Conditions: Healthy
Keywords: ALXN1210 Pharmacokinetics Pharmacodynamics Safety Immunogenicity
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
This study evaluated the safety and tolerability of single and multiple doses (400 and 800 milligrams \[mg\]) of ALXN1210 following intravenous administration to healthy Japanese participants.

Detailed description:
A total of 3 cohorts were enrolled sequentially. Participants received different doses per Cohorts: Cohort 1, 400 mg single dose; Cohort 2, 800 mg single dose; and Cohort 3, 800 mg every 4 weeks for a total of 5 doses. The Safety Review Committee (SRC) conducted a review of the available clinical and safety data after the last participants in the 400 mg cohort (Cohort 1) completed Day 15 to determine if dose escalation to the single dose 800 mg (Cohort 2) could proceed. The SRC then conducted a review of all available clinical and safety data after the last participants in Cohort 2 completed Day 15 to determine if dosing of Cohort 3 could begin. A 120-day (Cohort 1) or 140-day (Cohort 2) Follow-up Period was performed for safety, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity assessments. Participants in Cohort 3, however, had a 185-day Follow-up Period for safety, PK, PD, and immunogenicity assessments after the fifth dose of study drug.

Arms:
arm 1: A single dose of ALXN1210 was administered intravenously. arm 2: A single dose of ALXN1210 was administered intravenously. arm 3: ALXN1210 (800 mg) was administered intravenously every 4 weeks for a total of 5 doses.

Interventions: intervention 1: ALXN1210
Intervention descriptions: intervention 1: Participants received a single dose (400 mg or 800 mg) and multiple doses (800 mg) of ALXN1210.

Protocol document:
Prot_000.pdf: 
A Phase 1, Open-label, Single Ascending and Multiple Set 
Dose Study to Evaluate the Safety, Tolerability, 
Immunogenicity, Pharmacokinetics, and Pharmacodynamics 
of ALXN1210 Administered Intravenously to Healthy 
Japanese Subjects 
Unique Protocol ID: 
ALXN1210-HV-104 
NCT Number: 
NCT05288816 
EudraCT Number: 
2015-005468-40 
Date of Protocol: 
24 August 2016 
 


 
1. 
TITLE PAGE 
ALXN1210 
ALXN1210-HV-104 
A PHASE 1, OPEN-LABEL, SINGLE ASCENDING AND MULTIPLE SET 
DOSE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, 
IMMUNOGENICITY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS OF ALXN1210 ADMINISTERED 
INTRAVENOUSLY TO HEALTHY JAPANESE SUBJECTS 
Sponsor 
Alexion Pharmaceuticals, Inc. 
100 College Street 
New Haven, CT 06510 
United States 
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: 
12 January 2016 
Date of Amendment 1: 
24 August 2016 
IND Number: 
128367 
EudraCT Number:                  2015-005468-40 
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.” 
 
PPD
PPD
PPD
PPD
PPD
PPD


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for ALXN1210.  I have read the 
ALNX1210-HV-104 protocol and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. I agree 
to conduct the study in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with the International Conference on Harmonisation 
(ICH)/Good Clinical Practices (GCP) and applicable to regulatory requirements.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
CONTRACT RESEARCH ORGANIZATION: 
 
Richmond Pharmacology Ltd. 
St George’s University of London 
Cranmer Terrace 
Tooting 
London 
SWQ17 ORE 
Telephone: 
 
 
 
 
Page 2 of 85 
 
CONFIDENTIAL 
PPD


PPD


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 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: 
 
 
Page 4 of 85 
 
CONFIDENTIAL 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Alexion Pharmaceuticals, Inc. 
Name of Investigational Product: 
ALXN1210 
Name of Active Ingredient: 
ALXN1210 
Title of Study: A Phase 1, Open-Label, Single Ascending and Multiple Set Dose Study to Evaluate the Safety, 
Tolerability, Immunogenicity, Pharmacokinetics, and Pharmacodynamics of ALXN1210 Administered 
Intravenously to Healthy Japanese Subjects 
Protocol No. ALXN1210-HV-104 
EudraCT number: 2015-005468-40 
Study center(s): 
This study will be conducted by Richmond Pharmacology Ltd. at the following facility: 
St George’s University of London 
Cranmer Terrace 
Tooting 
London 
SWQ17 ORE 
Telephone: 
 
Studied period (years):  
Estimated date first subject enrolled: April 2016 
Estimated date last subject completed: April 2017 
Phase of development: 1 
 
Study Rationale: 
The purpose of the study is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics (PK), and 
pharmacodynamics (PD) of single and multiple doses of ALXN1210 in healthy Japanese subjects. Data from this 
study will be used to determine whether results obtained in Japanese subjects are comparable to results obtained in 
non-Japanese subjects. 
 
ALXN1210 is a humanized monoclonal antibody (mAb) that inhibits terminal complement.  It specifically binds 
the terminal complement protein C5 thereby inhibiting its cleavage to C5a and C5b during complement activation. 
This inhibition not only prevents the release of the pro-inflammatory mediator C5a, but also inhibits the formation 
of the cytolytic pore C5b-9.  The mechanism of action described here provides a mechanistic 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 single intravenous (IV) doses of 200 mg and 
400 mg in a single ascending dose (SAD) study (Study ALXN1210-HV-101, N = 14) and in multiple IV doses of 
400 mg and 800 mg on an every 4 week (Q4W) regimen in an ongoing multiple ascending dose (MAD) study 
(Study ALXN1210-HV-102, N = 16). The starting doses of ALXN1210 in these two studies were selected to 
assess safety in healthy volunteers but also 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.  
 
Persons exposed to a terminal complement inhibitor for C5 are known to be at an increased risk of infections 
caused by encapsulated organisms, in particular Neisseria meningitidis. Subjects might be at risk of infection by 
uncommon serogroups (particularly A, C, Y, W135, and X), although meningococcal disease due to any serogroup 
may occur. To address this risk, all subjects in this study will be vaccinated against N meningitidis with tetravalent 
meningococcal conjugate vaccine (MCV4), serogroup B meningococcal vaccine, and prophylactic antibiotic 
treatment will be administered as an additional precaution in this study. A serum bactericidal antibody (SBA) titer 
 
Page 5 of 85 
 
CONFIDENTIAL 
PPD


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
against meningococcus Group A, C, W135, and Y will be performed at screening to exclude subjects without an 
immune response. Unless the PI 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). 
Objectives: 
Primary:  
• 
To evaluate the safety and tolerability of single and multiple doses of ALXN1210 following IV 
administration to healthy Japanese subjects.  
Secondary: 
• 
To investigate the immunogenicity of ALXN1210 in healthy Japanese subjects. 
• 
To characterize the PK of single and multiple doses of ALXN1210 in healthy Japanese subjects.  
• 
To evaluate the PD effects of ALXN1210 as assessed by total and free C5 concentrations and chicken red 
blood cell (cRBC) hemolysis in healthy Japanese subjects. 
Methodology:  
This is a Phase 1, open-label, single ascending and multiple set dose study designed to evaluate the safety, 
tolerability, immunogenicity, PK, and PD of ALXN1210 in healthy Japanese subjects.   
A total of 3 cohorts and up to 16 subjects are planned for evaluation. The cohorts will be enrolled sequentially and 
all subjects will receive IV ALXN1210:  
• 
Cohort 1, 400 mg single dose (N = 4) 
• 
Cohort 2, 800 mg single dose (N = 4) 
• 
Cohort 3, 800 mg Q4W for a total of 5 doses (N = 6 to 8) 
A Safety Review Committee (SRC) will review the available clinical and safety data at the following points in the 
study to determine whether dose escalation or continuation may proceed: 1) after the last subject in the 400 mg 
cohort (Cohort 1) has completed Day 15 to determine if dose escalation to 800 mg may proceed (Cohort 2); 2) after 
the last subject in the 800 mg cohort (Cohort 2) has completed Day 15 to determine if repeat dosing with 800 mg 
may begin (Cohort 3); and 3) after at least 4 subjects in the 800 mg multiple dose cohort (Cohort 3) have 
completed Day 15 to determine if dosing in Cohort 3 may continue. Dose escalation or continuation will proceed 
as scheduled and the study will continue as long as no prespecified toxicity events occur. Dose continuation within 
Cohort 3 after Period 2 will proceed following review of the available safety and tolerability data by the PI in 
accordance with the protocol’s toxicity rules. Minimum data requirements do not apply for the PI review; however, 
it is expected to include available data up to 14 days after each dose. 
 
Up to 2 subjects per cohort may be added if 2 or more subjects discontinue before Day 15 (first dose only for 
Cohort 3) for reasons other than drug-related AEs, and after consultation with the SRC. All enrolled subjects will 
be included in analyses as appropriate. Subjects who have been dosed and who withdraw from the study will be 
followed for safety assessments through the last study visit, if possible.  
 
Subjects in Cohorts 1 and 2 (Single Ascending Dose [SAD] Phase) will participate in the study for up to 27 or 30 
weeks, respectively, including a screening period of up to 70 days, followed by a 120-day (Cohort 1) or 140-day 
(Cohort 2) dosing and observation period for safety, immunogenicity, PK, and PD assessments after study drug 
administration. Subjects in Cohort 3 (Multiple Set Dose [MSD] Phase) will participate in the study for 
approximately 52 weeks, including a screening period of up to 70 days, a treatment period of 112 days, and a 
185-day observation period for safety, immunogenicity, PK, and PD assessments after the fifth dose of study drug. 
Subjects in Cohort 1 will utilize contraception for a minimum of 6 months after last dose, whereas subjects in 
Cohorts 2 and 3 will utilize contraception for a minimum of 8 months after last dose.  
 
 
Page 6 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Number of subjects (planned):  
Up to 16 subjects are planned for evaluation of the primary and secondary objectives, and a maximum of 22 
subjects could be enrolled and dosed. See the synopsis section “Methodology” regarding addition of subjects who 
withdraw or are withdrawn from the study after dosing. The total number of subjects dosed (including potential 
added subjects) will remain within a maximum of 6 subjects each in Cohorts 1 and 2 and 10 subjects in Cohort 3, 
for a maximum of 22 subjects in this study.  
Diagnosis and main criteria for inclusion:  
All subjects must adhere to the following inclusion/exclusion criteria.  Subjects who fail to meet eligibility criteria 
may not be rescreened for participation in the study unless the condition 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 Japanese males or females aged 25 through 55 years, inclusive (subjects must have lived outside 
of Japan for ≤ 10 years and be first generation Japanese, defined as born in Japan and having 4 biologic 
grandparents who are ethnic Japanese). 
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 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 must use highly effective contraception as defined below, 
starting at screening and continuing until at least 6 months (Cohort 1) or 8 months (Cohorts 2 and 3) after 
the last dose of ALXN1210. 
 
Highly effective contraceptive methods for females are as follows*: 
 
Page 7 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
− 
Oral 
− 
Intravaginal 
− 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− 
Oral 
− 
Injectable 
− 
Implantable 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
 
*It is recommended that heterosexually active female subjects of childbearing age who take oral 
contraceptives and penicillin V, or any other antibiotics with the potential to reduce the effectiveness of 
hormonal contraception, should use a barrier method (eg, condom or diaphragm and spermicide) in 
addition to the oral contraceptive medication. 
 
Male subjects with a female spouse/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 (Cohort 1) or 8 months (Cohorts 2 and 3) after the last dose of ALXN1210. 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 (Cohort 1) or 8 months (Cohorts 2 and 3) after the last dose of 
ALXN1210. Male subjects must not donate sperm during the screening and treatment periods and for at 
least 6 months (Cohort 1) or 8 months (Cohorts 2 and 3) after the last dose of ALXN1210. 
 
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) 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 the past 6 months 
3. History of any Neisseria infection 
4. History of unexplained, recurrent infection, or infection requiring treatment with systemic antibiotics 
within the last 90 days prior to dosing.  
 
Page 8 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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 infection. 
10. History of latent or active tuberculosis or exposure to endemic areas within 8 weeks prior to the screening 
visit. 
11. Female subjects who are breastfeeding or are 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 drug administration. 
12. Positive serum pregnancy test at screening or Day –1. 
13. Serum creatinine greater than the upper limit of normal (ULN) of the reference range of the testing 
laboratory at screening or 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 at 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 cells (WBC) < 3.0 × 103/μL; 
absolute neutrophils < 2.0 × 103/μL; and platelets < 150 or > 400 × 103/μL at screening or 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 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 
experimental small-molecule therapy within 30 days prior to dosing on Day 1. 
19. Participation in more than one clinical study of a mAb, or participation in a clinical study of a 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. Major surgery or hospitalization within 90 days prior to dosing. 
21. Contraindication to receiving MCV4 and/or serogroup B vaccine, including severe allergic reaction to a 
previous dose of MCV4 and/or serogroup B vaccine; severe allergy to any vaccine component; or 
previous diagnosis of Guillain-Barré syndrome. 
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 (anaphylaxis, 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 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 of dosing or more than 499 mL of blood within 
 
Page 9 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
56 days of dosing. 
30. History of continuous topical/inhaled or systemic steroid use > 1 month 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/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 1 month 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 the first dosing. 
36. Subjects with any medical history, conditions, or risks which, 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 is formulated at pH 7.0 and each vial contains 150 mg of ALXN1210, in 10 mM sodium phosphate, 
150 mM NaCl, 0.02% polysorbate 80, and water for IV administration.  ALXN1210 is presented as a sterile, 
preservative-free 10 mg/mL solution for IV administration and is supplied in 20-mL single-use vials.  
 
ALXN1210 will be administered by IV infusion at a fixed rate of 686 mg/hr, excluding interruption for safety or 
technical reason.  
Duration of treatment:  
Screening period: up to 70 days  
Dosing and observation periods:  For Cohorts 1 and 2, single dose of ALXN1210 on Day 1, followed by an 
observation period of 119 days (Cohort 1) or 139 days (Cohort 2). For Cohort 3, a total of 5 doses of ALXN1210 
on Days 1, 29, 57, 85, and 113, followed by an observation period of 185 days. Subjects will be followed for 
safety, PK, PD, and immunogenicity assessments. 
Reference therapy, dosage and mode of administration:  
None   
Criteria for evaluation: 
Safety evaluation: 
Safety assessments will include physical examination findings, vital signs measurements, immunogenicity (anti-
drug antibody [ADA]) testing, laboratory evaluations, electrocardiogram (ECG) results, infusion 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 June 14, 2010. Laboratory evaluations include 
hematology, chemistry, and coagulation panels, CBC with differential, urinalysis, and pregnancy testing for female 
subjects. The potential risks of ALXN1210, specifically the risk of infection, will be reviewed with the subjects at 
screening and on a regular basis throughout the course of the study, after dosing. Subjects will meet with the 
investigator or designee to discuss the potential safety risks of ALXN1210 and address any safety concerns on the 
part of the subject at the time points shown in the Schedule of Assessments. During the second, third, and fourth 
dosing periods of Cohort 3, the subjects will be contacted by telephone to assess selected safety information. 
 
Pharmacokinetics: 
Table 1s: Collection Time Points for Serum Concentrations of ALXN1210  
Collection Time Points for Cohort 1 
(Days 1-120) 
On Day 1 before dosing (within 15 min prior to the start of infusion [SOI]); end-of-infusion (EOI), 
30 min after the EOI, and at the following time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 
(24 hr), Day 3 (48 hr), Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 
hr), Day 36 (840 hr), Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 
90 (2136 hr), and Day 120 (2856 hr)  
 
 
Page 10 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Collection Time Points for Cohort 2 
(Days 1-140) 
On Day 1 before dosing (within 15 min prior to the start of infusion [SOI]); end-of-infusion (EOI), 
30 min after the EOI, and at the following time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 
(24 hr), Day 3 (48 hr), Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 
hr), Day 36 (840 hr), Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 
90 (2136 hr), Day 120 (2856 hr), and Day 140 (3336 hr) 
Collection Time Points for Cohort 3  
Period 1  
(Days 1-28) 
On Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, at the following 
time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), Day 5 (96 hr); Day 8 
(168 hr), Day 15 (336 hr), and Day 22 (504 hr) 
Period 2  
(Days 29-56) 
Before dosing on Day 29 (within 15 min prior to the SOI), EOI on Day 29, 30 min after the EOI, at 
the following time points:  Day 29 (4 hr and 8 hr), Day 30 (24 hr), Day 31 (48 hr), Day 33 (96 hr), 
and Day 43 (336 hr) 
Period 3  
(Days 57-84) 
Before dosing on Day 57 (within 15 min prior to the SOI), EOI on Day 57, 30 min after the EOI, at 
the following time points:  Day 57 (4 hr and 8 hr), Day 58 (24 hr), Day 59 (48 hr), Day 61 (96 hr), 
and Day 71 (336 hr) 
Period 4  
(Days 85-112) 
Before dosing on Day 85 (within 15 min prior to the SOI), EOI on Day 85, 30 min after the EOI, at 
the following time points:  Day 85 (4 hr and 8 hr), Day 86 (24 hr), Day 87 (48 hr), Day 89 (96 hr), 
and Day 99 (336 hr) 
Period 5 and 
Follow-up  
(Days 113-298) 
Before dosing on Day 113 (within 15 min prior to SOI), EOI and 30 min after the EOI on Day 113, at 
the following time points:  Day 113 (4 hr and 8 hr), Day 114 (24 hr), Day 115 (48 hr), Day 117 
(96 hr), Day 120 (168 hr), Day 127 (336 hr), Day 134 (504 hr), Day 141 (672 hr), Day 148, Day 155, 
Day 162, Day 169, Day 183, Day 197, Day 225, Day 253, and Day 298 
 
Using noncompartmental PK methods, the serum concentrations versus time data will be used to derive the 
following PK parameters: maximum observed serum concentration (Cmax) after each dose, time to maximum 
observed serum concentration (tmax), the observed minimum serum concentrations (Cmin) just prior to Periods 2 to 5 
(and 28 days after Period 5 dose) for Cohort 3, area under the serum concentration versus time curve from time 0 
to the last quantifiable concentration (AUCt) after each dose, area under the curve from time 0 (dosing) to the end 
of the dosing interval (AUCτ), apparent terminal-phase elimination rate constant (λz), terminal elimination half-life 
(t½), total clearance (CL), volume of distribution (Vss), assessment of steady-state, and accumulation at steady state. 
The relationship between ALXN1210 exposure and PD markers may be assessed, and dose proportionality in PK 
parameters may be assessed.  
Pharmacodynamics: 
Blood samples for the analyses of total and free C5 levels and cRBC hemolysis will be collected at the time points 
listed in the following tables. Additional biomarker assays may be conducted as an exploratory analysis on 
collected samples. 
Table 2s: Collection Time Points for Serum C5 Levels and cRBC Hemolysis  
Collection Time Points for Cohort 1  
(Days -1-120) 
On Day -1, on Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, and 
at the following time points (relative to  SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), and 
Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 hr), Day 36 (840 hr), 
Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 90 (2136 hr), and Day 
120 (2856 hr) 
Collection Time Points for Cohort 2 
(Days -1-140) 
On Day -1, on Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, and 
at the following time points (relative to  SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), and 
Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 hr), Day 36 (840 hr), 
Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 90 (2136 hr), Day 120 
(2856 hr), and Day 140 (3336 hr) 
Collection Time Points for Cohort 3  
Period 1  
(Days -1-28) 
On Day -1, on Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, at 
the following time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), Day 5 
(96 hr), Day 8 (168 hr), Day 15 (336 hr), and Day 22 (504 hr) 
Period 2  
(Days 29-56) 
Before dosing on Day 29 (within 15 min prior to the SOI), EOI on Day 29, 30 min after the EOI, at 
the following time points:  Day 29 (4 hr and 8 hr), Day 30 (24 hr), Day 31 (48 hr), Day 33 (96 hr), 
and Day 43 (336 hr) 
 
Page 11 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Period 3  
(Days 57-84) 
Before dosing on Day 57 (within 15 min prior to the SOI), EOI on Day 57, 30 min after the EOI, at 
the following time points:  Day 57 (4 hr and 8 hr), Day 58 (24 hr), Day 59 (48 hr), Day 61 (96 hr), 
and Day 71 (336 hr) 
Period 4  
(Days 85-112) 
Before dosing on Day 85 (within 15 min prior to the SOI), EOI on Day 85, 30 min after the EOI, at 
the following time points:  Day 85 (4 hr and 8 hr), Day 86 (24 hr), Day 87 (48 hr), Day 89 (96 hr), 
and Day 99 (336 hr) 
Period 5 and 
Follow-up  
(Days 113-298) 
Before dosing on Day 113 (within 15 min prior to SOI), EOI and 30 min after the EOI on Day 113, at 
the following time points:  Day 113 (4 hr and 8 hr), Day 114 (24 hr), Day 115 (48 hr), Day 117 (96 
hr), Day 120 (168 hr), Day 127 (336 hr), Day 134 (504 hr), Day 141 (672 hr), Day 148, Day 155, 
Day 162, Day 169, Day 183, Day 197, Day 225, Day 253, and Day 298 
 
Immunogenicity: 
 
Table 3s: Collection Time Points for Serum Samples for Analyses of Antidrug Antibodies to ALXN1210  
Collection Time Points for Cohort 1  
(Days 1-120) 
Pre-dose on Day 1, and on Day 15, Day 29, Day 57, Day 90, and Day 120 
Collection Time Points for Cohort 2 
(Days -1-140) 
Pre-dose on Day 1, and on Day 15, Day 29, Day 57, Day 90, Day 120, and Day 140 
Collection Time Points for Cohort 3  
Periods 1 to 5 
(Days 1-298) 
Pre-dose on Day 1; on Day 8, Day 15, and Day 22 after Dose 1; on Day 29 prior to Dose 2 and on Day 
43 after Dose 2; on Day 57 prior to Dose 3 and on Day 71 after Dose 3; on Day 85 prior to Dose 4 and 
on Day 99 after Dose 4; on Day 113 prior to Dose 5 and on Day 120, Day 141, Day 169, Day 197, 
Day 225, Day 253, and Day 298 following Dose 5 
 
Please refer to the Study Operation Manual (SOM) for time windows for collection, and to the laboratory manual 
for details on sample collection including blood volume requirements. 
 
No more than 470 mL of blood will be taken within each 16-week period in accordance with the guidance of NHS 
Blood and Transplant (http://www.blood.co.uk/about-blood/how-the-body-replaces-blood/). 
Statistical methods: 
The sample size of 4 subjects in each of the single-dose cohorts (Cohorts 1 and 2) and 6 to 8 subjects in the 800 mg 
multiple-dose cohort will allow for the characterization of the central tendency of PK parameters as they relate to 
ALXN1210 and to gain initial knowledge of PK/PD relationships in Japanese subjects. To ensure future modeling 
and simulations are accurate, it is preferred to estimate the PK parameters with a maximum imprecision of < 25% 
following the IV administration of ALXN1210. Six subjects in Cohort 3 will provide 23.3% maximum imprecision 
for the estimation of area under the serum concentration versus time curve from time 0 extrapolated to infinity 
(AUC∞), in terms of the relative distance of the lower 90% confidence limit from the observed PK parameter that 
will be obtained with 80% assurance and assuming the within-subject SD of the log-transformed AUC∞ is as much 
as 0.19.  
 
All continuous variables will be summarized by cohort and time point with descriptive statistics (the number of 
nonmissing values, mean, SD, median, minimum, and maximum). All categorical variables will be summarized by 
cohort and time point with frequency counts and percentages. 
 
All subjects dosed with 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 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 
postdose during the study. 
 
Individual PK parameters (including descriptive statistics: geometric mean, geometric coefficient of variation 
[CV], arithmetic mean, SD, arithmetic CV, median, minimum, and maximum) will be determined for the 
ALXN1210-treated subjects. The PK data may be assessed for dose proportionality. The PK data may be explored 
for time linearity. 
 
 
Page 12 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
The PD effects of ALXN1210 will be evaluated by assessing serum total and free C5 concentrations and cRBC 
hemolysis over time, using descriptive statistics, and the ALXN1210 concentration required for complete terminal 
complement inhibition based on PD effects evaluated. An exploratory analysis of ALXN1210 concentrations and 
PD responses assessed at similar time points may be performed. 
 
Page 13 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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 ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Background .................................................................................................................22 
5.1.1. 
Clinical Studies ...........................................................................................................22 
5.1.2. 
Nonclinical Studies .....................................................................................................23 
5.1.3. 
General Considerations for This Study.......................................................................23 
5.1.4. 
Potential Risks ............................................................................................................23 
5.1.4.1. 
Infections (Neisseria meningitidis and Other Encapsulated Organisms) ...................23 
5.1.4.2. 
Immunogenicity and Hypersensitivity ........................................................................24 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Primary Objective .......................................................................................................25 
6.2. 
Secondary Objectives .................................................................................................25 
7. 
ENDPOINTS ..............................................................................................................26 
7.1. 
Safety Endpoints .........................................................................................................26 
7.2. 
Pharmacokinetic Endpoints ........................................................................................26 
7.3. 
Pharmacodynamic Endpoints .....................................................................................26 
8. 
INVESTIGATIONAL PLAN .....................................................................................28 
8.1. 
Overall Study Design ..................................................................................................28 
8.2. 
Number of Subjects ....................................................................................................29 
8.3. 
Dose Rationale ............................................................................................................29 
8.4. 
Criteria for Dose Continuation and Dose Escalation ..................................................30 
8.4.1. 
Dose Escalation, Dose Continuation, and Suspension/Stopping Rules ......................30 
8.4.2. 
Individual Subject Dose Continuation and Suspension/Stopping Rules ....................32 
8.5. 
Safety Review Committee ..........................................................................................32 
8.6. 
Criteria for Study Termination ...................................................................................32 
 
Page 14 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
9. 
SCHEDULES OF ASSESSMENTS ..........................................................................34 
10. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................46 
10.1. 
Subject Inclusion Criteria ...........................................................................................46 
10.2. 
Subject Exclusion Criteria ..........................................................................................47 
10.3. 
Subject Withdrawal Criteria .......................................................................................50 
11. 
TREATMENT OF SUBJECTS ..................................................................................51 
11.1. 
Description of Study Drug ..........................................................................................51 
11.2. 
Infection ......................................................................................................................51 
11.2.1. 
Vaccine and Antibiotic Prophylaxis ...........................................................................51 
11.2.2. 
Risk of Infection Reminders .......................................................................................52 
11.3. 
Prior and Concomitant Medications and Procedures ..................................................52 
11.4. 
Permitted Medications ................................................................................................53 
11.5. 
Restrictions .................................................................................................................53 
11.6. 
Treatment Compliance ................................................................................................53 
11.7. 
Randomization and Blinding ......................................................................................54 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................55 
12.1. 
Study Drug ..................................................................................................................55 
12.2. 
Study Drug Packaging and Labeling ..........................................................................55 
12.3. 
Study Drug Storage .....................................................................................................55 
12.4. 
Study Drug Preparation ..............................................................................................55 
12.4.1. 
ALXN1210 Dose Preparation .....................................................................................55 
12.4.2. 
In-Use Shelf Life ........................................................................................................56 
12.5. 
Administration ............................................................................................................56 
12.6. 
Management of Potential Drug Infusion Reactions ....................................................56 
12.7. 
Study Drug Accountability .........................................................................................57 
12.8. 
Study Drug Handling and Disposal ............................................................................57 
13. 
PHARMACOKINETIC ASSESSMENTS .................................................................58 
13.1. 
Blood Sample Collection ............................................................................................58 
13.2. 
Criteria for Evaluation ................................................................................................59 
13.3. 
Sample Analysis .........................................................................................................59 
14. 
PHARMACODYNAMIC ASSESSMENTS ..............................................................60 
14.1. 
Blood Sample Collection ............................................................................................60 
14.2. 
Criteria for Evaluation ................................................................................................60 
 
Page 15 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
14.3. 
Sample Analysis .........................................................................................................60 
15. 
IMMUNOGENICITY ASSESSMENTS....................................................................61 
15.1. 
Blood Sample Collection ............................................................................................61 
15.2. 
Criteria for Evaluation ................................................................................................61 
15.3. 
Sample Analysis .........................................................................................................61 
16. 
ASSESSMENT OF SAFETY .....................................................................................62 
16.1. 
Safety Parameters .......................................................................................................62 
16.1.1. 
Demographic/Medical History ...................................................................................62 
16.1.2. 
Vital Signs ..................................................................................................................62 
16.1.3. 
Weight and Height ......................................................................................................62 
16.1.4. 
Physical Examination .................................................................................................62 
16.1.5. 
Electrocardiogram .......................................................................................................63 
16.1.6. 
Laboratory Assessments .............................................................................................63 
16.1.6.1. 
Hematology .................................................................................................................63 
16.1.6.2. 
Blood Chemistry .........................................................................................................63 
16.1.6.3. 
Coagulation .................................................................................................................63 
16.1.6.4. 
Urinalysis and Urine Chemistry .................................................................................63 
16.1.6.5. 
Virus Serology ............................................................................................................64 
16.1.6.6. 
Drug and Alcohol Screen ............................................................................................64 
16.1.6.7. 
Pregnancy Testing ......................................................................................................64 
16.1.6.8. 
Tuberculosis ................................................................................................................64 
16.1.6.9. 
Complement Activity ..................................................................................................64 
16.1.6.10. Serum Bactericidal Antibody .....................................................................................65 
17. 
ADVERSE EVENT MANAGEMENT ......................................................................66 
17.1. 
Definition of an Adverse Event ..................................................................................66 
17.2. 
Definition of a Serious Adverse Event .......................................................................67 
17.3. 
Severity Assessment ...................................................................................................68 
17.4. 
Causality Assessment .................................................................................................68 
17.5. 
Outcome ......................................................................................................................69 
17.6. 
Recording Adverse Events .........................................................................................69 
17.7. 
Reporting of Serious Adverse Event(s) to the Sponsor ..............................................70 
17.8. 
Exposure During Pregnancy and Lactation ................................................................70 
17.9. 
Reporting Requirements .............................................................................................71 
 
Page 16 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
17.9.1. 
Sponsor .......................................................................................................................71 
17.9.2. 
Investigator .................................................................................................................71 
18. 
DATA COLLECTION ...............................................................................................72 
19. 
STATISTICS ..............................................................................................................73 
19.1. 
Statistical Analysis Plan Summary .............................................................................73 
19.2. 
Analysis Populations ..................................................................................................73 
19.3. 
Sample Size and Power ..............................................................................................73 
19.4. 
Descriptive Statistics ..................................................................................................74 
19.5. 
Demographics, Baseline Characteristics, and Subject Disposition ............................74 
19.6. 
Safety Analysis ...........................................................................................................74 
19.7. 
Pharmacokinetic Analysis ..........................................................................................75 
19.8. 
Pharmacodynamic and Immunogenicity Analyses .....................................................75 
19.9. 
Interim Analysis ..........................................................................................................75 
20. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................76 
20.1. 
Study Monitoring ........................................................................................................76 
20.2. 
Audits and Inspections ................................................................................................76 
20.3. 
Institutional Review Board/Independent Ethics Committee ......................................77 
20.4. 
Safety Review Committee ..........................................................................................77 
20.5. 
Regulatory Agency .....................................................................................................77 
21. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
22. 
ETHICS ......................................................................................................................79 
22.1. 
Ethics Review .............................................................................................................79 
22.2. 
Ethical Conduct of the Study ......................................................................................79 
22.3. 
Written Informed Consent ..........................................................................................79 
22.4. 
Urgent Safety Measures ..............................................................................................79 
23. 
DATA HANDLING AND RECORDKEEPING .......................................................80 
23.1. 
Inspection of Records .................................................................................................80 
23.2. 
Retention of Records ..................................................................................................80 
24. 
PUBLICATION POLICY ..........................................................................................81 
25. 
LIST OF REFERENCES ............................................................................................82 
26. 
APPENDICES ............................................................................................................83 
26.1. 
Appendix 1 ..................................................................................................................84 
26.2. 
Appendix 2 ..................................................................................................................85 
 
Page 17 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Terms ............................................................................................20 
Table 3: 
Toxicity Rules .............................................................................................................31 
Table 4: 
Individual Progression Rules ......................................................................................32 
Table 5: 
Schedule of Assessments: Cohorts 1 and 2 (Refer to Table 6 for 
Pharmacokinetics, Pharmacodynamics, Immunogenicity, Infusion Site 
Evaluation, Vital Signs, and ECG Collection Time Points Required on Day 
1) .................................................................................................................................35 
Table 6: 
Cohort 1 and 2: Pharmacokinetics, Pharmacodynamics, Immunogenicity, 
Infusion Site Evaluation, Vital Signs, and ECG Collection Time Points ...................38 
Table 7: 
Schedule of Assessments: Cohort 3; Screening, Doses 1 to 4 (Refer to 
Table 8  for Period 5 and Follow-up) .........................................................................39 
Table 8: 
Schedule of Assessments: Cohort 3; Period 5 and Follow-up ....................................42 
Table 9: 
Cohort 3: Follow-Up and Early Termination Procedures for Subjects Who 
Discontinue During Periods 1 to 4..............................................................................44 
Table 10: Cohort 3: Pharmacokinetics, Pharmacodynamics, Immunogenicity, Infusion 
Site Evaluation, Vital Signs, and ECG Collection Time Points Required on 
Each Dosing Day ........................................................................................................45 
Table 11: Investigational Product ...............................................................................................51 
Table 12: Dosing Reference Chart for ALXN1210 Dose Preparation .......................................55 
Table 13: Infusion Volume and Duration ...................................................................................56 
Table 14: Collection Time Points for Serum Concentrations of ALXN1210 ............................58 
Table 15: Collection Time Points for Serum C5 Levels and cRBC Hemolysis .........................60 
Table 16: Collection Time Points for Serum Samples for Immunogenicity Analyses of 
Antidrug Antibodies to ALXN1210 ...........................................................................61 
Table 17: Estimation of the Maximum Imprecision in the Estimate of PK Parameters 
for Selected Sample Sizes ...........................................................................................73 
 
 
Page 18 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
LIST OF FIGURES 
Figure 1: 
Study Diagram ............................................................................................................29 
 
 
Page 19 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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  
%CV  
percent coefficient of variance  
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 0 extrapolated to infinity 
AUCt  
area under the serum concentration versus time curve from time 0 to the last quantifiable 
concentration 
AUCτ  
area under the serum concentration versus time curve from time 0 (dosing) to the end of the 
dosing interval 
BMI  
body mass index  
BP  
British Pharmacopoeia 
C5b-9  
terminal complement complex  
CAP  
complement alternative pathway  
CDC 
complement-dependent cytotoxicity 
CL  
total clearance  
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  
EOI  
end of infusion  
ET 
Early Termination 
GCP  
Good Clinical Practice  
GLP  
Good Laboratory Practice  
HBcAg 
hepatitis B core antigen 
HbsAg 
hepatitis B surface antigen 
HBV  
hepatitis B virus  
HCV  
hepatitis C virus  
HIV  
human immunodeficiency virus  
ICF  
informed consent form  
ICH  
International Conference on Harmonisation  
IEC 
independent ethics committee 
IRB 
institutional review board 
IV  
intravenous  
mAb  
monoclonal antibody  
MAC 
membrane attack complex 
MAD 
multiple ascending dose 
MCV4  
meningococcal conjugate vaccine  
MSD 
multiple set dose 
OP 
outpatient 
 
Page 20 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
PD  
pharmacodynamic(s)  
Ph. Eur. 
European Pharmacopoeia 
PNH  
paroxysmal nocturnal hemoglobinuria  
PK  
pharmacokinetic(s)  
QTcF  
QT interval corrected using Fridericia’s formula  
RBC  
red blood cell  
SAD  
single ascending dose  
SAE  
serious adverse event  
SOI  
start of infusion  
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  
Vss  
volume of distribution  
WBC  
white blood cell  
 
 
Page 21 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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 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 the formation of the cytolytic pore-forming membrane attack complex (MAC) 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] or atypical hemolytic uremic syndrome [aHUS]). These disorders of uncontrolled 
complement activation are chronic and progressive, with severe morbidities and significant 
premature mortality. 
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 single intravenous (IV) doses of 
200 mg and 400 mg in a single ascending dose (SAD) study (Study ALXN1210-HV-101, 
N = 14) and in multiple IV doses of 400 mg and 800 mg on an every 4 week (Q4W) regimen in 
an ongoing multiple ascending dose (MAD) study (Study ALXN1210-HV-102, N = 16). The 
starting doses of ALXN1210 in these two studies were selected to assess safety in healthy 
volunteers but also 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 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 (AUCt, AUC∞, and 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.  
• Following single IV infusion (200- and 400-mg) dose administrations of ALXN1210, 
all 6 PD variables showed dose-dependent reductions from Baseline. The effect of 
ALXN1210 on these PD variables was immediately evident after EOI. At the EOI, 
 
Page 22 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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 ADA through Day 150. 
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 has been observed. 
Please refer to the current edition of the ALXN1210 Investigator's Brochure for detailed results. 
5.1.3. 
General Considerations for This Study 
The planned Phase 1 study will be performed in healthy Japanese subjects. Data from this study 
will be used to determine whether results of safety, immunogenicity, PK, and PD investigations 
obtained in non-Japanese subjects may be extrapolated to Japanese subjects.  
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, an additional conservative step of treating 
subjects with prophylactic antibiotics is planned, in addition to MCV4 vaccination at least 
56 days prior to dosing with ALXN1210 (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). The serum bactericidal antibody (SBA) titer to the tetravalent vaccine will be 
established. Subjects who are not already vaccinated will also receive vaccination for serogroup 
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 and emerging data from the ALXN1210 program. Unless the PI 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 by 
 
Page 23 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Day 50 for Cohort 1, Day 140 for Cohort 2, and Day 298 for Cohort 3). Analysis of blood 
samples to establish actual complement activity based on an in vitro liposome immunoassay 
(LIA) will be used as confirmation. The analysis will take place approximately 2 to 5 weeks 
prior to the anticipated end of antibiotic prophylaxis. All subjects will be monitored closely for 
signs of infection throughout the study.  
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 meaningful. The consequences of an 
immune reaction to a therapeutic protein range from transient appearance of antibodies, without 
any clinical consequence, to severe, life-threatening conditions. Potential clinical consequences 
also may include severe hypersensitivity-type reactions, decrease in efficacy and induction of 
autoimmunity, including antibodies to the endogenous form of the protein (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 (Sampson 2006). The signs and symptoms include 
headache, fever, facial flushing, pruritus, myalgia, nausea, chest tightness, dyspnea, vomiting, 
erythema, abdominal discomfort, diaphoresis, shivers, 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 drug administration. 
 
Page 24 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and tolerability of single and 
multiple doses of ALXN1210 following IV administration to healthy Japanese subjects. 
6.2. 
Secondary Objectives 
Secondary objectives are as follows: 
• To investigate the immunogenicity of ALXN1210 in healthy Japanese subjects. 
• To characterize the PK of single and multiple doses of ALXN1210 in healthy 
Japanese subjects.  
• To evaluate the PD effects of ALXN1210 as assessed by total and free C5 
concentrations and chicken red blood cell (cRBC) hemolysis in healthy Japanese 
subjects. 
 
Page 25 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
7. 
ENDPOINTS 
Safety, immunogenicity, PK, and PD endpoints are described in the sections to follow. Timing of 
assessments is displayed in the Schedules of Assessments. 
7.1. 
Safety Endpoints 
Safety endpoints include the following: 
• Change from baseline in physical examination assessments 
• Change from baseline in vital signs 
• Incidence of antidrug antibody (ADA) measured via immunogenicity testing 
• Change from baseline in electrocardiogram (ECG) parameters 
• Change from baseline in laboratory measurements 
• Incidence of AEs and SAEs 
7.2. 
Pharmacokinetic Endpoints 
The following PK parameters will be evaluated: 
• Cmax 
• Time to maximum observed serum concentration (tmax) 
• Observed minimum serum concentrations (Cmin) just prior to Doses 2 to 5, and 28 
days after the 5th dose  
• Area under the serum concentration versus time curve from time 0 to the last 
quantifiable concentration (AUCt) after each dose 
• AUC from time 0 (dosing) to the end of the dosing interval (AUCτ)  
• Apparent terminal-phase elimination rate constant (λz) 
• t½ 
• Total body clearance of drug from the serum (CL) 
• Volume of distribution at steady state (Vss) 
• Assessment of steady state 
• Accumulation at steady state 
7.3. 
Pharmacodynamic Endpoints 
Pharmacodynamic effects will be evaluated as follows: 
• Change in serum total and free C5 concentration over time  
• Change in cRBC hemolysis over time 
 
Page 26 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
• ALXN1210 concentration required for terminal complement inhibition based on PD 
effects evaluated 
 
Page 27 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
8. 
INVESTIGATIONAL PLAN 
8.1. 
Overall Study Design 
This is a Phase 1, open-label, single ascending and multiple set dose study designed to evaluate 
the safety, tolerability, immunogenicity, PK, and PD of ALXN1210 in healthy Japanese subjects.   
All subjects are to be screened for eligibility in the study after providing written informed 
consent to participate. 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.  
A total of 3 cohorts and up to 16 subjects are planned for evaluation. The cohorts will be enrolled 
sequentially and all subjects will receive IV ALXN1210:  
• Cohort 1, 400 mg single dose (N = 4) 
• Cohort 2, 800 mg single dose (N = 4) 
• Cohort 3, 800 mg Q4W for a total of 5 doses (N = 6 to 8) 
A Safety Review Committee (SRC) will conduct a review of the available clinical and safety 
data after the last subject in the 400 mg cohort (Cohort 1) has completed Day 15 to determine if 
dose escalation to 800 mg may proceed (Cohort 2). The SRC will conduct a review of all 
available clinical and safety data after the last subject in the 800 mg cohort (Cohort 2) has 
completed Day 15 to determine if dosing in Cohort 3 may begin. Dose escalation to the multiple 
repeated dose phase will proceed as scheduled and the study will continue as long as no 
prespecified toxicity events occur (see Table 3). Dose continuation within Cohort 3 after 
Period 2 will proceed following review of the available safety and tolerability data by the PI in 
accordance with the protocol’s toxicity rules. Minimum data requirements do not apply for the PI 
review; however, it is expected to include available data up to 14 days after each dose. 
Up to 2 subjects per cohort may be added if 2 or more subjects discontinue before Day 15 (first 
dose only for Cohort 3) for reasons other than drug-related AEs, and after consultation with the 
SRC. All enrolled subjects will be included in analyses as appropriate.  Subjects who have been 
dosed and who withdraw from the study will be followed for safety assessments through the last 
study visit, if possible.   
Subjects in Cohorts 1 and 2 will participate in the study for up to 27 or 30 weeks, respectively, 
including a screening period of up to 70 days, followed by a 120-day (Cohort 1) or 140-day 
(Cohort 2) dosing and observation period for safety, immunogenicity, PK, and PD assessments 
after study drug administration. Subjects in Cohort 3 will participate in the study for 
approximately 52 weeks, including a screening period of up to 70 days, a treatment period of 112 
days, and a 185-day observation period for safety, immunogenicity, PK, and PD assessments 
after the fifth dose of study drug.  
 
Page 28 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Figure 1: 
Study Diagram 
 
8.2. 
Number of Subjects 
Up to 16 subjects are planned for evaluation of the primary and secondary objectives, and a 
maximum of 22 subjects could be enrolled and dosed.  See the synopsis section “Methodology” 
regarding addition of subjects who withdraw or are withdrawn from the study after dosing. The 
total number of subjects dosed (including potential added subjects) will remain within a 
maximum of 6 subjects each in Cohorts 1 and 2 and 10 subjects in Cohort 3, for a maximum of 
22 subjects in this study. 
8.3. 
Dose Rationale 
The geometric mean (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 IV infusion (200- 
and 400-mg) dose administrations of ALXN1210 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 ongoing Study ALXN1210-HV-102, ALXN1210 IV doses of 400 every 
4 weeks and 800 mg every 4 weeks are being studied to assess PK, PD, and tolerability in 
healthy volunteers.  The PK, PD, and tolerability data from the non-Japanese studies (Study 
ALXN1210-HV-101 and Study ALXN1210-HV-102) will be compared with the data from the 
current study to assess PK, PD, and tolerability bridging between Japanese and non-Japanese 
healthy volunteers. In the current study, dose escalation (400 mg to 800 mg single dose) and dose 
progression (800 mg single dose to 800 mg multiple dose) will be decided upon SRC review of 
the safety and tolerability data from the preceding cohort. 
 
Page 29 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
8.4. 
Criteria for Dose Continuation and Dose Escalation  
For the purpose of this protocol, progression rules are based on toxicity (ie, clinically significant 
AEs which are assessed as at least possibly related to the investigational medicinal product). For 
the purpose of this protocol, the term “dose escalation” is defined as progression to the next 
cohort. 
For the purpose of this protocol, the term “suspension” is defined as no further study drug will be 
administered at the dose level and that further dose escalation/continuation will be suspended. If 
a dose level is suspended, an ad hoc SRC meeting will be held. 
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; 
v4.03, published June 14, 2010) will be used to grade AEs (see Section 17.3). 
Abnormal laboratory and other tests should always be repeated before grading in order to ensure 
consistency and to exclude technical errors. If applicable, diurnal variations in laboratory 
parameters and other measurements as well as baseline status should be taken into account when 
assessing whether abnormal laboratory values constitute a drug-related AE and when grading 
AEs. 
8.4.1. 
Dose Escalation, Dose Continuation, and Suspension/Stopping Rules 
To determine if escalation to the next cohort should occur, the SRC will review the available 
safety data after Day 15 of the last subject in Cohort 1. Study assessments through Day 15 must 
be completed for a minimum of 3 subjects to determine if it is appropriate to escalate to 
Cohort 2. Dose escalation will occur based on the recommendation of the SRC (Section 8.5). The 
same process will be followed for escalation from Cohort 2 to Cohort 3. Study assessments 
through Day 15 of each dose must be completed for a minimum of 3 subjects to determine if it is 
appropriate to begin dosing in Cohort 3. Dose escalation will occur based on the 
recommendation of the SRC.  
Dose continuation in Cohort 3 will occur based on review by the SRC of data from at least 
4 subjects through Day 15 post first dose.  
Dose escalation and dose continuation will proceed as described in Table 3 and will be limited 
by whether these toxicity rules are met. 
 
Page 30 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 3: 
Toxicity Rules 
CTCAE 
Grade 
Severity/  
Seriousness 
Reversibility 
Number of 
Subjects 
Affected 
Action 
Effect on Dose 
Progression/ 
Escalation 
1 
Mild 
N/A 
N/A 
Next dose determined by 
SRC 
N/A 
2 
Moderate 
Showing signs 
of reversibility; 
i.e. event which 
shows signs of 
improvement in 
the judgment of 
investigator 
≤ 2 subjects in 
different SOC* 
≤ 2 subjects in 
same SOC 
OR 
3 subjects in 
different SOC* 
Dose level may continue  
OR 
be extended 
AND  
Dose escalation  on hold 
until results of 
continuation or extension 
are available 
Following 
continuation or 
extension, dose 
escalation may 
proceed as per clinical 
study protocol 
≥ 3 subjects in 
same SOC 
OR 
≥ 4 subjects in 
different SOC* 
Dose level suspended 
Dose continuation, 
extension, or 
escalation requires 
substantial amendment 
Showing no 
signs of  
reversibility 
≥ 2 subjects* 
3 
Severe 
Showing signs 
of reversibility; 
i.e. event which 
shows signs of 
improvement in 
the judgment of 
investigator 
1 subject* 
Dose level may continue  
OR 
be extended 
AND  
Dose escalation  on hold 
until results of 
continuation or extension 
are available 
Following 
continuation or 
expansion, dose 
escalation may 
proceed as per the 
clinical study protocol 
≥ 2 subjects* 
Dose level suspended  
Dose continuation, 
extension, or 
escalation requires 
substantial amendment 
Showing no 
signs of  
reversibility 
≥ 1 subject*  
 
4 
Life-
threatening 
N/A 
≥ 1 subject 
Study suspended 
Study continuation 
requires substantial 
amendment 
5 
Fatal  
N/A 
Serious 
N/A 
≥ 1 subject 
Study suspended 
Study continuation 
requires substantial 
amendment 
Abbreviations: N/A = not applicable; SOC = system organ class; SRC = Safety Review Committee. 
* Within 2 weeks from each dose 
 
Page 31 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
8.4.2. 
Individual Subject Dose Continuation and Suspension/Stopping Rules 
Individual dose continuation rules are presented in Table 4. These rules apply to study 
drug-related AEs and SAEs in individual subjects enrolled. 
Table 4: 
Individual Progression Rules 
AE Grade 
Severity 
Action 
1 
Mild 
No action required. 
2 
Moderate 
Study drug administration may continue at the same dose if the SRC considers 
it safe for the subject. 
3 
Severe 
Study drug administration will be discontinued. 
4 
Life-threatening 
Study drug administration will be discontinued. 
5 
Fatal 
Serious 
N/A 
Abbreviation: N/A = not applicable 
8.5. 
Safety Review Committee 
The SRC is composed of the medical monitor, biostatistician, pharmacovigilance representative, 
clinical pharmacologist, and principal investigator. The membership, schedule of meetings, data 
required for each safety review, and requirements for documenting meeting discussions and 
outcome will be outlined in a charter to which the SRC adhere. 
Since its primary function will be to ensure subject safety, the members of the SRC will have 
access to all safety data.  
The SRC will review the available clinical and safety data at the following points in the study to 
determine whether dose escalation or continuation may proceed:  
• After the last subject (minimum of 3) in the 400 mg cohort (Cohort 1) has completed 
Day 15 to determine if dose escalation to 800 mg may proceed (Cohort 2). 
• After the last subject (minimum of 3) in the 800 mg cohort (Cohort 2) has completed 
Day 15 to determine if repeat dosing with 800 mg may begin (Cohort 3). 
• After at least 4 subjects in the 800 mg multiple dose cohort (Cohort 3) have completed 
Day 15 to determine if dosing in Cohort 3 may continue. Dose escalation or continuation 
will proceed as scheduled and the study will continue as long as no prespecified toxicity 
events occur. 
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 and Table 4 are met that warrant the suspension of dosing or the study. 
The SRC may make recommendations regarding safety issues, study conduct, and modifying (ie, 
exploring the dose cohort further, suspending dose cohort(s), exploring lower dosing regimens), 
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 may warrant termination of the study include, but are not limited to:  
 
Page 32 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
• 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. 
 
Page 33 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
9. 
SCHEDULES OF ASSESSMENTS 
The timing of overall study procedures is provided in the Schedules of Assessments as follows: 
• Cohorts 1 and 2 (Table 5) 
• Cohort 3 
− Screening and Doses 1 through 4 (Table 7) 
− Dose 5 and follow up (Table 8) 
− Follow up/ET for subjects who discontinue during Doses 1 through 4 (Table 9) 
The timing of PK, PD, immunogenicity, infusion site evaluation, vital signs and ECG collection 
procedures is provided for: 
• Cohorts 1 and 2 (Table 6) 
• Cohort 3 (Table 10) 
 
 
Page 34 of 85 
 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 5: 
Schedule of Assessments: Cohorts 1 and 2 (Refer to Table 6 for Pharmacokinetics, Pharmacodynamics, 
Immunogenicity, Infusion Site Evaluation, Vital Signs, and ECG Collection Time Points Required on Day 1) 
 
Screening 
Treatment Period 
Follow-up Period 
Study Day 
–1 
1 
2 
3 
5 
8 
15 
22 
29 
36 
43 
50 
57 
71 
90 
120 
140 
(C2)16 
Status (OP, PC, or CRU) 
OP 
CRU 
Day -1 
CRU 
Day 1 
CRU 
Day 2 
CRU 
Day 3 
CRU 
Day 5 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
MCV4 immunization 
(Day -56)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal serogroup 
B immunization (Day -56 
and Day -28)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum bactericidal 
antibody (meningococcus 
Group A, C, W135, and 
Y)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB test 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
HIV, types 1 and 2 screen 
X 
 
 
 
 
 
 
 
 
 
Complement activity4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CH505 
 
X 
 
 
 
 
 
 
 
 
X 
(C1) 
 
X 
(C1) 
 
X 
(C2) 
X 
(C2) 
X 
(C2) 
X 
(C2) 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
Height, weight, BMI6 
X 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test7 
X 
X 
 
 
 
 
 
 
 
X 
X 
Admittance to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
ECG (triplicate)9 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Cardiac telemetry9 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry10 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Hematology10 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Coagulation10 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Urinalysis and urine 
chemistry10 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Study drug administration 
 
X 
 
 
 
 
 
 
 
 
 
 
Page 35 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 5: 
Schedule of Assessments: Cohorts 1 and 2 (Refer to Table 6 for Pharmacokinetics, Pharmacodynamics, 
Immunogenicity, Infusion Site Evaluation, Vital Signs, and ECG Collection Time Points Required on Day 1) 
(Continued) 
Study Day 
Screening 
Treatment Period 
Follow-up Period 
–1 
1 
2 
3 
5 
8 
15 
22 
29 
36 
43 
50 
57 
71 
90 
120 
140 
(C2)16 
Status (OP, PC, or CRU) 
OP 
CRU 
Day -1 
CRU 
Day 1 
CRU 
Day 2 
CRU 
Day 3 
CRU 
Day 5 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples8 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X 
X 
X 
PD panel (serum C5, 
cRBC hemolysis)8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X 
X 
X 
Immunogenicity (ADA)8 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
Infusion site 
evaluation8,11 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
 
Concomitant 
medications 
 
←---Monitored continuously---→ 
Adverse events12 
 
←---Monitored continuously---→ 
Antibiotic prophylaxis13 
←---Daily until CH50 normalizes ---→ 
Discharge from CRU14 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Discuss safety risks with 
subject15 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA = antidrug antibody; BMI = body mass index; C1 = Cohort 1; C2 = Cohort 2; CRU = clinical research unit; ECG = electrocardiogram; ET = early 
termination; HIV = human immunodeficiency virus; ICF = informed consent form; MCV4 = meningococcal conjugate vaccine; OP = outpatient; PC = phone call; PD = 
pharmacodynamic; PK = pharmacokinetic; TB = tuberculosis.  
1 Permissible windows for study assessments are described in the Study Operations Manual (SOM). 
2 Signed and dated EC-approved ICF must be obtained before any study-specific screening procedures are performed. 
3 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.  
4 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. 
5 The sample drawn on Day -1 will be stored for future analysis should the post-dose sample indicate that complement has not normalized. The post-dose sample will be taken on 
Day 36 (Cohort 1) or Day 71 (Cohort 2); if complement has not normalized, additional samples will be obtained on Day 50 for Cohort 1 and Days 90, 120 and 140 for Cohort 2. 
Interim CH50 samples may be taken at the discretion of the investigator to allow for samples taken between Days 120 and 140. Once a normal CH50 result is obtained, antibiotic 
prophylaxis can be stopped and additional CH50 samples are not required; if the Day 140 CH50 sample is not normal, the baseline sample will be analyzed and the investigator 
will contact the subject regarding whether antibiotic prophylaxis must be further extended. 
6 Height at Screening only. 
7 Serum pregnancy test at Screening and urine pregnancy test at other visits as indicated for all female subjects. Positive urine pregnancy results should be confirmed by serum 
test. 
8 See Table 6 for pharmacokinetics, pharmacodynamics, immunogenicity, infusion site evaluation, vital signs, and ECG collection time points required on each dosing day. 
9 Continuous cardiac registration predose through the duration of infusion. 
Page 36 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 5: 
Schedule of Assessments: Cohorts 1 and 2 (Refer to Table 6 for Pharmacokinetics, Pharmacodynamics, 
Immunogenicity, Infusion Site Evaluation, Vital Signs, and ECG Collection Time Points Required on Day 1) 
(Continued) 
10 Clinical safety laboratory measurements on Day 1 will be collected 4 hours post dose. Follicle-stimulating hormones and estradiol levels will be measured at screening to 
confirm postmenopausal status, as described in Section 16.1.6.2. 
11 Induration or reaction < 1 cm will not be listed as an AE unless it persists for more than 24 hours. Pain at site of infusion will be assessed using a visual assessment scale (0-10). 
12 Collection of AEs and SAEs will begin after the ICF is signed. 
13 Subjects will receive oral penicillin V 500 mg twice daily (equivalent to 1,600,000 units) for the duration of the reduced complement activity, depending on their dose cohort 
assignment as described in Section 11.2.1. The first dose of antibiotic will be administered on Day -1 in the evening, prior to Day 1 (first dose) of ALXN1210. A suitable system 
(such as text messaging) will be used for daily monitoring of subjects’ compliance with the antibiotic prophylaxis regimen. 
14 Subjects will be discharged from the CRU after completing all assessments on Day 5. 
15 Subjects will be provided a safety card with information for the healthcare provider and participant on symptoms of meningitis infection as well as contact information. This 
information will be reviewed with the subjects on a regular basis throughout the study (as indicated), and on the day of discharge.  
16 Day 140 assessments are for Cohort 2 subjects only. Cohort 1 subjects will not undergo Day 140 assessments. 
 
Page 37 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 6: 
Cohort 1 and 2: Pharmacokinetics, Pharmacodynamics, Immunogenicity, Infusion Site Evaluation, Vital Signs, 
and ECG Collection Time Points  
 
Pre 
dose 
EOI 
Post 
EOI 
Post SOI 
Collection Time Relative 
to Dose 
pre 
EOI 
30 min 
15 
min 
30 min 
60 
min 
1.5 
hr 
2 hr 
4 hr 
8 hr 
18 
hr 
24 
hr 
30 
hr 
36 
hr 
48 
hr 
Study Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
3 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (triplicate) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Infusion site evaluation 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
 
X 
Vital signs2 
X 
X 
 
X 
X 
(C2) 
X 
X 
X 
X 
X 
 
X 
 
 
X 
PK samples 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
PD panel (serum C5, 
cRBC hemolysis) 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
Immunogenicity (ADA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ADA = antidrug antibody; C2 = Cohort 2; ECG = electrocardiogram; EOI = end of infusion; PD = pharmacodynamic; PK = pharmacokinetic; SOI = start of 
infusion.  
1 Permissible windows for study assessments are described in the Study Operations Manual (SOM). 
2 30-min post-SOI vitals for Cohort 2 only. 
 
Page 38 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 7: 
Schedule of Assessments: Cohort 3; Screening, Doses 1 to 4 (Refer to Table 8  for Period 5 and Follow-up) 
 
Screening 
Period 1 
Periods 2, 3, and 4 
Doses 1 and 2 Study Day 
 
–1 
1 
2 
3 
5 
8 
15 
22 
28 
29 
30 
31 
33 
36 
43 
50 
Dose 3 Study Day 
 
 
 
 
 
 
 
 
56 
57 
58 
59 
61 
64 
71 
78 
Dose 4 Study Day 
 
 
 
 
 
 
 
 
84 
85 
86 
87 
89 
92 
99 
106 
Day relative to start of 
dosing period 
 
-1 
1 
2 
3 
5 
8 
15 
22 
-1 
1 
2 
3 
5 
8 
15 
22 
Status (OP, PC, or CRU) 
OP 
CRU 
Day  
-1 
CRU 
Day 
1 
CRU 
Day 
2 
CRU 
Day 
3 
CRU 
Day 
5 
OP 
OP 
OP 
CRU 
Day -1 
CRU 
Day 1 
CRU  
Day 2 
CRU 
Day 3 
OP 
PC 
OP 
PC 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent2 
X 
 
 
 
 
 
 
 
 
MCV4 immunization 
(Day -56)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal 
serogroup B 
immunization (Day -5 
and Day -28)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum bactericidal 
antibody (meningococcus 
Group A, C, W135, and 
Y)3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON TB test 
X 
 
 
 
 
 
 
 
 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
HIV, types 1 and 2 
screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complement activity4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CH505 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
Height, weight, BMI6 
X 
X 
 
 
 
 
 
 
 
 
Pregnancy test7 
X 
X 
X 
 
 
 
 
 
 
 
Admittance to CRU 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
ECG (triplicate)9 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
Cardiac telemetry9 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Chemistry10 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematology10 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Page 39 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 7: 
Schedule of Assessments: Cohort 3; Screening, Doses 1 to 4 (Refer to Table 8 for Period 5 and Follow-up) 
(Continued) 
 
Screening 
Period 1 
Periods 2, 3, and 4 
Doses 1 and 2 Study 
Day 
 
–1 
1 
2 
3 
5 
8 
15 
22 
28 
29 
30 
31 
33 
36 
43 
50 
Dose 3 Study Day 
 
 
 
 
 
 
 
 
56 
57 
58 
59 
61 
64 
71 
78 
Dose 4 Study Day 
 
 
 
 
 
 
 
 
84 
85 
86 
87 
89 
92 
99 
106 
Day relative to start of 
dosing period 
 
-1 
1 
2 
3 
5 
8 
15 
22 
-1 
1 
2 
3 
5 
8 
15 
22 
Status (OP, PC, or 
CRU) 
OP 
CRU 
Day  
-1 
CRU 
Day 
1 
CRU 
Day 
2 
CRU 
Day 
3 
CRU 
Day 
5 
OP 
OP 
OP 
CRU 
Day -1 
CRU 
Day 1 
CRU  
Day 2 
CRU 
Day 3 
OP 
PC 
OP 
PC 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation10 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis and urine 
chemistry10 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Study drug 
administration11 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
PK samples8 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X  
 
X 
 
PD panel (serum C5, 
cRBC hemolysis)8 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X  
 
X 
 
Immunogenicity 
(ADA)8 
 
 
X 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
Infusion site 
evaluation8,12 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
Concomitant 
medications 
 
X 
←---Monitored continuously---→ 
Adverse events13 
 
X 
←---Monitored continuously---→ 
Antibiotic prophylaxis14 
X 
←---Daily---→ 
Discharge from CRU15 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
Discuss safety risks with 
subject16 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Abbreviations: ADA = antidrug antibody; BMI = body mass index; CRU = clinical research unit; ECG = electrocardiogram; HIV = human immunodeficiency virus; ICF = 
informed consent form; MCV4 = meningococcal conjugate vaccine; OP = outpatient; PC = phone call; PD = pharmacodynamic; PK = pharmacokinetic; TB = tuberculosis.  
1 Permissible windows for study assessments are described in the Study Operations Manual (SOM). 
2 Signed and dated EC-approved ICF must be obtained before any study-specific screening procedures are performed. 
3 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.  
4 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. 
5 The CH50 sample drawn on Day -1 will be stored for future analysis should all the post-dose samples indicate that complement has not normalized.  
Page 40 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 7: 
Schedule of Assessments: Cohort 3; Screening, Doses 1 to 4 (Refer to Table 8 for Period 5 and Follow-up) 
(Continued) 
6 Height at Screening only. 
7 Serum pregnancy test at Screening and urine pregnancy test as indicated for all female subjects. Positive urine pregnancy results should be confirmed by serum test. 
8 See Table 9 for pharmacokinetics, pharmacodynamics, immunogenicity, infusion site evaluation, vital signs, and ECG collection time points required on each dosing day. 
9 Continuous cardiac registration predose through the duration of infusion. 
10 Clinical safety laboratory measurements on Day 1 Period 1 will be collected 4 hours post dose. Follicle-stimulating hormones and estradiol levels will be measured at screening 
to confirm postmenopausal status, as described in Section 16.1.6.2. 
11 Subjects who discontinue from the study before Dose 5 will be followed for 185 days after the last dose and instructed to return for follow-up visits (see Table 9). Subjects who 
discontinue the study after Dose 5 will be instructed to return for study visits through Day 298. 
12 Induration or reaction < 1 cm will not be listed as an AE unless it persists for more than 24 hours. Pain at site of infusion will be assessed using a visual assessment scale (0-10). 
13 Collection of AEs and SAEs will begin after the ICF is signed. 
14 Subjects will receive oral penicillin V 500 mg twice daily (equivalent to 1,600,000 units) for the duration of the reduced complement activity, depending on their dose cohort 
assignment as described in Section 11.2.1. The first dose of antibiotic will be administered on Day -1 in the evening, prior to the Day 1 (first dose) of ALXN1210. A suitable 
system (such as text messaging) will be used for daily monitoring of subjects’ compliance with the antibiotic prophylaxis regimen.  
15 For Dose 1 and 5, subjects will be discharged from the CRU after completing all assessments on Day 5. For Doses 2 to 4, subjects will be discharged from the CRU on Day 3 
after completing all assessments through 48 hours. 
16 Subjects will be provided a safety card with information for the healthcare provider and participant on symptoms of meningitis infection as well as contact information. This 
information will be reviewed with the subjects on a regular basis throughout the study (as indicated), and on the day of discharge. 
 
Page 41 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 8: 
Schedule of Assessments: Cohort 3; Period 5 and Follow-up 
 
Period 5 
Follow-Up Post Period 5 
Dose 5 Study Day 
112 
113 
114 
115 
117 
120 
127 
134 
141 
148 
155 
162 
169 
183 
197 
225 
253 
298 
Day relative to 
dosing  
-1 
1 
2 
3 
5 
8 
15 
22 
 
 
 
 
 
 
 
 
 
 
Status (OP or CRU) 
CRU 
Day -1 
CRU 
Day 1 
CRU 
Day 2 
CRU 
Day 3 
CRU 
Day 5 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
X 
 
 
 
 
 
 
 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (triplicate)3 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
Cardiac telemetry4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry5 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Hematology5 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Coagulation5 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
Urinalysis and urine 
chemistry5 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
CH50 assay6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Study drug 
administration7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK samples3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum C5, 
cRBC hemolysis)3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
(ADA)3 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Infusion site 
evaluation3,8 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
←---Monitored continuously---→ 
Adverse events 
X 
←---Monitored continuously---→ 
Antibiotic 
prophylaxis9 
X 
←---Daily until CH50 normalizes ---→ 
Discharge from 
CRU10 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discuss safety risks 
with subject11 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA = antidrug antibody; CRU = clinical research unit; ECG = electrocardiogram; ICF = informed consent form; OP = outpatient; PD = pharmacodynamic; PK = 
pharmacokinetic. 
1 Permissible windows for study assessments are described in the Study Operations Manual (SOM). 
2 Urine pregnancy test for all female subjects as indicated. Positive urine pregnancy results should be confirmed by serum test 
3 See Table 10 for pharmacokinetics, pharmacodynamics, immunogenicity, infusion site evaluation, vital signs, and ECG collection time points required on each dosing day.  
Page 42 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 8: 
Schedule of Assessments: Cohort 3; Period 5 and Follow-up (Continued) 
4 Continuous cardiac registration pre-dose through the duration of infusion. 
5 Clinical safety laboratory measurements on Day 113 of Period 5 will be collected 4 hours post dose.  
6 CH50 sample will be taken on Days 197, 225, 253, and 298. Interim CH50 samples may be taken at the discretion of the PI to allow for samples taken between Days 197, 225, 
253, and 298. Once a normal CH50 result is obtained, antibiotic prophylaxis can be stopped and additional CH50 samples are not required; if the Day 298 CH50 sample is not 
normal, the baseline sample will be analyzed and the investigator will contact the subject regarding whether antibiotic prophylaxis must be further extended. 
7 Subjects who discontinue from the study before Dose 5 will be followed for 185 days after the last dose and instructed to return for follow-up visits (see Table 9). Subjects who 
discontinue the study after Dose 5 will be instructed to return for study visits through Day 298. 
8 Indurations or reactions < 1 cm will not be listed as an AE unless it persists for more than 24 hours. Pain at site of infusion will be assessed using a visual assessment scale 
(0-10). 
9 Subjects will receive oral penicillin V 500 mg twice daily (equivalent to 1,600,000 units) for the duration of the reduced complement activity, depending on their dose cohort 
assignment as described in Section 11.2.1. Subjects will receive the first dose on Day -1 in the evening. A suitable system (such as text messaging) will be used for daily 
monitoring of subjects’ compliance with the antibiotic prophylaxis regimen.  
10 For Dose 5, subjects will be discharged from the CRU after completing all assessments on Day 5.  
11 Subjects will be provided a safety card with information for healthcare provider and participant on symptoms of meningitis infection and contact information. This information 
will be reviewed with the subjects on a regular basis throughout the study (as indicated), and on the day of discharge. 
Page 43 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 9: 
Cohort 3: Follow-Up and Early Termination Procedures for Subjects Who Discontinue During Periods 1 to 4 
Days Relative to Last Dose 
28 
35 
42 
49 
56 
70 
84 
112 
140 
168 
185 
ET 
Dose 1 Study Day 
29 
36 
43 
50 
57 
71 
85 
113 
141 
169 
186 
 
Dose 2 Study Day 
57 
64 
71 
78 
85 
99 
113 
141 
169 
197 
214 
 
Dose 3 Study Day 
85 
92 
99 
106 
113 
127 
141 
169 
197 
225 
242 
 
Dose 4 Study Day 
113 
120 
127 
134 
141 
155 
169 
197 
225 
253 
270 
 
Status (OP or CRU) 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test2 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Physical examination 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (triplicate) 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Chemistry 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Hematology 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Coagulation 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Urinalysis and urine chemistry 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
CH503 
 
 
 
 
 
 
 
X 
 
X 
X 
 
PK samples 
X 
X 
X 
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 
Immunogenicity (ADA) 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant medications 
←---Monitored continuously---→ 
X 
Adverse events 
←---Monitored continuously---→ 
X 
Antibiotic prophylaxis4 
←---Daily until CH50 normalizes ---→  
 
Discuss safety risks with subject5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ADA = antidrug antibody; CRU = clinical research unit; ECG = electrocardiogram; ET= Early Termination; ICF = informed consent form; OP = outpatient; 
PD = pharmacodynamic.  
1  Permissible windows for study assessments are described in the SOM. 
2 Urine pregnancy test for all female subjects. Positive urine pregnancy results should be confirmed by serum test. 
3 CH50 samples will be taken 112, 168, and 185 days relative to last dose. Once a normal CH50 result is obtained, antibiotic prophylaxis can be stopped and additional CH50 
samples are not required; if the CH50 sample 185 days after last dose is not normal, the baseline sample will be analyzed and the investigator will contact the subject regarding 
whether antibiotic prophylaxis must be further extended. 
4 Subjects will receive oral penicillin V 500 mg twice daily (equivalent to 1,600,000 units) for the duration of the reduced complement activity, depending on their dose cohort 
assignment as described in Section 11.2.1. The first dose of antibiotic will be administered on Day -1 in the evening, prior to the Day 1 (first dose) of ALXN1210. A suitable 
system (such as text messaging) will be used for daily monitoring of subjects’ compliance with the antibiotic prophylaxis regimen. 
5 Subjects will be provided a safety card with information for healthcare provider and participant on symptoms of meningitis infection and contact information. This information 
will be reviewed with the subjects on a regular basis throughout the study (as indicated). 
 
Page 44 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
 
 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
Table 10: 
Cohort 3: Pharmacokinetics, Pharmacodynamics, Immunogenicity, Infusion Site Evaluation, Vital Signs, and 
ECG Collection Time Points Required on Each Dosing Day 
 
Pre 
dose 
EOI 
Post 
EOI 
Post SOI 
Collection Time 
Relative to Dose 
pre 
EOI 
30 min 
15 min 
30 min 
60 min 
1.5 hr 
2 hr 
4 hr 
8 hr 
18 hr 
24 hr 
30 hr 
36 hr 
48 hr 
Dose 1 Study Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
3 
Dose 2 Study Day 
29 
29 
29 
29 
29 
29 
29 
29 
29 
29 
29 
30 
30 
30 
31 
Dose 3 Study Day 
57 
57 
57 
57 
57 
57 
57 
57 
57 
57 
57 
58 
58 
58 
59 
Dose 4 Study Day 
85 
85 
85 
85 
85 
85 
85 
85 
85 
85 
85 
86 
86 
86 
87 
Dose 5 Study Day 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
114 
114 
114 
115 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (triplicate) 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Infusion site evaluation 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
 
X 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK samples 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
PD panel (serum C5, 
cRBC hemolysis) 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
Immunogenicity (ADA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ADA = antidrug antibody; ECG = electrocardiogram; EOI = end of infusion; PD = pharmacodynamic; PK = pharmacokinetic; SOI = start of infusion.  
1 Permissible windows for study assessments are described in the SOM. 
 
Page 45 of 85 
CONFIDENTIAL 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 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 Japanese males or females aged 25 through 55 years, inclusive (subjects must 
have lived outside of Japan for ≤ 10 years and be first generation Japanese, defined as 
born in Japan and having 4 biologic grandparents who are ethnic Japanese). 
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 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 must use highly effective contraception as 
defined below, starting at screening and continuing until at least 6 months (Cohort 1) or 
8 months (Cohorts 2 and 3) after the last dose of ALXN1210. 
Highly effective contraceptive methods for females are as follows*: 
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable  
• Intrauterine device  
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion 
 
Page 46 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
* It is recommended that heterosexually active female subjects of childbearing age who 
take oral contraceptives and penicillin V, or any other antibiotics with the potential to 
reduce the effectiveness of hormonal contraception, should use a barrier method (eg, 
condom or diaphragm and spermicide) in addition to the oral contraceptive 
medication. 
Male subjects with a female spouse/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 (Cohort 1) or 8 months (Cohorts 2 
and 3) after the last dose of ALXN1210. 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 (Cohort 1) or 8 months (Cohorts 2 and 3) 
after the last dose of ALXN1210. Male subjects must not donate sperm during the 
screening and treatment periods and for at least 6 months (Cohort 1) or 8 months 
(Cohorts 2 and 3) after the last dose of ALXN1210. 
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) 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  
 
Page 47 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
• 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 the past 6 months 
3. History of any Neisseria infection 
4. History of unexplained, recurrent infection; or infection requiring treatment with 
systemic antibiotics within the last 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 
infection. 
10. History of latent or active tuberculosis or exposure to endemic areas within 8 weeks prior 
to the screening visit. 
11. Female subjects who are breastfeeding or are 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 drug 
administration.  
12. Positive serum pregnancy test at screening or Day –1. 
13. Serum creatinine greater than the upper limit of normal (ULN) of the reference range of 
the testing laboratory at screening or 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 at 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 
cells (WBC) < 3.0 × 103/μL; absolute neutrophils < 2.0 × 103/μL; and platelets < 150 or 
> 400 × 103/μL at screening or Day –1. Complete blood count (CBC) clinical laboratory 
results that are considered clinically relevant and unacceptable by the investigator at 
Day –1. 
 
Page 48 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
16. History of complement deficiency or complement activity below 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. 
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 a mAb, or participation in a clinical study 
of a 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. Major surgery or hospitalization within 90 days prior to dosing. 
21. Contraindication to receiving MCV4 and/or serogroup B vaccine, including severe 
allergic reaction to a previous dose of MCV4 and/or serogroup B vaccine; severe allergy 
to any vaccine component; or previous diagnosis of Guillain-Barré syndrome. 
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 (anaphylaxis, 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 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 of dosing or more than 
499 mL of blood within 56 days of dosing. 
30. History of continuous topical/inhaled or systemic steroid use > 1 month 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. 
32. Regular use of nonprescription, over-the-counter medications, including herbal 
remedies/supplements, within 14 days prior to study drug administration. Multivitamins, 
 
Page 49 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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 1 month 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 the first dosing. 
36. Subjects with any medical history, conditions or risks, which in the opinion of the 
investigator, may interfere with the subject's full participation in the study, or compliance 
with the protocol, or pose any additional risk for the subject, or confounds 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/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.  
Unless the PI 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). 
 
Page 50 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
11. 
TREATMENT OF SUBJECTS 
11.1. 
Description of Study Drug 
The investigational product is described in Table 11. 
 
Table 11: 
Investigational Product 
 
Investigational Product 
Product Name 
ALXN1210 
Dosage Form 
Sterile solution for intravenous administration 
Unit Dose 
150 mg/vial 
Route of Administration 
Intravenous 
Physical Description 
Sterile, preservative-free solution 
Manufacturer 
Alexion Pharmaceuticals, Inc. 
BP= British Pharmacopoeia; Ph. Eur. = European Pharmacopoeia.  
 
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:  
1. MCV4 vaccination at least 56 days prior to dosing with ALXN1210 (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, and the booster must be 
administered at least 28 days prior to dosing on Day 1, with at least 28 days between 
the first and second injections. 
3. Prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 
1,600,000 units) for the duration of the reduced complement activity, ie, until 
complement activity is predicted to be restored to normal based on the expected drug 
concentration, and based on the in vitro hemolytic activity assay analysis for the 
cohort at 2 to 5 weeks prior to the planned termination of the antibiotic prophylaxis 
(see Section 5.1.4.1).  
 
Page 51 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
The first dose of antibiotic will be administered orally on Day –1 in the evening, prior to the 
Day 1 (first dose) of ALXN1210. 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 multiple-
dose study of ALXN1210: 
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 and Kings College 
Hospital NHS Foundation 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 session (see the Informed Consent Form [ICF], Part 2, Risk of 
Side Effects). 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 ICF, will take place at specific time points throughout the study as noted in the 
Schedules 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 informed consent until the first dose of study drug) and concomitant 
medications (any drug or substance taken by the subject after the first dose of study drug until 
completion of the last study visit) will be recorded on the subject’s case report form. 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 the first dose of study drug) 
and concomitant procedures (any therapeutic intervention [eg, surgery/biopsy, physical therapy] 
performed after the first dose of study drug until completion of the last study visit) will be 
recorded on the subject’s case report form. 
 
Page 52 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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. 
Concomitant procedures are not allowed unless medically indicated. 
The use of concomitant therapies defined above must be recorded. Adverse events related to 
administration of these therapies or procedures must be documented. 
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 (coffee, tea, chocolate) are prohibited for at least 
24 hours prior to admission through discharge from the clinical unit, and for 24 hours prior to 
each follow-up visit. 
Alcohol: Alcohol use is prohibited 48 hours prior to admission until discharge from the clinical 
unit, and for 24 hours prior to each follow-up visit. 
Meals: No outside food or drink is permitted at the clinical site. 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 
infusion (SOI) until discharge from the clinical unit. 
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 investigative site 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 site to ensure compliance with the 
protocol, and communicate with sites on a regular basis regarding study protocol 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 clinical site’s standard operating procedures. 
 
Page 53 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
11.7. 
Randomization and Blinding 
This is an open-label study (subjects and on-site medical/nursing staff and pharmacy staff are 
aware of study drug/dose assignment). Eligible subjects who meet the inclusion/exclusion 
criteria will be sequentially enrolled and assigned to receive ALXN1210. Once a subject 
identification number has been assigned to 1 subject, it may not be assigned to another subject. 
 
Page 54 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT 
12.1. 
Study Drug 
Each vial of study drug contains 150 mg of ALXN1210 in 10 mM sodium phosphate, 
150 mM sodium chloride, 0.02% polysorbate 80, and Water for Injection. ALXN1210 is 
formulated at pH 7.0 and is presented as a sterile, preservative-free 10-mg/mL solution for IV 
administration, supplied in 20-mL single-use vials, and will be diluted in 0.9% Sodium Chloride 
Injection European Pharmacopoeia (Ph. Eur.) or British Pharmacopoeia (BP) and administered 
by IV infusion at a fixed rate of 686 mg/h, excluding interruption for safety or technical reasons. 
ALXN1210 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 Investigator’s Brochure 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. 
12.4. 
Study Drug Preparation 
Preparation of ALXN1210 doses must be performed in accordance with site-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 as indicated in Table 12. 
12.4.1. 
ALXN1210 Dose Preparation 
ALXN1210 will be diluted with 0.9% Sodium Chloride Injection Ph. Eur. or BP and 
administered by IV infusion at a fixed rate of 686 mg/h, excluding interruption for safety or 
technical reasons.   
Table 12: 
Dosing Reference Chart for ALXN1210 Dose Preparation  
Cohort 
ALXN1210 Dose  
(mg) 
ALXN1210 Volume 
per Dose  
(mL) 
Diluent Volume 
 per Dose  
(mL) 
Infusion 
Volume  
(mL) 
1 
1 dose of 400 mg 
40 
40 
80 
2 
1 dose of 800 mg 
80 
80 
160 
3 
5 doses of 800 mg each 
80 
80 
160 
Please refer to the pharmacy manual for additional dose preparation instructions. 
 
Page 55 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
12.4.2. 
In-Use Shelf Life 
ALXN1210 will be diluted with 0.9% Sodium Chloride Injection Ph. Eur. or BP before 
administration (dosing solution). The dosing solution is stable for 6 hours at room temperature 
15°C to 25°C (59°F to 77°F) and for 24 hours at 2°C to 8°C (36°F to 46°F). The expiration date 
and time of the dosing solution is calculated from the time dose preparation is complete. The 
dose must be administered within the expiration date and time. 
12.5. 
Administration 
All doses of ALXN1210 will be administered by IV infusion, using IV sets with in-line filters, at 
a fixed rate of 686 mg/h (equivalent to 137 mL/h), excluding interruption for safety or technical 
reason. Infusion volume and duration is summarized in Table 13. Infusion of a subject must be 
completed before starting the infusion of the next subject in the same cohort. For further 
information regarding the preparation and administration of study drug, please see the Pharmacy 
Manual. 
Table 13: 
Infusion Volume and Duration 
Cohort 
ALXN1210 Dose (mg) 
Infusion 
Volume 
(mL) 
Infusion 
Duration  
(Minutes)* 
Infusion 
Rate 
(mg/h) 
Infusion 
Rate  
(mL/h) 
Concentration 
of Dosing 
Solution 
(mg/mL) 
1 
1 dose of 400 mg  
80 
50 
686 
137 
5.0 
2 
1 dose of 800 mg 
160 
90 
686 
137 
5.0 
3 
5 doses of 800 mg each 
160 
90 
686 
137 
5.0 
*Infusion durations are approximate. 
For safety reasons, subjects will remain supine or semi-reclined for the time of drug 
administration and until at least 2 hours after end of infusion (EOI). Failure of subjects to comply 
with this requirement does not constitute a deviation from the protocol if it is medically 
necessary, procedurally required, or to go to the bathroom. When appropriate, subjects will be 
accompanied by a staff member during ambulation. 
Time of dosing (t = 0) will be defined as ALXN1210 SOI. All procedures will be performed in 
relation to SOI or EOI as described in the Schedules of Assessments (Section 9). 
12.6. 
Management of Potential Drug Infusion Reactions 
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 
its 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. 
 
Page 56 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
To ensure that reactions can be dealt with promptly there will be at least 15 minutes between the 
end of infusion in one subject and the start of infusion in the next subject; no more than 
4 subjects will be dosed per day. Any reactions will be treated and taken into account in the dose 
continuation/escalation and toxicity rules. 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 resulting 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. 
12.7. 
Study Drug Accountability 
The study site must maintain accurate records demonstrating dates and amount of study drug 
received from Alexion, to whom dispensed (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 site, the investigator must obtain prior 
approval by Alexion. The investigator must notify Alexion, in writing, of the method, date, and 
location of 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. 
 
Page 57 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
13. 
PHARMACOKINETIC ASSESSMENTS 
13.1. 
Blood Sample Collection 
No more than 470 mL of blood will be taken within each 16-week period. This allows for 
regeneration of RBCs and is in accordance with the guidance of NHS Blood and Transplant 
(http://www.blood.co.uk/about-blood/how-the-body-replaces-blood/). Please refer to the 
laboratory manual for specific details regarding blood volumes. 
After study drug administration, blood samples for the determination of serum ALXN1210 
concentrations will be collected at the time points indicated in the Schedules of Assessments 
(Section 9), with the actual blood sampling dates and times being recorded and used in the PK 
calculations. The timing of PK sample collection may be altered based on initial PK results to 
ensure appropriate PK monitoring. The number of PK sampling time points for any given subject 
will not exceed the currently planned number of time points.  
Serum concentrations will be collected at the time points indicated in Table 14. 
Table 14: 
Collection Time Points for Serum Concentrations of ALXN1210  
Collection Time Points for Cohort 1  
(Days 1-120) 
On Day 1 before dosing (within 15 min prior to the start of infusion [SOI]); end-of-infusion (EOI), 
30 min after the EOI, and at the following time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 
(24 hr), Day 3 (48 hr), Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 
hr), Day 36 (840 hr), Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 
90 (2136 hr), and Day 120 (2856 hr)  
Collection Time Points for Cohort 2 
(Days 1-140) 
On Day 1 before dosing (within 15 min prior to the start of infusion [SOI]); end-of-infusion (EOI), 
30 min after the EOI, and at the following time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 
(24 hr), Day 3 (48 hr), Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 
hr), Day 36 (840 hr), Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 
90 (2136 hr), Day 120 (2856 hr), and Day 140 (3336 hr) 
Collection Time Points for Cohort 3  
Period 1  
(Days 1-28) 
On Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, at the following 
time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), Day 5 (96 hr); Day 8 
(168 hr), Day 15 (336 hr), and Day 22 (504 hr) 
Period 2  
(Days 29-56) 
Before dosing on Day 29 (within 15 min prior to the SOI), EOI on Day 29, 30 min after the EOI, at 
the following time points:  Day 29 (4 hr and 8 hr), Day 30 (24 hr), Day 31 (48 hr), Day 33 (96 hr), 
and Day 43 (336 hr) 
Period 3  
(Days 57-84) 
Before dosing on Day 57 (within 15 min prior to the SOI), EOI on Day 57, 30 min after the EOI, at 
the following time points:  Day 57 (4 hr and 8 hr), Day 58 (24 hr), Day 59 (48 hr), Day 61 (96 hr), 
and Day 71 (336 hr) 
Period 4  
(Days 85-112) 
Before dosing on Day 85 (within 15 min prior to the SOI), EOI on Day 85, 30 min after the EOI, at 
the following time points:  Day 85 (4 hr and 8 hr), Day 86 (24 hr), Day 87 (48 hr), Day 89 (96 hr), 
and Day 99 (336 hr) 
Period 5 and 
Follow-up  
(Days 113-298) 
Before dosing on Day 113 (within 15 min prior to SOI), EOI and 30 min after the EOI on Day 113, at 
the following time points:  Day 113 (4 hr and 8 hr), Day 114 (24 hr), Day 115 (48 hr), Day 117 
(96 hr), Day 120 (168 hr), Day 127 (336 hr), Day 134 (504 hr), Day 141 (672 hr), Day 148, Day 155, 
Day 162, Day 169, Day 183, Day 197, Day 225, Day 253, Day 298 
Please refer to the SOM for time windows for collection, and to the laboratory manual for details 
on sample collection including blood volume requirements. 
 
Page 58 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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.  
13.3. 
Sample Analysis 
Detailed instructions on the procedure for collection, processing, storage, and shipment of the 
blood samples for PK analysis will be provided in the laboratory manual. All sample analysis 
will be performed by Alexion or designee. 
 
Page 59 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
14. 
PHARMACODYNAMIC ASSESSMENTS 
14.1. 
Blood Sample Collection 
Blood samples for analyses of total and free C5 concentrations, cRBC hemolysis, and potentially 
other measures of C5 activation will be collected at the time points indicated in Table 15.  
Table 15: 
Collection Time Points for Serum C5 Levels and cRBC Hemolysis 
Collection Time Points for Cohort 1  
(Days -1-120) 
On Day -1, on Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, and 
at the following time points (relative to  SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), and 
Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 hr), Day 36 (840 hr), 
Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 90 (2136 hr), and Day 
120 (2856 hr) 
Collection Time Points for Cohort 2  
(Days -1-140) 
On Day -1, on Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, and 
at the following time points (relative to  SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), and 
Day 5 (96 hr), Day 8 (168 hr), Day 15 (336 hr), Day 22 (504 hr), Day 29 (672 hr), Day 36 (840 hr), 
Day 43 (1008 hr), Day 50 (1176 hr), Day 57 (1344 hr), Day 71 (1680 hr), Day 90 (2136 hr), Day 120 
(2856 hr), and Day 140 (3336 hr) 
Collection Time Points for Cohort 3  
Period 1  
(Days -1-28) 
 
On Day -1, on Day 1 before dosing (within 15 min prior to the SOI), EOI, 30 min after the EOI, at 
the following time points (relative to SOI on Day 1): 4 hr, 8 hr, Day 2 (24 hr), Day 3 (48 hr), Day 5 
(96 hr), Day 8 (168 hr), Day 15 (336 hr), and Day 22 (504 hr) 
Period 2  
(Days 29-56) 
Before dosing on Day 29 (within 15 min prior to the SOI), EOI on Day 29, 30 min after the EOI, at 
the following time points:  Day 29 (4 hr and 8 hr), Day 30 (24 hr), Day 31 (48 hr), Day 33 (96 hr), 
and Day 43 (336 hr) 
Period 3  
(Days 57-84) 
Before dosing on Day 57 (within 15 min prior to the SOI), EOI on Day 57, 30 min after the EOI, at 
the following time points:  Day 57 (4 hr and 8 hr), Day 58 (24 hr), Day 59 (48 hr), Day 61 (96 hr), 
and Day 71 (336 hr) 
Period 4  
(Days 85-112) 
Before dosing on Day 85 (within 15 min prior to the SOI), EOI on Day 85, 30 min after the EOI, at 
the following time points:  Day 85 (4 hr and 8 hr), Day 86 (24 hr), Day 87 (48 hr), Day 89 (96 hr), 
and Day 99 (336 hr) 
Period 5 and 
Follow-up  
(Days 113-298) 
Before dosing on Day 113 (within 15 min prior to SOI), EOI and 30 min after the EOI on Day 113, at 
the following time points:  Day 113 (4 hr and 8 hr), Day 114 (24 hr), Day 115 (48 hr), Day 117 (96 
hr), Day 120 (168 hr), Day 127 (336 hr), Day 134 (504 hr), Day 141 (672 hr), Day 148, Day 155, 
Day 162, Day 169, Day 183, Day 197, Day 225, Day 253, and Day 298 
 
Please refer to the SOM for time windows for collection, and to the laboratory manual for details 
on sample collection including blood volume requirements. 
14.2. 
Criteria for Evaluation 
All subjects providing PD samples will be included in the PD analysis population. 
14.3. 
Sample Analysis 
Detailed instructions on the procedure for collecting, processing, storing, and shipping of blood 
samples for PD analysis will be provided in the laboratory manual. All sample analysis will be 
performed by Alexion or designee. 
 
Page 60 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
15. 
IMMUNOGENICITY ASSESSMENTS 
15.1. 
Blood Sample Collection 
Samples for ADA will be collected at the time points indicated in Table 16. 
Table 16: 
Collection Time Points for Serum Samples for Immunogenicity Analyses of 
Antidrug Antibodies to ALXN1210  
Collection Time Points for Cohort 1  
(Days 1-120) 
Pre-dose on Day 1, and on Day 15, Day 29, Day 57, Day 90, and Day 120 
Collection Time Points for Cohort 2  
(Days 1-140) 
Pre-dose on Day 1, and on Day 15, Day 29, Day 57, Day 90, Day 120, and Day 140 
Collection Time Points for Cohort 3  
Periods 1 to 5 
(Days 1-298) 
Predose on Day 1; on Day 8, Day 15, and Day 22 after Dose 1; on Day 29 prior to Dose 2 and on Day 
43 after Dose 2; on Day 57 prior to Dose 3 and on Day 71 after Dose 3; on Day 85 prior to Dose 4 and 
on Day 99 after Dose 4; on Day 113 prior to Dose 5 and on Day 120, Day 141, Day 169, Day 197, 
Day 225, Day 253, and Day 298 following Dose 5 
 
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 time windows for collection, and to the laboratory manual for details 
on sample collection including blood volume requirements. 
15.2. 
Criteria for Evaluation 
All subjects providing a predose and a postdose sample for ADA will be included in the 
immunogenicity analysis population. 
15.3. 
Sample Analysis 
The immunogenicity assay will evaluate ADA to ALXN1210. Detailed instructions on the 
procedure for collecting, processing, storing, and shipping blood samples for immunogenicity 
analysis will be provided in the laboratory manual. All sample analyses will be performed by 
Alexion or designee. 
 
Page 61 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
16. 
ASSESSMENT OF SAFETY 
Safety assessments will include physical examination findings, vital signs measurements, 
immunogenicity (antidrug antibody [ADA]) testing, laboratory evaluations, ECGs, infusion site 
evaluations (eg, bleeding, bruising, erythema, swelling, induration, and pain), and monitoring of 
AEs. Adverse events will be graded according to CTCAE v4.03, published June 14, 2010. 
Laboratory evaluations will include hematology, chemistry, and coagulation panels, CBC with 
differential, urinalysis, and a serum pregnancy test for female subjects. The potential risks of 
ALXN1210, specifically the risk of infection, will be reviewed with the subjects at screening and 
on a regular basis throughout the course of the study, after dosing. Subjects will meet with the 
investigator or designee to discuss the potential safety risks of ALXN1210 and address any 
safety concerns on the part of the subject at the time points shown in the Schedule of 
Assessments. During the second, third, and fourth dosing periods of Cohort 3, the subjects will 
be contacted by telephone to assess selected safety information. 
16.1. 
Safety Parameters 
Clinical and laboratory assessments will be performed to assess safety of ALXN1210. The 
timing of the assessments is described in the Schedules of Assessments (Section 9). Any 
abnormal result should be followed until resolution or stabilization. 
16.1.1. 
Demographic/Medical History 
A review of demographic parameters, including age, gender, race, and ethnicity will be 
performed as described in the Schedules of Assessments (Section 9). A complete medical history 
will be taken and documented. 
16.1.2. 
Vital Signs 
Vital signs will be taken after the subject has been resting in the supine or semi-recumbent 
position for at least 5 minutes and will include temperature (°C; oral), respiratory rate, supine 
blood pressure, and pulse. The timing of vital sign assessments is described in the Schedules 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. 
16.1.3. 
Weight and Height 
Weight, height, and BMI will be recorded as described in the Schedules of Assessments 
(Section 9). 
16.1.4. 
Physical Examination 
Each examination will include the following assessments: general appearance; skin; head, ear, 
eye, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous 
system; and musculoskeletal. 
 
Page 62 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
16.1.5. 
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 Schedules of Assessments (Section 9). In addition, 
continuous cardiac registration will be performed at each dose administration from predose 
through the duration of infusion. 
Heart rate, PR, QRS, RR, and QT will be measured and corrected QTcF intervals will be 
calculated. 
16.1.6. 
Laboratory Assessments 
Blood samples for analysis of hematology, clinical chemistry, coagulation, urinalysis/urine 
chemistry, virus serology, and drug/alcohol screening parameters will be collected as described 
in the Schedules 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 Study Manual. 
16.1.6.1. Hematology 
Blood will be analyzed for the following hematology parameters: platelet, RBC, 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 Schedules of Assessments (Section 9). 
16.1.6.2. 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 Schedules of Assessments (Section 9). 
16.1.6.3. 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 Schedules of Assessments (Section 9). 
16.1.6.4. 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. 
 
Page 63 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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 Schedules of 
Assessments (Section 9). 
16.1.6.5. 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 hepatitis B core antibody (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. 
16.1.6.6. 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). Alcohol breath 
tests will be performed. If positive prior to dosing, dosing will not proceed. 
Timing of urine drug and alcohol breath tests are described in the Schedules of Assessments 
(Section 9). 
16.1.6.7. Pregnancy Testing 
Pregnancy testing (beta human chorionic gonadotrophin) will be performed in all female subjects 
(Section 17.8). The timing of pregnancy testing is described in Schedules of Assessments 
(Section 9). 
16.1.6.8. Tuberculosis 
Blood samples for a QuantiFERON®-TB test will be collected as described in the Schedules of 
Assessments (Section 9). 
16.1.6.9. 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.  
Blood samples will be collected at baseline and during follow-up for measurement of CH50 
activity using an in vitro liposome immunoassay to confirm normalization of complement 
activity. If a normal CH50 result is obtained from a subject’s CH50 sample collected during 
 
Page 64 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
follow-up, antibiotic prophylaxis can be stopped and the additional scheduled CH50 samples are 
not required. If the last CH50 sample is not normal, the baseline sample may be analyzed (see 
Schedules of Assessments in Section 9) and the investigator will contact the subject regarding 
whether antibiotic prophylaxis must be further extended. 
16.1.6.10. Serum Bactericidal Antibody  
An SBA titer against meningococcus Group A, C, W135, and Y will be performed at screening. 
Titer measurements will be used to exclude subjects without an immune response from being 
dosed. 
 
Page 65 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
17. 
ADVERSE EVENT MANAGEMENT 
The investigator is responsible for detecting, assessing, documenting and reporting all AEs. All 
AEs will be recorded from the signing of informed consent 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. 
17.1. 
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, which 
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: 
• Drug overdose 
• Drug withdrawal 
• Drug misuse 
• Drug interactions 
• Extravasation 
 
Page 66 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
• Exposure during pregnancy 
• 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 gall bladder) 
• Pre-existing diseases or conditions present 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) 
17.2. 
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 Room visit 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 which 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 
 
Page 67 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
prevent 1 of the other outcomes listed in the definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug 
abuse. 
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. 
17.3. 
Severity Assessment 
All AEs will be graded according to criteria from CTCAE v4.03, published June 14, 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. 
17.4. 
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 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. 
 
Page 68 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
• 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 event, corresponds 
with the known pharmaceutical profile, improvement on discontinuation, 
reappearance on rechallenge. 
17.5. 
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. 
17.6. 
Recording Adverse Events 
All observed or volunteered AEs, regardless of dose cohort or causal relationship, must be 
reported as described in Section 17.4 (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 gall bladder). 
 
Page 69 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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. 
17.7. 
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 site 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 the same contact information. 
Additional follow-up information, if required or available, should be entered into the case report 
form and sent to sponsor within 24 hours of the investigator or study site staff becoming aware 
of this additional information via the reporting process outlined above. These reporting timelines 
need to be followed for all initial SAE cases and follow-up versions of the initial cases. 
For all SAEs, the investigator must provide the following: 
• Appropriate and requested follow-up information in the time frame detailed above 
• Causality of the serious event(s) 
• Outcome of the serious event(s) 
• Medical records and laboratory/diagnostic information 
17.8. 
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 method 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 continue in 
 
Page 70 of 85 
 
 
 
CONFIDENTIAL 
 
PPD
PPD


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
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. 
17.9. 
Reporting Requirements 
This protocol will use the current Investigator’s Brochure as the Reference Safety Document. 
The expectedness and reporting criteria of an SAE will be determined by Alexion, based on the 
Reference Safety Document. 
17.9.1. 
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 which 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, Ethics Committees, and the investigator. 
17.9.2. 
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 in the case report form, and are retrieved by or submitted to the 
sponsor at regular monthly intervals, or more frequently during the course of the investigation. 
 
Page 71 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
18. 
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 in the case report form. This information will be provided to the respective study 
sites by means of electronic or manual queries. 
The investigator or designee will prepare and maintain adequate and accurate source documents 
(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. 
 
Page 72 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
19. 
STATISTICS 
19.1. 
Statistical Analysis Plan Summary 
A formal statistical analysis plan 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. 
19.2. 
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, cRBC hemolysis data, or other data measuring C5 activation to enable the 
evaluation of the PD effects. The PD population will be used for PD summaries. 
The immunogenicity analysis population will consist of all subjects who have a predose and 
postdose ADA sample collected. 
19.3. 
Sample Size and Power 
The sample size of 4 subjects in each of the single-dose cohorts (Cohorts 1 and 2) and 6 to 
8 subjects in the 800 mg multiple-dose cohort will allow for the characterization of the central 
tendency of PK parameters as they relate to ALXN1210 and to gain initial knowledge of PK/PD 
relationships in Japanese subjects. To ensure future modeling and simulations are accurate, it is 
preferred to estimate the PK parameters with a maximum imprecision of < 25% following the IV 
administration of ALXN1210. Six subjects in Cohort 3 will provide 23.3% maximum 
imprecision (Table 17) for the estimation of area under the serum concentration versus time 
curve from time 0 extrapolated to infinity (AUC∞), in terms of the relative distance of the lower 
90% confidence limit from the observed PK parameter that will be obtained with 80% assurance 
and assuming the within-subject SD of the log-transformed AUC∞ is as much as 0.19. 
Table 17: 
Estimation of the Maximum Imprecision in the Estimate of PK Parameters 
for Selected Sample Sizes 
Number of Subjects on Active 
Maximum Imprecision (%) 
4 
33.6 
6 
23.3 
8 
18.9 
 
Page 73 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
19.4. 
Descriptive Statistics 
All continuous variables will be summarized by cohort and time point with descriptive statistics 
(the number of nonmissing values, mean, SD, median, minimum, and maximum). All categorical 
variables will be summarized by cohort and time point with frequency counts and percentages. 
Treatment group refers to all dose cohorts of ALXN1210. 
19.5. 
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 treatment group. Demographics and baseline 
characteristics will be summarized for all subjects by each treatment dose and overall. 
19.6. 
Safety Analysis 
Safety analyses will be performed on the safety population, and will be reported by each 
treatment dose. 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 treatment dose and overall, by severity, and by relationship to study 
drug. 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 signs and laboratory assessments (chemistry, CBC with 
differential, and urinalysis) will be summarized by each treatment dose. Laboratory parameter 
values will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE; v4.03, published June 14, 2010). Shift tables by treatment group 
will be produced for these 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 postdose 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 treatment dose. 
An outlier analysis will be performed that will summarize the frequency and percentage of 
subjects who meet any of the following outlier criteria at each visit by treatment group: 
• QT, QTcF interval > 450 msec 
• QT, QTcF interval > 480 msec 
• QT, QTcF interval > 500 msec 
• QT, QTcF interval increases from baseline > 30 msec 
• QT, QTcF interval increases from baseline > 60 msec 
 
Page 74 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
All concomitant medications will be coded using the WHO Drug Dictionary, and the frequency 
and percentage of concomitant medications will be summarized. 
19.7. 
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 using 
Phoenix WinNonlin 6.3 or higher. 
The following PK parameters will be derived: maximum observed serum concentration (Cmax) 
after each dose, time to maximum observed serum concentration (tmax), the observed minimum 
serum concentrations (Cmin) just prior to Periods 2 to 5 (and 28 days after Period 5 dose) for 
Cohort 3, area under the serum concentration versus time curve from time 0 to the last 
quantifiable concentration (AUCt) after each dose, area under the curve from time 0 (dosing) to 
the end of the dosing interval (AUCτ), apparent terminal-phase elimination rate constant (λz), 
terminal elimination half-life (t½), total clearance (CL), volume of distribution (Vss), assessment 
of steady-state, and accumulation at steady state. Assessment of dose proportionality and time 
linearity in PK parameters may be conducted. 
19.8. 
Pharmacodynamic and Immunogenicity Analyses 
The PD effects of ALXN1210 administered intravenously 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 initially performed on samples collected as described in the 
Schedules of Assessments (Section 9). 
An exploratory PK/PD analysis may be performed. 
Immunogenicity, as measured by ADA, will be summarized in tabular form by treatment dose 
and by-subject listings. 
19.9. 
Interim Analysis 
Interim analyses may be performed as needed. 
 
Page 75 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
20. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
20.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Alexion 
(sponsor) will visit the investigational study site to: 
• 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 or designee will have regular contact with the 
investigational site, for 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 in the case report form, and that investigational product 
accountability checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the case 
report form 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; 
• Confirm AEs and SAEs have been properly documented in the case report form, and 
confirm 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. 
20.2. 
Audits and Inspections 
Authorized representatives of the sponsor or designee, a regulatory authority, or an IRB/IEC may 
visit the site 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 Conference on Harmonisation (ICH), and any applicable 
regulatory requirements. The investigator should contact the sponsor or designee immediately if 
contacted by a regulatory agency about an inspection. 
 
Page 76 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
20.3. 
Institutional Review Board/Independent Ethics Committee 
The investigator must obtain IRB/IEC approval for the clinical study. 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. 
20.4. 
Safety Review Committee 
Since its primary function will be to ensure subject safety, the members of the SRC will have 
access to all safety data. For additional details regarding the SRC, please see Section 8.5. 
20.5. 
Regulatory Agency 
As required by the United Kingdom regulatory agency, 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. 
 
Page 77 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
21. 
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 20.2 for more details 
regarding the audit process. 
 
Page 78 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
22. 
ETHICS 
22.1. 
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 enrolling 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 any 
protocol amendments prior to implementation at the study site. 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. 
22.2. 
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. 
22.3. 
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. 
22.4. 
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. 
 
Page 79 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
23. 
DATA HANDLING AND RECORDKEEPING 
23.1. 
Inspection of Records 
The sponsor or designee will be allowed to conduct site 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. 
23.2. 
Retention of Records 
The clinical site will maintain adequate study records according to local regulatory requirements 
after completion or termination of 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 clinical site 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 any documentation relating to the study, the investigator must permit access 
to such records. 
 
Page 80 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
24. 
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. 
 
Page 81 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
25. 
LIST OF REFERENCES 
 
 1.  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. 
 2.  Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ. Thrombocytopenia caused 
by the development of antibodies to thrombopoietin. Blood 2001 Dec 1;98(12):3241-8. 
 3.  Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, 
Brown SG, Camargo CA, Jr., Cydulka R, Galli SJ, et al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. 
J.Allergy Clin.Immunol. 2006 Feb;117(2):391-7. 
 4.  Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. 
Clin.Microbiol.Rev. 1991 Jul;4(3):359-95. 
 5.  Yazdankhah SP, Caugant DA. Neisseria meningitidis: an overview of the carriage state. 
J.Med.Microbiol. 2004 Sep;53(Pt 9):821-32. 
 6.  Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen 
DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal 
nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011 Jun 
23;117(25):6786-92. 
 7.  Leeds Teaching Hospitals NHS Trust, Kings College Hospital NHS Foundation Trust.  
National Specialised Commissioning Team (NSCT) Service Specification Paroxysmal 
Nocturnal Haemoglobinuria (PNH). 2013. 
 8.  Zuber J, Fakhouri F, Roumenina LT, Loirat C, Fremeaux-Bacchi V. Use of eculizumab for 
atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat.Rev.Nephrol. 2012 
Nov;8(11):643-57. 
 
 
 
Page 82 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
26. 
APPENDICES 
 
 
Page 83 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
26.1. 
Appendix 1 
Acute Infusion Reactions Algorithm 
 
 
Page 84 of 85 
 
 
 
CONFIDENTIAL 
 


Protocol ALXN1210-HV-104 
 
Alexion Pharmaceuticals, Inc. 
Amendment 1, 24 August 2016 
 
26.2. 
Appendix 2 
United Kingdom Resuscitation Council Anaphylaxis Algorithm 
 
 
 
Page 85 of 85 
 
 
 
CONFIDENTIAL 
 

SAP_001.pdf: 
A Phase 1, Open-label, Single Ascending and Multiple Set 
Dose Study to Evaluate the Safety, Tolerability, 
Immunogenicity, Pharmacokinetics, and Pharmacodynamics 
of ALXN1210 Administered Intravenously to Healthy 
Japanese Subjects 
Unique Protocol ID: 
ALXN1210-HV-104 
NCT Number: 
NCT05288816 
EudraCT Number: 
2015-005468-40 
Date of SAP: 
09 October 2016 
 


Clinical Study Report 
 
ALXN1210-HV-104 
16.1 Study Information 
 
 
 
 
 
Alexion Confidential 
 
9. 
DOCUMENTATION OF STATISTICAL METHODS 
 
• Statistical Analysis Plan, Final Version 2.0, Dated 09 Oct 2016 


Statistical Analysis Plan 
Pharmacology 
SPONSOR'S REFERENCE NUMBER: ALXN1210•HV•104 
EUDRACT NUMBER: 2015-005468-40 
RPL STUDY CODE: C15045 
STATISTICAL ANALYSIS PLAN 
A Phase 1, Open-Label, Single Ascending and Multiple Set Dose 
Study to Evaluate the Safety, Tolerability, Immunogenicity, 
Pharmacokinetics, and Pharmacodynamics of ALXN1210 
Administered Intravenously to Healthy Japanese Subjects 
FINAL VERSION 2.0, 09 OCT 2016 
Issued by:
Richmond Pharmacology 
Statistician 
Approved by:
Richmond Pharmacology (Consultant - ICRC) 
Statistician 
Approved by:
Richmond Pharmacology 
Research Director 
Approved by:
Senior Medical Director 
Alexion Pharmaceuticals, Inc 
Approved by:
Director, Biostatistics 
Alexlon Pharmaceuticals, Inc 
Approved by:
Associate Director, Clinical Pharmacology 
Alexion Pharmaceuticals, Inc 
C15045 (ALXN1210-HV_104) SAP Final 2.0- 090ct2016 
Signature ..
Date ... 
.
Date ... f.!.
Date ••.•• 
.. 
..... 
Signature ..................... . 
Date ............................ . 
Signature • .-, _,,.t .... •.• , • ._..,,U .. t 
Date ........
Signature ..
Date .. 
9. !. .... ?.-.?.!. ;6 
Page 1 of 13 
I 
I 
[ 
• 
> l 
I 
Alexion Confidential
Page 2 of 15
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan 
Pharmacology 
SPONSOR'S REFERENCE NUMBER: ALXN1210-HV-104 
EUDRACT NUMBER: 2015•005468-40 
RPL STUDY CODE: C15045 
STATISTICAL ANALYSIS PLAN 
A Phase 1, Open-Label, Single Ascending and Multiple Set bose 
Study to Evaluate the Safety, Tolerability, Immunogenicity, 
Pharmacokinetics, and Pharmacodynamics of ALXN1210 
Administered Intravenously to Healthy Japanese Subjects 
FINAL VERSION 2.0, 09 OCT 2016 
Issued by:
Richmond Pharmacology 
Statistician 
Approved by: 
Richmond Pharmacology (Consultant- ICRC) 
Statistician 
Approved by
Rlchmond Pharmacology 
Research Director 
Approved by: 
Senior Medical Direetor 
Alexion Pharmaceuticals, Inc 
Approved by:
Director, Biostatistics 
Alexlon Pharmaceuticals, Inc 
Approved by: 
Associate Director, Clinical Pharmacology 
Alexion Pharmaceuticals, Inc 
C15045 (ALXN1210-HV_104) SAP Flnal2.0- 090ct2016.doG 
Signature .................... .. 
Date ................... , .....•... 
Signature ..................... . 
Date ............................ . 
Signature ..................... . 
Date ............................ . 
1 
OcA 
z..ol-b 
Date ............................ . 
Signature ..
Date .. /i. .. 
Signature ..................... . 
Date ............................ . 
Page 1 of 13 
Alexion Confidential
Page 3 of 15
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 2 of 13 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation or 
Specialist Term  
Explanation  
λz  
apparent terminal- elimination rate constant  
ADA 
antidrug antibody 
AE  
adverse event  
AUC∞ 
area under the serum concentration versus time curve from time 
0 extrapolated to infinity 
AUCt  
area under the serum concentration versus time curve from time 
0 to the last quantifiable concentration 
AUCτ  
area under the serum concentration versus time curve from time 
0 to the end of the dosing interval (tau) 
BLQ 
below the level of quantification 
BMI  
body mass index  
CL  
total body clearance  
Cmax  
maximum observed serum concentration  
Cmin  
minimum observed serum concentration  
CSR 
clinical study report 
cRBC  
chicken red blood cell 
CV 
coefficient of variation 
ECG  
electrocardiogram  
IMP 
Investigational Medicinal Product 
IV  
intravenous  
LLQ 
lower limit of quantification 
MedDRA 
medical dictionary for regulatory activities 
PD  
pharmacodynamic(s)  
PI 
principal investigator 
PK  
pharmacokinetic(s)  
PT 
preferred term 
QTcB  
QT interval corrected using Bazett’s formula  
QTcF  
QT interval corrected using Fridericia’s formula  
R 
accumulation ratio 
RPL 
Richmond Pharmacology Ltd 
SAE  
serious adverse event  
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
SD 
standard deviation 
SOC 
system organ class 
SRC  
safety review committee  
TEAE 
treatment-emergent adverse event 
TFL 
tables figures and listings 
t½ 
terminal elimination half-life  
tmax  
time to maximum observed serum concentration  
Vss  
volume of distribution at steady state 
WHO 
world health organization 
 
Alexion Confidential
Page 4 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 3 of 13 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................. 2 
1. 
INTRODUCTION ................................................................................... 4 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................... 4 
2.1 
Study objectives ............................................................................ 4 
2.2 
Endpoints ...................................................................................... 4 
3. 
NUMBER OF SUBJECTS AND RANDOMIZATION ......................................... 5 
3.2 
Number and Source of Subjects ....................................................... 5 
3.3 
Randomization and Blinding............................................................. 5 
4. 
STATISTICAL ANALYSES ....................................................................... 6 
4.1. 
Analysis Populations ....................................................................... 6 
4.2. 
Sample Size and Power ................................................................... 6 
4.3. 
Demographics, Baseline Characteristics, and Subject Disposition.......... 7 
4.4. 
Safety Analysis .............................................................................. 7 
4.5 
Pharmacokinetic Analysis ................................................................ 9 
4.6     Dose Proportionality ..................................................................... 11 
4.7. 
Pharmacodynamic Analyses ........................................................... 11 
4.8. 
Immunogenicity Analyses .............................................................. 12 
4.9 
Methods for Withdrawals, Missing Data, and Outliers ........................ 12 
4.10 
Protocol deviations ....................................................................... 12 
5. 
CONVENTIONS ................................................................................... 12 
Alexion Confidential
Page 5 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 4 of 13 
 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to define the variables and 
analysis methodology to address the study objectives. 
Final Protocol Amendment 1 dated 24 Aug 2016 was used in the preparation of 
this SAP. 
Pharmacokinetic parameters will be calculated by Alexion or its designee. 
Richmond Pharmacology Ltd (RPL) is responsible for performing statistical 
analyses. Tables, figures, and listings will be produced using Statistical Analysis 
Software (SAS) V9.2 or higher. 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study objectives 
The objectives of this study are: 
Primary 
 
To evaluate the safety and tolerability of single and multiple doses of 
ALXN1210 following intravenous (IV) administration to healthy Japanese 
subjects. 
Secondary 
 
To investigate the immunogenicity of ALXN1210 in healthy Japanese 
subjects. 
 
To characterize the pharmacokinetics (PK) of single and multiple doses of 
ALXN1210 in healthy Japanese subjects. 
 
To evaluate the pharmacodynamics (PD) effects of ALXN1210 as assessed 
by total and free C5 concentrations and chicken red blood cell (cRBC) 
hemolysis in healthy Japanese subjects. 
2.2 
Endpoints 
Safety, immunogenicity, PK, and PD endpoints are described in the sections to 
follow. Timing of assessments is displayed in the Schedules of Assessments. 
Safety Endpoints 
Safety endpoints include the following: 
 
Change from baseline in physical examination assessments 
 
Change from baseline in vital signs 
 
Incidence of antidrug antibody (ADA) measured via immunogenicity 
testing 
 
Change from baseline in electrocardiogram (ECG) parameters 
 
Change from baseline in laboratory measurements 
 
Incidence of Adverse Events (AE) and Serious Adverse Events (SAE) 
Pharmacokinetic Endpoints 
The following PK parameters will be evaluated: 
Alexion Confidential
Page 6 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 5 of 13 
 
 
Observed maximum serum concentration following all ALXN1210 doses 
(Cmax) following single dose (Cohort 1 and 2) and doses 1 and 5 (Cohort 
3); 
 
Dose-normalized Cmax, following single dose (Cohort 1 and 2) and doses 1  
and 5 (Cohort 3);  
 
Time to maximum observed serum concentration (tmax) following single 
dose (Cohort 1 and 2) and doses 1 and 5 (Cohort 3); 
 
Trough serum concentrations (Ctrough) just prior to Doses 2 to 5, and 28 
days after the 5th dose (Cohort 3); 
 
Area under the serum concentration versus time curve from time 0 to the 
last quantifiable concentration (AUCt) after single dose (Cohort 1 and 2) 
and after dose 5 (Cohort 3); 
 
Dose-normalized AUCt after single dose (Cohort 1 and 2) and following 
dose 5 (Cohort 3); 
 
AUC from time 0 (dosing) to the end of the dosing interval  (AUC) 
following doses 1 and 5 (Cohort 3). Following Dose 5, calculated over 
dosing interval (28 days); 
 
Terminal-phase elimination rate constant (λz) after single dose (Cohort 1 
and 2) and after dose 5 (Cohort 3); 
 
Terminal elimination half-life (t½) after single dose (Cohort 1 and 2) and 
after dose 5 (Cohort 3); 
 
Total body clearance of drug from the serum (CL) after single dose (Cohort 
1 and 2) and after dose 5 (Cohort 3); 
 
Volume of distribution at steady state (Vss) (Cohort 3); 
 
Assessment of steady state (Cohort 3); 
 
Accumulation at steady state (R) after the fifth dose (Cohort 3). 
Pharmacodynamic Endpoints 
Pharmacodynamic effects will be evaluated as follows: 
 
Change in serum total and free C5 concentration over time 
 
Change in cRBC hemolysis over time 
 
ALXN1210 concentration required for complete terminal complement 
inhibition based on PD effects evaluated. 
 
3. 
NUMBER OF SUBJECTS AND RANDOMIZATION 
3.2 
Number and Source of Subjects 
Up to 16 subjects are planned for evaluation of the primary and secondary 
objectives, and a maximum of 22 subjects could be enrolled and dosed. The total 
number of subjects dosed (including potential added subjects) will remain within 
a maximum of 6 subjects each in Cohorts 1 and 2 and 10 subjects in Cohort 3, 
for a maximum of 22 subjects in this study. 
3.3 
Randomization and Blinding 
This is an open-label study (subjects and on-site medical/nursing staff and 
pharmacy staff are aware of study drug/dose assignment). Eligible subjects who 
meet the inclusion/exclusion criteria will be sequentially enrolled and assigned to 
Alexion Confidential
Page 7 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 6 of 13 
 
receive ALXN1210. Once a subject identification number has been assigned to 1 
subject, it may not be assigned to another subject. 
4. 
STATISTICAL ANALYSES 
In general, descriptive statistics for continuous variables will include number of 
non-missing values, mean, standard deviation (SD), median, minimum, and 
maximum, by treatment group. 
Descriptive statistics for PK parameters will include number of observations, 
arithmetic mean, SD, arithmetic coefficient of variation (CV), geometric mean, 
geometric CV, median, minimum and maximum, by treatment group. 
Descriptive statistics for PD parameters will include number of observations, 
arithmetic mean, SD, median, minimum, and maximum, by treatment group. 
Categorical variables will be 
summarized using frequency counts 
and 
percentages by treatment group.  
Treatment group refers to all dose cohorts of ALXN1210. 
Baseline will be defined as the last value of the assessment recorded prior to first 
administration of Investigational Medicinal Product (IMP). For post-dose 
assessments the first scheduled value will be used for summary analysis if 
repeated measurements are made at a time-point. 
Deviations from the planned analyses will be described in the final integrated 
clinical study report. 
4.1. 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 analysis. 
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 analysis. 
The immunogenicity analysis population will consist of all subjects who have a 
pre-dose and post-dose ADA samples collected. 
Inclusion and exclusion from each analysis set will be decided at the Data Review 
Meeting prior to database lock. 
4.2. Sample Size and Power 
The sample size of 4 subjects in each of the single-dose cohorts (Cohorts 1 and 
2) and 6 to 8 subjects in the 800 mg multiple-dose cohort will allow for the 
characterization of the central tendency of PK parameters as they relate to 
ALXN1210 and to gain initial knowledge of PK/PD relationships in Japanese 
subjects. To ensure future modeling and simulations are accurate, it is preferred 
to estimate the PK parameters with a maximum imprecision of < 25% following 
the IV administration of ALXN1210. Six subjects in Cohort 3 will provide 23.3% 
Alexion Confidential
Page 8 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 7 of 13 
 
maximum imprecision (Table 1) for the estimation of area under the serum 
concentration versus time curve from time 0 extrapolated to infinity (AUC∞), in 
terms of the relative distance of the lower 90% confidence limit from the 
observed PK parameter that will be obtained with 80% assurance and assuming 
the within-subject SD of the log-transformed AUC∞ is as much as 0.19. 
Table 1: 
Estimation of the Maximum Imprecision in the Estimate of PK 
Parameters for Selected Sample Sizes 
Number of Subjects on 
Active 
Maximum Imprecision (%) 
4 
33.6 
6 
23.3 
8 
18.9 
4.3. 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 treatment group. Demographics and baseline characteristics will be 
summarized for all subjects by each treatment dose and overall on the safety 
population. If the remaining populations are different from the safety population, 
separate demographic tables will be produced. Continuous variables will be 
summarized using n, arithmetic mean, standard deviation, median, minimum, 
and maximum whereas categorical variables will be summarized by frequency 
and percentage by treatment group. 
4.4. Safety Analysis 
Safety analyses will be performed on the safety population, and will be reported 
by each treatment dose. 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. 
Adverse Events 
The incidence of treatment-emergent (after dosing) AEs (TEAEs) will be 
summarized using the safety population. The Medical Dictionary for Regulatory 
Activities (MedDRA®) dictionary Version 19.0 (or higher) will be used to classify 
all AEs reported during the study by System Organ Class (SOC) and preferred 
term (PT). A summary of adverse events including the incidence of subjects who 
experience TEAEs and incidence of TEAEs (number of events) will be presented 
for each treatment dose and overall, by severity and by relationship to study 
drug. SAEs will be summarized by system organ class and preferred term for 
each treatment dose and overall, by severity, and by relationship to study drug.  
SAEs and AEs resulting in withdrawal from the study will be listed. Subjects 
having multiple AEs within a category (e.g., overall, system organ class and 
preferred term) will be counted once in that category. For severity tables, a 
subject's most severe event within a category will be counted. In each table, 
Alexion Confidential
Page 9 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 8 of 13 
 
SOC will be presented in descending order of overall incidence rate (alphabetical 
order will be used in case of equal rates). 
Medical history 
Medical history data will be coded using MedDRA® dictionary Version 19.0 (or 
higher) and listed individually. 
Study drug administration 
Study drug administration data will be listed individually. 
Vital signs 
Vital signs data (systolic and diastolic blood pressure, heart rate, oral 
temperature, and respiration rate) will be listed for individual subjects. Summary 
statistics (n, arithmetic mean, SD, median, minimum, and maximum) of absolute 
values and changes from baseline will be calculated for each parameter by each 
treatment dose. 
Laboratory data  
Safety Laboratory parameters (blood chemistry hematology, coagulation and 
urinalysis) will be listed and abnormal parameters flagged as high (H) or low (L). 
Changes from baseline (continuous variables) will be summarized by each 
treatment dose based on scheduled values.  
For summary statistics, the lab value with “<” will be replaced with numeric 
value by removing the “<” sign. In the listings the values will be displayed as 
originally reported by the laboratory. 
Laboratory parameter values will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE; v4.03, 
published June 14, 2010). Parameters, not present in the above referenced 
document will not be graded. Shift tables by treatment group will be produced 
for these laboratory parameters by grade. 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.  
Individual profiles will be presented for the following laboratory parameters: GGT, 
ALT, AST, Hb, Creatinine, RBC, WBC, Potassium, Sodium, Uric Acid, Albumin, 
Total Protein and neutrophils. 
ECG 
The ECG parameters will be measured at the specified time-points, including 
heart rate, PR, RR, QRS, QT and QTcF intervals. For summary statistics the 
average of all time-point ECG readings will be calculated, as well as changes 
from pre-treatment baseline values will be assessed by each treatment dose. 
An outlier analysis will be performed that will summarize the frequency and 
percentage of subjects who meet any of the following outlier criteria at each visit 
by treatment group as follows: 
 
QT, QTcF interval > 450 msec 
 
QT, QTcF interval > 480 msec 
 
QT, QTcF interval > 500 msec 
Alexion Confidential
Page 10 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 9 of 13 
 
 
QT, QTcF interval increases from baseline > 30 msec 
 
QT, QTcF interval increases from baseline > 60 msec 
Previous and concomitant medications 
All previous and concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary version June 1, 2015 and the frequency and 
percentage of concomitant medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) and Preferred name. 
Physical examination 
Physical examination data will be listed. Change from baseline to each visit will 
be presented for each item of the Physical Examination separately, using shift 
tables. 
Infusion site evaluation 
Data from the Infusion site evaluations will be listed individually. 
Visual assessment scale for pain at infusion site 
Data from the Pain at infusion site will be listed. 
4.5 
Pharmacokinetic Analysis 
All serum concentration data will be listed for each individual subject and 
summarized at each time point by treatment group using the following 
descriptive statistics.   
• 
N (the number of subjects) 
• 
Arithmetic mean 
• 
SD 
• 
Arithmetic CV (inter-subject coefficients of variation) 
• 
Geometric mean 
• 
Geometric CV (inter-subject coefficients of variation) 
• 
Median 
• 
Minimum 
• 
Maximum. 
When a Below the Level of Quantification (BLQ) value occurs in a profile before 
the first measurable concentration, it is assigned a value of zero concentration. 
When a BLQ value occurs after a measurable concentration in a profile and is 
followed by a value above the Lower Level of Quantification (LLQ), then the BLQ 
will be omitted following visual inspection of the serum concentration versus time 
profile to assess the appropriateness of this assignment. When a BLQ value 
occurs at the end of a collection profile (after the last quantifiable concentration), 
the value is treated as missing data. When two BLQ values occur in succession, 
the profile is deemed to have terminated at the first BLQ value and any 
subsequent concentrations are omitted from PK calculations. 
Samples with no reportable value due to a bioanalytical issue or missing samples 
should be set to missing, and will not be included in the PK calculations. 
Alexion Confidential
Page 11 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 10 of 13 
 
When calculating the mean or median value for a concentration at a given time 
point, all BLQ values will be set to zero except when an individual BLQ falls 
between two quantifiable values, in which case it will be omitted. 
For tabulation, graphical representation and calculation purposes, all samples 
with no reportable value (or missing samples) observed after dosing will be set 
to missing. 
The figures of individual and mean concentrations versus nominal time on linear 
and semi-log scale will be plotted. 
The individual serum concentration data for ALXN1210-treated subjects, with 
actual sampling dates and times calculated relative to the start of the infusion, 
will be used to derive the PK parameters by non-compartmental analyses using 
Phoenix WinNonlin 6.3 or higher. 
The following PK parameters will be estimated: 
 
Observed maximum serum concentration following all ALXN1210 doses 
(Cmax) following single dose (Cohort 1 and 2) and doses 1 and 5 (Cohort 
3); 
 
Dose-normalized Cmax, following single dose (Cohort 1 and 2) and doses 1 
and 5 (Cohort 3); 
 
Time to maximum observed serum concentration (tmax) following single 
dose (Cohort 1 and 2) and doses 1 and 5 (Cohort 3); 
 
Trough serum concentrations (Ctrough) just prior to Doses 2 to 5, and 28 
days after the 5th dose (Cohort 3); 
 
Area under the serum concentration versus time curve from time 0 to the 
last quantifiable concentration (AUCt) after single dose (Cohort 1 and 2) 
and after dose 5 (Cohort 3); 
 
Dose-normalized AUCt after single dose (Cohort 1 and 2) and following 
dose 5 (Cohort 3); 
 
AUC from time 0 (dosing) to the end of the dosing interval (AUC) 
following doses 1 and 5 (Cohort 3). Following Dose 5, calculated over 
dosing interval (28 days); 
 
Terminal-phase elimination rate constant (λz) after single dose (Cohort 1 
and 2) and after dose 5 (Cohort 3); 
 
Terminal elimination half-life (t½) after single dose (Cohort 1 and 2) and 
after dose 5 (Cohort 3); 
 
Total body clearance of drug from the serum (CL) after single dose (Cohort 
1 and 2) and after dose 5 (Cohort 3); 
 
Volume of distribution at steady state (Vss) (Cohort 3); 
 
Assessment of steady state (Cohort 3); 
 
Accumulation at steady state (R) after the fifth dose (Cohort 3). 
All pharmacokinetic parameters will be listed for each individual subject and 
summarized by treatment group using the following descriptive statistics. 
• 
N (the number of subjects) 
• 
Arithmetic mean 
• 
SD 
• 
CV 
• 
Geometric mean 
• Geometric CV 
Alexion Confidential
Page 12 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 11 of 13 
 
• 
Median 
• 
Minimum 
• 
Maximum 
 
Some PK parameters may not be calculated for all or some subjects if the 
concentration data are not deemed to be amenable to evaluation. Explanations 
for PK parameters that could not be estimated may be provided in the Clinical 
Study Report (CSR). 
4.6     Dose Proportionality 
Dose proportionality of the 400mg and 800mg ALXN1210 doses may be assessed 
for the following PK parameters: 
 
dose-normalized AUCt 
 
dose-normalized Cmax  (Cohort 1, 2 and Cohort 3 after first dose) 
The parameters will be analyzed using the power model [1], where the ratio of 
geometric means and the corresponding 90% confidence interval will be derived. 
Dose proportionality will be concluded if the 90% confidence interval of the ratio 
contains 1. 
 
4.7. 
Pharmacodynamic Analyses 
The PD effects of ALXN1210 administered IV will be evaluated as follows: 
 
Changes and percent changes in serum Total C5 and Free C5 
concentration over time. 
 
Change and percent change in cRBC hemolysis over time. 
 
ALXN1210 concentration required for complete terminal complement 
inhibition based on PD effects evaluated. 
 
PD data will be listed for each individual subject and absolute (observed values) 
as well as changes and percent changes from baseline will be summarized at 
each time point by treatment dose using the following descriptive statistics.   
• 
N (the number of subjects) 
• 
Arithmetic mean 
• 
SD  
• 
Median 
• 
Minimum 
• 
Maximum. 
 
Individual percent change from baseline versus actual time and mean percent 
change from baseline versus nominal time will be presented for each PD 
parameter. 
 
Alexion Confidential
Page 13 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 12 of 13 
 
4.8. 
Immunogenicity Analyses 
Immunogenicity, as measured by anti-drug antibodies, will be summarized in 
tabular form (number and percentage of subjects developing ADA) by treatment 
dose and will be presented in by-subject listings. 
Immunogenicity data will be listed for each individual subject and will be 
summarized at each time point by treatment dose using the following descriptive 
statistics, if applicable.   
• 
N (the number of subjects) 
• 
Arithmetic mean 
• 
SD 
• 
Median 
• 
Minimum 
• 
Maximum. 
4.9 
Methods for Withdrawals, Missing Data, and Outliers 
The individual serum concentration data, and the actual time for IMP 
administration and blood sampling will be used throughout the analyses. If there 
is any doubt in the actual time a sample is taken, then the scheduled time will be 
used. For PK data analysis, please see Section 4.5 Pharmacokinetic Analysis for 
the handling of missing and BLQ values. For PD data analysis, there will be no 
imputation for missing values. 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
AEs with unknown start date/time will be assumed to be treatment-emergent 
unless the end date/time is known to be before the first administration of IMP. 
Otherwise missing or partial dates will be listed as such. 
There will be no further imputation of missing data i.e. subjects who prematurely 
discontinue from the study will not be included in summary statistics or analyses 
beyond the time of discontinuation. If a subject is withdrawn from study 
treatment but continues to participate in the study, the data collected will be 
included according to the treatment initially received for the Safety set. 
Depending on the extent of missing values, the appropriateness of the methods 
described for handling missing data may be reassessed prior to database lock (to 
examine the sensitivity of results to handling of missing data). 
4.10 
Protocol deviations 
A protocol deviation is defined as a lack of compliance with the protocol which 
may interfere with the outcome of the trial. The protocol deviations will be 
identified and reviewed throughout the study, reviewed by PI/Sponsor and 
graded as minor or major. The final review will be performed at the Data Review 
Meeting prior to database lock. The protocol deviations will be listed.  
5. 
CONVENTIONS 
All listings will be ordered by treatment and subject number and will include all 
enrolled subjects. All data will be presented by the dose level of treatment. 
Alexion Confidential
Page 14 of 15


Statistical Analysis Plan 
 
 
C15045 (ALXN1210-HV_104) SAP Final 2.0 - 09Oct2016.doc 
Page 13 of 13 
 
For all tables, except PK parameter tables, descriptive statistics for min, max will 
be presented with the same number of decimal digits as the original values, and 
with one more decimal digit than the original data for mean and median; 
standard deviation will be reported with 2 or more decimal digits than the 
original. 
For PK, the individual and summaries of PK parameter results will be reported in 
3 significant digits in the listings and in the tables with the following exceptions: 
 
Tmax will be presented as follows: individual minimum, and maximum 
values will be reported exactly as the raw data are reported 
 
% CV will be presented to 1 decimal place 
Page layout of tables and listings in landscape mode will be produced in Microsoft 
Word.  Details of page layout will be provided in the tables figures and listings 
(TFL) shell document. 
 
Alexion Confidential
Page 15 of 15