504 h); Day 29 (672 h); Day 36 (840 h); Day 43 
(1008 h); Day 50 (1176 h); Day 57 (1344 h); Day 71 (1680 h); Day 90 (2136 h); Day 
120 (2856 h); Day 150 (3576 h); and Day 200 (4776 h). 
Please refer to the SOM for the time windows for collection, and to the laboratory manual for 
details on sample collection, including the serum volume requirements. 
13.2. 
Criteria for Evaluation 
All subjects providing an adequate number of serum PK samples to characterize a 
concentration-time profile will be included in the PK analysis population. All subjects providing 
PD samples will be included in the PD analysis population. 
13.3. 
Sample Analysis 
Detailed instructions on the procedure for collection, processing, storage, and shipment of the 
serum samples for PK and PD analyses will be provided in the laboratory manual. All sample 
analyses will be performed by Alexion or designee. 
 
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14. 
IMMUNOGENICITY ASSESSMENTS 
14.1. 
Serum Sample Collection 
Serum samples will be collected at the following time points: pre-dose (within 15 minutes prior 
to SOI), and on Days 15 (336 h), 29 (672 h), 57 (1344 h), 90 (2136 h), 120 (2856 h), 150 
(3576 h), and 200 (4776 h) and analyzed for ADA to ALXN1210.   
Further characterization of antibody response may be conducted as appropriate based on PK/PD 
and safety data of ALXN1210. 
Please refer to the SOM for the time windows for collection, and to the laboratory manual for 
details on sample collection, including the serum volume requirements. 
14.2. 
Criteria for Evaluation 
All subjects who provide a pre-dose and a post-dose sample for ADA will be included in the 
immunogenicity analysis population. 
14.3. 
Sample Analysis 
The immunogenicity assay will evaluate ADA to ALXN1210. Detailed instructions on the 
procedure for collecting, processing, storing, and shipping serum samples for immunogenicity 
analysis will be provided in the laboratory manual. All sample analyses will be performed by 
Alexion or designee. 
 
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15. 
ASSESSMENT OF SAFETY 
Safety assessments will include TB testing, physical examination findings, vital sign 
measurements, immunogenicity (ADA) testing, laboratory evaluations, ECGs, infusion site and 
injection site evaluations (eg, bleeding, bruising, erythema, swelling, induration, and pain), and 
monitoring of AEs. Adverse events will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events v4.03 (CTCAE v4.03), published 
14 Jun 2010. Laboratory evaluations will include hematology, chemistry, and coagulation panels; 
CBC with differential; urinalysis; and serum pregnancy test for female subjects.  
15.1. 
Safety Parameters 
Clinical and laboratory assessments will be performed to assess safety of ALXN1210. The 
timing of the assessments is described in the Schedule of Assessments (Section 9). Abnormal 
results should be followed until resolution or stabilization. 
15.1.1. 
Demographic/Medical History 
A review of demographic parameters, including age, gender, race, and ethnicity will be 
performed as described in the Schedule of Assessments (Section 9). A complete medical history 
will be taken and documented in the eCRF. 
15.1.2. 
Vital Sign Measurements 
Vital sign measurements will be taken after the subject has been resting in the supine or 
semirecumbent position for at least 5 minutes and will include temperature (°C; oral), respiratory 
rate, supine blood pressure, and pulse. The timing of vital sign measurements is described in the 
Schedule of Assessments (Section 9). Out-of-range blood pressure or pulse measurements will 
be repeated at the investigator’s discretion. Any confirmed, clinically significant vital sign 
measurements will be recorded as AEs. 
15.1.3. 
Weight, Height, and BMI 
Weight, height, and BMI will be recorded as described in the Schedule of Assessments 
(Section 9). 
15.1.4. 
Physical Examination 
Each examination will include the following assessments: general appearance; skin; head, ears, 
eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous 
system; and musculoskeletal system. 
15.1.5. 
Electrocardiogram  
A triplicate 12-lead ECG will be obtained after the subject has been resting for at least 5 minutes. 
The timing of ECGs is described in the Schedule of Assessments (Section 9). In addition, 
continuous cardiac registration will be performed at each dose administration from pre-dose to 
end of IV infusion in Cohort 2 and from pre-dose to 3 hours post end of SC injection in Cohorts 
1a and 1b. 
 
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Heart rate, PR, QRS, RR, and QT will be measured and corrected QTcF intervals will be 
calculated. 
15.1.6. 
Laboratory Assessments 
Blood samples for analysis of hematology, clinical chemistry, coagulation, and virus serology, 
and urine samples for urinalysis, urine chemistry, and drug and alcohol screens will be collected 
as described in the Schedule of Assessments (Section 9). Clinical laboratory evaluations will be 
performed by a local laboratory. Abnormal results should be followed up as appropriate. 
Handling and shipping clinical laboratory samples will be outlined in the laboratory manual. 
15.1.6.1. Hematology 
Blood samples will be analyzed for the following hematology parameters: platelet, red blood cell 
(RBC) count, and WBC counts; automated differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils); hemoglobin; hematocrit; and RBC indices (mean corpuscular volume, 
mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration). 
The timing of hematology assessments is described in the Schedule of Assessments (Section 9). 
15.1.6.2. Blood Chemistry 
Blood samples will be analyzed for the following clinical chemistry parameters: blood urea 
nitrogen; creatinine; glucose; sodium; phosphorus; potassium; chloride; total carbon dioxide; 
total calcium; magnesium; AST; ALT; gamma-glutamyltransferase; alkaline phosphatase; lactate 
dehydrogenase; total, direct, and indirect bilirubin; uric acid; albumin; and total protein. 
Considering that indirect bilirubin is calculated from total and direct bilirubin values, indirect 
bilirubin results will not be available if direct bilirubin is below the limit of quantification. 
Serum follicle-stimulating hormone level and estradiol concentrations will be measured at 
screening for postmenopausal female subjects to confirm their postmenopausal status. 
The timing of chemistry assessments is described in the Schedule of Assessments (Section 9). 
15.1.6.3. Coagulation 
Blood samples will be analyzed for prothrombin time, international normalized ratio, and partial 
thromboplastin time. 
The timing of coagulation assessments is described in the Schedule of Assessments (Section 9). 
15.1.6.4. Urinalysis and Urine Chemistry 
Urinalysis will include specific gravity, pH, glucose, protein, blood, and ketones. A microscopic 
examination of urine samples will be performed only on abnormal findings. 
Urine samples will also be sent to the pathology laboratory to measure protein and creatinine in 
order to calculate the urine protein:creatinine ratio. 
The timing of urinalysis and urine chemistry assessments is described in the Schedule of 
Assessments (Section 9). 
 
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15.1.6.5. Virus Serology 
Blood samples collected at screening will be analyzed for HIV-1, HIV-2, HBsAg, and HCV 
antibody titers. 
Hepatitis B surface antigen testing is required for all subjects prior to enrollment. Subjects with 
positive HBsAg will not be enrolled. 
For subjects with negative HBsAg, the following testing algorithm will be required: 
1. If HBcAb is negative, the subject is eligible to enroll.  
2. If HBcAb is positive, the hepatitis B surface antibody (HBsAb) will be tested. 
a. If both HBcAb and HBsAb are positive, the subject is eligible to enroll. 
b. If HBcAb is positive and HBsAb is negative, the subject will not be enrolled. 
15.1.6.6. Drug and Alcohol Screen 
A urine sample for drug screen will be analyzed for the following compounds: amphetamines, 
barbiturates, benzodiazepines, cocaine, methadone, opiates, phencyclidine, methamphetamine, 
3,4-methylenedioxy-methamphetamine, and tetrahydrocannabinol (cannabinoids). An alcohol 
breath test will be performed. If positive prior to dosing, dosing will not proceed. 
Timing of urine drug and alcohol breath tests are described in the Schedule of Assessments 
(Section 9). 
15.1.6.7. Pregnancy Testing 
Pregnancy testing (beta human chorionic gonadotropin) will be performed in all female subjects 
(Section 16.8). The timing of pregnancy testing is described in Schedule of Assessments 
(Section 9). 
15.1.6.8. Tuberculosis 
Serum samples for a QuantiFERON-TB test will be collected as described in the Schedule of 
Assessments (Section 9). 
15.1.6.9. Complement Activity 
A suitable assay for determining complement activity, such as CAP ELISA/C5 (hemolysis) 
inhibition, will be performed at screening to confirm subjects do not have a complement 
deficiency. Subjects found to be complement deficient will be excluded from participating in the 
study. 
Serum samples will be collected at baseline and during follow-up for measurement of CH50 
activity using an in vitro LIA to confirm normalization of complement activity. If a normal 
CH50 result is obtained from a subject’s first CH50 sample collected during follow-up, antibiotic 
prophylaxis can be stopped and the second scheduled CH50 sample is not required. If the first 
and second CH50 samples are not normal, the baseline sample may be analyzed, and further 
CH50 samples will be taken until complement activity has been restored (see Schedule of 
Assessments in Section 9). 
 
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15.1.6.10. Serum Bactericidal Antibody  
An SBA titer against meningococcal serogroups A, C, W135, and Y will be performed at 
screening (see Schedule of Assessments in Section 9). Titer measurements will be used to 
exclude subjects without an immune response from being dosed. 
15.1.6.11. Injection or Infusion Site Evaluation 
Subcutaneous injection or IV infusion site evaluations will be performed as described in 
Section 9. Pain at the site of SC injection or IV infusion will be assessed using a Visual Analog 
Scale (0-10). Pain will not be assessed pre-dose. Indurations or reactions ≤ 1 cm in size will not 
be listed as an AE unless they persist for more than 24 hours. 
15.1.6.12. Immunogenicity Evaluation 
Serum samples will be analyzed for ADA. The timing of ADA serum sample collection is 
described in the Schedule of Assessments (Section 9). 
 
 
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16. 
ADVERSE EVENT MANAGEMENT 
The investigator is responsible for detecting, assessing, documenting, and reporting all AEs. All 
AEs will be recorded from the signing of ICF until study completion. There is no time limit for 
SAEs that are considered causally related. 
All observed or volunteered AEs, regardless of causal relationship, must be reported and 
recorded in the data capture system. Adverse events reported by the subject and/or parent or legal 
guardian, and/or identified in response to an open-ended question from study personnel, or 
revealed by observation, physical examination, or other study procedures must be collected and 
recorded. 
16.1. 
Definition of an Adverse Event 
An AE is defined as any unfavorable and unintended sign (eg, including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product or 
procedure, whether or not considered related to the medicinal product or procedure, that occurs 
during the course of the clinical study. 
Exacerbations of a chronic or intermittent pre-existing condition, including either an increase in 
frequency and/or intensity of the condition, are all to be considered AEs. 
Abnormal test findings may be considered AEs. If an abnormal laboratory value is identified, 
investigators are strongly encouraged to report a diagnosis, or a sign or symptom, rather than an 
isolated abnormal test value. An abnormal test finding should be documented as an AE if any of 
the following conditions are met: 
• Is associated with a sign or symptom 
• Requires additional diagnostic testing (repeat tests are not considered additional testing) 
• Requires a medical or surgical intervention 
• Leads to a change in study dosing outside of the protocol-defined dosing or leads to 
discontinuation from the study 
• Requires significant additional treatment 
• Does not meet any of the conditions above; however, the investigator or sponsor 
considers the result clinically significant or meeting the definition of an AE. 
This definition also includes the signs or symptoms resulting from the following: 
• Drug overdose 
• Drug withdrawal 
• Drug misuse 
• Drug interactions 
• Extravasation 
• Exposure during pregnancy 
 
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• Exposure via breastfeeding 
• Medication error 
• Occupational exposure 
An AE does not necessarily include the following: 
• Medical or surgical procedures (eg, surgery, endoscopies, tooth extraction, transfusion); 
the condition that leads to the procedure is the AE (eg, laparoscopic cholecystectomy is 
the procedure or treatment for an SAE of necrotic gallbladder) 
• Pre-existing diseases or conditions, present at or detected prior to the screening 
evaluation, that do not worsen 
• Situations where an untoward medical occurrence has not occurred (eg, hospitalization 
for elective surgery, if planned prior to the start of the study; social and/or convenience 
admissions) 
16.2. 
Definition of a Serious Adverse Event  
Any AE that fulfills any 1 of the criteria listed below must be recorded as an SAE. 
An SAE is described as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life threateninga 
3. Requires hospitalization or prolongation of hospitalizationb. Hospitalization does not 
necessarily include the following: 
• Rehabilitation/hospice/nursing facility 
• Emergency department visit of less than 24 hours 
• Elective or preplanned admission/surgery/day surgery 
• Protocol-specified admission 
• Admission for a pre-existing condition not associated with either a new AE or with 
worsening of a pre-existing AE 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Is an important medical eventc 
a The term “life threatening” in the definition of “serious” refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more 
severe. 
b Hospitalization requires inpatient admission or prolongation of an existing hospitalization. The AEs that are 
associated with hospitalization or prolongation of hospitalization are considered SAEs. 
c Important medical event: Medical and scientific judgment should be exercised in deciding whether expedited 
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 subject or may require intervention to 
prevent 1 of the other outcomes listed in the definition above. These should also usually be considered serious. 
 
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Examples of such events are intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
Severity and seriousness must be differentiated. Severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE, as described above. 
16.3. 
Severity Assessment 
All AEs will be graded according to the following criteria from CTCAE v4.03, published 
14 Jun 2010.  
• 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. Adverse events characterized as intermittent 
require documentation of onset and duration of each episode, if the severity of the intermittent 
event changes. 
16.4. 
Causality Assessment 
An investigator causality assessment must be provided for all AEs (both nonserious and serious). 
This assessment must be recorded in the data capture system and on any additional forms, as 
appropriate. The definitions for the causality assessments are as follows: 
• Not related (unrelated): This relationship suggests that there is no association between 
the investigational product and the reported event. 
• Unlikely related: This relationship suggests that the clinical picture is highly 
consistent with a cause other than the investigational product, but attribution cannot 
be made with absolute certainty, and a relationship between the investigational 
product and AE cannot be excluded with complete confidence. 
• Possibly related: This relationship suggests that treatment with the investigational 
product may have caused or contributed to the AE; ie, the event follows a reasonable 
temporal sequence from the time of study drug administration, and/or follows a 
known response pattern to the investigational product, but could also have been 
produced by other factors. 
• Probably related: This relationship suggests that a reasonable temporal sequence of 
the event with the investigational product administration exists, as well as the likely 
association of the event with the investigational product. This will be based upon the 
known pharmacological action of the investigational product, known or previously 
reported adverse reactions to the investigational product or class of drugs, or 
judgment based on the investigator’s clinical experience. 
 
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• Definitely related: Temporal relationship to the investigational product. Other 
conditions (concurrent illness, concurrent medication reaction, or 
progression/expression of disease state) do not appear to explain the event; the event 
corresponds with the known pharmaceutical profile; improvement on discontinuation; 
reappearance on rechallenge. 
16.5. 
Outcome 
For all AEs, regardless of causal relationships, the investigator must follow up regarding the 
outcome of the event until the event or sequelae either resolve or stabilize. Adverse event 
outcomes must be recorded in the data capture system and on any additional forms, as 
appropriate. 
If a subject experiences an SAE with an outcome of death, the following procedures are to be 
performed: 
• The SAE resulting in death should have an outcome documented as death/fatal, with 
an end date being the date of death. 
• If the subject had additional AE/SAEs that were ongoing at the time of death, these 
events would be documented as ongoing with no end date. 
• Only 1 event should have an outcome of death/fatal, unless an autopsy report or 
investigator states otherwise. 
16.6. 
Recording Adverse Events 
All observed or volunteered AEs, regardless of dose cohort or causal relationship, must be 
reported as described in Section 16.4 (Causality Assessment). 
For all AEs, the investigator must do the following: 
1. Determine the AE outcome 
2. Determine if the event meets criteria for an SAE 
3. Assess AE severity 
4. Determine AE causality 
Adverse events must be documented in clear, unambiguous medical terms. Study personnel are 
advised not to use abbreviations or acronyms. 
For each AE, record on the data capture system only the diagnosis; do not report the 
characteristic signs and symptoms of the diagnosis as additional AEs. 
If a diagnosis is not available, record each sign and symptom as an AE; when a diagnosis 
becomes available, study personnel are to update the source document and the data capture 
system with the relevant diagnosis only. 
For medical or surgical procedures (eg, surgery, endoscopies, tooth extraction, transfusion), the 
condition/diagnosis that leads to the procedure should be recorded as the AE (eg, laparoscopic 
cholecystectomy is the procedure or treatment for an SAE of necrotic gallbladder). 
 
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All AEs that later increase in frequency and or severity (medical and scientific judgment should 
be exercised by the investigator) will be considered new AEs, and will be recorded on a new line 
in the data capture system. 
Withdrawal due to an AE or SAE must be clearly differentiated from withdrawal due to other 
reasons. 
16.7. 
Reporting of Serious Adverse Event(s) to the Sponsor 
All AEs must be assessed by the investigator to determine if they meet criteria for an SAE. All 
SAEs must be reported to Alexion or designee immediately, or within 24 hours of the 
investigator and/or study center staff becoming aware of the event, regardless of the presumed 
relationship to the study drug. 
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 E-mail or fax to the contact information provided below: 
E-mail: 
 
Fax: 
 
When further information becomes available, the SAE should be updated with the new 
information and reported immediately via E-mail or fax using the same contact information. 
Additional follow-up information, if required or available, should be entered into the eCRF and 
sent to sponsor within 24 hours of the investigator or study center staff becoming aware of this 
additional information via the reporting process outlined above. These reporting timelines need 
to be followed for all initial SAE cases and follow-up versions of the initial cases. 
For all SAEs, the investigator must provide the following: 
• Appropriate and requested follow-up information in the time frame detailed above 
• Causality of the serious event(s) 
• Outcome of the serious event(s) 
• Medical records and laboratory/diagnostic information 
16.8. 
Exposure During Pregnancy and Lactation 
Pregnancy data will be collected during this study for all subjects. 
For all Alexion products, both in development or postapproval, exposure during pregnancy must 
be recorded and followed. Exposure during pregnancy, also called exposure in utero, can be the 
result of either maternal exposure or transmission of drug product via semen following paternal 
exposure. 
If a female subject participating in this study or a male subject’s female partner becomes or is 
found to be pregnant while being treated or exposed to study drug, the investigator must submit 
the “Pregnancy Reporting and Outcome/Breast Feeding Form” to Alexion or designee via the 
same methods as SAE reporting. Female subjects who become pregnant will be discontinued 
from dosing, but will continue to be followed for safety where feasible. Male subjects may 
 
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continue in the study if an accidental pregnancy of their female partner occurs despite adequate 
contraception. 
The female subject should be followed until the outcome of the pregnancy is known 
(spontaneous miscarriage, elective termination, normal birth or congenital abnormality), even if 
the subject discontinues study drug or discontinues from the study. When the outcome of the 
pregnancy becomes known, the form should be updated and returned to Alexion or designee. If 
additional follow-up is required, the investigator will be requested to provide the information. 
Pregnancy in itself is not regarded as an AE, unless there is a suspicion that investigational 
product may have interfered with the effectiveness of a contraceptive medication. However, 
complications of pregnancy and abnormal outcomes of pregnancy are AEs, and many may meet 
criteria for an SAE. Complications of pregnancy and abnormal outcomes of pregnancy, such as 
ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly, would meet the criteria of an SAE and therefore should be reported as an SAE. 
Elective abortions without complications should not be handled as an AE. 
Exposure of an infant to an Alexion product during breastfeeding should also be reported on the 
“Pregnancy Reporting and Outcome/Breast Feeding Form.” Any AEs an infant experiences 
following breastfeeding are to be reported to Alexion or designee. 
16.9. 
Reporting Requirements 
This protocol will use the current IB as the reference safety document. The expectedness and 
reporting criteria of an SAE will be determined by Alexion, based on the Reference Safety 
Document. 
16.9.1. 
Sponsor 
The sponsor or legal representative is responsible for notifying the relevant regulatory authorities 
of SAEs meeting the reporting criteria. The sponsor will inform the investigator of any safety 
issues that may arise during the course of the study. Any safety issue that may alter the current 
benefit-risk assessment of the study drug will be reported by the sponsor (or delegate) on an 
expedited basis to health authorities, IRBs or IECs, and the investigator. 
16.9.2. 
Investigator 
The investigator must fulfill all local regulatory requirements for investigators conducting 
clinical studies. It is the investigator’s responsibility to notify the IRB or IEC of all reportable 
SAEs that occur. Alexion will notify investigators of all unexpected, serious, drug-related events 
(7/15 Day Safety Reports) that occur during the clinical study. The investigator is responsible for 
notifying the IRB or IEC of these additional SAEs.  
Adverse events are recorded on the eCRF, and are submitted to the sponsor at regular monthly 
intervals, or more frequently during the course of the investigation. 
 
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17. 
DATA COLLECTION 
All clinical raw data will be recorded promptly, accurately, and legibly, either electronically or 
on paper. A detailed list of the type (electronic or paper) and location for all source data will be 
included in the Trial Master File. All raw data will be preserved in order to maintain data 
integrity. The investigator or designee will assume the responsibility of ensuring the 
completeness, accuracy, and timeliness of the clinical data. 
At each scheduled monitoring visit, the investigator or designee will cooperate with the 
sponsor’s representative(s) for the periodic review of study documents to ensure the accuracy 
and completeness of the data. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies on the eCRF. This information will be provided to the respective study centers by 
means of electronic or manual queries. 
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 subject receiving 
study drug. 
The investigator will allow sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/IEC to have direct access to all documents pertaining to the 
study. 
 
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18. 
STATISTICS 
18.1. 
Statistical Analysis Plan Summary 
A formal statistical analysis plan (SAP) will be developed and finalized before database lock. 
Statistical analyses will be performed by Richmond Pharmacology Ltd. Pharmacokinetic 
parameters will be calculated by Nuventra Pharma Sciences using Phoenix® WinNonlin® 6.3 or 
higher (Certara, Inc, Princeton, NJ). Tables, figures, and listings will be produced using an 
automated system (Certara L.P.). 
Any deviations from the planned analyses will be described in the final integrated clinical study 
report. 
18.2. 
Analysis Populations 
The safety population will consist of all subjects who receive at least 1 dose of study drug. 
Subjects in this population will be used for the safety analysis. 
The PK population will consist of all subjects who have sufficient serum concentration data to 
enable the calculation of PK parameters. The PK population will be used for PK summaries. 
The PD population will consist of all subjects who have sufficient total and free 
C5 concentration data and cRBC hemolysis data. The PD population will be used for PD 
summaries. 
The immunogenicity analysis population will consist of all subjects who have a pre-dose and 
post-dose ADA sample collected. 
18.3. 
Sample Size and Power 
A total evaluable sample size of 36 subjects, 24 ALXN1210 SC subjects from Cohort 1 and 
12 ALXN1210 IV subjects from Cohort 2, will provide > 80% power to infer that the lower 
bound of a 90% confidence interval for the ratio of the bioavailability of ALXN1210 SC to IV is 
> 0.4 assuming an absolute bioavailability of 0.6 and a coefficient of variation of 0.35. 
Additionally, 6 subjects will receive placebo SC, 2 in Cohort 1a and 4 in Cohort 1b.  
Randomization to Cohort 1a will be conducted in a 2:1 ratio, and Cohort 1b in a 5:1 ratio, to 
receive either ALXN1210 SC or placebo SC. This brings the total planned number of subjects to 
N=42. 
18.4. 
Descriptive Statistics 
In general, descriptive statistics for continuous variables will include number of nonmissing 
values, arithmetic mean, standard deviation, median, minimum, and maximum. Descriptive 
statistics for PK parameters will include number of observations, arithmetic mean, standard 
deviation, arithmetic coefficient of variation (%CV), median, minimum, maximum, geometric 
mean and geometric %CV. Categorical variables will be summarized using percentages and 
frequency counts, by cohort and time point.  
 
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18.5. 
Demographics, Baseline Characteristics, and Subject Disposition 
All subjects will be included in the summary of subject disposition, which will summarize the 
frequency and percentage of subjects screened and treated who completed or discontinued from 
the study, along with reason for discontinuation, by cohort. Demographics and baseline 
characteristics will be summarized for all subjects by each cohort and overall. 
18.6. 
Safety Analysis 
Safety analyses will be performed on the safety population, and will be reported by each cohort. 
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, physical 
examinations, and vital sign measurements, and will be presented using descriptive statistics. No 
inferential statistical analyses are planned on the safety parameters of this study. The incidence 
of treatment-emergent AEs and SAEs will be summarized, by system organ class and preferred 
term for each cohort and overall, by relationship to study drug. Treatment-emergent AEs will 
also be summarized by cohort and overall by severity. Serious AEs and AEs resulting in 
withdrawal from the study will be listed. Subjects having multiple AEs within a category (eg, 
overall, system organ class, preferred term) will be counted once in that category. For severity 
tables, a subject’s most severe event within a category will be counted. 
Changes from baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
CBC with differential, and urinalysis) will be summarized by each cohort. Laboratory parameter 
values will be graded according to the CTCAE. Shift tables by cohort will be produced for these 
laboratory parameters. These tables will summarize the number of subjects with each baseline 
grade relative to the reference ranges and changes to the worst highest grade assessed post-dose 
during the study. 
The ECG parameters will be measured at the specified time points, including heart rate, PR, RR, 
QRS, QT, and corrected QTcF intervals. The average of the triplicate ECG readings at the time 
points collected will be calculated, and changes from pretreatment baseline values will be 
assessed by each cohort. 
An outlier analysis will be performed that will summarize the frequency and percentage of 
subjects who meet any of the following outlier criteria at each visit by cohort: 
• QT, QTcF interval > 450 msec 
• QT, QTcF interval > 480 msec 
• QT, QTcF interval > 500 msec 
• QT, QTcF interval increases from baseline > 30 msec 
• QT, QTcF interval increases from baseline > 60 msec 
All concomitant medications will be coded using the WHO Drug Dictionary, and the frequency 
and percentage of concomitant medications will be summarized. 
 
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18.7. 
Pharmacokinetic Analysis 
The individual serum concentration data for ALXN1210-treated subjects, with actual sampling 
dates and times, will be used to derive the PK parameters by noncompartmental analyses 
methods using Phoenix WinNonlin 6.3 or higher. 
The following PK parameters will be derived: maximum observed serum concentration (Cmax), 
time to maximum observed serum concentration (Tmax), area under the serum concentration 
versus time curve from time zero to the last quantifiable concentration (AUCt) area under the 
curve from time zero to infinity (AUC∞), terminal elimination rate constant (λz), terminal 
elimination half-life (T½), total clearance (CL or CL/F), and volume of distribution (Vd or Vd/F). 
The geometric means ratio (ALXN1210 SC/ALXN1210 IV) and its 90% CI will be computed 
for Cmax, AUCt, and AUC∞, and will be tabulated. The CI will be computed using the between-
subject variance. Assessments of concentration over time will be presented.  
Further details will be provided in the Statistical Analysis Plan (SAP). 
 
18.8. 
Pharmacodynamic and Immunogenicity Analyses 
The PD effects of ALXN1210 SC and IV will be evaluated by assessing changes in serum total 
and free C5 concentrations, cRBC hemolysis, and other measures of C5 activation over time. 
Analyses will be performed on samples collected as described in the Schedule of Assessments 
(Section 9).  
Immunogenicity, as measured by ADA, will be summarized in tabular form by cohort and 
by-subject listings. 
18.9. 
Interim Analysis 
An interim analysis may be performed as needed. 
 
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19. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
19.1. 
Study Monitoring 
Before a study center can enter a subject into the study, a representative of Alexion (sponsor) 
will visit the investigational study center to do the following: 
• Determine the adequacy of the facilities; 
• Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of the sponsor or designee. 
During the study, a monitor from the sponsor and/or designee will have regular contact with the 
study center, to do the following: 
• Provide information and support to the investigator; 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded on the eCRF, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data on the eCRF 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts); 
• Record and report any protocol deviations not previously sent to the sponsor or 
designee; and 
• Confirm that AEs and SAEs have been properly documented on the eCRF, and 
confirm that any SAEs have been forwarded to the sponsor or designee, and those 
SAEs that met criteria for reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
19.2. 
Audits and Inspections 
Authorized representatives of the sponsor or designee, a regulatory authority, or an IRB/IEC may 
visit the study center to perform audits or inspections, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported, according to the protocol, Good Clinical 
Practice (GCP) guidelines of the International Council for Harmonisation (ICH), and any 
applicable regulatory requirements. The investigator is expected to contact the sponsor 
immediately if contacted by a regulatory agency about an inspection. 
 
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19.3. 
Institutional Review Board/Independent Ethics Committee 
The investigator must obtain IRB/IEC approval for the clinical study (see Section 21.1). Initial, 
subsequent, and ongoing IRB/IEC approvals, and all materials approved by the IRB/IEC for this 
study, including the subject consent form and recruitment materials, must be maintained by the 
investigator and made available for inspection. 
19.4. 
Safety Review Committee 
Since its primary function will be to ensure subject safety, the members of the SRC will have 
access to all clinical and safety data. For additional details regarding the SRC, please see 
Section 8.5. 
19.5. 
Regulatory Agency 
As required by the Medicines and Healthcare products Regulatory Agency (MHRA), a Clinical 
Trial Application will be submitted before the beginning of the study and a Notice of Acceptance 
Letter must be received prior to screening.  
 
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20. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor or 
designee may conduct a quality assurance audit. Please see Section 19.2 for more details 
regarding the audit process. 
 
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21. 
ETHICS 
21.1. 
Ethics Review 
The final study protocol and the final version of the ICF must be approved or given a favorable 
opinion in writing by an IRB/IEC, as appropriate. The investigator must submit written approval 
to the sponsor or designee prior to screening subjects. 
The investigator is responsible for informing the IRB/IEC of any amendment to the protocol, in 
accordance with local regulatory requirements. The IRB/IEC must review and approve all 
protocol amendments prior to implementation at the study center. The IRB/IEC will review the 
protocol at least annually or as local regulations require. In addition, the IRB/IEC must approve 
all advertising used to recruit subjects for the study. 
The investigator is also responsible for informing the IRB/IEC of any reportable serious adverse 
drug reactions from any other study conducted with the investigational product. The sponsor or 
designee will provide this information to the investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC, according to local regulations and guidelines. 
21.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH, GCP, applicable regulatory requirements, 
and Alexion’s policy on bioethics. 
21.3. 
Written Informed Consent 
The investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated ICF must be obtained before conducting any study procedures, 
and documented in the subject’s study record. 
The investigator must maintain the original of all signed ICF versions. A copy of the signed 
ICF(s) must be given to the subject. 
21.4. 
Urgent Safety Measures 
If an event occurs that is related to the conduct of the study or the development of the study drug, 
and this new event is likely to affect the safety of subjects, the sponsor and the investigator will 
take appropriate urgent safety measures to protect subjects against any immediate hazard. The 
sponsor will work with the investigator to ensure the IRB/IEC is notified. The sponsor will also 
inform the Medicines and Healthcare Products Regulatory Agency (MHRA). 
 
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22. 
DATA HANDLING AND RECORDKEEPING 
22.1. 
Inspection of Records 
The sponsor or designee will be allowed to conduct study center visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts, and study source documents, and other records relative to study conduct. See also 
Section 20 regarding audits. 
22.2. 
Retention of Records 
The study center will maintain adequate study records according to local regulatory requirements 
after completion or termination of the study or for a minimum period of 5 years. After that 
period, the sponsor will be contacted to determine whether the study records will be forwarded to 
the sponsor, destroyed, or kept at the study center or another facility for a longer period of time, 
at the sponsor's expense. If it becomes necessary for the sponsor or designee or the regulatory 
authority to review documentation relating to the study, the investigator must permit access to 
such records. 
 
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23. 
PUBLICATION POLICY 
The terms for publication are outlined in the Clinical Study Agreement, Statement of Agreement, 
or the Master Clinical Study Agreement. Refer to these documents for further details and 
information. 
 
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24. 
LIST OF REFERENCES 
Bugelski PJ, Achuthanandam R, Capocasale RJ, Treacy G, Bouman-Thio E. Monoclonal 
antibody-induced cytokine-release syndrome. Expert.Rev.Clin.Immunol. 2009 Sep;5(5):499-521. 
Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, 
Ugo V, Teyssandier I, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients 
treated with recombinant erythropoietin. N.Engl.J.Med. 2002 Feb 14;346(7):469-75. 
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25. 
APPENDICES 
Appendix 1 Acute Infusion Reactions 
Appendix 2 United Kingdom Resuscitation Council Anaphylaxis Algorithm 
 
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APPENDIX 1. ACUTE INFUSION REACTIONS ALGORITHM 
 
 
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APPENDIX 2. UNITED KINGDOM RESUSCITATION COUNCIL 
ANAPHYLAXIS ALGORITHM 
 
 
 
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