A Partially Randomized, Sequential Cohort, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Subcutaneous Ravulizumab Coadministered With rHuPH20 in Healthy Adult Volunteers
Phase: PHASE1
Conditions: Healthy
Sponsor: Alexion Pharmaceuticals, Inc.

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Protocol Title: 
A Partially Randomized, Sequential Cohort, Single Ascending Dose Study to Assess the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Subcutaneous 
Ravulizumab Coadministered With rHuPH20 in Healthy Adult Volunteers 
Protocol Number: ALXN1210-HV-105 
Amendment Number: 1 
Compound Number: ALXN1210 
USAN/INN: Ravulizumab 
Short Title: Pharmacokinetic Study of Ravulizumab Administered Subcutaneously With 
rHuPH20 in Healthy Adult Volunteers 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Sponsor Address:  
100 College Street 
New Haven CT 06510 
USA 
Regulatory Agency Identifying Number(s): 
Date of Amendment: 
Not applicable 
EUDRACT Number: 
2017-004931-35 
Approval Date:  20 JUL 2018 
NCT #NCT05396742

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Sponsor Signatory: 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
Medical Monitor Name and Contact Information  
 
100 College Street 
New Haven CT 06510 USA 
Telephone: 
 
24-hour Emergency Contact: 
 
 
 

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INVESTIGATOR’S AGREEMENT 
 
I have read the ALXN1210-HV-105 study protocol and agree to conduct the study in accordance 
with this protocol, all applicable government regulations, the principles of the ICH E6 
Guidelines for Good Clinical Practice, and the principles of the World Medical Association 
Declaration of Helsinki. I also agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  
 
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date 
 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 1 
20 Jul 2018 
Original Protocol 
17 May 2018 
 
Amendment 1 (20 Jul 2018) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
Overall Rationale for the Amendment 
To align contraception language with national guidelines and address minor inconsistencies as 
described below. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.2 
Exclusion 
Criteria 
Changed exclusion criterion no. 16 for 
use of nonprescription medications 
from 7 days to 14 days prior to dosing 
on Day 1. 
Alignment of exclusion criterion with 
requirements stated in Section 6.5, 
Concomitant Therapy. 
Table 2: 
Schedule of 
Activities – 
Visit 2 
Through Visit 
14 
Added pregnancy testing on Day 57 
and Day 120. 
Additional pregnancy testing is appropriate for 
a trial in healthy subjects with requirements for 
highly effective contraception for an extended 
period. 
Section 6.6 
Contraception 
Guidance 
• Removed definition of non-
childbearing potential, replaced 
with cross reference to Appendix 
where required information is 
presented.  
• Replaced definition of highly 
effective contraception.  
• Added restriction on ova donation 
for female subjects. 
Alignment with guidelines from Clinical Trial 
Facilitation Group (CFTG). 
Section 10.4 
Appendix 4: 
Pregnancy 
Information 
Added specific FSH level requirement 
for establishing postmenopausal 
state. 
Clarification. 
 
 

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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
1.1. 
Synopsis ......................................................................................................................10 
1.2. 
Schema ........................................................................................................................13 
1.3. 
Schedule of Activities .................................................................................................14 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Study Rationale ...........................................................................................................18 
2.2. 
Background .................................................................................................................18 
2.3. 
Benefit/Risk Assessment ............................................................................................19 
2.3.1. 
Infections With Neisseria meningitidis ......................................................................19 
2.3.2. 
Injection Site Reactions ..............................................................................................20 
2.3.3. 
Immunogenicity and Hypersensitivity ........................................................................20 
2.3.4. 
Conclusion ..................................................................................................................20 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................21 
4. 
STUDY DESIGN .......................................................................................................22 
4.1. 
Overall Design ............................................................................................................22 
4.2. 
Scientific Rationale for Study Design ........................................................................24 
4.3. 
Justification for Dose ..................................................................................................24 
4.4. 
End of Study Definition ..............................................................................................25 
5. 
STUDY POPULATION .............................................................................................26 
5.1. 
Inclusion Criteria ........................................................................................................26 
5.2. 
Exclusion Criteria .......................................................................................................26 
5.3. 
Study Restrictions .......................................................................................................29 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................29 
5.3.2. 
Caffeine, Alcohol, and Tobacco .................................................................................29 
5.3.3. 
Activity .......................................................................................................................30 
5.4. 
Screen Failures and Replacements .............................................................................30 
5.4.1. 
Criteria for Study Termination ...................................................................................30 
6. 
STUDY DRUG ...........................................................................................................31 
6.1. 
Study Drug Administered ...........................................................................................31 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................32 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................33 
6.4. 
Study Drug Compliance .............................................................................................34 
6.5. 
Concomitant Therapy .................................................................................................34 
6.6. 
Contraception Guidance .............................................................................................34 
6.7. 
Dose Modification ......................................................................................................35 
6.7.1. 
Toxicity Rules for Adverse Events Deemed Related to Study Drug ..........................36 
6.8. 
Intervention After the End of the Study .....................................................................37 
7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................38 
7.1. 
Discontinuation of Study Drug ...................................................................................38 
7.2. 
Subject Discontinuation/Withdrawal From the Study ................................................38 
7.3. 
Lost to Follow-up .......................................................................................................38 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................39 
8.1. 
Efficacy Assessments .................................................................................................39 
8.2. 
Safety Assessments .....................................................................................................39 
8.2.1. 
Physical Examination .................................................................................................39 
8.2.2. 
Vital Signs ..................................................................................................................39 
8.2.3. 
Electrocardiograms .....................................................................................................39 
8.2.4. 
Laboratory Assessments .............................................................................................39 
8.2.4.1. 
Virus Serology ............................................................................................................40 
8.2.4.2. 
Vaccine Titer ..............................................................................................................40 
8.2.4.3. 
Immunogenicity Assessments ....................................................................................40 
8.2.5. 
Drug and Alcohol Screen ............................................................................................41 
8.2.6. 
Pregnancy Testing ......................................................................................................41 
8.2.7. 
Tuberculosis Testing ...................................................................................................41 
8.2.8. 
Injection or Infusion-Site Evaluation ..........................................................................41 
8.2.9. 
Vaccine and Antibiotic Prophylaxis ...........................................................................41 
8.2.10. 
Risk of Infection Reminders .......................................................................................42 
8.3. 
Adverse Events and Serious Adverse Events .............................................................42 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................42 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................43 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................43 

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8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................43 
8.3.5. 
Pregnancy ...................................................................................................................43 
8.3.6. 
Management of Potential Adverse Events During Study Drug 
Administration ............................................................................................................44 
8.3.7. 
Study Drug Administration Reactions ........................................................................44 
8.3.7.1. 
Infusion-site Reactions ...............................................................................................44 
8.3.7.2. 
Infusion-associated Reactions ....................................................................................44 
8.4. 
Treatment of Overdose ...............................................................................................44 
8.5. 
Pharmacokinetics ........................................................................................................45 
8.6. 
Pharmacodynamics .....................................................................................................45 
8.7. 
Genetics ......................................................................................................................45 
8.8. 
Biomarkers ..................................................................................................................45 
8.9. 
Medical Resource Utilization and Health Economics ................................................45 
9. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................46 
9.1. 
Statistical Hypotheses .................................................................................................46 
9.2. 
Sample Size Determination ........................................................................................46 
9.3. 
Populations for Analyses ............................................................................................46 
9.4. 
Statistical Analyses .....................................................................................................46 
9.4.1. 
Efficacy Analyses .......................................................................................................46 
9.4.2. 
Safety Analyses ..........................................................................................................46 
9.4.3. 
Other Analyses ............................................................................................................47 
9.4.3.1. 
Pharmacokinetic Analyses ..........................................................................................47 
9.4.3.2. 
Pharmacodynamic Analyses .......................................................................................48 
9.4.3.3. 
Immunogenicity Analysis ...........................................................................................48 
9.5. 
Interim Analyses .........................................................................................................48 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................49 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................49 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................49 
10.1.2. 
Informed Consent Process ..........................................................................................49 
10.1.3. 
Data Protection ...........................................................................................................50 
10.1.4. 
Dissemination of Clinical Study Data ........................................................................50 
10.1.5. 
Data Quality Assurance ..............................................................................................50 

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10.1.6. 
Source Documents ......................................................................................................51 
10.1.7. 
Study and Site Closure................................................................................................51 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................52 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................54 
Serious Adverse Event Definition .................................................................................................54 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ................................55 
Reporting of Serious Adverse Events ............................................................................................57 
10.4. 
Appendix 4: Pregnancy Information ..........................................................................58 
Definitions 58 
Woman of Childbearing Potential .................................................................................................58 
Women in the Following Categories are Not Considered Women of Childbearing 
Potential ......................................................................................................................58 
Pregnancy Testing ..........................................................................................................................58 
Collection of Pregnancy Information.............................................................................................58 
10.5. 
Appendix 5: Abbreviations .........................................................................................60 
10.6. 
Appendix 6: Acute Infusion Reaction Algorithm .......................................................62 
10.7. 
Appendix 8: United Kingdom Resuscitation Council Anaphylaxis Algorithm .........63 
10.8. 
Appendix 10: Protocol Amendment History ..............................................................63 
Amendment 1 (20 Jul 2018) ..........................................................................................................64 
11. 
REFERENCES ...........................................................................................................65 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities – Screening Through Visit 1 ..................................................14 
Table 2: 
Schedule of Activities – Visit 2 Through Visit 14 .....................................................17 
Table 3: 
Study ALXN1210-HV-105 Objectives and Endpoints ..............................................21 
Table 4: 
ALXN1210-HV-105 Study Design ............................................................................24 
Table 5:  
Pharmacokinetic Exposure Margins Estimated for the Proposed 
Ravulizumab/rHuPH20 Subcutaneous Dose Cohorts Using the Highest 
Intravenous Dose Cohort From Study ALXN1210-HV-102 as the Reference ..........25 
Table 6: 
Dose Reference Chart for Study ALXN1210-HV-105 ..............................................31 
Table 7: 
Study ALXN1210-HV-105 Dose Continuation/Escalation Decision Pathway ..........36 
Table 8: 
Study ALXN1210-HV-105 Analysis Sets ..................................................................46 
Table 9: 
Protocol-Required Safety Laboratory Assessments ...................................................53 

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Table 10: Abbreviations and Specialist Terms ...........................................................................60 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Partially Randomized, Sequential Cohort, Single Ascending Dose Study to 
Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of 
Subcutaneous Ravulizumab Coadministered With rHuPH20 in Healthy Adult Volunteers 
Short Title: Pharmacokinetic Study of Ravulizumab Administered Subcutaneously With 
rHuPH20 in Healthy Adult Volunteers 
Rationale: Ravulizumab subcutaneous (SC) is being developed to provide patients with a 
self-administered dosing option that will eliminate the patient burden associated with intravenous 
(IV) infusions (eg, loss of work time, disruption of routine associated with prolonged infusion 
times). Recombinant human hyaluronidase PH20 (rHuPH20), the active ingredient in the 
commercial product Hylenex® recombinant (hyaluronidase human injection), was approved by 
the US Food and Drug Administration in 2005 as an adjuvant to increase the dispersion and 
absorption of other injected drugs. Recombinant human hyaluronidase PH20 is a dispersion 
agent that modifies the permeability of connective tissue through the hydrolysis of hyaluronic 
acid (HA), a polysaccharide found in the intercellular ground substance of connective tissue. 
Recombinant human hyaluronidase PH20 hydrolyzes HA by splitting the glucosaminidic bond 
between C1 of an N-acetylglucosamine moiety and C4 of a glucuronic acid moiety. This 
depolymerization of HA results in a transient reduction in the viscosity of the gel-like phase of 
the extracellular matrix and increased hydraulic conductance that facilitates the dispersion and 
absorption of injected drugs, and may also increase their bioavailability. Coadministration of 
ravulizumab SC with rHuPH20 is expected to facilitate a larger amount of ravulizumab to be 
administered at a single time, thereby potentially allowing less frequent dosing.  
Study ALXN1210-HV-105 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
− 
To estimate the absolute bioavailability of 
ravulizumab SC/rHuPH20  
− 
To assess the safety and tolerability of 
ravulizumab SC/rHuPH20  
− 
Serum concentration of ravulizumab will be 
used to determine the GMR of the AUC 
values 
− 
Safety assessed by incidence of TEAEs and 
SAEs, physical examination, vital sign 
measurements, clinical laboratory and 
electrocardiogram results, and measurement 
of ADA 
Secondary 
 
To estimate the relative bioavailability of 
ravulizumab SC/rHuPH20 compared with 
ravulizumab SC 
Serum concentration of ravulizumab will be used 
to determine the GMR of the AUC values 
To explore the PD effects of ravulizumab SC 
coadministered with rHuPH20 
− 
Change in serum levels of total and free C5 
concentrations over time  
− 
Change in ex vivo cRBC hemolysis activity 
over time 
Abbreviations: ADA = antidrug antibodies; AUC = area under the concentration time curve; C5 = complement 
component 5; cRBC = chicken red blood cell; GMR = geometric mean ratio; PD = pharmacodynamic(s); 
rHuPH20 = recombinant human hyaluronidase PH20; SAE = serious adverse events; SC = subcutaneous; 
TEAE = treatment-emergent adverse events. 

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Overall Design: 
This is a Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), immunogenicity, and absolute and relative bioavailability of single 
ascending doses of ravulizumab SC coadministered with recombinant human hyaluronidase 
PH20 (rHuPH20) compared to a single dose of ravulizumab IV 400 mg or a single dose of 
ravulizumab SC 400 mg in 48 healthy adult subjects. Five treatment cohorts are planned.  A 
Safety Review Committee (SRC) will evaluate the study data for subject safety and make 
recommendations on dose escalation, dose modification, or termination of the study. When 
cohorts are being enrolled in parallel, subject assignment to a cohort will be done through 
randomization. Subjects may be randomly assigned up to 7 days prior to dosing on Day 1. The 
study will be conducted at a single site in the United Kingdom. 
• Eighteen subjects will be randomly assigned in a 1:2 ratio between the first 2 cohorts 
to receive either a single dose of ravulizumab SC 400 mg (Cohort 1, n = 6) or a single 
dose of ravulizumab SC 500 mg/rHuPH20 10,000 units (Cohort 2, n = 12).  
• The SRC will review Cohort 2 ravulizumab SC/rHuPH20 safety data and make their 
recommendation for escalating the dose of the ravulizumab SC/rHuPH20 
combination cohort.  
• If the SRC recommendation following the review of data from Cohort 2 is to initiate 
the next cohort and proceed with the planned dose escalation, 18 subjects will be 
randomly assigned in a 2:1 ratio between Cohort 3 (n = 12) and Cohort 5 (n = 6) to 
receive either a single dose of ravulizumab SC 1000 mg/rHuPH20 20,000 units or a 
single dose of ravulizumab IV 400 mg, respectively. 
− The SRC will subsequently review Cohort 3 ravulizumab SC/rHuPH20 safety 
data and make their recommendation to proceed with planned dose escalation in 
Cohort 4 or a reduced dose in Cohort 4. 
− Whether the recommendation is to initiate Cohort 4 with the planned dose 
escalation or at a reduced dose, 12 subjects will be enrolled in Cohort 4 to receive 
a single dose of ravulizumab SC/rHuPH20 (dose to be determined based on SRC 
recommendation).  
• If the SRC recommendation following the review of ravulizumab SC/rHuPH20 safety 
data from Cohort 2 is to proceed with Cohort 3 at a reduced dose, 18 subjects will be 
randomly assigned in a 2:1 ratio between Cohort 3 (n = 12) and Cohort 5 (n = 6) to 
receive either a single dose of ravulizumab SC/rHuPH20 (dose to be determined 
based on SRC recommendation) or a single dose of ravulizumab IV 400 mg, 
respectively. 
− In this scenario, Cohort 4, if conducted, will be enrolled at a reduced dose, 
following completion of Cohort 3 based on SRC review of 
ravulizumab SC/rHuPH20 safety data from Cohort 3 and a favorable 
recommendation to enroll subjects in Cohort 4. 
− This protocol allows for reduced doses to be administered to subjects in Cohorts 3 
and 4, based on SRC recommendation, without a protocol amendment. If a 

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reduced dose is administered, the SRC reduced dose recommendation will be 
documented on the escalation/progression approval form. 
• If the SRC determines that no further ravulizumab SC/ rHuPH20 combination dosing 
cohorts should be enrolled following Cohort 2, then Cohort 5 may still be enrolled as 
a stand-alone cohort at the discretion of the Sponsor. 
• Sentinel dosing will be employed in Cohorts 1 through 4 (ie, 2 subjects in a cohort 
with 12 subjects and 1 subject in a cohort with 6 subjects will be dosed prior to 
dosing the remaining subjects within the cohort). The remaining subjects in a cohort 
will be dosed at least 24 hours following dosing of the sentinel subjects.  
• The SRC will review all available safety data through 168 hour (Day 8) assessments 
to determine initiation of the next dose cohort. 
• At the Sponsor’s discretion, and after consultation with the SRC, up to 16 additional 
subjects may be enrolled as replacement subjects if a subject discontinues prior to 
Day 50 for reasons other than drug-related adverse events. 
ALXN1210-HV-105 Study Design 
Cohort 
N 
Study Drug 
Route 
(SC/IV) 
Planned Dose 
1 
6 
ravulizumab 
SC 
400 mg 
2 
12 
ravulizumab/rHuPH20 
SC 
500 mg/10,000 units 
3 
12 
ravulizumab/rHuPH20 
SC 
1000 mg/20,000 units 
4 
12 
ravulizumab/rHuPH20 
SC 
2000 mg/40,000 units 
5 
6 
ravulizumab 
IV 
400 mg 
Abbreviations: IV = intravenous; N = number [of subjects]; rHuPH20 = recombinant human hyaluronidase PH20; 
SC = subcutaneous. 
Number of Subjects: 
An appropriate number of subjects will be screened and assigned to each cohort, as described in 
the table above, to allow for approximately 48 subjects to complete the study. 
Intervention Groups and Duration: 
The planned study duration is approximately 39 weeks: up to 70 days for screening and 
approximately 200 days for dosing and follow-up. For the first 5 days during the Dosing and 
Follow-up Period, subjects will be admitted to an inpatient facility. Dosing will be staggered 
within and between cohorts, but the end of study for each individual subject is anticipated to be 
Day 200 or the time point at which complement activity has normalized, if later than Day 200. 
Safety Review Committee: 
The SRC will review all available safety data for at least the first 168 hours after dose 
administration from a given cohort in order to determine whether to initiate the next cohort and 
escalate the dose of ravulizumab SC/rHuPH20. Data through 168 hours must be available for at 
least 11 of the 12 subjects. Dose escalation will occur based on the recommendation of the SRC 
and only applies to Cohorts 3 and 4. SRC decisions will be documented in study minutes and 
archived in the trial master file. 

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1.2. 
Schema 
Study ALXN1210-HV-105 Schematic 
 
Screening Period 
Up to 70 Days
Dosing and Follow-up Period
200 Daysa
Cohort 1
N = 6
Ravulizumab SC 400 mg
Cohort 2 
N =  12
Ravulizumab SC 500 mg/
rHuPH20 10, 000 units 
Cohort 3
N =  12
Ravulizumab SC 1000 mg/
rHuPH20 20, 000 units 
Screening
Cohort 4
N =  12
Ravulizumab SC 2000 mg/ 
rHuPH20 40,000 units 
D1 b
Screening
Screening
D1 b
Screening
Screening
D1 b
Cohort 5
N =  6
Ravulizumab IV 400 mg 
D1 
D1 b
 
 
 
Note: Subjects will be randomly assigned to Cohort 1 or Cohort 2, randomly assigned to Cohort 3 or Cohort 5, and 
sequentially assigned to Cohort 4. 
a Dosing will be staggered, but the end of study for each subject is Day 200 or the time point at which complement  
activity has normalized, if later than Day 200. 
b For Cohorts 1 through 4, a sentinel dosing approach will be used (ie, 2 subjects in a cohort with 12 subjects and 
1 subject in a cohort with 6 subjects will be dosed prior to dosing the remaining subjects within the cohort). 
Abbreviations: D = day; IV = intravenous; N = number [of subjects]; SC = subcutaneous. 
 

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1.3. 
Schedule of Activities 
Table 1: 
Schedule of Activities – Screening Through Visit 1 
 
 
Visit 1 
Study Day 
Screenin
g 
Day –1 
 
Day 1 
Day 
2 
Day 
3 
Day 
5 
Assessmentsa 
Day –70  
to Day –2 
Admit 
Day –1 
Predose 
 
0 h 
(SOI) 
EOI 
(SC)b 
30 
min 
post 
SOI  
2 h 
post 
SOI  
4 h 
post 
SOI  
8 h 
post 
SOI  
24 h 
 
48 h 
 
96 h 
 
Status (OP or CRU) 
OP 
Admit 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU 
CRU
c 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
MCV4 immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal serogroup B 
immunizatione 
X 
 
 
 
 
 
 
 
 
 
 
 
Vaccine titer (meningococcal 
serogroups A, C, W135, and Y)f 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Height, weight, and BMI 
X 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON®-TB test 
X 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
X 
X 
 
 
 
 
 
 
 
X 
 
 
Hematology 
X 
X 
 
 
 
 
 
 
 
X 
 
 
Coagulation 
X 
X 
 
 
 
 
 
 
 
X 
 
 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV(types 1 and 2) screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Complement activityg 
X 
 
 
 
 
 
 
 
 
 
 
 
CH50 
 
 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy testh 
X 
X 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis (via dipstick) 
X 
X 
 
 
 
 
 
 
 
X 
 
X 
Urine drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
Vital sign measurements 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
Xi 
 
 
 
 
 
 
X 
 
 
Cardiac telemetryj 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Randomizationk 
 
 
X 
 
 
 
 
 
 
 
 
 

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Visit 1 
Study Day 
Screenin
g 
Day –1 
 
Day 1 
Day 
2 
Day 
3 
Day 
5 
Assessmentsa 
Day –70  
to Day –2 
Admit 
Day –1 
Predose 
 
0 h 
(SOI) 
EOI 
(SC)b 
30 
min 
post 
SOI  
2 h 
post 
SOI  
4 h 
post 
SOI  
8 h 
post 
SOI  
24 h 
 
48 h 
 
96 h 
 
Study drug administration 
 
 
 
X 
 
 
 
 
 
 
 
 
PK samples 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
PD panel (serum C5, cRBC 
hemolysis) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion/injection site evaluationl 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Immunogenicity (ravulizumab 
ADA) 
 
 
X 
 
 
 
 
 
 
 
 
 
Review potential safety risks of 
ravulizumabm 
X 
X 
X 
X 
Concomitant medications 
 
←Monitor continuously (after ICF is signed at screening)→ 
Adverse eventsn 
 
←Monitor continuously (after ICF is signed at screening)→ 
Prophylactic antibiotic txo 
 
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the study operations manual. 
b The EOI sample applies to the SC cohorts only and should be obtained within 10 min after the completion of SC infusion. 
c Subject will be discharged from the CRU after completing all Day 5 assessments. Subjects will be provided a “Study Participant ID card” with information for 
healthcare provider and subject on symptoms of meningitis infection. 
d Signed and dated EC-approved ICF must be obtained before any study-specific screening procedures are performed. 
e 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 dosing on Day 1, and vaccination for serogroup B meningococcal infections will be administered at least 56 days prior to Day 1 dosing with a 
booster administered at least 28 days prior to dosing on Day 1. 
f For subjects with a documented vaccine titer within 6 months prior to screening, the titer does not need to be repeated. 
g Complement activity, confirmed by a suitable assay such as CAP ELISA/C5 (hemolysis) inhibition, will be performed at screening to confirm subjects do not have 
a complement deficiency. 
h Serum pregnancy test for all female subjects of childbearing potential to confirm that a female subject is not pregnant prior to dosing. 
i On Day 1, triplicate 12-lead ECGs will be performed predose and approximately 15 minutes after the EOI (Cohorts 1 through 4 only). 
j Continuous cardiac registration predose and until 3 hours after the SC injection (Cohorts 2, 3, and 4). 
k Planned randomization for Cohorts 1, 2, 3, and 5 may be up to 7 days prior to dosing on Day 1. 
l Injection site evaluations will be performed within 15 minutes after EOI and ± 15 minutes of the other scheduled times on Day 1. 
m The Investigator or qualified designee will meet with the subject at each visit to discuss the potential safety risks of ravulizumab, and to address any safety 
concerns of the subject. 
n Collection of adverse events and serious adverse events will begin after ICF signing.  
o Subjects will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units), beginning on the evening of Day -
1 through Day 200, or until complement activity has normalized (as determined by CH50 assay). 

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Abbreviations: ADA = antidrug antibody; AE = adverse event; BMI = body mass index; CAP = complement alternative pathway; cRBC = chicken red blood cell; 
CRU = clinical research unit; ECG = electrocardiogram; EOI = end-of-infusion/injection; h = hour; HIV = human immunodeficiency virus; ICF = informed consent 
form; IV = intravenous; MCV4 = tetravalent meningococcal conjugate vaccine; min = minute; OP = outpatient; PD = pharmacodynamic(s); PK = pharmacokinetic 
(s) SC = subcutaneous; SOI = start-of-infusion/injection; TB = tuberculosis; tx = treatment.

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Table 2: 
Schedule of Activities – Visit 2 Through Visit 14 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visit 11 
Visit 12 
Visit 13 
Visit 14 
Proceduresa 
Day 8 
(168h ± 2) 
Day 
15 
Day 
22 
Day 
29 
Day 
36 
Day 
43 
Day 
50  
Day 
57  
Day 71  
Day 92  
Day 
120  
Day 
150 
Day 200 / 
ET 
Status (OP or CRU) 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
OP 
Physical examination 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
Vital sign 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Biochemistry 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Hematology 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Coagulation 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Urinalysis (via dipstick) 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Serum pregnancy test 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
CH50 testing 
 
 
 
 
 
X 
 
Xb 
 
 
 
 
 
Pharmacokinetic 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacodynamics 
panel (serum C5, 
cRBC hemolysis)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity 
(ravulizumab ADA) 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Review potential safety 
risks of ravulizumabc 
←Discuss potential safety risks of ravulizumab→ 
Concomitant 
←Monitor continuously (after ICF is signed at screening)→ 
Adverse eventsd 
←Monitor continuously (after ICF is signed at screening)→ 
Prophylactic antibiotic 
txe
←Antibiotic prophylaxis→ 
a Permissible windows for study assessments are described in the study operations manual. 
b Additional samples may be taken after Day 57 if complement has not normalized. 
c The Investigator or qualified designee will meet with the subject at each visit to discuss the potential safety risks of ravulizumab, and to address any safety 
concerns on the part of the subject. 
d Collection of adverse events and serious adverse events will begin after ICF signing. 
e Subjects will be administered prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 1 × 106 units) through Day 200 or until 
complement activity has normalized (as determined by CH50 assay). 
Abbreviations: ADA = antidrug antibody; cRBC = chicken red blood cell; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; h = hour; 
ICF = informed consent form; OP = outpatient; tx = treatment. 

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2. 
INTRODUCTION 
2.1. 
Study Rationale 
The subcutaneous (SC) formulation of ravulizumab is being developed to provide patients with a 
self-administered dosing option that will eliminate the patient burden associated with IV 
infusions (eg, loss of work time, disruption of routine associated with dosing frequency, and 
prolonged infusion times). The purpose of this study is to evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, absolute and relative 
bioavailability of single ascending doses of ravulizumab SC coadministered with recombinant 
human hyaluronidase PH20 (rHuPH20). 
Recombinant human hyaluronidase PH20, the active ingredient in the commercial product 
Hylenex® recombinant (hyaluronidase human injection), was approved by the US Food and Drug 
Administration in 2005 as an adjuvant to increase the dispersion and absorption of other injected 
drugs. Recombinant human hyaluronidase PH20 is a transiently and locally-acting permeation 
enhancer that increases the dispersion and absorption of other injected agents. Recombinant 
human hyaluronidase PH20 depolymerizes hyaluronic acid (HA) at the injection site causing 
rapid decrease in the viscosity of the extracellular matrix, allowing bulk fluid flow and 
facilitating dispersion and absorption of coadministered agents (rHuPH20 Investigator’s 
Brochure, 2018).  
Recombinant human hyaluronidase PH20 has been injected SC immediately prior to another 
therapeutic agent or coadministered SC to healthy subjects and patients in 28 clinical studies 
conducted under the rHuPH20 US IND, including studies with single doses up to 96,000 units. 
No safety concerns were identified in these studies (rHuPH20 Investigator’s Brochure, 2018). In 
addition, rHuPH20 is an excipient in 3 marketed products (Herceptin® SC, HyQvia®, and 
MabThera SC®) available collectively in at least 50 countries, including countries in the 
European Union (approvals on file at Alexion).  
Data from Study ALXN1210-SC-101 suggest that bioavailability of ravulizumab SC alone is 
< 100%. While coadministration of ravulizumab SC with rHuPH20 may improve bioavailability, 
it is expected to facilitate a larger amount of ravulizumab to be administered as a single dose, 
thereby potentially allowing less frequent dosing.  
Ravulizumab IV has been administered safely to healthy subjects in single doses (ravulizumab 
IV 200 mg and 400 mg) and multiple doses on a 4-week regimen (ravulizumab 400 mg and 
800 mg). Ravulizumab SC has been administered safely to healthy subjects in single doses 
(ravulizumab SC 400 mg). In patients with paroxysmal nocturnal hemoglobinuria (PNH), IV 
doses much greater than those evaluated in Study ALXN1210-HV-102 (ie, up to 5400 mg every 
12 weeks) are being evaluated for an extended period (up to 3 years). Data obtained from 
patients administered 5400 mg IV every 12 weeks provide a significant systemic PK margin for 
the proposed SC doses. Data have shown both multiple doses ravulizumab IV and a single dose 
of ravulizumab SC to be safe and well-tolerated.  
2.2. 
Background 
Ravulizumab was engineered from eculizumab to preserve immediate and complete C5 
inhibition while providing sustained complement inhibition throughout a prolonged dosing 
interval (1 month or longer). Ravulizumab and eculizumab share > 99% amino-acid sequence 

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homology. Ravulizumab is a recombinant, humanized protein produced in Chinese hamster 
ovary (CHO) cells and was designed through minimal targeted engineering to substitute 4 amino 
acids in the eculizumab heavy chain. Two of these substitutions are in the complementarity 
determining regions, enhancing the pH-dependence of ravulizumab binding to C5; the other 2 are 
in the Fc binding region which improves recycling of ravulizumab into the vascular space instead 
of degrading. These changes were specifically designed (and have subsequently been proven) to 
increase the half-life of ravulizumab relative to eculizumab, increasing the duration of terminal 
complement inhibition, while preserving both the high degree of specificity for binding to C5 
and the effectorless nature of the antibody. 
Recombinant human hyaluronidase PH20 is a glycosylated single chain protein with up to 447 
amino acids, synthesized in CHO cells. Recombinant human hyaluronidase PH20 degrades HA 
under physiologic conditions and acts as a spreading factor in vivo. Therefore, when combined 
(co-mixed) or coformulated with certain injectable drugs, rHUPH20 facilitates the absorption 
and dispersion of these drugs by temporarily reducing resistance to bulk fluid flow in the SC 
space. The permeability barrier in these tissues is restored to preinjection levels within 24 to 
48 hours after injection of rHuPH20. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of ravulizumab and 
rHuPH20 are provided in their respective Investigator’s Brochures (IB). 
2.3. 
Benefit/Risk Assessment 
This is a healthy volunteer study and there is no direct benefit to study subjects. Identified and 
potential risks are described below.  
More detailed information about the known and expected benefits/risks and expected adverse 
events of ravulizumab and rHuPH20 is provided in their respective IBs. 
2.3.1. 
Infections With Neisseria meningitidis  
A risk associated with complete terminal complement inhibition, such as that anticipated with 
ravulizumab, is infection with 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 this clinical study, normal healthy subjects will experience an induced transient state of 
complement deficiency, therefore subjects will receive the MCV4 vaccination at least 56 days 
prior to dosing with ravulizumab (if not vaccinated with MCV4 within the last 2 years and 
4 months, or if adequate documentation to verify previous vaccination is unavailable). A titer to 
the tetravalent vaccine will be established prior to enrollment to confirm immunization status. 
Subjects who are not already vaccinated for serotype B meningococcal infections will also 
receive that vaccination at least 56 days prior to Day 1 dosing with a booster administered at 
least 28 days prior to dosing on Day 1. 
In addition to vaccination against N meningitidis with MCV4 and the serogroup B vaccine, all 
subjects will be treated with prophylactic antibiotics (oral penicillin V 500 mg twice daily) for 
the duration of reduced complement activity. Unless the Investigator and Sponsor agree to an 
alternative regimen, all subjects will take prophylactic antibiotics (oral penicillin V 500 mg twice 
daily) until complement activity has normalized. If penicillin is not tolerated, second-line 
antibiotics (eg, ciprofloxacin) will be initiated. 

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Analysis of serum samples to establish actual complement activity will be performed using a 
CH50 in vitro liposome immunoassay (LIA). The analysis will take place approximately when 
complement activity is expected to normalize. Results will be used to confirm that complement 
activity has returned to normal and once confirmed, prophylactic antibiotic treatment can be 
stopped. All subjects will be closely monitored for signs of infection throughout the study.  
2.3.2. 
Injection Site Reactions 
Injection site reactions are a potential risk with any agent administered subcutaneously. Sporadic 
localized transient erythema has been observed at the site of injection in a nonclinical study with 
large volume SC administration of rHuPH20 formulated in the same buffer intended for 
ravulizumab SC (50 mM sodium phosphate, 25 mM arginine, 5% sucrose, and 
0.05% polysorbate 80, pH 7.4). Monitoring for injection site reactions will be conducted as part 
of routine safety assessments for this study. 
2.3.3. 
Immunogenicity and Hypersensitivity 
As with any humanized mAb, ravulizumab has the potential to be immunogenic and may be 
associated with hypersensitivity reactions. During the ravulizumab development program, a 
small proportion of patients were positive for ravulizumab ADAs; these were laboratory findings 
with no clinical manifestations. No hypersensitivity reactions have been observed in clinical 
studies with ravulizumab.  
Antibodies to rHuPH20 have been observed and evaluated in several nonclinical and clinical 
studies. No clinical signs or symptoms have been associated with positive anti-rHuPH20 
antibody titers in clinical studies with rHuPH20, and no rHuPH20-neutralizing antibody activity 
has been detected (rHuPH20 Investigator’s Brochure, 2018). 
Monitoring of immunogenicity for ravulizumab is in place for this study as specified in the 
Schedule of Activities (Table 1 and Table 2) and Section 10.7 (Appendix 6).  
2.3.4. 
Conclusion 
This is the first time that the SC formulation of ravulizumab will be combined with rHuPH20 to 
facilitate a larger amount of ravulizumab SC delivered as a single infusion. Healthy volunteers 
are the appropriate population for this single-dose study, as they will enable PK and PD 
assessments without the potential of confounding effects due to other disease activity, 
comorbidities, or medications. This healthy subject study has been designed to minimize risk to 
the subjects participating: it is a single dose study with strict inclusion/exclusion criteria 
(Section 5.1 and Section 5.2) and there is a robust safety monitoring and risk mitigation plan in 
place. The single SC doses to be studied in healthy volunteers in this study are predicted to be 
within the safety exposure margins from healthy subjects or patients with PNH following IV 
dosing. In addition, available healthy subject data, as well as extensive patient data from the 
ongoing PNH and aHUS clinical programs support the initiation of Study ALXN1210-HV-105 
in healthy subjects.   
As this is a healthy volunteer study, there is no direct benefit to study subjects. The data obtained 
from this healthy volunteer study may inform future clinical studies in patients with PNH or 
other indications under study. 

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3. 
OBJECTIVES AND ENDPOINTS 
The study objectives and corresponding endpoints are presented in Table 3. 
Table 3: 
Study ALXN1210-HV-105 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
− 
To estimate the absolute bioavailability of 
ravulizumab SC/rHuPH20  
− 
To assess the safety and tolerability of 
ravulizumab SC/rHuPH20  
− 
Serum concentration of ravulizumab will be 
used to determine the GMR of the AUC 
values 
− 
Safety assessed by incidence of TEAEs and 
SAEs, physical examination, vital sign 
measurements, clinical laboratory  and 
electrocardiogram results, and measurement 
of ADA 
Secondary 
 
To estimate the relative bioavailability of 
ravulizumab SC/rHuPH20 compared with 
ravulizumab SC 
Serum concentration of ravulizumab will be used 
to determine the GMR of the AUC values 
To explore the PD effects of ravulizumab SC 
coadministered with rHuPH20 
− 
Change in serum levels of total and free C5 
concentrations over time  
− 
Change in ex vivo cRBC hemolysis activity 
over time 
Abbreviations: ADA = antidrug antibody; AUC = area under the concentration time curve; C5 = complement 
component 5; cRBC = chicken red blood cell; GMR = geometric mean ratio; PD = pharmacodynamic(s); 
rHuPH20 = recombinant human hyaluronidase PH20; SAE = serious adverse event; SC = subcutaneous; 
TEAE = treatment-emergent adverse events. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), immunogenicity, and absolute and relative bioavailability of single 
ascending doses of ravulizumab SC coadministered with rHuPH20 compared to a single dose of 
ravulizumab IV 400 mg or a single dose of ravulizumab SC 400 mg in 48 healthy adult subjects 
across treatment cohorts (Table 4). A Safety Review Committee (SRC) will evaluate the study 
data for subject safety and make recommendations on dose escalation, dose modification, or 
termination of the study. When cohorts are being enrolled in parallel, subject assignment to a 
cohort will be done through randomization. Subjects may be randomized up to 7 days prior to 
dosing on Day 1. The study will be conducted at a single site in the United Kingdom (UK). 
• Eighteen subjects will be randomly assigned in a 1:2 ratio between the first 2 cohorts 
to receive either a single dose of ravulizumab SC 400 mg (Cohort 1, n = 6) or a single 
dose of ravulizumab SC 500 mg/rHuPH20 10,000 units (Cohort 2, n = 12).  
• The SRC will review Cohort 2 ravulizumab SC/rHuPH20 safety data and make their 
recommendation for escalating the dose of the ravulizumab SC/rHuPH20 cohort.  
• If the SRC recommendation following the review of data from Cohort 2 is to initiate 
the next cohort and proceed with the planned dose escalation, 18 subjects will be 
randomly assigned in a 2:1 ratio between Cohort 3 (n = 12) and Cohort 5 (n = 6) to 
receive either a single dose of ravulizumab SC 1000 mg/rHuPH20 20,000 units or a 
single dose of ravulizumab IV 400 mg, respectively. 
− The SRC will subsequently review Cohort 3 ravulizumab SC/rHuPH20 safety 
data and make their recommendation to proceed with planned dose escalation in 
Cohort 4 or a reduced dose in Cohort 4. 
− Whether the SRC recommendation is to initiate Cohort 4 with the planned dose 
escalation or at a reduced dose, 12 subjects will be enrolled in Cohort 4 to receive 
a single dose of ravulizumab SC/rHuPH20 (dose to be determined based on SRC 
recommendation).  
• If the recommendation following the review of ravulizumab SC/rHuPH20 safety data 
from Cohort 2 is to proceed with Cohort 3 at a reduced dose, 18 subjects will be 
randomly assigned in a 2:1 ratio between Cohort 3 (n = 12) and Cohort 5 (n = 6) to 
receive either a single dose of ravulizumab SC/rHuPH20 (dose to be determined 
based on SRC recommendation) or a single dose of ravulizumab IV 400 mg, 
respectively. 
− In this scenario, Cohort 4, if conducted, will be enrolled at a reduced dose, 
following completion of Cohort 3 based on SRC review of 
ravulizumab SC/rHuPH20 safety data from Cohort 3 and a favorable 
recommendation to enroll subjects in Cohort 4. 
− This protocol allows for reduced doses to be administered to subjects in Cohorts 3 
and 4, based on SRC recommendation, without a protocol amendment. If a 

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reduced dose is administered, the SRC reduced dose recommendation will be 
documented on the escalation/progression approval form. 
• If the SRC determines that no further ravulizumab SC/ rHuPH20 combination dosing 
cohorts should be enrolled following Cohort 2, then Cohort 5 may still be enrolled as 
a stand-alone cohort at the discretion of the Sponsor. 
• Sentinel dosing will be employed in Cohorts 1 through 4 (ie, 2 subjects in a cohort 
with 12 subjects and 1 subject in a cohort with 6 subjects will be dosed prior to 
dosing the remaining subjects within the cohort). Remaining subjects in a cohort will 
be dosed at least 24 hours following dosing of the sentinel subjects.  
• The SRC will review all available safety data through 168 hour (Day 8) assessments 
to determine initiation of the next dose cohort. 
• At the Sponsor’s discretion, and after consultation with the SRC, up to 16 additional 
subjects may be enrolled as replacement subjects if any subject discontinues prior to 
Day 50 for reasons other than drug-related adverse events (AE). 
An appropriate number of subjects will be screened and randomly or sequentially assigned to 
each cohort to allow for approximately 48 subjects to complete the study. In order to minimize 
selection bias in treatment assignment, subjects who are randomized or assigned subject numbers 
will have them assigned consecutively at the point of study drug dosing, in the same order as 
they have become eligible. 
The planned study duration is approximately 39 weeks; up to 70 days for screening and 
approximately 200 days for dosing and follow-up. 
For the first 5 days during the Dosing and Follow-up Period, subjects will be admitted to an 
inpatient facility. Dosing will be staggered within and between cohorts, but the end of study for 
each individual subject is anticipated to be Day 200 or the time point at which complement 
activity has normalized, if later than Day 200. 
 

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Table 4: 
ALXN1210-HV-105 Study Design 
Cohort 
N 
Study Drug 
Route 
(SC/IV) 
Planned Dose 
1 
6 
ravulizumab 
SC 
400 mg 
2 
12 
ravulizumab/rHuPH20 
SC 
500 mg/10,000 units 
3 
12 
ravulizumab/rHuPH20 
SC 
1000 mg/20,000 units 
4 
12 
ravulizumab/rHuPH20 
SC 
2000 mg/40,000 units 
5 
6 
ravulizumab 
IV 
400 mg 
Abbreviations: IV = intravenous; N = number [of subjects]; rHuPH20 = recombinant human hyaluronidase PH20; 
SC = subcutaneous. 
4.2. 
Scientific Rationale for Study Design 
• As this is the first study of ravulizumab SC/rHuPH20, a single ascending dose design 
was chosen for initial assessment of the safety and tolerability, PK, and PD of the 
combination cohorts. 
• This study is being conducted in healthy subjects and not patients so that the 
assessments are not confounded by disease activity, comorbidities, or concomitant 
medications.  
• A sentinel dosing paradigm is being used since this is the first administration of 
ravulizumab SC/rHuPH20, and it is also the first administration of ravulizumab SC 
400 mg administered as a single infusion.  Previous studies of ravulizumab SC 
utilized 4 separate injections of 100 mg each. 
• The ravulizumab IV cohort will provide the reference arm for assessing absolute 
bioavailability. Data from earlier ravulizumab IV studies in healthy subjects cannot 
be used for this purpose, as these data were generated using a different bioanalytical 
assay for quantitation of ravulizumab. 
• The ravulizumab SC cohort will provide a reference arm for relative bioavailability 
and to understand the impact of the addition of rHuPH20 to ravulizumab SC. 
• The 200-day washout period corresponds to nearly 5 half-lives where ravulizumab is 
expected to be completely eliminated from the systemic circulation and complement 
activity restored to normal with near-baseline levels in the study subjects. The 
expected terminal elimination half-life for the highest SC dose being evaluated in this 
study is approximately 42 days. 
4.3. 
Justification for Dose 
This is the first time ravulizumab SC will be combined with rHuPH20 for coadministration in 
humans. The starting dose of ravulizumab 500 mg was determined via PK modelling and 
simulation studies using data from the Phase 1 Study ALXN1210-SC-101 and the 
ravulizumab IV clinical development program. The escalating ravulizumab doses proposed in 
this protocol allow for two-fold dose escalations at each dose level and are justified based upon 
the safety, tolerability, and PK margins generated from previous clinical studies. Table 5 
summarizes the PK exposure margins estimated for the planned dose levels for the combined SC 
Cohorts 2, 3 and 4 in this study using the PK exposures from the highest IV dose cohort in 
healthy volunteers in Study ALXN1210-HV-102 (800 mg every 4 weeks) as the reference. The 

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estimated margins illustrate that PK exposures to ravulizumab expected following the planned 
single doses in the SC Cohorts 2, 3 and 4 in this study are well within those previously evaluated 
clinically and determined to be well-tolerated. The estimated exposure at the planned doses in 
this study is expected to be less than that of the healthy subjects who received multiple doses of 
ravulizumab IV 800 mg every 4 weeks in Study ALXN1210-HV-102 (ie, an approximately 
9-month duration of effect). It is noteworthy that in patients with PNH, IV doses much greater 
than those evaluated in Study ALXN1210-HV-102 (ie, up to 5400 mg every 12 weeks) are being 
studied for an extended period (up to 3 years) and those doses have been well-tolerated.  
Recombinant human hyaluronidase PH20 has been safely administered via SC injection/infusion 
in combination with large proteins, up to a maximum volume of 30 mL (Chari, 2017; Usmani, 
2016; Wasserman, 2012). Recombinant human hyaluronidase PH20 administered SC has been 
generally well-tolerated; the most commonly reported adverse reactions were mild, transient, 
local, injection site reactions (ISRs) (rHuPH20 Investigator’s Brochure, 2018). The rHuPH20 
dose (2,000 U/mL) combined with the ravulizumab SC dose is based upon the previous clinical 
experience in 28 clinical studies with rHuPH20 conducted under the rHuPH20 US IND and data 
from 3 marketed products Herceptin® SC, HYQVIA®, and MabThera® SC.  
Table 5:  
Pharmacokinetic Exposure Margins Estimated for the Proposed 
Ravulizumab/rHuPH20 Subcutaneous Dose Cohorts Using the Highest Intravenous 
Dose Cohort From Study ALXN1210-HV-102 as the Reference 
Pharmacokinetic Exposure Margins for Ravulizumab/rHuPH20 Subcutaneous Cohortsa 
Cohort 2 
Cohort 3 
Cohort 4 
Cmax  
AUC∞  
Cmax  
AUC∞  
Cmax  
AUC∞  
8.2 
13.4 
4.1 
6.7 
2.1 
3.4 
a A potential improvement in ravulizumab SC bioavailability due to rHuPH20 was accounted for in the margin 
estimation.  
Abbreviations: AUC∞ = area under the concentration versus time curve from zero to infinity; Cmax = maximum 
observed serum concentration; SC = subcutaneous. 
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed all visits of the 
study including the last scheduled visit specified in the Schedule of Activities (Table 1 and 
Table 2). 
The end of the study is defined as the last scheduled visit for the last subject, specified in the 
Schedule of Activities (Table 1 and Table 2). No further study assessments beyond CH50 
evaluation, as needed based on individual subject results, will be performed after Day 200. 

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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
Age/Sex 
1. Male or female subject must be at least 18 and 65 years of age, inclusive, at the time of 
signing the informed consent. 
Weight 
2. Body weight within 60 – 90 kg, inclusive, and body mass index within the range 18 –
 29.9 kg/m2, inclusive. 
Pregnancy  
3. Negative serum pregnancy test at screening and Day -1 
Contraception 
4. Female subjects of childbearing potential and male subjects with female partners of 
childbearing potential must be willing to follow protocol-specified contraception 
guidance while on treatment and for up to 8 months after last dose of study drug 
(described in Section 6.6).  
Other Inclusion Criteria 
5. QT interval corrected using the Fridericia’s formula (QTcF) ≤ 450 msec for male subjects 
and ≤ 470 msec for female subjects at screening and prior to dosing on Day 1. 
6. Documented vaccination with MCV4 at least 56 days and not more than 2 years, 
4 months prior to dosing. Documentation must include a positive titer to confirm an 
immune response before study drug administration.  
7. 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.  
8. Satisfactory medical assessment with no clinically significant or relevant abnormalities as 
determined by medical history, physical examination, vital signs, 12-lead ECG, and 
clinical laboratory evaluation (hematology, biochemistry, coagulation, and urinalysis) 
that is reasonably likely to interfere with the subject's participation in or ability to 
complete the study, or to potentially confound interpretation of study results, as assessed 
by the Investigator. 
Informed Consent 
9. Willing and able to give written informed consent as described in Section 10.1 
(Appendix 1) which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 

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Medical Conditions 
1. Current or recurrent disease (eg, cardiovascular, hematological, neurological, endocrine, 
immunological, rheumatological, renal, hepatic or gastrointestinal or other conditions) 
that or could affect clinical assessments or clinical laboratory evaluations. 
2. Current or relevant history of physical or psychiatric illness that are not stable or may 
require a change in treatment, use of prohibited therapies during the study or make the 
subject unlikely to fully comply with the requirements of the study or complete the study, 
or any condition that presents undue risk from the investigational product or study 
procedures. 
3. Any other significant disease or disorder which, in the opinion of the Investigator, may 
put the subject at risk. 
4. History of any Neisseria infection. 
5. History of unexplained, recurrent infection, or infection requiring treatment with systemic 
antibiotics within 90 days prior to dosing on Day 1. 
6. History of complement deficiency or complement activity below the reference range as 
evaluated at screening. 
7. History of malignancy with the exception of a nonmelanoma skin cancer or carcinoma 
in-situ of the cervix that has been treated with no evidence of recurrence within 5 years. 
8. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody 
titer). 
9. Acute or chronic hepatitis B virus 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: 
a. If hepatitis B core antibody (HBcAb) is negative, the subject is eligible to enroll.  
b. 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 
10. Acute or chronic hepatitis C virus infection (evidenced by antibody titer). 
11. Active systemic viral or fungal infection within 14 days prior to dosing. 
12. History of latent or active tuberculosis (TB) or exposure to endemic areas within 8 weeks 
prior to the screening visit. 
13. Documented history of allergy to penicillin or cephalosporin. 
14. History of significant allergic reaction (eg, anaphylaxis or angioedema) to any product 
(eg, food, pharmaceutical). 
Prior/Concomitant Therapy 
15. Use of prescription medications (excluding oral contraceptives) within 14 days prior to 
dosing on Day 1, except with prior approval of the Sponsor.  

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16. Regular use of nonprescription, over-the-counter medications, including herbal remedies 
and supplements, within 14 days prior to dosing on Day 1. Multivitamins, paracetamol 
(acetaminophen) ≤ 2 g per day, and topical skin products without significant systemic 
absorption are allowed. 
Prior/Concurrent Clinical Study Experience 
17. Participation (ie, last protocol-required study visit) in a clinical study within 90 days 
before initiation of dosing on Day 1. 
18. Participation in more than 1 clinical study of a mAb, or participation (ie, last 
protocol-required study visit) in a clinical study of a mAb within the 12 months prior to 
screening, during which the subject was exposed to the active study drug. 
Diagnostic Assessments 
19. Positive or indeterminate QuantiFERON®-TB test indicating possible tuberculosis (TB) 
infection. 
20. Presence of fever (confirmed body temperature > 37.6°C) (eg, a fever associated with a 
symptomatic viral or bacterial infection) within 14 days prior to dosing on Day 1. 
21. Serum creatinine greater than the upper limit of normal (ULN) of the reference range of 
the testing laboratory at screening or on Day -1. 
22. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > ULN of the 
reference range of the testing laboratory at screening or > 1.5 × ULN of the reference 
range of the testing laboratory on Day -1. 
23. Any clinically significant abnormal hematological parameters (per the Investigator’s 
discretion). 
24. Positive urine drug toxicology screen at screening or on Day -1. 
25. Alcohol consumption within 48 hours prior to study drug administration or positive 
alcohol breath test on Day -1. 
26. Donation of plasma within 7 days prior to dosing on Day 1. Donation or loss (excluding 
volume drawn at screening) of more than 50 mL of blood within 30 days prior to dosing 
or more than 499 mL of blood within 56 days prior to dosing on Day 1. 
Other Exclusion Criteria 
27. Female subjects who are breastfeeding. 
28. Subjects who are in intimate and prolonged contact with (defined as living under the 
same roof or providing personal care to) people younger than 2 years of age or older than 
65 years of age, or who are either immunocompromised or have one of the following 
underlying medical conditions: anatomic or functional asplenia (including sickle cell 
disease); congenital complement, properdin, factor D, or primary antibody deficiencies; 
acquired complement deficiencies (eg, those receiving eculizumab); or HIV. 
29. Subjects who are one of the following: 
a. Professionals who are exposed to environments of greater risk for meningococcal 
disease  

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b. Research, industrial, and clinical laboratory personnel who are routinely exposed to 
N meningitidis 
c. Military personnel during recruit training (military personnel may be at increased risk 
of meningococcal infection when accommodated in close quarters)  
d. Daycare center workers  
e. Those living on a college or university campus  
f. Those who plan to travel during the course of the study to or have travelled to 
endemic areas for meningococcal meningitis (eg, India, Sub-Saharan Africa, 
pilgrimage to Saudi Arabia for Hajj) within 6 months prior to dosing 
30. Immunization with a live-attenuated vaccine 28 days prior to dosing on Day 1 or planned 
vaccination during the course of the study (except for the vaccination planned by the 
study protocol). Immunization with inactivated or recombinant influenza vaccine is 
permitted. 
31. Prior exposure to ravulizumab or eculizumab. 
32. Major surgery or hospitalization within 90 days prior to dosing on Day 1. 
33. History of allergy or hypersensitivity to excipients of ravulizumab (eg, polysorbate 80), 
rHuPH20, or other hyaluronidases. 
34. Currently smokes > 10 cigarettes daily (former smokers may be permitted to enroll at the 
Investigator’s discretion) and is unwilling to refrain from smoking while a resident in the 
clinical research unit or comply with the smoking restrictions detailed in Section 5.3.2. 
35. History of illicit drug abuse, history of significant alcohol abuse within 1 year prior to the 
screening visit, or clinical evidence of substance and/or alcohol abuse within the 2 years 
before screening. Alcohol abuse is defined as regular weekly intake of more than 14 units 
(for both males and females), using the following NHS alcohol tracker 
http://www.nhs.uk/Tools/Pages/drinks-tracker.aspx.  
5.3. 
Study Restrictions 
5.3.1. 
Meals and Dietary Restrictions 
• Subjects are required to abstain from ingesting food containing poppy seeds within 
24 hours prior to admission. 
• No outside food or drink is permitted at the inpatient facility. All meals and snacks 
will be provided. Subjects will receive standard meals and snacks at scheduled times 
during confinement. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
Subjects will be required to abstain from: 
• Ingesting caffeine- or xanthine-containing products (eg, coffee, tea, cola drinks, and 
chocolate) 24 hours before admission through discharge from the inpatient facility, 
and 24 hours before each study follow-up visit. 
• Ingesting alcohol 24 hours before admission through discharge from the inpatient 
facility, and 24 hours before each study follow-up visit.  

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• Smoking tobacco products from 2 hours before admission through discharge from the 
inpatient facility. 
5.3.3. 
Activity 
Subjects will be required to abstain from strenuous physical activity 48 hours prior to blood 
draws for clinical safety laboratory testing. 
5.4. 
Screen Failures and Replacements 
Screen failures are defined as subjects who consent to participate in the clinical study and are not 
subsequently assigned to study drug due to failure to meet eligibility criteria. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure subjects to 
meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and occurrence of any serious adverse event (SAE). 
Subjects who do not meet the criteria for participation in this study (ie, screen failures) may be 
rescreened. Any abnormal laboratory parameter(s) resulted outside of the reference range at 
screening may be repeated per the Investigator’s discretion for the purpose of further 
determining eligibility. 
In order to meet minimum data requirements for SRC meetings, subjects who withdraw consent 
from the study within the first 7 days may be replaced. Subjects who withdraw consent between 
Days 7 and 50 may be replaced at the Sponsor’s discretion. 
5.4.1. 
Criteria for Study Termination 
The Investigator, competent authority, or Sponsor may terminate the study for reasonable cause. 
Conditions that warrant termination of the study include, but are not limited to, the following: 
• Discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the 
study 
• Decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the study drug 
• Failure of the Investigator to comply with the approved protocol, pertinent guidelines, 
and/or regulations 
• Submission of knowingly false information from the Investigator to the Sponsor 
and/or regulatory authorities 

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6. 
STUDY DRUG 
Study drug is defined as any investigational drug product(s), marketed product(s), or placebo, 
intended to be administered to a subject according to the protocol. 
6.1. 
Study Drug Administered 
The study drug composition and doses to be administered in this study are presented in Table 6. 
Table 6: 
Dose Reference Chart for Study ALXN1210-HV-105 
Study Drug 
Name: 
Ravulizumab IV 
Ravulizumab SC 
rHuPH20 
Ravulizumab 
SC/rHuPH20  
Dosage 
Formulation: 
 
Ravulizumab IV is 
formulated at pH 7.0 
and each vial 
contains 300 mg of 
ravulizumab in 
10 mM sodium 
phosphate, 150 mM 
sodium chloride, 
0.02% polysorbate 
80.  
 
Each vial contains 
10 mg/mL. 
Ravulizumab SC 
is formulated at 
pH 7.4 and each 
vial contains 
1100 mg of 
ravulizumab in 
50 mM sodium 
phosphate, 25 
mM arginine, 5% 
sucrose, and 
0.05% 
polysorbate 80.  
 
Each vial contains 
100 mg/mL. 
rHuPH20 is 
supplied as 
ENHANZE® drug 
product (EDP) is 
supplied in vials as 
a sterile, single-
dose, injectable 
liquid at 
approximately 
110 kU/mL. The 
solution has a pH 
of 6.5 and contains 
130 mM sodium 
chloride, 10 mM 
L-Histidine/ 
hydrochloride as a 
buffer, 10 mM 
L-Methionine, and 
0.2% w/w 
polysorbate 80.  
 
The solution is 
filled to 0.5 mL in a 
2-mL glass vial. 
Ravulizumab 
SC/rHuPH20 is 
formulated per the 
individual 
components of the 
drug product. 
Unit Dose 
Strength(s)/ 
Dosage Level(s): 
400 mg 
400 mg 
NA 
ravulizumab SC 
500 mg/rHuPH20 
10,000 units 
 
ravulizumab SC 
1000 mg/rHuPH20 
20,000 units 
 
ravulizumab SC 
2000 mg/rHuPH20 
40,000 units 
Route of 
Administration  
IV 
SC 
SC 
SC 

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Study Drug 
Name: 
Ravulizumab IV 
Ravulizumab SC 
rHuPH20 
Ravulizumab 
SC/rHuPH20  
Dosing 
Instructions: 
 
A single dose of 
ravulizumab IV will 
be administered via 
IV infusion and 
80 mL of 
ravulizumab IV will 
be administered at a 
maximum infusion 
rate of 333mL/hr, for 
a minimum infusion 
duration of 
approximately 
15 minutes. 
 
Use of an in-line 
filter for infusion is 
required. 
A single dose of 
ravulizumab SC 
will be 
administered via 
SC infusion 
administered by a 
syringe pump. 
 
The total volume 
to be 
administered will 
be 4 mL at an 
infusion rate of 
0.5 mL/min. 
NA 
Ravulizumab will be 
co-mixed with EDP 
in empty, sterile 
20-mL glass vials. A 
single dose of 
ravulizumab 
SC/rHuPH20 will be 
administered via SC 
infusion, 
administered via an 
infusion pump.  
 
 
The total volume to 
be administered for 
the combination 
cohorts will be 
5.23 mL in Cohort 2, 
10.46 mL in Cohort 
3, and 20.91 mL in 
Cohort 4 at an 
infusion rate of 
2 mL/min.. 
Packaging and 
Labeling 
Additional 
instructions are 
provided in the 
pharmacy 
manual. 
Ravulizumab IV 
drug product will be 
provided in a 
single-use, USP/Ph 
Eur Type 1 clear 
and colorless glass 
vial, stoppered with 
a gray butyl rubber 
stopper, and sealed 
with aluminum seal 
with a 
polypropylene 
flip-off cap.  
Ravulizumab SC 
drug product will 
be provided in a 
single-use, 
USP/Ph Eur Type 
1 clear and 
colorless glass 
vial, stoppered 
with a gray butyl 
rubber stopper, 
and sealed with 
aluminum seal 
with a 
polypropylene 
flip-off cap. 
rHuPH20 for 
coadministration 
will be provided as 
single-use, 
USP/Ph Eur Type I 
clear and colorless 
glass vial. 
Individual 
components of 
ravulizumab SC/ 
rHuPH20 drug 
product will be 
packaged and 
labeled according to 
their respective 
manufacturers. 
Manufacturer 
Alexion 
Alexion 
Halozyme 
Alexion/Halozyme 
Abbreviations: IV = intravenous; NA = not applicable; SC = subcutaneous. 
Source: rHuPH20 Investigator’s Brochure (2018), pharmacy manual 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and that any discrepancies are 
reported and resolved before use of the study drug. 
2. Only subjects enrolled in the study may receive study drug and only authorized site staff 
may supply or administer study drug. All study drugs must be stored in a secure, 
environmentally controlled, and monitored (manually or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized 
site staff. 

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3. Preparation of ravulizumab IV, ravulizumab SC, and the ravulizumab SC/rHuPH20 drug 
products must be performed in accordance with local standards by qualified pharmacy 
personnel at the investigative site. 
4. The handling and preparation of materials used to prepare and administer the study drug 
must be carried out using aseptic techniques for sterile products. For each subject, doses 
will be prepared as required per the dose cohort.  
5. The entire dosing apparatus (ie, syringe and infusion tubing) should be weighed before 
and after infusion and the weights recorded for the purpose of recoding the exact dose 
administered. 
6. Recombinant human hyaluronidase PH20 will be supplied as ENHANZE drug product 
(EDP; 1 mg/mL [0.5 mg of active ingredient per vial; approximately 110,000 units/mg]) 
in 2-mL single use glass vials.  
7. The volume of drug product to be prepared will be based on the cohort to which a subject 
is assigned. For Cohort 1, ravulizumab will be administered undiluted via SC infusion 
administered by a syringe pump. For Cohorts 2 through 4, ravulizumab will be co-mixed 
with EDP in empty, sterile glass vials. A single dose of ravulizumab SC/rHuPH20 will be 
administered via SC infusion administered by a syringe pump. For Cohort 5, the IV 
admixture will consist of ravulizumab diluted in a 1:1 ratio with 0.9% sodium chloride, 
Ph Eur, or BP. Do not flush the IV infusion line. The rate at which study drug will be 
administered in Cohorts 1 through 4 will be provided in the pharmacy manual. 
8. The Investigator or qualified designee is responsible for study drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition 
records). 
Additional instructions are provided in the pharmacy manual.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. Eligible subjects who meet all inclusion and no exclusion criteria 
will be assigned unique numbers for enrollment and randomization. Randomization will only be 
used when cohorts are being enrolled in parallel. 
• In order to minimize selection bias in treatment assignment, subjects will be 
randomly or sequentially assigned subject numbers, depending upon cohort, up to 
7 days prior to dosing on Day 1, in the same order as they have become eligible. 
• Sentinel dosing will be employed in Cohorts 1 through 4 (ie, 2 subjects in a cohort 
with 12 subjects and 1 subject in a cohort with 6 subjects will be dosed prior to 
dosing the remaining subjects within the cohort). Remaining subjects within the 
cohort will be dosed at least 24 hours following dosing of the sentinel subjects. 
• At the Sponsor’s discretion, and after consultation with the SRC, up to 16 additional 
subjects may be enrolled as replacement subjects if any subject discontinues prior to 
Day 50 for reasons other than drug-related AE. 
• Study numbers will not be reallocated once assigned. 
 

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6.4. 
Study Drug 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 center 
personnel will ensure that all subjects are adequately informed about the specific study drug 
dosing regimen required for compliance with the study protocol. 
6.5. 
Concomitant Therapy 
Subjects must abstain from taking prescription or nonprescription drugs (including vitamins and 
dietary or herbal supplements) within 14 days before the start of study drug until completion of 
the follow-up visit, unless, in the opinion of the Investigator and Sponsor, the medication will not 
interfere with the study.  
Multivitamins, paracetamol (acetaminophen) (at doses of ≤ 2 g/day), and topical skin products 
without significant systemic absorption are permitted for use during the study at the 
Investigator’s discretion. Topical skin products should not be administered at the site of study 
drug injection from 24 hours prior until 24 hours following study drug administration. Subjects 
are also permitted to receive a booster vaccine, if required. 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the medical monitor if required. Concomitant procedures are not allowed 
unless medically indicated. 
6.6. 
Contraception Guidance 
Female subjects who are documented as being of non-childbearing potential as defined in 
Section 10.4 (Appendix 4) are exempt from contraception requirements.   
Female subjects of childbearing potential, if heterosexually active, must use highly effective or 
acceptable contraception as defined below. Antibiotic prophylaxis is required during this study, 
which can compromise the efficacy of hormonal contraception. Therefore, subjects using 
hormonal contraception must also use barrier contraception (eg, condom or diaphragm with 
spermicide) for the duration of antibiotic prophylaxis. 
Highly effective contraceptive methods for females are as follows: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation as follows: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation as 
follows: 
− Oral 
− Injectable 
− Implantable 

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• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
Male subjects, if heterosexually active and with a female spouse or partner of childbearing 
potential or a pregnant or breastfeeding spouse or partner, must agree to use barrier contraception 
(male condom). 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. Male subjects must not donate sperm and female subjects must 
not donate ova. 
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 
Contraception must start during screening and continue after the end of the systemic exposure of 
the study drug as specified below: 
• Cohorts 1 and 5 – contraception must continue for at least 6 months after last dose. 
Male subjects must not donate sperm and female subjects must not donate ova until at 
least 6 months after last dose. 
• Cohorts 2, 3, and 4 – contraception must continue for at least 8 months after last dose. 
Male subjects must not donate sperm and female subjects must not donate ova until at 
least 8 months after last dose. 
6.7. 
Dose Modification 
Decisions to continue, modify (explore the dose cohort further), or escalate dosing will be made 
by the Investigator and/or SRC as described in Table 7. The SRC may also make 
recommendations regarding safety issues, study conduct, or study suspension. The SRC is 
composed of the Sponsor's medical monitor, biostatistician, pharmacovigilance representative, 
clinical pharmacologist, and the Investigator. The membership roster, schedule of meetings, data 
required for each safety review, and requirements for documenting meeting discussions and 
outcome will be outlined in the SRC charter. 
The SRC will review all available safety and tolerability data from a given cohort for at least the 
first 168 hours after study drug administration in order to determine whether to escalate the 
ravulizumab SC/rHuPH20 dose and initiate the next cohort. Data through 168 hours must be 
available for at least 11 of the 12 subjects. Dose escalation or modification will occur based on 
the recommendation of the SRC to dose escalate and only applies to Cohort 3 and Cohort 4. 

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Table 7: 
Study ALXN1210-HV-105 Dose Continuation/Escalation Decision Pathway 
Dosing 
Decision 
Responsib
le Party 
Data to be Reviewed 
Documentation/Communication 
Methods 
Continuation 
from the 
sentinel subject 
to the 
remaining 
subjects in 
Cohort 1 
Investigato
r 
A minimum of 24 hours post-
dose safety and tolerability data 
from the sentinel subject. 
The Investigator will document the 
decision in an email to the Sponsor. 
The email does not require the 
Sponsor’s response, unless there is 
disagreement with the Investigator’s 
decision. 
Continuation 
from the 
sentinel 
subjects to the 
remaining 
subjects in 
Cohort 2 
Investigato
r 
A minimum of 24 hours post-
dose safety and tolerability data 
from the sentinel subjects.  
The Investigator will document the 
decision in an email to the Sponsor. 
The email does not require the 
Sponsor’s response, unless there is 
disagreement with the Investigator’s 
decision. 
Escalation to 
Cohort 3 
SRC 
A minimum of 168 hours post-
dose safety and tolerability data 
from at least 11 subjects (all of 
whom have received treatment) 
from the previous cohort that 
was on the next lowest dose 
level (and hence, next lowest 
exposure) of ravulizumab 
SC/rHuPH20. 
The SRC will document the decision 
on the escalation/progression 
approval form.  
Continuation 
from the 
sentinel 
subjects to the 
remaining 
subjects in 
Cohort 3 
Investigato
r 
A minimum of 24 hours post-
dose safety and tolerability data 
from the sentinel subjects. 
The Investigator will document the 
decision in an email to the Sponsor. 
The email does not require the 
Sponsor’s response, unless there is 
disagreement with the Investigator’s 
decision. 
Escalation to 
Cohort 4 
SRC 
A minimum of 168 hours post-
dose safety and tolerability data 
from at least 11 subjects (all of 
whom have received treatment) 
from the previous cohort that 
was on the next lowest dose 
level (and hence, next lowest 
exposure) of ravulizumab 
SC/rHuPH20.   
The SRC will document the decision 
on the escalation/progression 
approval form. 
Continuation 
from the 
sentinel 
subjects to the 
remaining 
subjects in 
Cohort 4 
Investigato
r 
A minimum of 24 hours post-
dose safety and tolerability data 
from the sentinel subjects. 
The Investigator will document the 
decision in an email to the Sponsor. 
The email does not require the 
Sponsor’s response, unless there is 
disagreement with the Investigator’s 
decision. 
Abbreviations: SC = subcutaneous; SRC = Safety Review Committee. 
6.7.1. 
Toxicity Rules for Adverse Events Deemed Related to Study Drug 

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These rules apply to AEs that are assessed as related to study drug by the Investigator. Dose 
continuation or escalation will proceed as scheduled (Table 7) and the study will continue as 
planned provided no prespecified toxicity events occur. 
• The entire study will be suspended if any life-threatening (Common Terminology 
Criteria for Adverse Events [CTCAE] v4.03; published 14 Jun 2010, Grade 4) or fatal 
(CTCAE Grade 5) SAEs occur. If any of the following occur, dosing within the 
affected cohort will be suspended and dose escalation cannot commence. Interim 
lower doses may be subsequently administered at the discretion of the SRC.  
− A treatment-related SAE, irrespective of the CTCAE grade, in 1 subject. This 
includes any subject potentially meeting the criteria for Hy’s Law 
(ALT ≥ 3 × ULN) and bilirubin ≥ 2 × ULN (ie, > 35% direct bilirubin) or 
ALT ≥ 3 × ULN and international normalized ratio (INR) > 1.5, if INR was 
measured, which may indicate severe liver injury (possibly Hy’s Law). 
− Severe (CTCAE Grade 3) nonserious treatment-related AEs in 2 subjects in the 
same cohort, independent of whether the AEs are within the same System Organ 
Class (SOC). 
For Cohorts 2 through 4 (ravulizumab SC/rHuPH20): 
• Any number of Grade 1 ISRs are permitted to allow continuation of dosing within a 
cohort and escalation to the next highest dose level.  
• Any number of Grade 2 ISRs that have resolved or reduced to Grade 1 by the time of 
the minimum data review period (168 hours post-dose) are permitted to allow 
continuation of dosing within a cohort and escalation to the next highest dose level. 
• If, at the end of the minimum data review period (168 hours post-dose) there are more 
than 2 subjects with ISRs that are still Grade 2, dose escalation cannot occur and the 
period of observation should be extended by a further 168 hours (or shorter, if all 
subjects recover to at least Grade 1 before that time point). If all affected subjects 
show sign of recovery (at least to Grade 1), dose escalation can then proceed. If all 
affected subjects remain at Grade 2 after the additional 168-hour observation period, 
the SRC will make the decision to either prolong further the observation period or 
progress to subsequent combination cohorts at a lower dose/smaller volume of study 
drug.  
6.8. 
Intervention After the End of the Study 
This is a healthy volunteer study and no follow-up intervention is planned. 

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7. 
DISCONTINUATION OF STUDY DRUG AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
Subjects who experience a severe reaction during study drug administration resulting in 
interruption without completion of the administration should undergo all scheduled safety, 
immunogenicity, PK, and PD evaluations required by the protocol (refer to Schedule of 
Activities, Table 1 and Table 2). Subjects will be instructed to present for all scheduled visits and 
undergo all procedures per protocol. 
7.2. 
Subject Discontinuation/Withdrawal From the Study 
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, compliance, or 
administrative reasons. 
• If the subject withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• Data to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed are specified in the Schedule of 
Activities (Table 1 and Table 2). 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject, reschedule the missed visit as soon as 
possible, counsel the subject about the importance of maintaining the assigned visit 
schedule, and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or similar 
methods). These contact attempts must be documented in the subject’s medical 
record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator or qualified designee will maintain a screening log 
to record details of all subjects screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
8.1. 
Efficacy Assessments  
No efficacy assessments will be obtained during this study. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are presented in the Schedule of Activities 
(Table 1 and Table 2).  
8.2.1. 
Physical Examination 
Each examination will include the following assessments: general appearance; skin; head, ears, 
eyes, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limbs; central nervous 
system; and musculoskeletal system. Height and weight (screening only) will also be measured 
and recorded. Body mass index will be calculated and recorded at screening. 
8.2.2. 
Vital Signs 
Vital sign measurements 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 measurements is 
described in the Schedule of Activities (Table 1 and Table 2). Out of range blood pressure or 
heart rate measurements will be repeated at the Investigator’s discretion. Confirmed, clinically 
significant vital sign measurements will be recorded as AEs. 
8.2.3. 
Electrocardiograms 
A triplicate 12-lead ECG will be obtained after the subject has been resting for at least 5 minutes. 
The timing of ECGs is described in the Schedule of Activities (Table 1 and Table 2). At each 
time point at which triplicate ECGs are required, 3 individual ECG tracings should be obtained 
as closely as possible in succession, but no more than 2 minutes apart. The full set of triplicates 
should be completed in less than 4 minutes, 30 seconds. In addition, continuous cardiac 
registration will be performed in Cohorts 2, 3, and 4 as specified in Table 1. 
8.2.4. 
Laboratory Assessments 
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2), must be 
conducted in accordance with the Schedule of Activities and the laboratory manual. Clinical and 
laboratory assessments will be performed by a local laboratory to assess safety of ravulizumab.  
• The Investigator must review the laboratory report, document this review, and record 
all clinically relevant changes occurring during the study in the AE section of the 
electronic case report form (eCRF). The laboratory reports must be filed with the 
source documents. 

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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study will be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or medical 
monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
− If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in subject 
management or are considered clinically significant by the Investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the eCRF.  
• The maximum amount of blood to be collected from each subject over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL. Repeat or unscheduled samples may be obtained for safety and/or eligibility 
reasons or if there are any technical issues with the samples. 
8.2.4.1. 
Virus Serology 
Blood samples collected at screening will be analyzed for HIV-1, HIV-2, HBsAg, and hepatitis 
C virus antibody titers. 
Hepatitis B surface antigen testing is required for all subjects prior to enrollment. Subjects with 
positive HBsAg will not be enrolled. 
8.2.4.2. 
Vaccine Titer 
A titer against meningococcal serogroups A, C, W135, and Y will be performed at screening 
(Schedule of Activities [Table 1 and Table 2]). Titer measurements will be used to exclude 
subjects without a confirmed immune response. 
8.2.4.3. 
Immunogenicity Assessments 
Antibodies to ravulizumab will be evaluated in serum samples collected from all subjects 
according to the Schedule of Activities (Table 1 and Table 2).  
Serum samples will be screened for antibodies that bind to ravulizumab and the titer of 
confirmed positive samples will be reported. The detection and characterization of antibodies to 
ravulizumab will be performed using a validated assay method by or under the supervision of the 
Sponsor. Samples may be banked for a period of up to 5 years in order to perform additional 
safety assessments, as necessary. 
Detailed instructions on the procedure for collecting, processing, storing, and shipping serum 
samples for immunogenicity analysis will be provided in the laboratory manual. 
 

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8.2.5. 
Drug and Alcohol Screen 
A urine sample for drug screen will be analyzed for the substances listed in Section 10.2 
(Appendix 2). Timing of urine drug and alcohol breath tests is specified in the Schedule of 
Activities (Table 1 and Table 2). 
8.2.6. 
Pregnancy Testing 
Pregnancy testing will be performed for all female subjects at the time points specified in the 
Schedule of Activities (Table 1 and Table 2). 
8.2.7. 
Tuberculosis Testing 
Serum samples for a QuantiFERON-TB test will be obtained at the time points specified in the 
Schedule of Activities (Table 1 and Table 2). 
8.2.8. 
Injection or Infusion-Site Evaluation 
Subcutaneous injection or IV infusion-site evaluations will be performed at the time points 
specified in the Schedule of Activities (Table 1 and Table 2). Injection site reactions (eg, 
indurations ≤ 1 cm in size) will not be listed as an AE unless they persist for more than 24 hours. 
8.2.9. 
Vaccine and Antibiotic Prophylaxis 
To mitigate the risk of N meningitidis infection associated with terminal complement inhibition, 
subjects in this study will be administered the following:  
1. A MCV4 vaccination at least 56 days prior to dosing of ravulizumab on Day 1 (if not 
vaccinated with MCV4 within the last 3 years, or if subjects have been previously 
vaccinated but there is not adequate documentation to verify prior vaccination).  
2. Two injections of the serogroup B meningococcal vaccine. The first injection must be 
administered at least 56 days prior to dosing on Day 1, with a booster administered at 
least 28 days prior to dosing on Day 1, with at least 28 days between the first and second 
injections. 
3. Prophylactic antibiotic treatment, oral penicillin V 500 mg twice daily (equivalent to 
1 × 106 units) until complement activity has normalized (as determined by CH50 assay).  
The first dose of antibiotic will be administered orally on Day -1 in the evening, prior to the 
Day 1 (dose administration) of study drug. For the outpatient portion of the study, subjects will 
be instructed to take the antibiotic approximately at the same times (twice daily) on each 
scheduled day. A suitable system (such as text messaging) will be used for daily monitoring of 
subjects’ compliance with the antibiotic prophylaxis regimen.  
The following observations support the administration of antibiotic prophylaxis in this 
single-dose study: 
1. Penicillin is the drug of choice in eradication of N meningitidis in carriers. 
2. Complement-deficient patients who received monthly injections with benzathine 
penicillin G as prophylaxis for recurrent meningococcal disease during a 2- to 4-year 
period experienced significantly fewer episodes of Neisseria infection than deficient 
individuals not receiving prophylaxis (Figueroa, 1991). 

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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 and is generally well-tolerated (Kelly, 2011; Leeds Teaching Hospitals NHS 
Trust, 2013). 
8.2.10. 
Risk of Infection Reminders 
Risk of infection will be explained and discussed with subjects during the informed consent 
process, occurring at the screening visit. In order to increase the risk awareness and promote 
quick disclosure of any potential signs or symptoms of infection experienced by the subjects 
during the course of the study, additional discussion and explanation of the potential risks, signs, 
and symptoms, as described in the ICF, will take place at specific time points throughout the 
study as noted in the Schedule of Activities (Table 1 and Table 2). Subjects will also be provided 
a safety card to carry with them at all times. 
8.3. 
 Adverse Events and Serious Adverse Events  
The definitions of an AE or SAE and specific reporting requirements are located in Section 10.3 
(Appendix 3). Adverse events will be reported to the Investigator or qualified designee by the 
subject (or, when appropriate, by a caregiver, surrogate, or the subject’s legally authorized 
representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the subject to discontinue the study drug (see Section 7).  
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information  
All AEs and SAEs will be collected from the signing of the ICF until the last follow-up visit. 
Medical occurrences that begin before the start of study drug and after obtaining informed 
consent will be recorded on the eCRF, and will be considered as medical history. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 10.3 (Appendix 3). The Investigator will submit updated SAE data to the Sponsor 
within 24 hours of the data being available. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of study 
participation (ie, after Day 200). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports to Sponsor are provided in Section 10.3 
(Appendix 3). 

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8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 10.3 [Appendix 3]). 
Further information on follow-up procedures is provided in Section 10.3 (Appendix 3). 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a study drug under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study drug under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• The Council for International Organizations of Medical Sciences or MedWatch 
reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
8.3.5. 
Pregnancy 
• Incidence of all pregnancies in female subjects and if indicated female sexual partners 
of male subjects will be collected after the administration of study drug and for at 
least 6 months (Cohorts 1 and 5) or 8 months (Cohorts 2, 3, and 4) thereafter. 
• Complications of abnormal pregnancy outcomes (eg, spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, and ectopic pregnancy) are AEs and may meet 
the criteria for SAEs (Section 10.3 [Appendix 3]).  
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy. Specific pregnancy information to be collected is 
outlined in Section 10.4 (Appendix 4). 

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8.3.6. 
Management of Potential Adverse Events During Study Drug Administration 
Infusion of other monoclonal antibodies has been associated with infusion reactions, with onset 
typically during or shortly after completion of the infusion. For this reason, subjects will be 
carefully observed during each infusion. 
Subjects will be closely monitored during and after study drug administration for any symptoms 
of anaphylaxis and other hypersensitivity reactions, including circulatory and/or respiratory 
changes or arrest, or urticaria, arthralgias, myalgias, or other signs of related reactions. Adequate 
treatment will be immediately available. Infusion-associated AEs may occur, and depending on 
their type and severity, discontinuation of infusion may be required. Subjects will be informed of 
early symptoms and signs of hypersensitivity reactions including hives, swollen face, eyelids, 
lips, or tongue, or trouble with breathing. An acute infusion reaction algorithm will be used to 
manage infusion-related reactions (Section 10.7 [Appendix 6: Acute Infusion Reactions 
Algorithm]). In this study, regular assessments to monitor infusion reactions and infusion-site 
reactions will be done. To ensure that reactions can be dealt with promptly, there will be at least 
15 minutes between the end of IV/SC infusion in 1 subject and the start of IV/SC infusion in the 
next subject. No more than 6 subjects assigned to receive ravulizumab IV will be dosed per day. 
Any reactions will be treated and taken into account in the dose continuation/escalation and 
toxicity rules (Table 7). If anaphylactic reactions occur, the current “UK Treatment Guideline for 
Anaphylactic Reactions” of the UK Resuscitation Council will be followed (Section 10.7 
[Appendix 7: United Kingdom Resuscitation Council Anaphylaxis Algorithm]). 
Subjects who experience a severe reaction during administration of study drug that results in 
discontinuation of study drug should undergo all scheduled safety, immunogenicity, PK, and PD 
evaluations required by the protocol. Subjects will therefore be instructed to attend all scheduled 
visits and undergo all procedures per protocol.  
8.3.7. 
Study Drug Administration Reactions 
8.3.7.1. 
Infusion-site Reactions 
Infusion-site reactions are defined as AEs localized to the site of IV or SC route of study drug 
administration, occurring at any time during study participation that are assessed by the 
Investigator to be possibly, probably, or definitely related to study drug. 
8.3.7.2. 
Infusion-associated Reactions 
Infusion-associated reactions are defined as systemic AEs (eg, fever, chills, flushing, alterations 
in heart rate and blood pressure, dyspnea, nausea, vomiting, diarrhea, and generalized skin 
rashes) occurring during or within 24 hours of the start of IV or SC infusion that are assessed by 
the Investigator to be possibly, probably, or definitely related to the study drug. 
8.4. 
Treatment of Overdose 
No cases of overdose have been reported during ravulizumab IV or SC clinical studies. A single 
dose of study drug will be administered and monitored by site personnel. 
 

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8.5. 
Pharmacokinetics 
Whole blood samples will be collected for measurement of serum concentrations of study drug 
as specified in the Schedule of Activities (Table 1 and Table 2). Additional samples may be 
collected during the study if warranted and agreed upon between the Investigator and the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
Additional details, including further handling and processing instructions and sampling time 
windows will be provided in the study laboratory manual. 
8.6. 
Pharmacodynamics 
After study drug administration, whole blood samples will be collected for measurement of 
serum free C5 concentrations, chicken red blood cell (cRBC) hemolytic activity, and potentially 
other measures of C5 activation as specified in the Schedule of Activities (Table 1 and Table 2). 
Additional samples may be collected during the study if warranted and agreed upon between the 
Investigator and the Sponsor.  
Serum samples will be collected at baseline and during follow-up for measurement of CH50 
activity using an in vitro LIA to confirm normalization of complement activity. If a normal 
CH50 result is obtained from a subject’s first CH50 sample collected during follow-up, antibiotic 
prophylaxis can be stopped and the second scheduled CH50 sample is not required. If the first 
and second CH50 samples are not normal, the baseline sample may be analyzed, and further 
CH50 samples will be taken until complement activity has been normalized. 
8.7. 
Genetics 
Genetics will not be evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers will not be evaluated in this study. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics data will not be evaluated in this study. 

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9. 
STATISTICAL METHODS AND PLANNED ANALYSES 
9.1. 
Statistical Hypotheses 
Not applicable. 
9.2. 
Sample Size Determination  
The sample size is based on PK rather than statistical considerations. A total sample size of 48 
subjects (6 subjects each in the control cohorts [Cohort 1 and 5] and 12 subjects each in the 
combination cohorts [Cohorts 2, 3, and 4]) will serve to estimate bioavailability. 
9.3. 
Populations for Analyses 
 The analysis sets are defined in Table 8. 
Table 8: 
Study ALXN1210-HV-105 Analysis Sets 
Set 
Description 
Safety 
All subjects who receive at least 1 dose of study drug 
Pharmacokinetic 
All subjects who have sufficient serum concentration data to enable the 
calculation of PK parameters 
Pharmacodynamic 
All subjects who have sufficient total and free C5 concentration data and 
cRBC hemolysis data which will enable the evaluation of the PD effects 
Immunogenicity 
All subjects who have a predose and post-dose ADA sample collected 
Abbreviations: ADA = antidrug antibody; C5 =  complement component 5; cRBC = chicken red blood cell; PD = 
pharmacodynamic(s); PK = pharmacokinetic(s). 
9.4. 
Statistical Analyses 
In general, descriptive statistics for continuous variables will include number of nonmissing 
values, arithmetic mean, standard deviation, median, minimum, and maximum. Descriptive 
statistics for PK parameters will include number of observations, arithmetic mean, standard 
deviation, arithmetic coefficient of variation (%CV), median, minimum, maximum, geometric 
mean and geometric %CV. Categorical variables will be summarized using percentages and 
frequency counts, by cohort and time point. 
A statistical analysis plan (SAP) will be developed and finalized before data cutoff/database lock 
and will further describe the subject populations to be included in the analyses, and procedures 
for accounting for missing, unused, and spurious data as appropriate. This section is a high-level 
summary of the planned statistical analyses of the primary and secondary endpoints. 
9.4.1. 
Efficacy Analyses 
No efficacy analyses will be performed for this study. 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Set and will be reported by each cohort.  
Safety analyses will include an analysis of all AEs, ECGs, clinical laboratory data, physical 
examinations, and vital sign measurements using descriptive statistics. No inferential statistical 
analyses are planned on the safety parameters of this study. The incidence of AEs and SAEs will 
be summarized, by SOC and Preferred Term for each cohort and overall, by relationship to study 

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drug. Adverse events will also be summarized by cohort and overall by severity. Serious AEs 
and AEs resulting in withdrawal from the study will be listed. Subjects having multiple AEs 
within a category (eg, overall, SOC, Preferred Term) will be counted once in that category. For 
severity tables, a subject’s most severe event within a category will be counted. 
Changes from baseline in vital sign measurements and laboratory assessments (eg, chemistry, 
cell blood count with differential, and urinalysis) will be summarized by each cohort. Laboratory 
parameter values will be graded according to the CTCAE. Shift tables by cohort will be 
produced for these laboratory parameters. These tables will summarize the number of subjects 
with each baseline grade relative to the reference ranges and changes to the worst highest grade 
assessed post-dose during the study. 
The ECG parameters will be measured at the specified time points, including heart rate, PR, RR, 
QRS, QT, and corrected QTcF intervals. The average of the triplicate ECG readings at the time 
points collected will be calculated, and changes from pretreatment baseline values will be 
assessed by each cohort. 
An outlier analysis will be performed that will summarize the frequency and percentage of 
subjects who meet any of the following outlier criteria at each visit by cohort: 
• QT, QTcF interval > 450 msec 
• QT, QTcF interval > 480 msec 
• QT, QTcF interval > 500 msec 
• QT, QTcF interval increases from baseline > 30 msec 
• QT, QTcF interval increases from baseline > 60 msec 
All concomitant medications will be coded using the World Health Organization Drug 
Dictionary, and the frequency and percentage of concomitant medications will be summarized. 
9.4.3. 
Other Analyses  
9.4.3.1. 
Pharmacokinetic Analyses 
The individual serum concentration data for ravulizumab IV-, ravulizumab SC/rHuPH20-, 
ravulizumab SC-treated subjects, with actual sampling dates and times, will be used to derive the 
PK parameters by noncompartmental analyses methods using Phoenix WinNonlin 6.3 or higher. 
The following PK parameters will be derived: maximum observed serum concentration (Cmax), 
time to maximum observed serum concentration (tmax), area under the serum concentration 
versus time curve from time 0 to the last quantifiable concentration (AUCt), area under the curve 
from time 0 (dosing) to time infinity (AUC0-∞), apparent terminal-phase elimination rate constant 
(λz), terminal elimination half-life (t½), total clearance (CL) or apparent clearance (CL/F), 
volume of distribution (Vd) or apparent volume of distribution (Vd/F), absolute bioavailability 
(F), and relative bioavailability (Frel). The absolute bioavailability for the ravulizumab 
SC/rHuPH20 cohorts will be defined by the ratio of the geometric means for the AUC0-∞ 
parameter for the ravulizumab SC/rHuPH20 cohort over the ravulizumab IV cohort. The relative 
bioavailability for the ravulizumab SC/rHuPH20 cohorts will be defined by the ratio of the 
geometric means for the AUC0-∞ parameter for the ravulizumab SC/rHuPH20 cohort over the 

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ravulizumab SC cohort. For the absolute and relative bioavailability estimates, a 95% CI for each 
of the ratio of the geometric means will be provided. 
Additional details will be provided in the SAP. 
9.4.3.2. 
Pharmacodynamic Analyses 
The PD effects of ravulizumab SC and IV will be evaluated by assessing changes in serum free 
C5 concentrations, cRBC hemolysis, and other measures of C5 activation over time as 
appropriate. 
9.4.3.3. 
Immunogenicity Analysis 
Immunogenicity, as measured by ADA, will be summarized for ravulizumab. 
9.5. 
Interim Analyses  
An interim assessment of PK data through Day 50 may be performed.  

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− Applicable International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
Informed Consent Process 
The Investigator will ensure that the subject is given full and adequate verbal 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. 

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If emerging study information warrants an update to ICF content, the subject will sign an ICF 
addendum. The site will retain the original addendum and a copy of the signed addendum will be 
provided to the subject. 
10.1.3. 
Data Protection 
• Subjects will be assigned a unique identifier. Any subject records or datasets that are 
transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
• The subject must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the subject.  
• The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.4. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on the US website 
www.clinicaltrials.gov, and EU website www.clinicaltrialsregister.eu/, or other publically 
accessible websites as appropriate and in accordance with local regulations. 
10.1.5. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. Study monitors will communicate with investigative sites on 
a regular basis regarding study protocol deviations. All protocol deviations will be 
appropriately documented by the Investigator or designee, and study monitors. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for a minimum of 5 years after study 

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completion unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another party without 
written notification to the Sponsor. Unless otherwise specified, procedures, data 
collection, and evaluation will be conducted as per the study center’s standard 
operating procedures. 
10.1.6. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected. The Investigator or designee will prepare and 
maintain adequate and accurate source documents (medical records, ECG readings, 
AE and concomitant medication reporting, raw data collection forms) designed to 
record all observations and other pertinent data for each subject. Source documents 
are filed at the Investigator’s site. 
• Data reported entered in the eCRF must be consistent with the source documents or 
the discrepancies must be explained. The Investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current medical 
records must be available. 
10.1.7. 
Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of subjects by the Investigator 
• Discontinuation of further study drug development 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests  
• The tests detailed in Table 9 will be performed by the local laboratory.  
• The maximum amount of blood to be collected from each subject over the duration of 
the study, including any extra assessments that may be required, will not exceed 
500 mL. Please refer to the laboratory manual for specific details regarding serum 
sampling volumes. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. Investigators must 
document their review of each laboratory safety report and indicate whether out of 
range results are clinically significant (“CS”) or not clinically significant (“NCS”). 

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Table 9: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
Red blood cell (RBC) 
count 
Free hemoglobin 
Hematocrit 
RBC Indices: 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
hemoglobin (MCH) 
%Reticulocytes 
White blood cell (WBC) 
count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry 
Lactate dehydrogenase 
Blood urea nitrogen 
(BUN) 
Potassium 
Aspartate 
aminotransferase 
(AST)/serum glutamic-
oxaloacetic transaminase 
(SGOT) 
Gamma 
glutamyltransferase 
(GGT) 
Total and direct bilirubin 
Indirect bilirubin 
 
Creatinine 
Sodium 
Chloride  
Potassium 
Alanine aminotransferase 
(ALT)/Serum glutamic-
pyruvic transaminase 
(SGPT) 
Total protein 
 
Glucose (nonfasting) 
 
Total carbon dioxide 
Alkaline phosphatase 
Albumin 
 
Coagulation 
Prothrombin time 
 
Partial thromboplastin 
time 
International normalized 
ratio 
Routine 
Urinalysis (by 
dipstick) 
- Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite,  
  leukocyte esterase 
 
- Microscopic examination (if any leucocytes, trace protein, nitrites, and blood [if not  
  menstruating] are abnormal) 
Other 
Screening Tests 
- Serum QuantiFERON-TB test 
 
- Urine alcohol and drug screen (to include at minimum: amphetamines,  
  barbiturates, benzodiazepines cocaine, opiates, phencyclidine, 
methamphetamine,  
  3,4-methylenedioxy-methamphetamine, methadone, and tetrahydrocannabinol  
  [cannabinoids]) 
 
- Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of  
  childbearing potential) 
 
- Human immunodeficiency virus (HIV)-1 and HIV-2 antibodies, hepatitis B surface  
  antigen (HBsAg), and hepatitis C virus (HCV).   
 
The results of each test must be entered into the eCRF. 
Complement 
Activity 
Complement activation 
products 
CH50 
Total and free C5 
 

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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
 
Adverse Event Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study subject, temporally 
associated with the use of study drug, whether or not considered related to the study drug. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study drug. 
 
Events Meeting the Adverse Event Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease). 
• 
New conditions detected or diagnosed after study drug administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Events NOT Meeting the Adverse Event Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Serious Adverse Event Definition 
If an event is not an AE per definition above, then it cannot be a SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 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. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or 
was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. 

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A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle) which may interfere with or prevent everyday life functions but 
do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
Adverse Event and Serious Adverse Event Recording 
• 
When an AE or SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE or SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records 
to the Sponsor or designee in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor or designee. In this case, all subject identifiers, with the exception of the subject 
number, will be redacted on the copies of the medical records before submission. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories from National Cancer Institute CTCAE v4.03, 
published 14 Jun 2010:  
• 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Grade 3: Severe (incapacitating, with inability to perform normal activities) 
• 
Grade 4: Life-threatening 
• 
Grade 5: Fatal 
 
Changes in the severity of an AE should be documented to allow an assessment of the AE 
duration at each level of intensity to be evaluated. Adverse events characterized as intermittent 
require documentation of onset and duration of each episode, if the severity of the intermittent 
event changes. 
 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
 

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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. An Investigator causality assessment must be provided for all 
AEs (both nonserious and serious). This assessment must be recorded in the data capture 
system and on any additional forms, as appropriate. The definitions for the causality 
assessments are as follows: 
− 
Not related (unrelated): This relationship suggests that there is no association between the 
investigational product and the reported event. 
− 
Unlikely related: This relationship suggests that the clinical picture is highly consistent 
with a cause other than the investigational product, but attribution cannot be made with 
absolute certainty, and a relationship between the investigational product and AE cannot 
be excluded with complete confidence. 
− 
Possibly related: This relationship suggests that treatment with the investigational product 
may have caused or contributed to the AE; ie, the event follows a reasonable temporal 
sequence from the time of study drug administration, and/or follows a known response 
pattern to the investigational product, but could also have been produced by other factors. 
− 
Probably related: This relationship suggests that a reasonable temporal sequence of the 
event with the investigational product administration exists, as well as the likely 
association of the event with the investigational product. This will be based upon the 
known pharmacological action of the investigational product, known or previously 
reported adverse reactions to the investigational product or class of drugs, or judgment 
based on the Investigator’s clinical experience. 
− 
Definitely related: Temporal relationship to the investigational product. Other conditions 
(concurrent illness, concurrent medication reaction, or progression/expression of disease 
state) do not appear to explain the event; the event corresponds with the known 
pharmaceutical profile; improvement on discontinuation; reappearance on rechallenge. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration will be 
considered and investigated. 
• 
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 the Sponsor, based 
on the Reference Safety Document. The Investigator will also consult the Investigator’s 
Brochure (IB) in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
− 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor or designee. However, it is very 
important that the Investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor or designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 

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Follow-up of Adverse Events and Serious Adverse Events 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide the Sponsor or designee with a copy of any postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor or designee within 24 
hours of receipt of the updated information. 
Reporting of Serious Adverse Events 
Serious Adverse Event Reporting to the Sponsor or Designee via Paper Case Report Form 
• 
All AEs must be assessed by the Investigator to determine if they meet criteria for an SAE. 
All SAEs must be reported to the Sponsor 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 email or facsimile to the contact information provided below: 
− 
Email:
 
− 
Facsimile: 
 
• 
Additional follow-up information, if required or available, should be entered into the eCRF 
and sent to Sponsor within 24 hours of the Investigator or study 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 
• 
If applicable, additional information such as relevant medical records should be submitted 
to the Sponsor via the email address or facsimile number noted above. 
• 
All forms and follow-up information submitted to the Sponsor (eg, discharge summary) 
should be kept in the appropriate section of the study file. 
 

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10.4. 
Appendix 4: Pregnancy Information 
Definitions 
Woman of Childbearing Potential  
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the Following Categories are Not Considered Women of Childbearing Potential 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• Note: Documentation can come from the site personnel’s review of the subject’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause and a documented serum follicle-stimulating hormone level 
≥ 40 mIU/mL during screening. A high FSH level in the postmenopausal range must 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
• Female subjects on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Pregnancy Testing 
• Women of childbearing potential should only be included after a negative serum 
pregnancy test. Additional pregnancy testing should be performed per the time points 
specified in the Schedule of Activities (Table 1 and Table 2). 
Collection of Pregnancy Information  
• Pregnancy data will be collected during this study for all subjects and a female 
spouse/partner of male subjects. Exposure during pregnancy (also referred to as 
exposure in utero) can be the result of either maternal exposure or transmission of 
drug product via semen following paternal exposure. 
• If a female subject participating in this study or a male subject’s female sexual partner 
of childbearing potential becomes or is found to be pregnant while being treated or 
exposed to study drug, the Investigator must submit the “Pregnancy Reporting and 
Outcome/Breast Feeding Form” to the Sponsor or designee via the same method as 

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SAE reporting. (Section 10.3 [Appendix 3]). When the outcome of the pregnancy 
becomes known, the form should be updated and submitted to the Sponsor’s GPV. If 
additional follow-up is required, the Investigator will be requested to provide the 
information. 
• Exposure of an infant to a Sponsor product during breastfeeding must also be 
reported (via the “Pregnancy Reporting and Outcome Form/Breastfeeding” form) and 
any AEs experienced by the infant must be reported to the Sponsor’s GPV or 
designee via facsimile or email (Section 10.3 [Appendix 3]). 
• A pregnancy in itself is not regarded as an AE unless there is a suspicion that the 
study drug may have interfered with the effectiveness of a contraceptive medication. 
However, complications of pregnancy and abnormal outcomes of pregnancy are AEs 
and may meet the criteria for an SAE (eg, ectopic pregnancy, spontaneous abortion, 
intrauterine fetal demise, neonatal death, or congenital anomaly). Elective abortions 
without complications should not be reported as AEs (Section 8.3.5). 
• Any female subject who becomes pregnant while participating in the study may not 
be withdrawn from the study. 
 

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10.5. 
Appendix 5: Abbreviations 
The following abbreviations and terms are used in this study protocol. 
Table 10: 
Abbreviations and Specialist Terms 
Abbreviation or 
Term  
 
Explanation  
ADA 
antidrug antibody 
AE  
adverse event  
aHUS 
atypical hemolytic uremic syndrome 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC∞ 
area under the serum concentration versus time curve from zero to infinity 
BMI  
body mass index  
CAP  
complement alternative pathway  
CH50 
50% hemolytic complement activity (screening test for deficiency of classical 
complement pathway in which hemolysis of liposomes sensitized by specific 
antibodies is measured; one CH50 unit is the volume or dilution of serum that lyses 
50% of liposomes) 
CL  
total body clearance of drug from the serum  
Cmax  
maximum observed serum concentration  
cRBC  
chicken red blood cell 
CRU 
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG  
electrocardiogram  
eCRF 
electronic case report form 
EOI  
End-of-infusion  
F 
absolute bioavailability 
Frel 
relative bioavailability 
FSH 
Follicle-stimulating hormone 
GCP  
Good Clinical Practice  
GPV 
Global Pharmacovigilance 
HA 
hyaluronic acid 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF  
informed consent form  
ICH  
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV  
intravenous(ly)  
mAb  
monoclonal antibody  
MCV4  
tetravalent meningococcal conjugate vaccine  
OP 
outpatient 
PD  
pharmacodynamic(s)  
PK  
pharmacokinetic(s)  
PNH 
paroxysmal nocturnal hemoglobinuria 
QTcF  
QT interval corrected using the Fridericia’s formula  

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Abbreviation or 
Term  
 
Explanation  
rHuPH20 
recombinant human hyaluronidase PH20 
SAE  
serious adverse event  
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SOC 
System Organ Class 
SOI  
Start-of-infusion 
SRC  
Safety Review Committee  
TB 
tuberculosis 
TEAE 
treatment-emergent adverse events 
ULN  
upper limit of normal  
Vd  
volume of distribution  

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10.6.
Appendix 6: Acute Infusion Reaction Algorithm 

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10.7. 
Appendix 8: United Kingdom Resuscitation Council Anaphylaxis Algorithm 
 
 
10.8. 
Appendix 10: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 

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Amendment 1 (20 Jul 2018) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
Overall Rationale for the Amendment 
To align contraception language with national guidelines and address minor inconsistencies as 
described below. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.2 
Exclusion 
Criteria 
Changed exclusion criterion no. 16 for 
use of nonprescription medications 
from 7 days to 14 days prior to dosing 
on Day 1. 
Alignment of exclusion criterion with 
requirements stated in Section 6.5, 
Concomitant Therapy. 
Table 2: 
Schedule of 
Activities – 
Visit 2 
Through Visit 
14 
Added pregnancy testing on Day 57 
and Day 120. 
Additional pregnancy testing is appropriate for 
a trial in healthy subjects with requirements for 
highly effective contraception for an extended 
period. 
Section 6.6 
Contraception 
Guidance 
• Removed definition of non-
childbearing potential, replaced 
with cross reference to Appendix 
where required information is 
presented.  
• Replaced definition of highly 
effective contraception.  
• Added restriction on ova donation 
for female subjects. 
Alignment with guidelines from Clinical Trial 
Facilitation Group (CFTG). 
Section 10.4 
Appendix 4: 
Pregnancy 
Information 
Added specific FSH level requirement 
for establishing postmenopausal 
state. 
Clarification. 
 
 

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11. 
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59th American Society of Hematology. 2017 Dec 11; Atlanta, GA. 
Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin 
Microbiol Rev. 1991 Jul;4(3):359-395. 
Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, et al. Long-term 
treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and 
improved survival. Blood. 2011 Jun 23;117(25):6786-6792. 
Leeds Teaching Hospitals NHS Trust, Kings College Hospital NHS Foundation Trust. National 
Specialised Commissioning Team (NSCT) Service Specification Paroxysmal Nocturnal 
Haemoglobinuria (PNH). 2013 
rHuPH20 Investigator’s Brochure. 2018 
Usmani SZ, Nahi H, Mateos M-V, Lokhorst HM, Chari A, Kaufman JL, et al. Open-Label, 
Multicenter, Dose Escalation Phase 1b Study to Assess the Subcutaneous Delivery of 
Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (PAVO). Blood. 
2016;128:1149 
Wasserman RL, Melamed I, Stein MR, Gupta S, Puck J, Engl W, et al. Recombinant human 
hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary 
immunodeficiency. J Allergy Clin Immunol. 2012 Oct;130(4):951-957 
Yazdankhah SP, Caugant DA. Neisseria meningitidis: an overview of the carriage state. J Med 
Microbiol. 2004 Sep;53(Pt 9):821-832.