Conditions: Migraine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
AMG 334 20160172 Pediatric Migraine PK Study.

Detailed description:
An Open-label, Randomized, Multiple-dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of AMG 334 in Children and Adolescents With Migraine

Arms:
arm 1: Subjects with a body weight at Day 1 of less than weight threshold. arm 2: Subjects with a body weight at Day 1 of weight threshold or more.

Interventions: intervention 1: AMG 334 Dose 1 intervention 2: AMG 334 Dose 2 intervention 3: AMG 334 Dose 3
Intervention descriptions: intervention 1: Subjects weighing less than weight threshold at Day 1 will be randomized to either Dose 1 or Dose 3.

Subjects weighing weight threshold or more at Day 1 will be randomized to either Dose 1 or Dose 2 intervention 2: Subjects weighing weight threshold or more at Day 1 will be randomized to either Dose 1 or Dose 2. intervention 3: Subjects weighing less than weight threshold at Day 1 will be randomized to either Dose 1 or Dose 3.

Protocol document:
Prot_000.pdf: 
Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 1 of 97 
CONFIDENTIAL 
 
 
Title:  A Phase I, Randomized, Open-label, Multiple-dose Study to Evaluate Safety, 
Tolerability, and Pharmacokinetics of AMG 334 in Children and Adolescents With 
Migraine 
 
AMG 334 
Amgen Protocol Number (AMG 334) 20160172 
NCT Number:  NCT03499119 
IND number BB-IND 116098 
 
Clinical Study 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Phone: (805) 447-1000 
 
Key Sponsor 
Contact(s): 
, MD, PhD 
Medical Monitor 
Phone:  
 
Email:  
   
, PhD 
Clinical Pharmacologist 
Phone: 
 
Email: 
  
 
 
, PhD  
Global Early Clinical Development Manager 
Phone:  
  
Email: 
 
 
Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
Amendment 5 Date: 
30 May 2017 
05 December 2017 
 
20 June 2018 
18 April 2019 
26 March 2020 
03 November 2021 
 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 2 of 97 
CONFIDENTIAL 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; for all other countries 1-805-447-1000. 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 3 of 97 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Phase I, Randomized, Open-label, 
Multiple-dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of AMG 334 
in Children and Adolescents with Migraine”, dated 03 November 2021, and agree to 
abide by all provisions set forth therein.  I agree to comply with the International Council 
for Harmonisation (ICH) Tripartite Guideline on Good Clinical Practice (GCP), 
Declaration of Helsinki, and applicable national or regional regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 4 of 97 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase I, Randomized, Open-label Multiple-dose Study to Evaluate Safety, 
Tolerability, and Pharmacokinetics of AMG 334 in Children and Adolescents with 
Migraine  
Study Phase:  1b  
Indication:  Migraine prevention 
Primary Objectives:  To evaluate the safety, tolerability, and pharmacokinetic (PK) 
profile following multiple subcutaneous (SC) doses of AMG 334 in children and 
adolescent subjects with migraine, respectively.  
Exploratory Objectives:  
Hypotheses:  Multiple SC doses of AMG 334 will be safe and well-tolerated, and the PK 
profiles will support further development of AMG 334 in children and adolescents with 
migraine, respectively.   
Primary Endpoints:   
 
Serum PK parameters of AMG 334 (eg, time to maximum concentration [tmax]), 
maximum observed concentration [Cmax], trough concentration (Ctrough), area under 
the concentration time curve (AUC) from 0 to 28 days (AUC0-28day) 
 
Treatment-emergent adverse events 
 
Changes in vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory safety 
tests, and neurological assessments 
Exploratory Endpoints:  
Study Design:   
This is a Phase 1b multicenter, randomized, open-label, multiple-dose study evaluating 
AMG 334 in male and female children (6 to < 12 years of age) and adolescents (12 to 
< 18 years of age) with migraine.  The study population will consist of 2 cohorts based 
on body weight enrolling a total of at least 52 subjects and up to approximately 
60 subjects in the study.  Cohort 1 will enroll at least 12 subjects and up to 
approximately 22 subjects in total with body weight of < 40 kg.  At least 9 subjects in 
Cohort 1 must be aged 6 to < 12 years including at least 2 subjects aged 6 to  
< 10 years, at the time of consent.  Cohort 2 will enroll at least 35 subjects and up to 
approximately 38 subjects in total with a body weight of ≥ 40 kg at baseline.  It is 
anticipated that most subjects in this cohort will be 12 to < 18 years of age.  Enrollment 
requirements for subjects in Cohort 1 and Cohort 2 will be tracked and administered via 
IVRS to ensure that the minimum number of subjects in each cohort is achieved.  


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 5 of 97 
CONFIDENTIAL 
 
 
Enrollment will be staggered by age category with adolescents (ie, subjects 12 to  
< 18 years of age)  starting enrollment first.   
Children 6 to < 12 years of age at the time of consent will participate in the initial 
treatment phase for a total of 12 weeks of treatment.  Adolescents 12 to < 18 years of 
age at time of consent will participate in the initial treatment phase for a total of 12 weeks 
of treatment after which they will have the option of continuing treatment in an optional 
40-week extension phase, for a total of 52 weeks of treatment.  A safety follow-up visit 
will take place 16 weeks after the last dose to complete end of study (EOS) 
assessments either (i) after completion of the initial 12 week treatment phase, (ii) after 
completion of the optional 40-week extension phase for those adolescents who choose 
to continue treatment, or (iii) after the last dose received before discontinuation of 
treatment during the study. 
Subjects weighing < 40 kg (Cohort 1) will receive a dose of either 35 mg or 70 mg for a 
total of at least 12 and up to approximately 15 subjects completing Week 12 
assessments.  Subjects weighing ≥ 40 kg (Cohort 2) will receive a dose of either 70 mg 
or 140 mg for a total of at least 26 and up to approximately 30 subjects completing Week 
12 assessments.  Treatments will be allocated to qualifying subjects in a randomized 
order within either cohort through IVRS.  Study drug (low-dose or high-dose AMG 334) 
will be administered in either cohort in an open-label fashion against a background of 
allowed concomitant medications, including agents for migraine prevention. 
It is anticipated that at least 52 and up to approximately 60 subjects will be enrolled in 
the study to ensure that at least 38 and up to approximately 45 subjects complete 
Week 12 assessments. 
During the initial treatment phase, each subject will receive a total of 3 SC doses of 
AMG 334 administered every 4 weeks (Q4W) as described in the Schedule of Activities 
(Table 1 and Table 2).  The study is expected to confirm a PK profile in pediatric 
subjects that is similar to that in adults, based on population PK analysis, and to provide 
preliminary safety data in each body-weight cohort supportive of the initiation of the 
AMG 334 Phase 3 studies in the pediatric population.  
All subjects will be administered AMG 334 against a background of allowed concomitant 
medications, including agents for migraine prevention (up to 2 treatments on a stable 
dose) and for acute treatment of migraine. 
Sample Size: 
A total of at least 52 subjects and up to approximately 60 subjects with migraine will be 
enrolled in Cohorts 1 and 2.  The rate of early discontinuation up to Week 12 
assessments is assumed to be 20% and similar across the two cohorts.  In Cohort 1, 
(< 40 kg), at least 12 subjects and up to approximately 22 subjects will be enrolled in 
order to have at least 12 and up to approximately 15 subjects completing Week 12 
assessments.  In Cohort 2, (≥ 40 kg), at least 35 subjects and up to approximately 
38 subjects will be enrolled in order to have at least 26 and up to approximately 
30 subjects completing Week 12 assessments.  All subjects in this study will be 
administered AMG 334.  The sample size for this study is based on clinical and practical 
considerations to adequately fulfil its objectives and to inform planned Phase 3 pediatric 
studies.  Assuming clearance (CL) and central volume of distribution (Vc) on mg/kg 
basis are similar between pediatric and adult subjects, and assuming percent coefficents 
of variation (%CV) for CL and Vc are 43% and 53%, respectively, (based on total 
between-subject-variability from adult population PK), the proposed sample size 
provides > 80% power to estimate 95% confidence interval (CI) of CL and Vc within 
60-140% of the true parameters for both weight cohorts  combined and across the two 
age categories.  


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 6 of 97 
CONFIDENTIAL 
 
 
Summary of Subject Eligibility Criteria:  
Male and female subjects ages 6 to < 18 years with a history of migraines at least twelve 
months prior to screening and with a frequency of ≥ 4 migraine days per month for three 
months prior to screening.  For a full list of eligibility criteria, please refer to Section 4.1 
and Section 4.2. 
It is anticipated that at least 52 and up to approximately 60 subjects in total will be 
enrolled in the study to ensure that at least 38 and up to approximately 45 subjects 
complete Week 12 assessments. 
Investigational Product   
Amgen Investigational Product Dosage and Administration:  
Investigational product (IP) (ie, AMG 334) will be dosed subcutaneously.  Doses are 
fixed, based on body weight taken at Day 1, and must not be adjusted for individual 
subjects during the study; eg due to changes in body weight.  Subjects weighing < 40 kg 
(Cohort 1) will receive a dose of either 35 mg or 70 mg.  Subjects weighing ≥ 40 kg 
(Cohort 2) will receive a dose of either 70 mg or 140 mg.  
AMG 334 will be packaged as 70 mg/mL in 1 mL or 140 mg/mL in 1 mL pre-filled 
syringes and 70 mg/mL vials.  Subjects in Cohort 1 (weighing < 40 kg) will be 
randomized in a 1:2 allocation ratio to low dose (35 mg AMG 334) or high dose (70 mg 
AMG 334).  Subjects in Cohort 2 (weighing ≥ 40 kg) will be randomized in a 1:4 
allocation ratio to low dose (70 mg AMG 334), or high dose (140 mg AMG 334).  The 
anatomical sites for administration of Investigational Product are the upper arm, upper 
thigh, or abdomen.   
Procedures:   
After written informed consent and assent are obtained, all screening tests and 
procedures will be performed within 21 days before the administration of the first dose of 
AMG 334 (Study Day 1), unless otherwise noted.   
Following the first AMG 334 dose administration on Day 1, all subjects will be monitored 
at the facility for at least 2 hours post-dose, at which point they will be discharged with 
instructions to return to the research facility according to the procedures provided in the 
Schedule of Activities (Table 1 and Table 2).  At the 12 Week visit, adolescent subjects 
may choose to continue onto the optional 40-week extension phase.  All subjects will be 
followed for 16 weeks after the last administration of AMG 334. 
Blood samples for PK,
, clinical laboratory safety assessments, 
and pharmacogenomic assessments will be collected.  Vital signs, physical 
examinations, and ECGs will be performed at predetermined time points throughout the 
study.  All adverse events and use of concomitant medications will be collected for the 
duration of the study, up to and including the EOS visit.  All treatment-emergent adverse 
events or laboratory abnormalities will be followed until resolution of the abnormality or 
until it is considered stable in the opinion of the investigator.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Activities (Table 1 and Table 2). 
Statistical Considerations:   
Descriptive statistics will be provided for selected demographic, safety, and PK data.  
Descriptive statistics on continuous measurements will include means, medians, 
standard deviations, first quartile (Q1), third quartile (Q3), minimum, and maximum, 
while categorical data will be summarized using frequency counts and percentages.  For 
a full description of statistical analysis methods, please refer to Section 10. 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 7 of 97 
CONFIDENTIAL 
 
 
The primary analysis of the safety and PK data will occur after all subjects in both body 
weight cohorts have completed the initial 12 Week treatment phase (ie, Week 12 
assessments).  No formal hypothesis testing will be performed; all analyses will be 
descriptive.  PK and safety data will include summaries by body weight cohort and 
AMG 334 treatment dosage group.  The review of the results of this primary analysis will 
inform further pediatric studies utilizing AMG 334. 
There are 2 interim analyses of PK and safety planned for this study.  The first interim 
analysis will occur when at least 6 adolescents (12 to < 18 years of age) have completed 
study Week 8 assessments.  The second interim analysis will occur when at least 
8 children (6 to < 12 years of age) have completed study Week 12 assessments.  For 
both interim analyses, PK data, adverse events, vital sign data, and laboratory data will 
be summarized.  The purpose of the first and second interim analysis is to inform the 
selection of AMG 334 doses to be evaluated in the Phase 3 pediatric AMG 334 studies.   
The final safety analysis for the study will be performed at the end of the trial, including 
the 40-week extension phase and the safety follow-up.  No formal hypothesis testing will 
be performed; all analyses will be descriptive. 
Sponsor:  Amgen Inc. 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 8 of 97 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
       
 
Q4W – Every 4 weeks; SC – Subcutaneous 
Cohorts assigned by Day 1 body weight 
Children 6 to < 12 years of age at the time of consent, will only participate in the initial treatment phase, for a total of 12 weeks of treatment.  
Adolescents 12 to < 18 years of age at time of consent will participate in the initial treatment phase after which they will have the option of  
continuing treatment in an optional 40-week extension phase. 
Subjects completing the initial 12 Week treatment phase and not participating in the optional 40-week extension phase will proceed directly  
to the Safety Follow-Up Visit. 
* Safety Follow-Up Visit will take place 16 weeks after last dose of IP 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 9 of 97 
CONFIDENTIAL 
 
 
Study Glossary 
Term/Abbreviation 
Explanation/Definition 
End of Study  
The time when the last subject is assessed or receives an intervention 
for evaluation in the study (ie, when the last subject completes the study, 
which includes the safety follow-up visit 16 weeks after the last dose of 
Investigational Product, or is discontinued from the study for other 
reasons) 
End of Follow-up 
defined as when the last subject completes the last protocol-specified 
assessment in the study  
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are conducted 
for an individual subject 
End of Treatment 
 
eSAE 
defined as the last assessment for the protocol specified treatment 
phase of the study for an individual subject 
electornic serious adverse event 
Primary Completion 
is defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoint(s), for 
the purposes of conducting the primary analysis (ie, when the last 
subject completes the 12 week assessment or is discontinued from the 
study) 
Source Data 
information from an original record or certified copy of the original record 
containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records or certified copies) (ICH Guideline 
(E6)).   
Study Day 1 
defined as the first day that protocol specified Investigational 
Product(s)/protocol-required therapies is/are administered to the subject 
Migraine Day 
Any calendar day in which the subject experiences a qualified migraine 
headache (onset, continuation, or recurrence of the migraine headache).  
A qualified migraine headache is defined as a migraine with or without 
aura, lasting for ≥ 30 minutes, and meeting at least one of the following 
criteria (a and/or b)  
a) ≥ 2 of the following pain features: 
• Unilateral or bilateral 
• Throbbing 
• Moderate to severe 
• Exacerbated with exercise/physical activity 
b) ≥ 1 of the following associated symptoms: 
• Nausea and/or vomiting 
• Photophobia and phonophobia (in pediatric patients 
photophobia and phonophobia can be inferred from behavior) 
If the subject took a migraine-specific medication (ie, triptan or 
ergotamine) during aura or to treat headache on a calendar day, then it 
will be counted as a migraine day regardless of the duration and pain 
features/associated symptoms. 
AAP 
American Academy of Pediatrics  


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 10 of 97 
CONFIDENTIAL 
 
 
Term/Abbreviation 
Explanation/Definition 
AE 
Adverse Event      
ALP 
alkaline phosphatase              
ALT 
alanine aminotransferase              
AST 
aspartate aminotransferase              
AUC 
Area under the concentration-time curve   
AUC0-28day 
Area under the concentration-time from 0 to 28 days after dose 
AUClast 
 
CBT 
CI 
area under the concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
cognitive-behavioral therapy 
confidence interval 
CL 
CGRP 
Clearance 
Calcitonin gene-related peptide     
Cmax 
Maximum concentration      
C-SSRS 
Columbia-Suicide Severity Rating Scale 
Ctrough 
Trough concentration   
CTCAE 
Common terminology criteria for adverse events  
DILI 
DMC 
drug-induced liver injury  
Data Monitoring Comittee            
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram       
eCRF 
Electronic case report form    
EDC 
electronic data capture             
EOS 
end-of-study               
ePPND 
pre-postnatal developmental study 
eSAE 
electronic serious adverse event  
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
GLP 
Good laboratory practice     
HepBsAg 
hepatitis B surface antigen            
HepCAb 
hepatitis C antibodies             
HIV 
Immunodeficiency Virus  
ICF 
informed consent form 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization 
ICHD 
The International Classification of Headache Disorders 
IEC 
Independent Ethics Committee     


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 11 of 97 
CONFIDENTIAL 
 
 
Term/Abbreviation 
Explanation/Definition 
IgG2 
immunoglobulin G2      
ICMJE 
International Committee of Medical Journal Editors 
INR 
international normalized ratio 
IP 
investigational product    
IPIM 
investigational product instruction manual 
IRB 
Institutional Review Board     
IUD 
intrauterine device 
IV 
Intravenous 
IVRS 
interactive voice response system 
Kd 
MAD 
dissociation equilibrium constant 
Multiple Ascending Dose     
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no observed adverse effect level   
NSAID 
non-Steroidal Anit-Inflatory 
OTC 
Over the Counter 
PCR 
polymerase chain reaction 
%CV 
percent coefficient variation 
PFS 
pre-filled syringe 
PHQ-A 
Patient Health Questionnaire for Adolescents (PHQ-A)  
PK 
pharmacokinetic       
Q1 
first quartile 
Q3 
third quartile 
QM, Q4W 
SAD 
every 4 weeks 
Single Ascending Dose 
SC 
subcutaneous       
TBIL 
total bilirubin 
tmax 
time to maximum concentration  
ULN 
upper limit of normal 
Vc 
central volume of distribution 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 12 of 97 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 4 
Study Design and Treatment Schema ............................................................................. 8 
Study Glossary ................................................................................................................ 9 
1. 
OBJECTIVES ....................................................................................................... 16 
1.1 
Primary ..................................................................................................... 16 
1.2 
Exploratory ................................................................................................ 16 
2. 
BACKGROUND AND RATIONALE ...................................................................... 16 
2.1 
Disease ..................................................................................................... 16 
2.1.1 
Migraines ................................................................................... 16 
2.1.2 
Targeting Calcitonin Gene-Related Peptide (CGRP) ................. 18 
2.2 
Amgen Investigational Product Background .............................................. 18 
2.2.1 
Toxicology ................................................................................. 18 
2.2.2 
AMG 334 Clinical Safety Summary ............................................ 20 
2.2.3 
Pharmacokinetics ...................................................................... 20 
2.3 
Risk Assessment ....................................................................................... 21 
2.4 
Rationale ................................................................................................... 21 
2.5 
Clinical Hypotheses ................................................................................... 22 
3. 
EXPERIMENTAL PLAN ........................................................................................ 23 
3.1 
Study Design ............................................................................................. 23 
3.2 
Number of Sites ........................................................................................ 24 
3.3 
Number of Subjects ................................................................................... 24 
3.4 
Replacement of Subjects .......................................................................... 24 
3.5 
Estimated Study Duration .......................................................................... 25 
3.5.1 
Study Duration for Subjects ....................................................... 25 
3.5.2 
End of Study .............................................................................. 25 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 25 
4.1 
Inclusion Criteria ....................................................................................... 26 
4.2 
Exclusion Criteria ...................................................................................... 26 
5. 
SUBJECT ENROLLMENT .................................................................................... 28 
5.1 
Allocation to Cohort (Initiation of Screening) and Treatment 
Assignment (Enrollment) ........................................................................... 29 
5.2 
Calls to Interactive Voice Response System (IVRS) .................................. 30 
6. 
TREATMENT PROCEDURES .............................................................................. 30 
6.1 
Classification of Product(s), Medical Device(s), and/or 
Combination Product(s) ............................................................................. 30 
6.2 
Investigational Product .............................................................................. 30 
6.2.1 
AMG 334 ................................................................................... 30 
6.2.1.1 
Dosage, Administration, and Schedule .................... 31 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 13 of 97 
CONFIDENTIAL 
 
 
6.2.2 
Medical Devices ........................................................................ 32 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 32 
6.3.1 
Criteria for Permanent Withholding of AMG 334 due to 
Potential Hepatotoxicity ............................................................. 32 
6.4 
Concomitant Therapy ................................................................................ 34 
6.5 
Alcohol and  Drug  Restrictions ................................................................. 35 
6.6 
Product Complaints ................................................................................... 35 
6.7 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period .................................................................................. 35 
7. 
STUDY PROCEDURES ....................................................................................... 35 
7.1 
Schedule of Activities ................................................................................ 35 
7.2 
General Study Procedures ........................................................................ 42 
7.2.1 
Informed Consent ...................................................................... 43 
7.2.2 
Medical History .......................................................................... 43 
7.2.3 
Height and Weight Measurements ............................................. 43 
7.2.4 
Vital Signs ................................................................................. 43 
7.2.5 
Physical Examination ................................................................ 43 
7.2.6 
Neurological Examination .......................................................... 43 
7.2.7 
Electrocardiogram ..................................................................... 44 
7.2.8 
Drug and  Alcohol Screening ..................................................... 44 
7.2.9 
Hepatitis B Surface Antigen, Hepatitis C Antibody 
Status ........................................................................................ 44 
7.2.10 
Pregnancy Test ......................................................................... 45 
7.2.11 
Patient Health Questionnaire– Adolescents (PHQ-A) ................ 45 
........... 45 
........... 45 
7.2.14 
Blood and Urine Assessments ................................................... 46 
7.2.14.1 
Pharmacokinetic Blood Sampling ............................ 47 
7.2.14.2 
Clinical Laboratory Assessments ............................. 47 
7.2.15 
Screening and Enrollment ......................................................... 48 
7.2.16 
Initial 12 Week Treatment Phase Visits ..................................... 49 
7.2.17 
Optional 40-Week Extension Phase .......................................... 50 
7.2.18 
End of Study Visit ...................................................................... 51 
7.3 
Antibody Testing Procedures .................................................................... 51 
7.4 
Biomarker Development ............................................................................ 52 
7.5 
Pharmacogenetic Studies ......................................................................... 53 
7.6 
Sample Storage and Destruction ............................................................... 53 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 54 
8.1 
Subjects’ Decision to Withdraw ................................................................. 54 
8.2 
Reasons for Removal From Treatment ..................................................... 55 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 14 of 97 
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8.3 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 55 
8.4 
Reasons for Removal From Study............................................................. 55 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 56 
9.1 
Definition of Safety Events ........................................................................ 56 
9.1.1 
Adverse Events ......................................................................... 56 
9.1.2 
Serious Adverse Events ............................................................ 56 
9.2 
Safety Event Reporting Procedures .......................................................... 57 
9.2.1 
Adverse Events ......................................................................... 57 
9.2.1.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 57 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 58 
9.2.2 
Reporting Serious Adverse Events After the 
Protocol-required Reporting Period ........................................... 60 
9.2.2.1 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 60 
9.2.2.2 
Adverse Device Effects: Recording, 
Evaluating, Reporting .............................................. 60 
9.3 
Pregnancy and Lactation Reporting .......................................................... 61 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 62 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 62 
10.1.1 
Study Endpoints ........................................................................ 62 
10.1.2 
Analysis Sets ............................................................................. 63 
10.1.3 
Covariates and Subgroups ........................................................ 63 
10.1.4 
Handling of Missing and Incomplete Data .................................. 63 
10.2 
Sample Size Considerations ..................................................................... 63 
10.3 
Planned Analyses ..................................................................................... 64 
10.3.1 
Interim Analyses ........................................................................ 64 
10.3.2 
Primary Analysis ........................................................................ 64 
10.3.3 
Final Safety Analysis ................................................................. 64 
10.4 
Planned Methods of Analysis .................................................................... 64 
10.4.1 
General Considerations ............................................................. 64 
10.4.2 
Primary Endpoints ..................................................................... 65 
10.4.2.1 
Pharmacokinetic Endpoints ..................................... 65 
10.4.2.2 
Treatment-Emergent Adverse Events ..................... 65 
10.4.2.3 
Safety Endpoints ..................................................... 65 
10.5 
Exploratory Endpoint ................................................................................. 66 
.......... 66 
.......... 66 
.......... 66 
11. 
REGULATORY OBLIGATIONS ............................................................................ 66 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 15 of 97 
CONFIDENTIAL 
 
 
11.1 
Informed Consent ...................................................................................... 66 
11.2 
Institutional Review Board/Independent Ethic Committee ......................... 67 
11.3 
Subject Confidentiality ............................................................................... 68 
11.4 
Investigator Signatory Obligations ............................................................. 68 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 68 
12.1 
Protocol Amendments and Study Termination .......................................... 68 
12.2 
Study Documentation and Archive ............................................................ 69 
12.3 
Study Monitoring and Data Collection ....................................................... 70 
12.4 
Investigator Responsibilities for Data Collection ........................................ 70 
12.5 
Language .................................................................................................. 71 
12.6 
Publication Policy ...................................................................................... 71 
12.7 
Compensation ........................................................................................... 72 
13. 
REFERENCES ..................................................................................................... 73 
14. 
APPENDICES ...................................................................................................... 76 
 
List of Tables 
Table 1.  Schedule of Activities ...................................................................................... 37 
Table 2.  Schedule of Activities ...................................................................................... 40 
Table 3.  Approximate Blood Volumes for Cohorts 1-2 in Initial 12 Week 
Treatment Phase .................................................................................... 46 
Table 4.  Approximate Blood Volumes for Optional 40-Week Extension Phase ............. 47 
Table 5.  List of Analytes ............................................................................................... 48 
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 77 
Appendix B.  Sample electronic Serious Adverse Event Contingency Report 
Form ....................................................................................................... 79 
Appendix C.  Pregnancy and Lactation Notification Forms ............................................ 82 
................ 84 
Appendix E.  Sample PHQ-A ......................................................................................... 96 
................................ 97 
 


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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple 
subcutaneous (SC) doses of AMG 334 in children and adolescent subjects with 
migraine, respectively. 
1.2 
Exploratory 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
2.1.1 
Migraines 
Migraine is a disabling disorder characterized by primary recurrent headaches lasting 
4 to 72 hours (if not treated) with at least two of the following pain characteristics: 
unilateral, pulsating, moderate or severe intensity, or aggravated by routine physical 
activity.  In addition, migraine attacks are often accompanied by nausea, vomiting, and 
sensitivity to light (photophobia) and sound (phonophobia) (International Classification of 
Headache Disorders 3rd edition [ICHD]) (IHS, 2013).  Children often have atypical  
clinical presentations; the younger the child, the more atypical the symptoms tend to be.  
Childhood migraines tend to be of shorter duration (often less than 4 hours or even 
1 hour (Francis, 2013); and are frequently bilateral (bi-temporal or bi-frontal).  
Furthermore, children may have difficulty describing light and sound sensitivity 
(Jacobs and Gladstein, 2012).  As a result, the current ICHD-III criteria (IHS, 2013) 
adapted 3 of the adult criteria mentioned above to apply to children:  a) by reducing the 
minimal migraine duration to 2 hours; b) by allowing the migraine headache to be 
bilateral; and c) by allowing photo- and phono-phobia to be inferred from a young child’s 
behavior.  
Migraine affects more than 10% of the world’s population (Robbins and Lipton, 2010), 
and affects approximately 18% of women and 6% of men in the United States and 
Europe annually (Stovner and Andree, 2010).  Prevalence figures for specific 
age-subgroups reveal a pattern of slowly increasing overall prevalence from childhood 


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into adolescence, with an overall prevalence of ~4% in the 5-12 year age group and 
equal prevalence in boys and girls (Arruda et al, 2010).  However, during adolescence , 
women progressively present higher migraine prevalence than men:  ~7% and 5% in 
girls and boys ages 12-17, respectively.   
Across the globe, the most frequently used acute migraine medications in adults include 
paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs; particularly ibuprofen, but 
children are also responsive to aspirin, naproxen, and diclofenac), and a class of 
serotonin 5-HT1B and 5-HT1D receptor agonists called triptans.  Often, the first prescribed 
remedies for migraines in children and adolescents are over-the-counter (OTC) 
analgesics, supplemented by non-pharmacological measures such as changes in 
lifestyle (good sleep hygiene, diet free of additives, regularity with meals and sleep, 
limited sun exposure, and regular physical activity, all of which seem particularly 
efficacious in younger children (Eidlitz-Markus et al, 2010) and complementary therapies 
such as relaxation, biofeedback, magnesium, or cognitive-behavioral therapy (CBT).  
Triptans have been used safely for years in pediatrics (Evers, 2013); however, only 
almotriptan (in US) and sumatriptan (in EU) are approved for use in adolescents 
(> 12 years of age).   
When the response to acute pharmacological treatments is not sufficient, often in 
combination with non-pharmacological measures and complementary therapies, it is 
recommended that children and adolescents with persistent disability initiate prophylactic 
pharmacologic treatment.  While no formal treatment guidelines exist for children, 
generally clinical practice dictates that prophylactic medications are considered when 
patients have > 3 migraine headaches per month or when migraines are so severe that 
they interrupt normal activities.  
 
 
.  Therapy choice is determined on an individual basis, depending on 
a patient‘s migraine frequency and severity, comorbid conditions, and concomitant 
medications.  Since available treatments used in pediatrics such as propranolol 
(approved in Finland in children > 7 years of age), topiramate (approved for adolescents 
in the US), and amitriptyline have adverse events that can negatively affect school and 
social life, there remains a clear unmet need for new prophylactic treatments for children 
and adolescents.  


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2.1.2 
Targeting Calcitonin Gene-Related Peptide (CGRP) 
Calcitonin gene-related peptide (CGRP) belongs to the calcitonin family of peptides and 
is widely expressed in the peripheral and central nervous systems including the 
trigeminal system, which is implicated in the pathophysiology of migraines.  CGRP is a 
nociceptive modulator and potent vasodilator that has been associated with migraine 
pathophysiology based on several lines of evidence:  1) it is expressed in the trigeminal 
system (Tajti et al, 1999), 2) CGRP levels are elevated in migraineurs during an attack 
(Bellamy et al, 2006; Gallai et al, 1995; Goadsby et al, 1988; Goadsby et al, 1990),  
3) triptans (approved acute abortive migraine medications) restore CGRP levels to 
normal after treatment in a time frame that corresponds to significant pain relief and 
alleviation of accompanying symptoms (Juhasz et al, 2005; Sarchielli et al, 2006),  
4) infusion of CGRP into migraine sufferers triggers the onset of a migraine headache  
(Lassen et al, 2002; Petersen et al, 2005), 5) small molecule CGRP receptor antagonists 
have demonstrated clinical efficacy in acute migraine reversal (Connor et al, 2009; 
Hewitt et al, 2009; Ho et al, 2008a; Ho et al, 2008b; Olesen et al, 2004), and 6) small 
molecule CGRP receptor antagonists and antibody CGRP ligand antagonists have 
demonstrated clinical efficacy in migraine prevention (Dodick et al, 2014a;  
Dodick et al, 2014b; Ho et al, 2014).  The consistent efficacy data provide strong clinical 
validation of CGRP as a promising target for treatment of migraine. 
2.2 
Amgen Investigational Product Background  
AMG 334 is a human monoclonal immunoglobulin (IgG2) against the CGRP receptor. 
AMG 334 binds to the CGRP receptor complex with high affinity (Kd of ~20 pM) which 
competitively and reversibly blocks the binding of the native ligand, CGRP.  AMG 334 
functions as a CGRP receptor antagonist.  
2.2.1 
Toxicology 
The preclinical toxicology data were generated in the cynomolgus monkey, as it was the 
only laboratory species in which AMG 334 had suitable binding and functional activity.  
The studies conducted included an exploratory 1-month repeat dose toxicology study 
(SC, twice weekly), a Good Laboratory Practice (GLP) 1-month repeat dose toxicology 
study (SC, twice weekly) with a single dose IV arm, a single dose SC cardiovascular, 
respiratory and neurobehavioral safety pharmacology study in the telemetered monkey, 
and an enhanced pre-postnatal developmental study with a 6-month postnatal 
evaluation.  In addition, in vitro human and monkey tissue cross-reactivity study with 


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fluorochrome-labeled AMG 334 was also conducted.  There were no significant findings 
in the toxicology studies that would predict a risk to human subjects.   
In the repeat-dose toxicology studies in cynomolgus monkeys, there were no 
AMG 334-related adverse effects on clinical signs, body weight, food consumption, 
ophthalmology, electrocardiogram (ECG), body temperature, respiration rate, clinical 
pathology parameters, macroscopic observations, or on organ weights.  
 
 
 
 
 
 
 
  The no observed adverse effect level (NOAEL) was determined to 
be the highest evaluated dose of 150 mg/kg administered twice weekly in the 3/6 month 
repeat-dose study (Cmax = 2620 g/mL; AUC = 15300 g day/mL). 
The enhanced pre-postnatal developmental study (ePPND) in cynomolgus monkeys 
demonstrated that there was no maternal toxicity observed, and there were no effects on 
fetal or infant losses or on growth and development through 6 months postpartum.  The 
mean maternal AMG 334 exposure values (AUClast and Cmax) were 4280 g∙day/mL and 
422 g/mL respectively.  During the postpartum evaluation phase, the mean 
maternal/infant serum AMG 334 concentrations on postpartum day or birthday 14, 28, 
and 91 were 66/117 g/mL, 23/46 g/mL, and 0.009/0.188 g/mL, respectively.  The 
mean infant serum concentrations during the first month after birth were approximately 
5- to 12-fold higher than the clinical Cmax at steady state to the potential adult therapeutic 
dose of 70 mg and 1.3 – 3.4-fold higher to the clinical dose of 140 mg.   
The absence of AMG 334-related findings in the repeated-dose toxicology studies in 
cynomolgus monkeys (age range of 2.5 years or older) and absence of AMG 334-related 
effects on infant growth and development through 6 months postpartum when the infants 
had significant exposure to AMG 334 during the first month after birth suggests that 
there are no differences in toxicological profiles between younger and older animals and 
there is no concern of unique age-related developmental toxicities.  This study further 
supports the clinical evaluation of AMG 334 in pediatrics.   


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A 52–week toxicity study with an 8-week recovery period, (study number 1770628), 
showed that twice weekly SC administration of 50 mg/kg AMG334 to juvenile 
cynomolgus monkeys was well tolerated without mortality, clinical signs of toxicity, or 
abnormalities during neurobehavioral observations, learning ability, cardiovascular 
investigations, bone mineral content and density, and skeletal development.  There were 
no toxicology findings in preclinical studies that predicted a risk to human subjects. 
2.2.2 
AMG 334 Clinical Safety Summary 
As of the cutoff date for this Investigator’s Brochure (IB) (10 February 2020), an 
estimated 4642 subjects (4255.37 subject-years [SY]) have been exposed to AMG 334 
in Amgen sponsored clinical studies and an estimated 2649 subjects (1647.74 SY) have 
been exposed to AMG 334 in Novartis-sponsored clinical studies.  In addition, since the 
international birth date (17 May 2018) of AMG 334 up to the IB cutoff date, the estimated 
exposure to AMG 334 in the marketed setting has been 405 224 patient-years in the 
Amgen territory and 90 161 patient-years in Novartis territories.  To date, AMG 334 has 
demonstrated a safety and tolerability profile that supports further development.  Refer to 
the AMG 334 IB for details. 
2.2.3 
Pharmacokinetics 
AMG 334 exhibited nonlinear PK after single-dose SC administrations over the dose 
range of 1 to 210 mg (Study 20101267).  AMG 334 exposure increased more than dose 
proportionally from 1 to 70 mg and appeared to increase approximately dose 
proportionally from 70 to 210 mg after a single SC administration of AMG 334.  The 
mean area under serum concentration time curve from time 0 to the last quantifiable 
time point (AUClast) increased from 171 to 652 μg•day/mL (3.8-fold) and mean  
Cmax increased from 6.25 to 15.2 μg/mL (2.4-fold) following the 3-fold increase in dose 
from 70 to 210 mg.  Following a 140 mg SC dose maximum serum AMG 334 
concentrations (Cmax) were attained at a median time (tmax) of 5.5 days  
(range 4-21 days).  The relative exposure as measured by the area under the 
concentration time curve (AUC) for SC administration compared with IV administration 
was approximately 54% for the 140 mg AMG 334 dose.  There was no apparent 
difference in PK parameters between the healthy and migraine subjects.  It is expected 
that AMG 334 administered SC every 4 weeks will be effective in migraine prevention in 
pediatric subjects.  The effective half-life is 28 days. 


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2.3 
Risk Assessment 
Aimovig is currently approved for the preventive treatment of migraine (episodic or 
chronic types) in adults in over 40 countries.  Doses greater than or equal to 70 mg and 
140 mg (the highest dose level in either cohort in this study) have been given to three 
cohorts of adults in a multiple ascending dose (MAD) Phase 1 study and four cohorts of 
adults in a single asceding dose (SAD) Phase 1 study; a cohort of healthy subjects and 
a cohort of migraine subjects received three doses of 140 mg SC every four weeks 
(QM), and one cohort of healthy subjects received a dose of 280 mg (administered on 
Day 1) followed by 2 doses of 210 mg SC (administered on Days 29 and 57).  In Phase 
2, a dose ranging study (20120178) tested 7 mg, 21 mg and 70 mg SC QM vs placebo.  
In Phase 3, the maximum dose of both pivotal Phase 3 studies in adults with chronic 
migraine (Study 20120295) and episodic migraine (Study 20120296) was 140 mg SC, 
QM.  In Phase 2 and Phase 3, 2417 subjects have been exposed at least 3 months to 
either 70 mg or 140 mg.  The identified risks for AMG 334 are documented in 
Appendix A of the currently approved IB ( Version 11.0, 10 February 2020).  A limited 
number of adverse drug reactions (injection site reactions, constipation, muscle spasm, 
and pruritus) have been identified at low frequencies ( 5%) in clinical trials.  In 
post-marketing settings, hypersensitivity reactions (including rash, angioedema and 
anaphylactoid reactions) and constipation with serious complications have been 
reported.  Available safety data for the clinical trials with AMG 334 are summarized in 
Section 7.3 of the AMG 334 IB, Annex 2. 
Risk mitigation strategies include the monitoring of vital signs, serial ECGs, and adverse 
events for all subjects at protocol defined time points.   
Pediatric Risk Assessment 
Beyond the expected relationship between AMG 334 PK and body weight, no additional 
significant PK covariates (at the dose levels to be tested) are expected in the various 
populations of migraine subjects, from age 6 years to adult.  Based on the known safety 
profile of AMG 334, it is anticipated that it will be safe and well tolerated in pediatric 
subjects.  
2.4 
Rationale 
Migraine headaches can have a significant impact on daily functioning, especially in 
terms of school performance and social life, despite the use of acute (abortive) 
treatments.  With the exception of approved use of propranolol in children > 7 years of 
age in Finland and the approval of topiramate for adolescents in the United States, 


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safety and efficacy have not been established definitively for other prophylactic agents in 
the pediatric population.  Moreover, because the side effects of propranolol and 
topiramate can negatively affect school and social life, there remains an unmet need for 
new prophylactic treatments.  Upon conclusion of these pediatric studies, AMG 334 
could provide a new treatment option for migraine prevention in children and 
adolescents 6 to < 18 years.  This study is designed to provide safety, tolerability, and 
PK data that will support the Phase 3 study in children (6 to < 12 years of age) and 
adolescents (12 to < 18 years of age). 
Four adequately powered and designed placebo-controlled clinical studies providing 
evidence for the efficacy of AMG 334 in migraine prevention in adults have been 
conducted.  Dose selection in this study is based on the results of these studies in 
adults, where AMG 334 was evaluated at SC doses of 70 mg QM and 140 mg QM for 
the treatment of episodic and chronic migraine.   
Body weight is the only significant covariate influencing the PK of AMG 334 in adults.  
This Phase 1 study is meant in part to confirm this finding in the pediatric population.  
Therefore, dosing in pediatric subjects is planned according to 2 body weight cohorts. 
Subjects weighing < 40 kg will receive either 35 mg or 70 mg SC AMG 334 and subjects 
weighing ≥ 40 kg will receive either 70 mg or 140 mg SC AMG 334.  Treatments will be 
allocated to qualifying subjects within either cohort in a randomized fashion using IVRS. 
The proposed dosing strategy in this study is expected to confirm that the PK profile of 
equivalent doses of AMG 334 in either cohort of pediatric subjects of both age 
categories combined (ie, 35 or 70 mg for subjects weighing < 40 kg, and 70 or 140 mg 
for those weighing ≥ 40 kg, respectively)  is similar to that previously established in 
adults receiving either 70 mg or 140 mg.  Body weights of the younger age group are 
expected to be roughly 50% of the older age group, the latter of which overlaps with 
adult body weights according to the US Centers for Disease Control  
(CDC NHANES 2009-2010).  Children with a body weight < 18 kg are excluded from this 
study.  The fifth percentile of body weight in 6-year old males is 19.5 kg and in 6-year old 
females is 18.4 kg, thus the body weight range in this study encompasses the 6-year old 
population (Diamond McDowell et al, 2008). 
2.5 
Clinical Hypotheses 
Multiple SC doses of AMG 334 will be safe and well-tolerated, and the PK profiles will 
support further development of AMG 334 in children and adolescents with migraine, 
respectively.   


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
The overall study design is described in the Study Design and Treatment Schema at the 
end of the protocol synopsis.   
This is a Phase 1b, multicenter, randomized, open-label, multiple-dose study evaluating 
AMG 334 in  male and female children (6 to < 12 years of age) and adolescents (12 to 
< 18 years of age) with migraine.  The study population will consist of 2 cohorts based 
on body weight enrolling a total of at least 52 subjects and up to approximately 
60 subjects in the study.   
Cohort 1 will enroll at least 12 subjects and up to approximately 22 subjects in total with 
body weight of < 40 kg.  At least 9 subjects in Cohort 1 must be aged 6 to < 12 years old 
including at least 2 subjects aged 6 to < 10 years old, at the time of consent.   
Cohort 2 will enroll at least 35 subjects and up to approximately 38 subjects in total with 
a body weight of ≥ 40 kg at baseline.  It is anticipated that most subjects in this cohort 
will be 12 to < 18 years of age.  Enrollment requirements for subjects in Cohort 1 and 
Cohort 2 will be tracked and administered via IVRS to ensure that the minimum number 
of subjects in each cohort is achieved.  Enrollment will be staggered by age category 
with adolescents (ie, subjects 12 to < 18 years of age)  starting enrollment first.  
Children 6 to < 12 years of age at the time of consent will participate in the initial 
treatment phase, for a total of 12 weeks of treatment.  Adolescents 12 to < 18 years of 
age at time of consent will participate in the initial treatment phase for a total of 12 weeks 
of treatment after which they will have the option of continuing treatment in an optional 
40-week extension phase, for a total of 52 weeks of treatment.  A safety follow- up visit 
will take place 16 weeks after the last dose to complete end of study (EOS) 
assessments either (i) after completion of the initial 12 week treatment phase, (ii) after 
completion of the optional 40-week extension phase for those adolescents who choose 
to continue treatment or (iii) after the last dose received before discontinuation of 
treatment during the study. 
Subjects weighing < 40 kg (Cohort 1) will receive a dose of either 35 mg or 70 mg for a 
total of at least 12 and up to approximately 15 subjects completing Week 12 
assessments.  Subjects weighing ≥ 40 kg (Cohort 2) will receive a dose of either 70 mg 
or 140 mg for a total of at least 26 and up to approximately 30 subjects completing 
Week 12 assessments.  Treatments will be allocated to qualifying subjects in a 


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randomized order within either cohort through IVRS.  Study drug (low-dose or high-dose 
AMG 334) will be administered in either cohort in an open-label fashion against a 
background of allowed concomitant medications, including agents for migraine 
prevention. 
It is anticipated that at least 52 and up to approximately 60 subjects will be enrolled in 
the study to ensure that at least 38 and up to approximately 45 subjects complete 
Week 12 assessments. 
During the initial treatment phase, each subject will receive a total of 3 SC doses of 
AMG 334 administered every 4 weeks (Q4W) as described in the Schedule of Activities 
(Table 1 and Table 2).  The study is expected to confirm a PK profile in pediatric 
subjects that is similar to that in adults, based on population PK analysis, and to provide 
preliminary safety data in each body weight cohort supportive of the initiation of the 
AMG 334 Phase 3 studies in the pediatric population.  All subjects will be administered 
AMG 334.  Concomitant use of agents for migraine prevention (up to 2 treatments on a 
stable dose) and for the acute treatment of migraine are permitted during the study.   
3.2 
Number of Sites 
The study will be conducted at approximately 16 sites within the United States.  If a site 
does not enroll subjects within 3 months of site initiation, the site may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
A total of at least 52 subjects and up to approximately 60 subjects with migraine will be 
enrolled in Cohorts 1 and 2, with at least 12 subjects and up to approximately 
22 subjects enrolled into Cohort 1 (< 40 kg) and at least 35 subjects and up to 
approximately 38 subjects enrolled into Cohort 2 (≥ 40 kg).  The number of subjects 
enrolled into Cohort 1 and Cohort 2 are considered sufficient in order to collect 
appropriate PK data and preliminary safety data able to support the initiation of the 
AMG 334 pediatric Phase 3 safety and efficacy studies.  This includes an anticipated 
rate of early discontinuations up to 20% over the first 12 weeks, which is expected to be 
similar across the two cohorts.  
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study may be replaced by 
another subject in the same body weight cohort at the discretion of the Amgen Medical 
Monitor in consultation with the Principal Investigator. 


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3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The estimated study duration for subjects completing only the initial 12 week treatment 
phase is up to 27 weeks, and includes:  
 
Up to 3 weeks for screening 
 
12 week treatment phase 
 
12 week safety follow-up phase (16 weeks after the last dose of AMG 334)  
The estimated study duration for subjects completing the initial 12 week treatment phase 
and the optional 40-week extension phase is up to 67 weeks, and includes 
 
Up to 3 weeks for screening 
 
12 week treatment phase 
 
Optional 40-week extension phase 
 
12 week safety follow-up phase (16 weeks after the last dose of AMG 334)  
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis (ie, when the 
last subject completes the 12 Week assessment or is discontinued from the study).  
End of Study:  The time when the last subject is assessed or receives an intervention 
for evaluation in the study (ie, when the last subject completes the study, which includes 
the safety follow-up visit 16 weeks after the last dose of Investigational Product, or is 
discontinued from the study for other reasons described in Section 8). 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion date will be the 
date when the last subject is assessed or receives an intervention for evaluation in the 
study (ie, last subject last visit). 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain pre-screening and screening logs of all 
potential study candidates which includes limited information about the potential 
candidate (eg, date of screening).   
Before any study-specific activities/procedure, the appropriate written informed consent 
and subject assent must be obtained.  In addition to written informed consent from a 


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legally acceptable representative, the assent of the child must also be obtained as 
appropriate to the age of the subject and/or based on local regulations. 
(see Section 11.1).  
4.1 
Inclusion Criteria 
101. Subject’s legally acceptable representative has provided informed consent and the 
subject has provided written assent based on local regulations and/or guidelines 
prior to any study-specific activities/procedures being initiated. 
102. Male and female children and adolescents 6 and < 18 years of age at time of 
consent  
103. Body weight ≥ 18 kg upon entry into screening 
104. History of migraines, with or without aura, according to the ICHD-III for at least 
12 months prior to the study screening 
105. Frequency of ≥ 4 migraine days per month in each of the 3 months prior to the 
study screening period 
106. Physical and neurological examinations, clinical laboratory values, and 12-lead 
ECGs are clinically acceptable to the investigator and Amgen medical monitor at 
screening 
4.2 
Exclusion Criteria 
201. Currently receiving treatment in another investigational device or drug study, or 
less than 30 days (small molecules), 90 days (biologic agents), or 5 half-lives 
(whichever is longer) since ending treatment on another investigational device or 
drug study(s).  Other investigational procedures while participating in this study are 
excluded.  
202. Use of more than 2 migraine prophylactic medications within 1 month prior to 
Study Day 1 (see Section 6.4). 
203. Taken opioid or butalbital-containing analgesics on ≥ 4 days per month for any 
indication in either month during the 2 months prior to screening 
204. History of migraine with brainstem aura or hemiplegic migraine headache 
205. Medical history or other condition that compromises the ability of the subject or 
legally acceptable representative to give appropriate informed consent and/or 
assent 
206. Malignancy except non-melanoma skin cancers or cervical cancer in situ within the 
last 5 years. 
207. History of hypertension 


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208. History of chronic or frequent clinically significant painful condition other than 
migraine  
209. History of chronic anemia 
210. Uncontrolled asthma or uncontrolled diabetes 
211. Vaccinations within 1 month of Study Day 1 
212. Major surgery within 6 months of Study Day 1 
213. Hospitalization > 24 hours within 28 days of Study Day 1  
214. Abnormal hepatic function: ALT or AST ≥ 2.0 times the upper limit of normal    
(ULN) for the age range, confirmed by repeated measure 
215. Abnormal renal function: creatinine ≥ 1.5 times the ULN for the age range,   
confirmed by repeated measure 
216. Known positive results for Human Immunodeficiency Virus (HIV)  
217. Positive Hepatitis B Surface Antigen (HepBsAg), Hepatitis B Core Antibody 
(HepBc Ab) (indicative of chronic Hepatitis B) or detectable hepatitis C virus 
Ribonucleic acid (RNA) by Polymerase Chain Reaction (PCR) (indicative of  active 
Hepatitis C – screening is generally done by Hepatitis C Antibody (HepCAb), 
followed by hepatitis C virus RNA by PCR if HepCAb is positive) 
218. Subject has known hypersensitivity or known allergy to any of the products to be 
administered during dosing 
219. Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge 
220. Subject was previously enrolled in this study 
221. Females of reproductive potential who are unwilling to practice an acceptable 
method(s) of effective birth control while on study through 16 weeks after receiving 
the last dose of study drug. Acceptable methods of effective birth control includes 
sexual abstinence (male, female), hormonal birth control, or intrauterine devices 
(IUDs). Barrier methods are acceptable if a condom with spermicide (male) is used 
in combination with diaphragm, cervical cap, or cervical sponge (female). 
Reproductive potential is defined as a female who has had at least one menstrual 
period, regardless of age 
222. Female who is breastfeeding or who plans to breastfeed while on study through 
16 weeks after receiving the last dose of study drug 


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223. Female of reproductive potential with a positive pregnancy test. Reproductive 
potential is defined as a female who has had at least one menstrual period, 
regardless of age 
224. Female subject planning to become pregnant during study through 16 weeks after 
receiving the last dose of study drug 
225. Male subjects with pregnant partners or whose partners plan to become pregnant 
during the study 
226. Positive illicit drug and/or alcohol test at screening 
227. Known substance abuse (eg alcohol, cannabis, illicit drugs) within 12 months of 
screening 
228. Inability, or unwillingness, to refrain from alcohol consumption during study 
participation 
229. Subject has moderate or severe depression based on: a total score of > 11 on the 
Patient Health Questionnaire modified for adolescents (PHQ-A) or investigator’s 
clinical judgment for children (Refer to Section 7.2.11)  
230. Subject has a history or evidence of suicidal ideation (endorsing item 4 or 5) or any 
suicidal behavior based on an assessment with the Columbia Suicide Severity 
Rating Scale (C-SSRS) at screening or at baseline 
231. History or evidence of any other clinically significant disorder, condition or disease 
that, in the opinion of the investigator or Amgen medical monitor, if consulted, 
would pose a risk to subject safety or interfere with the study evaluation, 
procedures or completion 
232. Subject deemed likely to require modification in migraine prophylactic medication 
during study participation in the opinion of the investigator or Amgen medical 
monitor 
5. 
SUBJECT ENROLLMENT 
Enrollment will be staggered by age category with adolescents (ie, subjects 12 to 
< 18 years of age)  starting enrollment first.   
Children 6 to < 12 years of age at the time of consent, will participate in the initial 
treatment phase, for a total of 12 weeks of treatment.  Adolescents 12 to < 18 years of 
age at time of consent will participate in the initial treatment phase for a total of  
12 weeks of treatment after which they will have the option of continuing treatment in an 
optional 40-week extension phase, for a total of 52 weeks of treatment.  A safety  
follow- up visit will take place 16 weeks after the last dose to complete  


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
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EOS assessments either (i) after completion of the initial 12 week treatment phase, (ii) 
after completion of the optional 40-week extension phase for those adolescents who 
choose to continue treatment or (iii) after the last dose received before discontinuation of 
treatment during the study. 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, assent, and all 
other subject information and/or recruitment material, if applicable.  All legally acceptable 
representatives must personally sign and date the informed consent form before 
commencement of study-specific procedures.  All subjects must provide appropriate 
assent before commencement of study-specific procedures.  Subjects are considered 
enrolled once the investigator has confirmed they meet all eligibility criteria. 
The Investigator is to document the enrollment decision and date, in the subject’s 
medical record and in/on the enrollment eCRF. 
Each subject and/or legal representative who signs the informed consent and assent 
enters into the screening period for the study and receives a unique subject identification 
number before any study procedures are performed.  The subject identification number 
will be assigned manually.  This number will be used to identify the subject throughout 
the clinical study and must be used on all study documentation related to that subject.  
Re-screening of subjects is acceptable upon discussion with and approval by the Amgen 
Medical Monitor. 
The unique study identification number will consist of 11 digits.  The first 3 digits will 
represent the last 3 digits of the protocol number (eg, 172).  The next 5 digits will 
represent the country code and site number (eg, 66003) and will be identical for all 
subjects at the site.  The last three digits will be assigned in sequential order as subjects 
are screened (eg, 001, 002, 003).  The subject identification number must remain 
constant throughout the entire clinical study; it must not be changed after initial 
assignment, including if a subject is rescreened.   
5.1 
Allocation to Cohort (Initiation of Screening) and Treatment 
Assignment (Enrollment)  
Subjects will be assigned to one of two cohorts based the subject’s body weight on 
Day 1.  Enrollment requirements for subjects in Cohort 1 and Cohort 2 will be tracked 
and administered via IVRS to ensure that the minimum number of subjects in each 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 30 of 97 
CONFIDENTIAL 
 
 
cohort is achieved.  Requests for initiation of screening procedures will be administered 
via IVRS. 
Randomization will be based on a schedule generated by Amgen before the start of the 
study and will be centrally executed using the IVRS.  Subjects eligible for randomization 
on Day 1 will receive a unique randomization number, which will be assigned in 
sequential order in which a subject met eligibility criteria and study staff dialed into IVRS.  
At no time will the same randomization number be assigned to more than one subject. 
Subjects in Cohort 1 (weighing < 40 kg) will be randomized in a 1:2 allocation ratio to low 
dose (35 mg AMG 334), or high dose (70 mg AMG 334).  Subjects in Cohort 2 (weighing 
≥ 40 kg) will be randomized in a 1:4 allocation ratio to low dose (70 mg AMG 334), or 
high dose (140 mg AMG334).  The treatment dose assigned and treatment assignment 
date are to be documented in the subject’s medical record.   
The treatment dose assigned (low-dose or high-dose of the body-weight cohort 
AMG 334) will be administered in either cohort in an open-label fashion. 
5.2 
Calls to Interactive Voice Response System (IVRS) 
Sites are to call the IVRS for the following:  to enter the subject into the initial screening 
phase and to randomize an eligible subject into the treatment phase.  
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s), Medical Device(s), and/or Combination 
Product(s) 
The Amgen Investigational Product used in this study is AMG 334. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of AMG 334. 
6.2 
Investigational Product 
Investigational Product(s) will be administered at the research facility by a qualified staff 
member.  A physician must be available at the time of administration of Investigational 
Product. 
6.2.1 
AMG 334 
AMG 334 will be manufactured and packaged by Amgen Inc.  The excipients are 
appropriate for the use in children, thus obviating the need for development of a 
separate pediatric formulation.  AMG 334 will be packaged in prefilled syringes 
containing either 1 mL of 70 mg/mL AMG 334 or 1 mL of 140 mg/mL AMG 334.   


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 31 of 97 
CONFIDENTIAL 
 
 
AMG 334 will also be packaged in 3 mL clear glass vials containing 1 mL of 70 mg/mL 
AMG 334.  
6.2.1.1 
Dosage, Administration, and Schedule 
A qualified staff member will administer the appropriate dose and number of AMG 334 
injections into the abdomen, the upper arm or the upper thigh, the 3 anatomical sites for 
administration of Investigational Product.  For subjects weighing < 40 kg at baseline 
(Cohort 1), one injection of either 35 mg (0.5 mL) or 70 mg (1 mL) will be administered. 
For subjects weighing ≥ 40 kg at baseline (Cohort 2) one injection of either 70 mg (1 mL) 
or 140 mg (1 mL) will be administered.  
Subjects in either cohort will be randomly assigned to one of two Investigational Product 
dose levels; doses are fixed and will not be adjusted for individual subjects during the 
study.  The anatomical sites for administration of Investigational Product are the upper 
arm, upper thigh, or abdomen. 
All subjects in this study will be administered AMG 334 against a background of allowed 
concomitant medications, including agents for migraine prevention. 
AMG 334 will be administered Q4W on Study Day 1, and on Study Days 29 (± 3 days) 
and 57 (± 3 days).  Adolescent subjects will have the option to participate in the optional 
40-week extension phase, receiving IP as noted in the Schedule of Activities (Table 1 
and Table 2), at the dose they received during the initial 12 Week treatment phase 
regardless of any changes in weight that might occur during the study.  All subjects will 
be monitored on site 2 hours post-dose on Day 1 for any acute reactions that might 
occur.  All subjects will be monitored on site for 30 minutes post-dose on Days 29 
and 57.  The post-dose safety monitoring will be extended for 2 hours if the subject 
shows any safety concerns post-dose during the last dosing visit.  The date, time, 
injection location, volume (full, partial, or none), and lot number of each treatment will be 
recorded in the subject’s source documents and on the appropriate eCRF.  The effects 
of overdose of AMG 334 are not known.  All overdose occurrences must be documented 
and corresponding adverse events must be recorded on the appropriate eCRF and in 
the source documents. 
The study may be terminated at any point in time at the discretion of the sponsor.  
Subjects who permanently discontinue IP during the initial 12 week treatment phase will 
have the EOS/Week 12 visit assessments performed and will then return for the safety 
follow-up visit 16 weeks after the last dose of Investigational Product.  Subjects who 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 32 of 97 
CONFIDENTIAL 
 
 
permanently discontinue IP during the 40-week extension phase will have the 
EOS/Week 52 visit assessments performed and then will return for the safety follow-up 
visit 16 weeks after the last dose of Investigational Product. 
6.2.2 
Medical Devices 
The following investigational combination product or medical device provided by Amgen 
for use in this study is the pre-filled syringe.   
The AMG 334 pre-filled syringe is a single-use, disposable, handheld manual injection 
device for fixed dose SC injection of [1 mL of 70 mg/mL] deliverable volume. 
Additional details are provided in the IPIM.   
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational Non-Amgen medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBIL]) 
or international normalized ratio [INR]) or signs/symptoms of hepatitis may meet the 
criteria for discontinuation of Investigational Product depending upon the clinical 
circumstances discussed below (as specified in the FDA Guidance for Industry 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009).  
6.3.1 
Criteria for Permanent Withholding of AMG 334 due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified. 
Important alternative causes for elevated AST/ALT and/or TBIL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, Herpes 
Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 


Product:  AMG 334 
Protocol Number:  20160172 
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 
Right-sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic Fatty Liver Disease including Steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
Amgen Investigational Product and other protocol-required therapies, as appropriate, 
should be withheld pending investigation into alternative causes of Drug Induced Liver 
Injury (DILI).  If Investigational Product(s) is/are withheld, the subject is to be followed for 
possible DILI.  Rechallenge may be considered if an alternative cause for impaired liver 
tests (ALT, AST, ALP) and/or elevated TBIL, is discovered and the laboratory 
abnormalities resolve to normal or baseline.  Permanent discontinuation of 
Investigational Product is recommended if all of the following apply: 
 
TBL > 2 x ULN or INR > 1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below: 
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3 x ULN 
 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent (eg, hepatobiliary tract disease, viral hepatitis, right-sided heart 
failure, hypotension or any cause of hypoxia to the liver causing ischemia, etc.) 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 34 of 97 
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Conditional withholding of investigational medicinal product or other protocol-required 
therapies is recommended if all of the following apply: 
 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation 
Any 
Any 
 
Any 
 
 
Any 
> 8 x ULN at any time 
> 5 x ULN but < 8 x ULN for ≥ 2 weeks 
> 5 x ULN but < 8 x ULN and unable to adhere 
to 
enhanced monitoring schedule 
> 3 x ULN with clinical signs or symptoms that 
are 
consistent with hepatitis (such as right upper 
quadrant pain/tenderness, fever, nausea, 
vomiting, and jaundice). 
 
OR: TBIL > 3 x ULN at any time 
 
OR: ALP > 8 x ULN at any time 
6.4 
Concomitant Therapy 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.7. 
All appropriate concomitant medications taken by a subject while on study are to be 
collected (therapy name, indication, dose, unit, frequency, start and stop dates). 
The subject may use up to 2 of the following medications with possible migraine 
prophylactic effects.  Doses must be stable within 1 month prior to the Day 1 visit and 
throughout the study.  Use of more than 2 of the following medications is prohibited 
within 1 month prior to the Day 1 visit and throughout the study. 
 
Divalproex sodium, sodium valproate, topiramate, carbamazepine, gabapentin 
 
Beta blockers (for example: atenolol, bisoprolol, metoprolol, nadolol, nebivolol, 
pindolol, propranolol, timolol) 
 
Tricyclic antidepressants (for example: amitriptyline, nortriptyline, protriptyline) 
 
Venlafaxine, desvenlafaxine, duloxetine, milnacipran 
 
Flunarizine, verapamil, lomerizine 
 
Lisinopril, candesartan 
 
Clonidine, guanfacine 
 
Cyproheptadine 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 35 of 97 
CONFIDENTIAL 
 
 
 
Methysergide 
 
Pizotifen 
 
Butterbur, feverfew, magnesium (≥ 9 mg/kg/day), riboflavin (≥ 25 mg/day) 
 
Botulinum toxin 
6.5 
Alcohol and  Drug  Restrictions 
Subject must refrain from alcohol consumption and cannabis use throughout the study.  
6.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors or partners for 
whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts. 
This includes any investigational/non-investigational product(s), device(s) or 
combination product(s) provisioned and/or repackaged/modified by Amgen:  AMG 334. 
Any product complaint(s) associated with an investigational product(s), 
non-investigational products(s), devices(s), or combination product(s) supplied by 
Amgen are to be reported. 
6.7 
Excluded Treatments, Medical Device Use, and/or Procedures 
During Study Period  
Medication excluded in the eligibility criteria (Section 4) are excluded for the duration of 
the study with the exception of vaccinations which are allowed after the completion of 
Day 85 assessments.  Any other exceptions (eg, medication given for the treatment of 
an adverse event) should be first discussed with Amgen. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Activities 
For Schedule of Activities refer to (Table 1 and Table 2).  Refer to the applicable 
supplemental laboratory and electrocardiogram manuals for detailed collection and 
handling procedures.   
Children 6 to < 12 years of age at the time of consent will participate in the initial 
treatment phase, for a total of 12 weeks of treatment.  Adolescents 12 to < 18 years of 
age at time of consent will participate in the initial treatment phase for a total of 12 weeks 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  03 November 2021 
Page 36 of 97 
CONFIDENTIAL 
 
 
of treatment after which they will have the option of continuing treatment in an optional 
40-week extension phase, for a total of 52 weeks of treatment.  A safety follow- up visit 
will take place 16 weeks after the last dose to complete EOS assessments either  
(i) after completion of the initial 12 week treatment phase, (ii) after completion of the 
optional 40-week extension phase for those adolescents who choose to continue 
treatment or (iii) after the last dose received before discontinuation of treatment during 
the study. 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date: 03 November 2021 
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Table 1.  Schedule of Activities  
Study Day g 
-21 to 
-2 
1 
 
8 
 
15 
 
 
 
29 
 
57 
 
64 
 
71 
 
85 
 
169 
 
Time (in hours)a 
 
 
Pre-
Dose 
0 
0.5 
2 
 
 
Pre-
Dose 
0 
0.5j 
Pre-
Dose 
0 
0.5j 
 
 
 
 
General & Safety Assessments 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weighti 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Heightc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs (BP, HR, TEMP) 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Physical Examination 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Neurological Examination 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
12-Lead Electrocardiogram 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
Serious Adverse Event 
Assessment: 
Collection/Recording/Reporting 
      X    
                                                                                                                                                    
Adverse Event Assessment: 
Collection/Recording/Reporting 
 
 
 
Adverse Device Effect 
Assessment: 
Collection/Recording/Reporting 
 
 
 
Concomitant Medications 
X 
 
Laboratory Assessments 
 
 
Clinical Chemistry 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
Clinical Hematology 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
Estimated Creatinine Clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
Drug and Alcohol Screening k 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hep C Ab, HepBc Ab, HbsAg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testb 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Page 1 of 2 
Footnotes defined on next page of the table 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date: 03 November 2021 
Page 38 of 97 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Activities 
Study Day g 
-21 to 
-2 
1 
 
8 
 
15 
 
 
 
29 
 
57 
 
64 
 
71 
 
85 
 
169 
 
Time (in hours)a 
 
 
Pre-
Dose 
0 
0.5 
2 
 
 
Pre-
Dose 
0 
0.5j 
Pre-
Dose 
0 
0.5j 
 
 
 
 
Questionairres 
 
Pediatric PHQ-A l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
 
Study Drug Administrationc h 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Collect blood for biomarker 
development 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Other 
 
Pharmacogenetics (optional)d 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 334 Serum PK Collection e f  
 
X 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
Page 2 of 2 
Footnotes defined on next page of the table 


Product:  AMG 334 
Protocol Number:  20160172 
Date: 03 November 2021 
Page 39 of 97 
CONFIDENTIAL 
 
 
Abbreviations:  BP = blood pressure;  ECG = electrocardiogram; ET =  Early Termination; HepBc Ab = hepatitis B core antibody; HBSAg – hepatitis B surface antigen; 
HepC Ab = hepatitis C antibody; HR = heart rate; PK = pharmacokinetic; Pre = pre-dose 
a   All time in hours are relative to AMG 334 administration 
b Females of reproductive potential only.  A serum pregnancy test will be performed at screening  At all other time points a urine pregnancy test will be performed, all 
performed pre-dose.  Female subjects who experience menarche while they are followed in the study will be subject to the pregnancy test as specified in the Schedule 
of Activities starting with the next scheduled assessment following their first menstrual period. 
c Allowable injection sites:  upper arm, thigh, abdomen (See Investigational Product Instruction Manual) 
d For subjects who provided informed consent/assent for the pharmacogenetic studies, DNA will be obtained from the cell pellet collected in the plasma tube used for 
the biomarker development sample.  Therefore, additional sampling is not required.  
e Samples for PK assessment will be serum 
f PK samples must be collected prior to administering AMG 334 
g A subject who discontinues the study during the initial 12 Week treatment phase, or chooses not to continue with the optional 40-week extension, will complete the 
Week 12 visit outlined in Table 1 and the safety follow-up visit 16 weeks after the last dose of IP as outlined in Table 1.  A subject who continues with the optional  
40- week extension  will complete the Week 12 visit outlined in Table 2.  A subject who discontinues IP or the study during the optional 40-week extension will complete 
the Week 52 visit and the safety follow-up visit 16 weeks after the last dose of Investigational Product as outlined in  Table 2. 
h Dose will be based on body weight collected pre-dose on Day 1. 
i Weight measured in kilograms to the nearest decimal fraction. 
j The post dose safety monitoring will be extended to 2 hours if they subject showed any safety concerns post-dose during the last dosing visit 
k Drug and alcohol testing will occur based on the Investigator’s discretion for children in Cohort 1  (See Section 7.2.15) 
l Pediatric PHQ-A for adolescent subjects only ((See Section 7.2.11 and Section 7.2.15) 
 
 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date: 03 November 2021 
Page 40 of 97 
CONFIDENTIAL 
 
 
Table 2.  Schedule of Activities  
Activity 
Optional 40-Week Open-Label Extension Phase (40 Weeks) 
Safety F/U 
Study Week 
12 
 
 
16 
 
 
20 
 
 
24 
 
28 
 
32 
 
36 
 
40 
 
44 
 
48 
52 or ET f 
16 Weeks after 
last Dose of IPf 
 
Study Daya 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
449 
General & Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Body Weightg 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Height 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs (BP, HR, TEMP) 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
Neurological Examination 
 
 
 
 
 
 
 
 
 
 
X 
 
Serious Adverse Event Assessment: 
Collection/Recording/Reporting 
 
Adverse Event Assessment: 
Collection/Recording/Recording 
  
Adverse Device Effect Assessment: 
Collection/Recording/Reporting 
 
Concomitant Medications 
  
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Clinical Hematology 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Drug and Alcohol Screening 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionairres 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administrationc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect blood for biomarker development 
 
 
 
 
 
 
 
 
 
 
 
X 
Page 1 of 2 
Footnotes defined on last page of the table 


Product:  AMG 334 
Protocol Number:  20160172 
Date: 03 November 2021 
Page 41 of 97 
CONFIDENTIAL 
 
 
Table 2.  Schedule of Activities 
Activity 
Optional 40-Week Open-Label Extension Phase (40 Weeks) 
Safety F/U 
Study Week 
12 
 
 
16 
 
 
20 
 
 
24 
 
28 
 
32 
 
36 
 
40 
 
44 
 
48 
52 or ET f 
16 Weeks after 
last Dose of IPf 
 
Study Daya 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
449 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
AMG 334 Serum PK Collectiond e  
X 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Page 2 of 2 
Abbreviations:  BP = blood pressure;  ECG = electrocardiogram; ET =  Early Termination; HepBc Ab = hepatitis B core antibody; HBSAg – hepatitis B surface antigen; 
HepC Ab = hepatitis C antibody; HR = heart rate; PK = pharmacokinetic; Pre = pre-dose 
a Each dosing visit during the optional 40-week extension has a visit window of ± 4 days. 
b Females of reproductive potential only.  A serum pregnancy test will be performed at screening  At all other time points a urine pregnancy test will be performed, all 
performed pre-dose.  Female subjects who experience menarche while they are followed in the study will be subject to the pregnancy test as specified in the Schedule 
of Activities starting with the next scheduled assessment following their first menstrual period. 
c Allowable injection sites:  upper arm, thigh, abdomen (See Investigational Product Instruction Manual) 
d Samples for PK assessment will be serum 
e PK samples must be collected prior to administering AMG 334. 
f A subject who discontinues the study during the initial 12 Week treatment phase, or chooses not to continue with the optional 40-week extension, will complete the 
Week 12 visit outlined in Table 1 and the safety follow-up visit 16 weeks after the last dose of IP as outlined in Table 1.  A subject who continues with the optional  
40- week extension  will complete the Week 12 visit outlined in Table 2.  A subject who discontinues IP or the study during the optional 40-week extension will complete 
the Week 52 visit and the safety follow-up visit 16 weeks after the last dose of Investigational Product as outlined in  Table 2. 
g Weight measured in kilograms to the nearest decimal fraction 


Product:  AMG 334 
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7.2 
General Study Procedures 
A signed and dated IRB/IEC-approved informed consent and appropriate subject assent 
must be obtained before any study-specific procedures are performed.  All subjects will 
be screened for eligibility before enrollment.  Only eligible subjects will be enrolled into 
the study. 
During the study, every effort should be made to perform study procedures as indicated 
in Schedule of Activities (Table 1 and Table 2).  Additional procedures deemed 
necessary as part of standard of care or as required by local laws and regulations may 
be performed at the investigator’s discretion.  Throughout the study, with the exception 
of the PK sample collections, the permitted time windows for scheduled assessments 
will be as follows: 
 
± 12 hours for Day 1 visit 
 
Each study visit during the initial 12 week treatment phase and safety follow-up 
(except Day 1) has a window ± 3 days  
 
Each study visit during the optional 40-week extension phase has a window of 
 ± 4 days  
Laboratory Assessments 
For a complete listing of laboratory test panels and analytes collected, please refer to 
Section 7.2.4.   
Repeat Assessments and Rescreening. 
Vital signs, ECGs, laboratory assessments, as well as drug and alcohol testing can be 
repeated during screening.  Whether a subject has failed screening after repeat 
assessment will be decided on a case-by-case basis at the discretion of the Principal 
Investigator.   
Investigators may re-screen a subject if the investigator is reasonably certain that 
reasons for screen failure will be resolved prior to or during a repeat screening attempt. 
Reasons to re-screen may include but are not limited to the following: 
 
Laboratory value(s) out of range due to sampling error or that might be within range 
after medically-appropriate supplementation.  
 
The subject has a medical condition that can be stabilized or resolved prior to the 
repeat screening attempt. 
 
Additional time is required following the subject’s last dose of an excluded 
medication. 
The decision to rescreen a subject will be made on a case-by-case basis at the 
discretion of the Amgen Medical Monitor in consultation with the Principal Investigator. 


Product:  AMG 334 
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7.2.1 
Informed Consent 
A signed informed consent and appropriate subject assent must be obtained from each 
subject prior to any study mandated procedures. 
7.2.2 
Medical History 
The Investigator or designee will collect a complete medical, psychiatric and surgical 
history that started within 21 days prior to enrollment through enrollment.  Medical 
history will include information on the subject’s concurrent medical conditions.  A 
detailed history of prior and/or concurrent use of alcohol, tobacco, and other drug use 
will be obtained.  All findings will be reported on the medical history eCRF. 
7.2.3 
Height and Weight Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms, to the 
nearest decimal fraction should be measured without shoes. 
7.2.4 
Vital Signs 
The following measurements must be performed: Systolic/Diastolic Blood Pressure, 
Heart Rate, and Temperature.  Subject must be in a supine position in a rested and calm 
state, back supported, and arm at heart level for at least 5 minutes before blood 
pressure assessments are conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The position 
selected for a subject should be the same that is used throughout the study and 
documented on the vital sign eCRF.  In children, blood pressure should be taken in the 
right arm, as normative values are obtained in the right arm.  Finally, the cuff size should 
be appropriate for the subject’s arm.  The temperature location selected for a subject 
should be the same that is used throughout the study and documented on the vital signs 
eCRF.  Record all measurements on the vital signs eCRF. 
7.2.5 
Physical Examination 
Physical examination will be completed as per standard of care.  The Investigator or 
qualified designee will perform a complete physical examination (excluding breast, 
genital, and rectal examination) at time points specified in the Schedule of Assessment 
(Table 1 and Table 2).  Abnormal measurements may be repeated at the discretion of 
the Investigator. 
7.2.6 
Neurological Examination 
Neurological examination will be completed as per standard of care.  Neurological 
examination findings should be recorded on the appropriate eCRF.   


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7.2.7 
Electrocardiogram 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before 12-lead ECG assessment is conducted.  If the subject is unable to be in the 
supine position, the subject should be in most recumbent position as possible. 
A single 12-lead ECG will be performed at time points designated in the Schedule of 
Activities (Table 1 and Table 2).  Data will be reported on the CRF.  The ECG must 
include the following measurements: Heart Rate, QRS, QTc, and PR intervals.  
Standard ECG machines should be used for all study-related ECG requirements.  The PI 
or designated site physician will review all ECGs.  Once signed, the original ECG tracing 
will be retained with the subject’s source documents.  At the request of the sponsor, a 
copy of the original ECG will be made available to Amgen. 
7.2.8 
Drug and  Alcohol Screening 
A urine screen for drugs with a high potential of abuse  will be performed at time points 
specified in the Schedule of Activities (Table 1 and Table 2).  Breath ethanol screens will 
be performed at time points specified in the Schedule of Activities (Table 1 and Table 2).  
Subjects with a positive drug test at screening may be retested once at the discretion of 
the investigator.  Subjects with a positive test for alcohol at screening will be asked to 
refrain from drinking alcohol for 24 hours prior to dosing on Day 1.  Subjects who test 
positive at Day 1 for drugs and alcohol, will not qualify for Investigational Product 
administration and will be withdrawn from study participation.  Drug and alcohol testing 
will occur based on the Investigator’s discretion for children in Cohort 1 (See  
Section 7.2.15). 
7.2.9 
Hepatitis B Surface Antigen, Hepatitis C Antibody Status 
HBs Ag, and HepC Ab titers will be assessed as specified in the Schedule of Activities 
(Table 1 and Table 2).  The result must be negative and will be documented in the 
source document but will not be recorded on the eCRF.  If Hepatitis B and/or Hepatitis C 
status is not known to be positive by serology,the following laboratory testing is required: 
 
Hepatitis B Surface Antigen (HepBsAg) and total Hepatitis B Core Antibody 
(HepBcAb)  
 
If results are HepBcAb positive or HepBsAg positive, no additional testing 
is necessary as subject meets exclusion criteria. 
 
Hepatitis C virus antibody 
 
If results are Hepatitis C virus antibody positive, no additional testing is 
necessary as subject meets exclusion criteria 


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7.2.10 
Pregnancy Test 
All female subjects of reproductive potential will have a serum pregnancy test performed 
at screening and a urine pregnancy test performed pre-dose at all dosing visits as 
specified in the Schedule of Activities (Table 1 and Table 2).  Subjects of reproductive 
potential with a positive result at screening or Day 1 will be excluded from the study.  
Female subjects who experience menarche while they are followed in the study will be 
subject to the pregnancy testing as specified in the Schedule of Activities (Table 1 and 
Table 2) starting with the next scheduled assessment following their first menstrual 
period. 
7.2.11 
Patient Health Questionnaire– Adolescents (PHQ-A) 
The PHQ-A is a 9-item questionnaire that assesses the severity of depression by 
evaluating each of the 9 DSM-IV criteria for depression validated in adolescent patients.  
Each item is scored as “0” (not at all) to “3” (nearly every day).  The total score is 
categorized into 4 severity grades:  none (0-4), mild depression (5-9), moderate 
depression (10-14), moderately severe depression (15-19), and severe depression  
(20-27).  The PHQ-A is intended to be self-administered by the subject and their parent.  
It can be completed in collaboration, but the answers need to be confirmed with the 
subject.  The PHQ-A should be administered to adolescent subjects only. 


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7.2.14 
Blood and Urine Assessments 
Table 3.  Approximate Blood Volumes for Cohorts 1-2 in Initial 12 Week Treatment 
Phase 
Test 
Volume (mL) per 
Collection 
Approximate 
Number of 
Collections 
Approximate Total 
Volume (mL) 
Chemistry and 
Hematology    
8 
5 
40 
Hep C Ab, HepBc Ab, 
HBsAg 
3.5 
1 
3.5 
Serum Pregnancy 
(female subjects of 
reproductive potential 
only) 
5 
1 
5 
Blood sample for PK 
0.5 
8 
4 
Optional Blood 
sample for 
pharmacogenetics  
Cell Pellet from 
Biomarker Plasma 
1 
0 
Biomarker Development 
   Serum 
5 
2 
10 
   Plasma 
5 
2 
10 
   Plasma CGRP 
6 
2 
12 
Total blood volume collected during the initial 12 week treatment 
phase (does not include safety follow-up) 
87 


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Table 4.  Approximate Blood Volumes for Optional 40-Week Extension Phase 
Test 
Volume (mL) per 
Collection 
Approximate 
Number of 
Collections 
Approximate Total 
Volume (mL) 
Chemistry and 
Hematology 
8 
3 
24 
Blood sample for PK 
0.5 
6 
3 
Total blood volume collected during the optional 40-week extension 
phase 
30 
Total blood volume collected during the initial 12 week treatment 
phase  
79 
Total blood volume collected during both the initial 12 week treatment 
phase and the optional 40-week extension phase (includes safety 
follow-up) 
109 
7.2.14.1 
Pharmacokinetic Blood Sampling 
Blood samples for PK testing are to be collected for the measurement of 
pharmacokinetic concentrations as stated in the Schedule of Activities (Table 1 and 
Table 2.). 
For PK serum collection, the permitted window for scheduled collection time points will 
be as follows: 
 
Pre-Dose samples on Day 1, Day 29, and Day 57 must be taken within  
1 hour prior to dosing 
 
± 3 days for Days 8, 15, 64, 71, and 85 (initial 12 week treatment phase) 
 
± 4 days for Days 85, 113, 169, 253, 365, and 449 (optional 40-week 
extension phase) 
7.2.14.2 
Clinical Laboratory Assessments 
The laboratory analytes listed in (Table 5) will be assessed at time points designated in 
Schedule of Activities (Table 1 and Table 2.). 


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Table 5.  List of Analytes 
Local Laboratory 
Chemistry 
Local Laboratory 
Hematology 
Local 
Laboratory 
Urinalysis 
Other 
Sodium 
Potassium 
Chloride 
Bicarbonate 
(CO2 or HCO3) 
Total protein 
Albumin 
Glucose 
Blood urea nitrogen 
Creatinine** 
Total creatine kinase 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
Alanine 
aminotransferase 
Aspartate 
aminotransferase 
Hemoglobin 
Hematocrit 
Mean corpuscular 
volume 
Platelets 
White blood cell 
Differential 
• 
Total neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Microscopic 
exam 
(performed at 
the 
discretion of the 
Investigator) 
Local Laboratory: 
• 
Serum Pregnancy* 
• 
Urine Pregnancy* 
• 
Urine Drug 
• 
Breath Alcohol 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis B total core 
antibody 
• 
Hepatitis C antibody 
 
Central Laboratory: 
• 
Pharmacokinetics 
• 
Pharmacogenetics 
       (optional) 
 
* Serum and urine pregnancy testing only for female subjects of reproductive potential 
** Estimated creatinine clearance derived from serum creatinine, age, weight and gender of subject. 
Additional procedures deemed necessary as part of standard of care or as required by 
local laws and regulations may be performed at the Investigator’s discretion. 
7.2.15 
Screening and Enrollment  
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Activities (Table 1 and Table 2.). 
 
Confirmation that the Informed Consent Form and Assent form have been signed  
 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
explore their possible association with subject safety and treatment effectiveness.  
Additionally demographic data will be used to study the impact pharmacokinetics of 
the protocol-required therapies 
 
Physical Examination as per standard of care  
 
Neurological Examination 
 
Medical and Surgical History 
 
Single 12-Lead ECG 
 
Height and Weight 
 
Vital signs (eg, blood pressure, heart rate temperature) 


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 
Laboratory Assessments: 
 
Chemistry Panel 
 
Hematology Panel 
 
Urinalysis 
 
Estimated Creatinine Clearance 
 
Serum Pregnancy Test (female subjects of reproductive potential) 
 
Drug and Alcohol screen (adolescents only; at Investigator’s discretion for 
children) 
 
Hepatitis serology testing 
 
Serious Adverse Event reporting 
 
Documentation of concomitant and rescue medications 
 
Patient Health Questionnaire (PHQ-A) (adolescents only) 
Subjects who fail screening may be re-screened upon discussion with and approval by 
the Amgen Medical Monitor.  A new informed consent and assent form must be signed 
unless it has been < 21 days since the previous ICF and assent signature was obtained. 
7.2.16 
Initial 12 Week Treatment Phase Visits 
The following procedures will be completed during the 12 week treatment phase at the 
times designated in the Schedule of Activities (Table 1 and Table 2.).  All visits during 
this phase, except Day 1 are ± 3 days. 
 
Body weight pre-dose 
 
Neurological exam pre-dose 
 
Vital signs (eg, blood pressure, heart rate, temperature) pre-dose and 30 minutes 
post-dose; also 2 hours post-dose on Day 1 only. 
 
Physical examination pre-dose and 30 minutes post-dose.; also 2 hours post-dose 
on Day 1 only. 
 
Single 12-Lead ECG pre-dose and 2 hours post-dose on Day 1 only. 
 
Laboratory Assessments: 
 
Chemistry Panel 
 
Hematology Panel 
 
Urinalysis 
 
Urine Pregnancy Test (female subjects of reproductive potential) 
 
Drug and Alcohol Screen 


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 
Serious Adverse Event reporting 
 
Adverse Event reporting 
 
Modified PedMIDAS pre-dose 
 
Documentation of concomitant and headache rescue medications. 
 
Collect blood for biomarker development pre-dose 
 
Pharmacogenetics (optional) pre-dose 
 
AMG 334 serum PK collection pre-dose 
 
Study drug administration (dose will be based on pre-dose body weight collected on  
Day 1) 
 
Following the AMG 334 dose administration at Day 1, all subjects will be monitored 
at the facility for at least 2 hours post-dose, at which point they will be discharged 
with instructions to return to the research facility according to the procedures 
provided in the Schedule of Activities (Table 1 and Table 2.).  Following the 
AMG 334 dose administration on Days 29 and 57, all subjects will be monitored at 
the facility for at least 30 minutes post-dose.  The post dose safety monitoring will be 
extended to 2 hours if the subject showed any safety concerns post-dose during the 
last dosing visit. 
7.2.17 
Optional 40-Week Extension Phase 
The following procedures will be completed during the optional 40-week extension 
phase, for adolescents who choose to continue treatment, at the times designated in the 
Schedule of Activities (Table 1 and Table 2.).  All visits during this phase are ± 4 days of 
the scheduled time point.  Children 6 to < 12 years of age will not be offered the option 
to enter the optional 40-week extension phase. 
 
Confirmation that the Informed Consent Form Appendix A has been signed 
 
Body weight (pre-dose) 
 
Vital signs (eg, blood pressure, heart rate, temperature) (pre-dose)  
 
Physical examination (pre-dose) 
 
Laboratory Assessments: 
 
Chemistry Panel 
 
Hematology Panel 
 
Urinalysis 
 
Urine Pregnancy Test pre-dose (female subjects of reproductive potential) 
 
Serious Adverse Event reporting 
 
Adverse Event reporting 


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 
Adverse Device Effect reporting 
 
Documentation of concomitant and headache rescue medications 
 
AMG 334 serum PK Sample (pre-dose) 
7.2.18 
End of Study Visit 
All Subjects will be followed for 16 weeks after the last administration of AMG 334. 
The following procedures will be completed during the final visit (Study Day 169, early 
termination or Day 449, if subject continued in the optional 40-week extension phase). 
 
Physical Examination as per standard of care  
 
Single 12-Lead ECG 
 
Height and Weight Measurements 
 
Vital signs (eg, blood pressure, heart rate, temperature) 
 
Laboratory Assessments: 
 
Chemistry Panel 
 
Hematology Panel 
 
Urinalysis 
 
Urine Pregnancy Test (female subjects of reproductive potential) 
 
Drug and  Alcohol Screen 
 
AMG 334 serum PK Sample 
 
Serious Adverse Event reporting 
 
Adverse Event reporting 
 
Adverse Device Effect reporting   
 
Documentation of concomitant and rescue medications 


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7.4 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development can be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity.  Amgen may attempt 
to develop test(s) designed to identify subjects most likely to respond positively or 
negatively to AMG 334.  
Blood (plasma and serum) samples will be collected for biomarker development on 
Day 1 and at the EOS visit (Day 169 or Day 449 if completing the optional 40-week 
extension) or Early Termination.  Amgen may attempt to develop blood tests designed to 
identify subjects most likely to respond positively or negatively to AMG 334.  
Biomarker development may be pursued by use of advanced biochemical analyses such 
as proteomic methods.  Refer to the laboratory manual for detailed collection and 
handling procedures for all biomarker development samples. 


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7.5 
Pharmacogenetic Studies 
If the subject (or legally acceptable representative) consents to the optional 
pharmacogenetic portion of this study, DNA analyses may be performed.  These 
optional pharmacogenetic analyses focus on inherited genetic variations to evaluate 
their possible correlation to the disease and/or responsiveness to the therapies used in 
this study.  The goals of the optional studies include the use of genetic markers to help 
in the investigation of migraine and/or to identify subjects who may have positive or 
negative response to AMG 334.  No additional samples are collected for this part of the 
study.  For subjects who consent to this/these analysis/analyses, DNA may be extracted.  
7.6 
Sample Storage and Destruction 
Any blood or PK samples collected according to the Schedule of Activities (Table 1 and 
Table 2.) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject (or legally acceptable representative), 
Amgen can do additional testing on remaining samples (ie, residual and back-up) to 
investigate and better understand migraine prevention the dose response and/or 
prediction of response to AMG 334 and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetics or other exploratory studies are not 
placed in the subject’s medical record and are not to be made available to the subject, 
members of the family, the personal physician, or other third parties, except as specified 
in the informed consent. 
The subject (or legally acceptable representative) retains the right to request that the 
sample material be destroyed by contacting the investigator.  Following the request from 
the subject (or legally acceptable representative), the Investigator is to provide the 


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sponsor with the required study and subject number so that any remaining blood 
samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The Sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the Investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the Sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.   
See Section 11.4 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
Investigational Product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
Investigator is to discuss with the subject the appropriate processes for discontinuation 
from Investigational Product, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Activities  
(Table 1 and Table 2.) including different options of follow-up (eg, in person, by 
phone/mail, through family/friends, in correspondence/communication with other treating 
physicians, from the review of medical records) and collection of data, including 
endpoints, adverse events.  Subjects who have discontinued Investigational Product 
and/or protocol required therapies or procedures should not be automatically removed 
from the study.  Whenever safe and feasible it is imperative that subjects remain 
on-study to ensure safety surveillance and/or collection of outcome data.  The 
Investigator must document the level of follow-up that is agreed to by the subject.   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 


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will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The Investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Reasons for Removal From Treatment  
Reasons for removal from protocol-required Investigational Product(s) or procedural 
assessments include any of the following:  
 
subject request  
 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, protocol-specified 
criteria  
 
pregnancy 
 
death  
 
lost to follow-up  
 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
8.3 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The Investigator and/or Sponsor can decide to withdraw a subject(s) from Investigational 
Product, medical device(s), and/or other protocol required therapies, protocol 
procedures, or the study as a whole at any time prior to study completion.   
Subjects may be eligible for continued treatment with Amgen Investigational Product(s) 
and/or other protocol required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.  
8.4 
Reasons for Removal From Study 
 
Reasons for removal of a subject from the study are: 
 
decision by Sponsor  
 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 


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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The Investigator is responsible for ensuring that any adverse events observed by the 
Investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (eg, more than usual fluctuation of disease) during the study, or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
The Investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or a medical device. Adverse device effects include adverse events resulting 
from insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional 
misuse of the device. 
9.1.2 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria 
 
Results in death (fatal) 
 
life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 


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 
congenital anomaly/birth defect 
 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an Investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug induced liver injury 
(DILI) (see Appendix A for DILI reporting criteria), or events that necessitate an 
emergency room visit, outpatient surgery, or urgent intervention   
9.2 
Safety Event Reporting Procedures 
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The Investigator is responsible for ensuring that all adverse events observed by the 
Investigator or reported by the subject that occur after the first dose of investigational 
product through the end of the safety follow-up visit (16 weeks after the last dose of 
investigational product) or EOS, whichever occurs later, are reported using the Event 
eCRF. 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
 
Dates of onset and resolution (if resolved), 
 
Severity [and/or toxicity per protocol],  
 
Assessment of relatedness to AMG 334 and/or the Amgen medical device (pre-filled 
syringe) and/or other protocol-required therapies and/or study mandated 
procedure/activity], and  
 
Action taken  
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in 
Appendix A.   
Since the criteria the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 CTCAE toxicity 
grading scale criteria (eg, laboratory abnormality reported as grade 4 without 
manifestation of life-threatening status), it will be left to the investigator’s judgment 
to also report these abnormalities as serious adverse events.  For any adverse event 


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that applies to this situation, comprehensive documentation of the event’s 
severity must be recorded in the subject medical records. 
The Investigator must assess whether the adverse event is possibly related to the 
Investigational Product.  This relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by the 
investigational product and/or medical device (pre-filled syringe [PFS])?   
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, device(s) and/or procedure (including any screening procedure(s)).  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity 
(eg, administration of Investigational Product,  protocol-required therapies, device(s)), 
and/or procedure?” 
The Investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the Investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
Reporting Procedures for Serious Adverse Events 
The Investigator is responsible for ensuring that all serious adverse events observed by 
the Investigator or reported by the subject that occur after signing of the informed 
consent through the end of safety follow-up visit (16 weeks after the last dose of 
Investigational Product) or EOS, whichever occurs later, are recorded in the subject’s 
medical record and are submitted to Amgen.  All serious adverse events must be 
submitted to Amgen within 24 hours following the Investigator’s knowledge of the event 
via the Event eCRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 


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Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
Investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Form/electronic Serious Adverse Event Contingency Report Form (which 
is a paper-based form).  For EDC studies where the first notification of a Serious 
Adverse Event is reported to Amgen via the electronic Serious Adverse Event 
Contingency Report Form, the data must be entered into the EDC system when the 
system is again available. 
The Investigator must assess whether the serious adverse event is possibly related to 
the Investigational Product.  This relationship is indicated by a “yes” or “no” response to 
the question:  Is there a reasonable possibility that the event may have been caused by 
the Investigational Product and/or medical device (pre-filled syringe [PFS])?  
Relatedness means that there are facts or reasons to support a relationship between 
Investigational Product and the event.  
The Investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure?”  
The Investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Event 
CRF). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and institutional 
review boards (IRBs) / independent ethics committees (IECs) in compliance with all 
reporting requirements according to local regulations and good clinical practice.  


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The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), Investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
Investigator is to report them to Amgen within 24 hours following the Investigator’s 
knowledge of the event.  
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
If further safety-related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study. 
9.2.2.1 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to  introduce bias when detecting adverse events and/or 
serious adverse events.  Open-ended and non-leading verbal questioning of the 
subject is the preferred method to inquire about adverse event occurrence.   
9.2.2.2 
Adverse Device Effects: Recording, Evaluating, Reporting 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices (Amgen pre-filled syringe). 
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures.  The Investigator is responsible for ensuring that all 
adverse device efforts observed by the Investigator or reported by the subject that occur 
after first dose of Investigational Product through the end of the safety follow-up visit 
(16 weeks after the last dose of Investigational Product) or end of study, whichever 
occurs later, are reported using the Event CRF. 


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Any adverse event resulting from an adverse device effect that occur during the study 
will be documented in the subject’s medical records, in accordance with the 
Investigator’s normal clinical practice, and on the Event CRF page. 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident. 
Product complaints are described in Section 6.6_Product_Complaints. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking AMG 334, report the pregnancy to Amgen Global Patient Safety as 
specified below. 
In addition to reporting any pregnancies occurring during the study, Investigators should 
report pregnancies that occur through 16 weeks after the last dose of AMG 334.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of the pregnancy.  Report a pregnancy on the Pregnancy 
Notification Form (Appendix C).  Amgen Global Patient Safety will follow-up with the 
Investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the Investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
Investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below. 
In addition to reporting a lactation case during the study, Investigators should report 
lactation cases that occur through 16 weeks after the last dose of protocol-required 
therapies.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the Investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Form (Appendix C).  Amgen Global Patient Safety will follow-up with the 
investigator regarding additional information that may be requested. 


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If a male subject's female partner becomes pregnant, the Investigator should discuss 
information regarding the birth outcome and health of the infant from the pregnant 
partner. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
Primary Endpoints:   
 
Serum PK parameters of AMG 334 (eg, time to maximum concentration [tmax]), 
maximum observed concentration [Cmax], trough concentration (Ctrough), and area 
under the concentration time curve (AUC) from 0 to 28 days (AUC0-28day) 
 
Treatment-emergent adverse events (AEs) 
 
Changes in vital signs, 12-lead electrocardiograms (ECGs), clinical laboratory safety 
tests, and neurological assessments 


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Exploratory Endpoints:  
10.1.2 
Analysis Sets 
The safety analysis set will consist of all randomized subjects who receive at least one 
dose of Investigational Product. 
10.1.3 
Covariates and Subgroups 
No subgroup analyses are planned. 
10.1.4 
Handling of Missing and Incomplete Data  
Data will be analyzed as is; no imputation of missing data is planned. 
10.2 
Sample Size Considerations 
The study population will consist of 2 cohorts based on body weight enrolling a total of at 
least 52 subjects up to approximately 60 subjects in the study.  Cohort 1 will enroll at 
least 12 subjects and up to approximately 22 subjects with body weight of < 40 kg at 
baseline.  It is anticipated that most subjects in this cohort will be 6 to < 12 years of age.  
Cohort 2 will enroll at least 35 subjects and up to approximately 38 subjects with a body 
weight of ≥ 40 kg at baseline.  It is anticipated that most subjects in this cohort will be  
12 to < 18 years of age.   
Subjects weighing < 40 kg (Cohort 1) will receive a dose of 35 mg or 70 mg for a total of 
at least 12 and up to approximately 15 subjects completing Week 12 assessments. 
Subjects weighing ≥ 40 kg (Cohort 2) will receive a dose of 70 mg or 140 mg for a total 
of at least 26 and up to approximately 30 subjects completing Week 12 assessments.  
The rate of early discontinuation up to Week 12 assessments is assumed to be 20% and 
similar across the two cohorts. 
All subjects in this study will be administered AMG 334.  The sample size for this study is 
based on clinical and practical considerations to adequately fulfil its objectives and to 
inform on planned phase 3 pediatric studies.  Assuming clearance (CL) and central 
volume of distribution (Vc) on mg/kg basis is similar between pediatric subjects and 
adults, and assuming %CV for CL and Vc are 43% and 53%, respectively, (based on 
total between-subject-variability from adult population PK), the proposed sample size 
provides > 80% power to estimate 95% CI of CL and Vc within 60-140% of the true 


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parameters for both weight cohorts combined and across the two age categories  
(Wang Y et al, 2012).  
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
There are 2 interim analyses of PK and safety planned for this study.  The first interim 
analysis will occur when at least 6 adolescents (12 to < 18 years of age) have completed 
study Week 8 assessments.  The second interim analysis will occur when at least 8 
children (6 to < 12 years of age) have completed study Week 12 assessments.  For both 
interim analyses, all available data will be cleaned and a database snapshot will 
occur.  PK data, AEs, vital sign data, and laboratory data will be summarized.  The 
purpose of the first and second interim analysis is to inform the selection of AMG 334 
doses to be evaluated in the Phase 3 pediatric AMG 334 studies.  Results from the 
interim analyses will be presented to the independent Data Monitoring Committee (DMC) 
responsible for reviewing and making recommendations regarding the Phase 3 pediatric 
AMG 334 studies.  The DMC will not review individual patient level data from this study 
or make recommendations regarding this study. 
10.3.2 
Primary Analysis 
The primary analysis of the safety and PK data will occur after all subjects in both body 
weight cohorts have completed the initial 12 week treatment phase.  All available data 
up to and including the data cutoff date will be cleaned and a database snapshot will 
occur.  No formal hypothesis testing will be performed; all analyses will be descriptive.  
The review of the results of this primary analysis will inform on further pediatric studies 
utilizing AMG 334.   
10.3.3 
Final Safety Analysis  
The final safety analysis for the study will be performed at the end of the trial.  All data 
will be cleaned and a database lock will occur.  No formal hypothesis testing will be 
performed; all analyses will be descriptive.  Safety data will include summaries by body 
weight and AMG 334 treatment dosage group.  Final Safety Analysis activities are 
commenced based on achieving the End of Trial milestone described in Section 3.5.2. 
10.4 
Planned Methods of Analysis 
10.4.1 
General Considerations 
No formal hypothesis testing will be performed.  Descriptive statistics will be provided for 
selected demographic, safety, and PK data for the safety analysis set.  Descriptive 
statistics on continuous measurements will include means, medians, standard 


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deviations, first quartile (Q1), third quartile (Q3), minimum, and maximum, while 
categorical data will be summarized using frequency counts and percentages. 
10.4.2 
Primary Endpoints 
10.4.2.1 
Pharmacokinetic Endpoints 
Serum AMG 334 concentrations will be determined using a validated assay.  Individual 
serum concentration-time plots for AMG 334 will be presented for each subject as well 
as mean concentration-time plots for each dose.  PK parameters will be estimated using 
either compartmental (eg PK modelling) or non-compartmental methods.  Actual dosing 
and sampling times will be used for calculation of PK parameters. Summary statistics will 
be generated for each PK parameter (eg, time to maximum concentration [tmax]), 
maximum observed concentration [Cmax], trough concentration (Ctrough), area under the 
concentration time curve (AUC) from 0 to 28 days (AUC0-28day).  
10.4.2.2 
Treatment-Emergent Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term according to the medical dictionary for regulatory 
activities (MedDRA) terminology.  Tables of fatal adverse events, serious adverse 
events, adverse events leading to withdrawal from IP or other protocol-required 
therapies, and significant treatment emergent adverse events will also be provided.  
Adverse events resulting in treatment discontinuation will be identified. 
10.4.2.3 
Safety Endpoints 
10.4.2.3.1 
Vital Signs 
Vital signs will be reviewed for each subject.  Summaries of heart rate and blood 
pressure data over time and change from baseline will be provided.  Depending on the 
extent and scope of change in other vital signs, summaries of other vital signs may be 
provided. 
10.4.2.3.2 
Electrocardiograms 
ECG data will be reviewed for each subject as per the standard of care for routine safety 
monitoring. 
10.4.2.3.3 
Clinical Laboratory Tests 
Hematology, chemistry and urinalysis data will be reviewed for each subject.  Depending 
on the size and scope of changes in laboratory data, summaries of laboratory data over 
time and/or changes from baseline over time may be provided. 


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10.4.2.3.4 
Neurological Assessments 
Neurological assessment data will be reviewed for each subject. 
10.5 
Exploratory Endpoint 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Study Manager to the Investigator.  
The written informed consent form is to be prepared in the language(s) of the potential 
subject population. 
Before a subject’s participation in the clinical study, the Investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol specific screening procedures or any 
Investigational Product(s) is/ are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
The investigator is also responsible for asking the subject (or legally acceptable 
representative) if the subject has a primary care physician and if the subject agrees to 
have his/her primary care physician informed of the subject’s participation in the clinical 
study.  If the subject agrees to such notification, the investigator is to inform the subject’s 
primary care physician of the subject’s participation in the clinical study.  If the subject 
does not have a primary care physician and the investigator will be acting in that 
capacity, the investigator is to document such in the subject’s medical record.   
The acquisition of informed consent is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 


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informed consent discussion.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
In this study, obtaining assent from the child and consent from the parents or legally 
authorized representative, except if the child is very young, as defined by local law.  A 
child is defined as a person who has not attained the legal age for consent for 
treatments or procedures involved in clinical investigations, under the applicable law of 
the jurisdiction in which the clinical investigation will take place.  The local IRB/IEC will 
determine the process for obtaining and documenting the assent process for pediatric 
subject, but should follow the guidelines established by the Department of Health and 
Human Services Office of Human Research Protections guidelines, which state an 
explanation of the procedures involved in the study should be made in a language 
appropriate to the child’s age, experience, maturity, and condition. 
11.2 
Institutional Review Board/Independent Ethic Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen Investigational Product. 
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The Investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The Investigator is responsible for obtaining annual IRB/IEC approval throughout the 
duration of the study.  Copies of the Investigator’s reports and the IRB/IEC continuance 
of approval must be sent to Amgen. 


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11.3 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained:   
 
Subjects are to be identified by a unique subject identification number   
 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations   
 
On the demographics page, in addition to the unique subject identification number, 
include the age at the time of enrollment   
 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations) 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in strict confidence by the investigator, except as described below 
In compliance with governmental/ICH GCP Guidelines, it is required that the Investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records 
for verification of study related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The Investigator is obligated to inform and obtain the consent of 
the subject to permit named such individuals to have access to his/her study related 
records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the Investigator or, in the case of 
multi-center studies, the coordinating Investigator. 
The coordinating Investigator, identified by Amgen, will be any or all of the following: 
a recognized expert in the therapeutic area an Investigator who provided significant 
contributions to either the design or interpretation of the study an Investigator 
contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The Investigator must send a copy of 


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the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen. 
Subjects may be eligible for continued treatment with Amgen Investigational Product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen Investigational Product(s), and by what mechanism, after 
termination of the study and before it is available commercially. 
12.2 
Study Documentation and Archive 
The Investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
 
Subject files containing completed informed consent forms, and subject identification 
list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 


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Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study related records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function  
(or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 
storage areas, laboratories) and review of study related records will occur to evaluate 
the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the electronic eCRFs must be 
maintained and readily available 
 
Updates to electronic eCRFs will be automatically documented through the 
software’s “audit trail” 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer 
 
The Investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that the Investigator inspected or reviewed 
the data on the eCRF, the data queries, and agrees with the content 
12.4 
Investigator Responsibilities for Data Collection 
The Investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 


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stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Activities (Table 1 and Table 2.), the Investigator can search publically 
available records [where permitted]) to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other Investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for Investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 


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Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals, which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved.  Authors should meet conditions 1, 
2, and 3 and 4 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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13. 
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Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of telcagepant 
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Damen L, Bruijn J, Verhagen AP, et al.  Prophylactic treatment of migraine in children.  
Part 2.  A systematic review of pharmacological trials.  Cephalalgia. 2006; 26:497-505. 
DiamondMcDowell, M. A., et al. (2008). "Anthropometric reference data for children and 
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antibody to calcitonin gene-related peptide, for the prevention of frequent episodic 
migraine: A randomised, double-blind, placebo-controlled, exploratory phase 2 trial. 
Lancet Neurol. 2014a;13:1100-1107. 
Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP, Grayzel DS. Safety 
and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for 
the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled 
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Eidlitz-Markus T, Haimi-Cohen, Y, Steier D, Zeharia A.  Effectiveness of 
Nonpharmacologic Treatment for Migraine in Young Children.  Headache.  2010;50:219 
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Evers S.  The efficacy of triptans in childhood and adolescence migraine.  Curr Pain 
Headache Rep.  2013;17:342. 
Francis MV.  Brief migraine episodes in children and adolescents – a modification to 
International Headache Society pediatric migraine (without aura) diagnostic criteria. 
SpringerPlus.  2013;2:77. 
Gallai V, Sarchielli P, Floridi A, et al. Vasoactive peptide levels in the plasma of young 
migraine patients with and without aura assessed both interictally and ictally. 
Cephalalgia. 1995;15:384-390. 
Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the 
extracerebral circulation of humans and the cat during activation of the trigeminovascular 
system. Ann Neurol. 1988;23:193-196. 
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral 
circulation of humans during migraine headache. Ann Neurol. 1990;28:183-187. 
Gunner KB, Smith HD, Ferguson LE.  Practice guideline for diagnosis and management 
of migraine headaches in children and adolescents:  part two.  J Pediatr Health Care.  
2008;22:52-59. 


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Hewitt D, Aurora S, Dodick D, et al. Efficacy and tolerability of the CGRP receptor 
antagonist MK-3207 for the acute treatment of migraine: a single attack randomized 
double-blind placebo-controlled adaptive dose ranging trial [abstract]. 14th Congress of 
the International Headache Society. 2009;LBOR3. 
Ho TW, Connor, KM, Zhang, Y, et al. Randomized controlled trial of the CGRP receptor 
antagonist telcagepant for migraine prevention. Neurol. 2014;83:958-966. 
Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK-0974 (telcagepant), 
a new oral antagonist of calcitonin gene-related peptide receptor, compared with 
zolmitriptan for acute migraine: A randomised, placebo-controlled, parallel-treatment 
trial. Lancet. 2008a;372:2115-2123. 
Ho TW, Mannix LK, Fan X, et al. MK-0974 Protocol 004 study group: Randomized 
controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of 
migraine. Neurology. 2008b;70(16):1304-1312. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013. http://www.icmje.org 
International Headache Society (IHS) Classification Committee.  The International 
Classification of Headache Disorders, 3rd edition (beta version). 
Cephalalgia.  2013;33:629–808. 
Jacobs H, Gladstein J.  Pediatric headache:  a clinical review.  Headache. 
2012;52:333-339.  
Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes 
parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and 
migraine headache during nitroglycerin induced migraine attack. Cephalalgia. 
2005;25(3):179-183. 
 
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may 
play a causative role in migraine. Cephalalgia. 2002;22:54-61. 
National Health and Nutrition Examination Survey, (NHANES).  2009-2010.  National 
Center for Health Statistics Hyattsville, MD 20782 
Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor 
antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 
2004;350:1104-1110. 
Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J. BIBN4096BS antagonizes human 
alpha-calcitonin gene related peptide-induced headache and extracerebral artery 
dilatation. Clin Pharmacol Ther. 2005 Mar;77:202-213. 


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Robbins, M. S. and R. B. Lipton (2010). "The epidemiology of primary headache 
disorders." Semin Neurol 30(2): 107-119. 
Sarchielli P, Pini LA, Zanchin G, et al. Clinical-biochemical correlates of migraine attacks 
in rizatriptan responders and non-responders. Cephalalgia. 2006;3:257-265.  
Stovner LJ, Andree C.  Prevalence of headache in Europe:  a review for the Eurolight 
project.  J Headache Pain.  2010;11:289-299. 
Tajti J, Uddman R, Möller S, Sundler F, Edvinsson L. Messenger molecules and 
receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst. 1999;76:176-183. 
Wang Y, Jadhav PR, Lala M, Gobburu JV.  Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies.  J Clin Pharmacol. 
2012;52(10):1601-6.  


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events Version 4 (CTCAE v4.03)  is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronicapplications/ctc.htm. 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.3 require 
the following: 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations have 
been concluded) 
The appropriate eCRF (eg, Event eCRF) that captures information necessary to facilitate 
the evaluation of treatment-emergent liver abnormalities is to be completed and sent to 
the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom Investigational Product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Section 6.3.1 or who experience AST or ALT elevations > 3 x ULN or 2-fold increase 
above baseline values for subjects with evaluated values before drug are to undergo a 
period of “close observation” until abnormalities return to normal or to the subject’s 
baseline levels.  Assessments that are to be performed during this period include:  
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), and 
INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the Investigational Product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 


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Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count (CBC) with differential to assess for eosinophilia 
 
Serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
CPK, haptoglobin, LDH, and peripheral blood smear 
 
Appropriate liver imaging if clinically indicated 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
Hepatology consult (liver biopsy may be considered in consultation with an hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all Investigational Product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding eCRFs. 
 
 


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Appendix B.  Sample electronic Serious Adverse Event Contingency Report Form 
 
 
 


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Appendix C.  Pregnancy and Lactation Notification Forms 
Pregnancy Notification Form  
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email 
(worldwide): svc-ags-in-us@amgen.com 
 
 
FORM-115199                    Version 1.0                                                                         Effective Date: 24-Sept-2018 
 
 
 
Lactation Notification Form 
Amgen Proprietary  Confidential 
1. Case Administrative Information 
Protocol/Study Number:  Erenumab (AMG 334) - 20160172 
 
 
Study Design:  Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2. Contact Information 
Investigator Name   
_ 
Site #   
 
 
Phone (  
)  
_ 
Fax (_     _)  
 
 
Email   
 
Institution   
 
Address    
 
 
3.  Subject Information 
Subject ID #   
_ 
Subject Gender: 
Female 
Male 
Subject age (at onset):       (in years) 
 
4.  Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
conception 
Frequency 
Route 
 
Start Date 
                 
AMG 334 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
 
5.  Pregnancy Information 
Pregnant female’s last menstrual period (LMP) 
mm   
/ dd______/ yyyy  
  
Unknown 
N/A 
 Estimated date of delivery   mm  
/ dd  
_/ yyyy  
 
If N/A, date of termination (actual or planned) mm   
 
/ dd   _/ yyyy  
 
 
Has the pregnant female already delivered? 
Yes 
No  
Unknown 
N/A 
If yes, provide date of delivery:  mm    
 
/ dd   
 
/ yyyy  
 
Was the infant healthy? 
Yes 
No 
Unknown 
N/A 
If any Adverse Event was experienced by the infant, provide brief details:  
 
 
 
 
 
 
Form Completed by: 
 
Print Name:    
 
 
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 


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g
y
 
Report to Amgen at: USTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com 
1. Case Administrative Information 
Protocol/Study Number: Erenumab (AMG 334) - 20160172  
 
 
Study Design:  Interventional 
Observational (If Observational: 
Prospective 
Retrospective) 
 
2.  Contact Information 
Investigator Name   
 
 
 
Site #   
 
 
Phone (  
)  
 
 
Fax (  
)  
 
 
Email   
 
Institution   
 
Address    
 
 
 3.  Subject Information 
Subject ID #   
 
 
 
 
 
Subject age (at onset):       (in years)
 
4.  Amgen Product Exposure 
 
Amgen Product 
Dose at time of 
breast feeding 
Frequency 
Route 
Start Date 
 
AMG 334 
mm  
/dd  
/yyyy  
 
 
Was the Amgen product (or study drug) discontinued? 
Yes 
No 
If yes, provide product (or study drug) stop date: mm    
/dd   
/yyyy  
 
Did the subject withdraw from the study? 
Yes 
No 
 
5.  Breast Feeding Information 
 
Did the mother breastfeed or provide the infant with pumped breast milk while actively taking an Amgen product? 
Yes 
No 
 
If No, provide stop date:  mm   
 /dd   
/yyyy  
 
Infant date of birth: mm  
/dd  
/yyyy  
  
Infant gender: 
Female 
Male 
 
Is the infant healthy? 
Yes 
No 
Unknown 
N/A 
 
 
If any Adverse Event was experienced by the mother or the infant, provide brief details:  
 
 
 
 
 
 
 
  Form Completed by: 
 
Print Name:    
 
 
 
Title:    
 
 
Signature:    
 
 
Date:    
 
 


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Appendix E.  Sample PHQ-A 
 


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Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 5 
Protocol Title:  A Phase I, Randomized, Open-label, Multiple-dose Study to Evaluate 
Safety, Tolerability, and Pharmacokinetics of AMG 334 in Children and Adolescents With 
Migraine 
Amgen Protocol Number: AMG 334 20160172 
NCT Number: NCT03499119 
IND Number BB-IND 116098 
 
Amendment Date: 
03 November 2021 
 
Rationale: 
The rationale of the amendment is to reflect the changes to the phase 1 trial agreed upon with 
the European Medicines Agency (EMA) in the pediatric investigation plan (PIP) modification.  
The modification of the PIP includes the following changes:  
 
Number of study participants of at least 52 subjects enrolled.   
 
At least 12 pediatric patients with body weight of less than 40 kg, from which:   
o At least 9 patients must be aged 6 to less than 12 years old  
o  At least 2 patients must be aged 6 to less than 10 years old 
 
In the statistical plan, the second interim analysis must occur when 8 or more children 
aged 6 to less than 12 years have completed week 12 assessments and must include all 
data collected for all subjects during the first 12 weeks of study. 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  26 March 2020 
Page 1 of 16 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Phase I, Randomized, Open-label, Multiple-dose Study to 
Evaluate Safety, Tolerability, and Pharmacokinetics of AMG 334 in Children and 
Adolescents With Migraine 
 
Amgen Protocol Number AMG 334 20160172 
IND number BB-IND 116098 
 
Amendment Date: 
26 March 2020 
 
Rationale: 
The protocol is being amended to:  
• 
Increase number of sites  
• 
Introduce enrolment caps for Cohort 1 age strata with stipulation of a maximum 
number of subjects to be enrolled under the adolescent and children between the 
ages of 10 - < 12yo (in line with PSP/PIP agreements) 
• 
Reduce enrolment barriers by redacting unnecessary eligibility requirements and 
reducing subject-level burden through optimization of in-clinic visits and blood 
sample collection  
Other changes include: 
• 
Modify protocol indication to migraine prevention throughout the protocol 
• 
Add clarity to protocol sections including:  Protocol Synopsis, Study Design, 
Experimental Plan 
• 
Update information in Background and Rationale 
• 
Update administrative, typographical and formatting throughout the protocol.  
Updates aligned with the current template. 
 
Approved 
 
 


Product:  AMG 334 
Protocol Number:  20160172
Date:  18 April 2019
Page 1 of 21
Confidential
Amendment 3
Protocol Title:  A Phase I, Randomized, Open-label, Multiple-dose Study to 
Evaluate Safety, Tolerability, and Pharmacokinetics of AMG 334 in Children and 
Adolescents with Migraine
Amgen Protocol Number AMG 334 20160172
IND number BB-IND 116098
Amendment Date:
18 April 2019
Rationale:

The purpose of this amendment is to allow the enrollment of children 6 to
< 12 years of age and to clarify that children 6 to < 12 years of age at the time of 
screening will only participate in the initial 12-week treatment phase, based on 
the totality of feedback received from both the FDA and EMA/PDCO. 
Adolescents 12 to < 18 years of age at time of screening will participate in the 
initial treatment phase for a total of 12 weeks of treatment after which they will 
have the option of continuing treatment in an optional 40 week extension phase, 
for a total of 52 weeks of treatment. A safety follow up visit will take place 
16 weeks after the last dose to complete EOS assessments either (i) after 
completion of the initial 12 week treatment phase, (ii) after completion of the 
optional 40 week extension phase for those adolescents who choose to continue 
treatment or (iii) after the last dose received before discontinuation of treatment 
during the study.

Study Schema footnote updates to clarify subject age groups and participation

Exclusion criterion 226 was updated to clarify that subjects testing positive for 
illicit drugs are excluded.

Exclusion criterion 227 was updated to maintain consistency with exclusion 
criterion 226.

Protocol Synopsis – Statistical Consideration was updated to clarify how data will 
be summarized and the purpose of the interim analyses.

Section 6.7 was updated to allow vaccinations after Day 85 assessments to allow 
flexibility for subjects needing vaccinations.

Page 2 of the Schedule of Assessments and Section 7.2.18 were updated to 
correct the timing of the neurological exam at Day 365 instead of on Day 449.

Section 7.2.5 Physical Examination was updated to allow the investigator to 
designate a qualified staff member to perform the physical examination.

Section 10.3.1 was updated to provide more details regarding the interim 
analysis.
Approved 
 
 


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Protocol Number:  20160172
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Page 2 of 21
Confidential

Updated Amgen contact information
Approved 
 
 


Product:  AMG 334  
Protocol Number:  20160172 
Date:  20 June 2018 
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CONFIDENTIAL
Amendment 2 
Protocol Title:  A Phase I, Randomized, Open-label, Multiple-dose Study to 
Evaluate Safety, Tolerability, and Pharmacokinetics of AMG 334 in Children and 
Adolescents with Migraine 
Amgen Protocol Number AMG 334 20160172 
IND number BB-IND 116098 
Amendment Date: 
20 June 2018 
Rationale: 
The purpose of this amendment is to implement the change requested by the FDA, 
which restricts enrollment of children ages 6 to <12 years old until the data from an 
ongoing juvenile toxicology study in cynomolgus monkeys become available.  
Inclusion criterion 104 was changed from requiring the diagnosis of migraine to a history 
of migraine to be consistent with how migraine is documented in clinic medical records. 
Exclusion criteria 217 was updated to clarify the Hepatitis B Core Antibody is also 
required.   
References to urine alcohol screening were removed to provide clarity throughout the 
protocol that only breath alcohol screening will be performed. 
Minor editorial changes have been made to improve overall clarity and consistency of 
the protocol language.  
Approved 
 
 


Product:  AMG 334 
Protocol Number:  20160172 
Date:  05 December 2017 
Page 1 of 49 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase I, Randomized, Open-label, Multiple-dose Study to 
Evaluate Safety, Tolerability, and Pharmacokinetics of AMG 334 in Children and 
Adolescents with Migraine 
 
 
Amgen Protocol Number AMG 334 20160172 
IND number BB-IND 116098  
 
Amendment Date: 
05 December 2017 
Rationale: 
The purpose of this amendment is to implement the change requested by the FDA, 
which is the inclusion of an additional low dose level to the study. In the original protocol 
a single dose was proposed for each body-weight cohort: 70 mg for the < 40 kg cohort 
and 140 mg for the ≥ 40 kg cohort.  In this amendment each body weight cohort will 
include 2 doses: subjects in cohort 1 (< 40 kg) will be randomized to either 35 mg or 
70 mg of AMG 334; subjects in cohort 2 (≥ 40 kg) will be randomized to either 70 mg or 
140 mg of AMG 334.  Due to this change, the overall number of subjects has been 
increased.  Cohort 1 will enroll at least 18 subjects and up to approximately 22 subjects 
with body weight of < 40 kg.  At least 15 subjects in cohort 1 will be aged 6 to < 12 years 
and at least 4 subjects will be aged 6 to < 10 years old.  Cohort 2 will enroll at least 
35 subjects and up to approximately 38 subjects with a body weight of ≥ 40 kg.  
Considering that body weight is the most important PK covariate, for consistency and 
clarity the 2 cohorts in the study are now categorized by body weight bands instead of 
age. 
Safety labs originally required at Day 28 and Day 56 visits were moved 1 day (ie, to Day 
29 and Day 58 visits respectively) in order to reduce the study burden for patients and 
parents while still collecting the necessary safety data.  Day 28 and Day 56 visits, which 
only included the above mentioned safety labs, have therefore been removed. 
The post dose observation period has been changed from 2 hours on Day 1, Day 29 and 
Day 57 visits to Day 1 visit only.  This change is also intended to reduce the study 
burden for patients and parents while keeping consistency with available AMG 334 
safety data in adults and with the pediatric phase 3 study protocols.  
Approved 
 
 


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Page 2 of 49 
CONFIDENTIAL 
 
 
Selection criteria have been modified to provide clarity on the concomitant medications 
allowed and excluded from the study.  The study population has not been changed.  
The 
 exploratory endpoint language has been modified to improve 
clarity.  The exploratory endpoint is: 
 
 
Minor editorial changes have been done to improve overall clarity and consistency of the 
protocol language.  
Approved 
 
 

SAP_001.pdf: 
Product:  AMG 334  
Protocol Number:  20160172 
Date:  17 March 2022 
Page 1 of 35 
CONFIDENTIAL 
 
 
Internal Use Only General Business 
Statistical Analysis Plan 
Protocol Title: 
A Phase I, Randomized, Open-label, Multiple-dose 
Study to Evaluate Safety, Tolerability, and 
Pharmacokinetics of AMG 334 in Children and 
Adolescents With Migraine 
Short Protocol Title: 
Phase I Safety and Pharmacokinetics Study of 
AMG 334 in Pediatric Subjects With Migraine 
Protocol Number: 
20160172 
NCT Number: 
NCT03499119 
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive,  
Thousand Oaks, CA, 91320, USA 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
Amendment 1 (v2.0) 
Amendment 2 (v3.0) 
Amendment 3 (v4.0) 
Amendment 4 (v5.0) 
Amendment 5 (v6.0) 
11 September 2017 
27 March 2018 
24 August 2018 
26 June 2019 
12 May 2021 
17 March 2022 
 
 


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Page 2 of 35 
CONFIDENTIAL 
 
 
Internal Use Only General Business 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
11SEP2017 
Original version 
Amendment 1 (v2.0) 
27MAR2018 
 
SAP Amendment 1 was triggered due 
to Protocol Amendment 1 dated 
05 December 2017. 
 
Editorial changes were made 
throughout the document to improve 
overall clarity. 
 
Section 3.1 updated to clarify the 
enrollment of subjects, number of 
subjects expected in each age group 
and cohort, and study schema. 
 
Section 3.2 updated to increase the 
sample size from 45 to 60 and added 
sample size calculation assumption 
and reference. 
 
Section 4.2 updated to specify body 
weight cohort as a sub-group analysis. 
 
Section 6.6 updated to clarify scope of 
data to be included for the two interim 
analyses. 
 
Section 7.1 updated to clarify that the 
second interim analysis will occur, to 
clarify the criteria of second interim 
analysis and scope of data to be 
included for second interim analysis. 
 
Section 7.2 and 7.3 updated to clarify 
the scope of data to be included for 
primary and final analysis and to 
mention that PK and safety data will 
be summarized by cohort and 
AMG 334 treatment group. 
 
Section 9.1 updated to clarify that 
summary results will be presented by 
body weight cohort and treatment 
group. 
 
Section 9.4 updated to remove Patient 
Health Questionnaire (PHQ-9) total 
score. 
 
Table 9-1 updated to clarify that 
summary results will be presented by 
body weight cohort and treatment 
group. 
 
Section 9.6.2 updated to remove 
adverse events of interest (EOI) and 
to update CTCAE version to 4.03. 
 
Section 9.6.3 updated to clarify that 
summary results will be presented by 
body weight cohort and treatment 


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Protocol Number:  20160172 
Date:  17 March 2022 
Page 3 of 35 
CONFIDENTIAL 
 
 
Internal Use Only General Business 
group and to clarify that shift tables 
and summary statistics will be 
presented for all laboratory 
parameters. 
 
Section 9.6.4 updated to remove 
respiratory rate from vital signs 
analysis. 
 
Section 9.7.1 updated to clarify that 
clearance and central volume of 
distribution on body weight basis may 
be summarized. 
 
Section 10 updated to clarify the 
change from protocol regarding the 
second interim analysis occurring 
irrespective of the timing of primary 
analysis. 
 
Added reference in section 11. 
Amendment 2 (v3.0) 
24AUG2018 
 
SAP Amendment 2 was triggered due 
to Protocol Amendment 2 dated 20 
June 2018. 
 
Editorial changes were made 
throughout the document to fix typos 
and improve overall clarity. “Cohort” is 
clarified as “body weight cohort” 
throughout the document. 
 
Section 3.1 updated to mention that 
the enrollment will be staggered by 
age categories with adolescents (12 to 
 18 years of age) starting enrollment 
first. Children  
(6 to  12 years of age) will be 
enrolled once data from on ongoing 
juvenile toxicology study in 
cynomolgus monkeys became 
available and are considered 
supportive of dosing in this younger 
subgroup of subjects. Study schema 
is also updated. 
 
Section 7.1 updated to clarify the 
scope of data to be summarized by 
GBS and CPMS group, status of 
database at the time of interim 
analyses and impact of data change 
during any analysis. 


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Protocol Number:  20160172 
Date:  17 March 2022 
Page 4 of 35 
CONFIDENTIAL 
 
 
Internal Use Only General Business 
 
Section 7.2 updated to clarify the 
status of database at the time of 
primary analysis. 
Amendment 3 (v4.0) 
26JUN2019 
 
SAP Amendment 3 was triggered due 
to Protocol Amendment 3 dated  
18 April 2019. 
 
Editorial changes were made 
throughout the document to improve 
overall clarity. 
 
Included previous SAP version 
numbers and date on front page. 
 
Included summary of changes from 
previous SAP versions.   
 
Updated list of sections/ sub-sections/ 
appendices (including removal of 
sections/ sub-sections/ appendices 
which were not applicable in this 
study).  
 
List of abbreviations updated to 
include all abbreviations used in this 
document and to remove 
abbreviations no longer in use in this 
document. 
 
Section 3.1 updated to clarify that 
children enrollment can begin and 
only adolescents will be given the 
option to continue in an optional 40-
week extension phase. Study schema 
is also updated along with the timing 
of safety assessment follow-up visit. 
 
Updated section 5 to improve the 
treatment-emergent adverse event 
and treatment-emergent serious 
adverse event definition to make it 
align with latest standard. 
 
Section 7.1 updated to align the 
purpose of second interim analysis 
with the first one. The role and scope 
of the DMC in the AMG 334 pediatric 
program has also been included for 
consistency with the phase 3 study 
protocols. 
 
Section 8.3 updated to remove 
imputation rule for partial or missing 
stop dates. 
 
Section 9.6.2 updated to mention the 
latest MedDRA version as 22.0. 


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 
Section 10 updated to align with latest 
protocol version (amendment 3 dated  
18 April 2019). 
Amendment 4 (v5.0) 
12MAY2021 
 
SAP Amendment 4 was mainly 
triggered due to Protocol Amendment 
4 dated 26 March 2020. Addition of an 
unplanned interim analysis in the SAP 
Amendment, as described in section 
7.1, is a deviation from the protocol 
amendment 4.  
 
Administrative updates reflecting 
protocol amendment 4 were made 
throughout the document. 
 
Editorial and typographical changes 
were made throughout the document 
to improve overall clarity. 
 
Section 3.1 is updated to align with 
the changes made in recent protocol 
amendment and to specify: 
o that age of subjects must be at 
consent (instead of screening).  
Note:  This update is made 
throughout the document for 
consistency. 
o that concomitant use of up to 2 
treatments for migraine prevention 
and acute treatment of migraine 
are permitted. 
o the randomization allocation ratio 
in the two body weight cohorts 
(refer to 6th paragraph of section 
3.1). 
 
Study Design and Treatment Schema 
is also updated, in Section 3.1, to align 
with above changes.  
 
Section 3.2 is updated to replace 
“weight bands” with “weight cohorts”. 
 
Section 4.2 is updated to remove the 
general description of analysis by 
body weight cohort. 
 
Section 5 is updated to add new sub-
sections to include more definitions 
and to update some old definitions. 
 
Section 6.1 is added to define Full 
Analysis Set. 
 
Section 6.2 is updated to clarify the 
scope of safety analysis set definition. 
 
Section 6.4 is updated to clarify that 
requirement for first interim analysis is 
to include “at least 6 adolescents (12 


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to  18 years of age)” instead of “at 
least 6 subjects”. 
 
Section 6.5 is added to define 
Extension Analysis Set. 
 
Section 7.1 is updated to include an 
unplanned interim analysis which will 
occur when 8 children (aged 6 to  12 
years) have completed study Week 12 
assessments. Also added the purpose 
and scope of this unplanned interim 
analysis. 
 
Section 9.1 is updated to clarify that 
analysis will be performed separately 
for initial treatment phase and optional 
extension phase. 
 
Section 9.2 is updated to add more 
milestones for subject accountability 
and key study dates and to add 
summary of subjects by study sites. 
 
Section 9.3 is updated to add protocol 
deviation summary for COVID-19 
control measures. 
 
Section 9.6.2 is updated to reflect 
latest MedDRA version of 24.0 and to 
clarify that summaries of AEs will be 
provided by treatment phase. 
 
Section 9.6.3 is updated to clarify 
about the liver function tests. 
 
Section 9.6.6 is updated to include 
summary of shift in pre- and post-
baseline ECG diagnosis. 
 
Section 9.6.9 is updated to clarify that 
subject listing will be provided for 
concomitant medication data. 
 
Section 9.7.1 is updated to clarify that 
all PK related analysis will be done by 
CPMS group. 
 
Section 9.7.3 is newly created for 
Neurological Assessment. Also added 
that summary of abnormalities will be 
provided. 


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 
Section 10 is updated since there is a 
change to the analyses specified in 
the study protocol, amendment 4 
dated 26 March 2020. Added details 
about the change. 
Amendment 5 (v6.0) 
17MAR2022 
 
SAP Amendment 5 was triggered due 
to Protocol Amendment 5 dated 3 
November 2021.  
 
Administrative updates reflecting 
protocol amendment 5 were made 
throughout the document. 
 
Number of subjects, aged 6 to  12 
years old, needed for second interim 
analysis is updated throughout the 
document. Also, total number of 
subjects required to be enrolled in the 
study, the requirement for number of 
subjects in 6 to  10 years age group 
and the minimum number of subjects 
needed in different cohorts/ age 
groups are also updated throughout 
the document. 
 
Section 5.1 is updated to amend 
treatment-emergent serious adverse 
events definition as per DES.  
 
Section 5.4.1 is updated to clarify 
study periods for ITP, OEP and entire 
study duration. 
 
Section 5.6 is updated to add the 
formula for calculation of IP duration. 
 
Section 6.2 is updated to clarify the 
scope of safety analysis set. 
 
Section 6.4 is updated to remove the 
unplanned interim analysis set 
definition. 
 
Section 7.1 is updated to remove the 
unplanned interim analysis 
description.  
 
Section 7.2 and 7.3 are updated to 
clarify that primary analysis will 
include safety data for ITP and final 
analysis will include safety data for 
entire study and separately for OEP. 
Also, clarified that PK data will be 
analyzed by CPMS. 
 
Section 9.1 is updated to clarify that 
safety summaries will be produced for 
entire study, ITP and OEP, as 
applicable, and by age group, where 
appropriate.  


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 
Section 9.6.2 is updated to reflect the 
latest MedDRA version of 24.1. Also, 
AE listing requirement is removed. 
 
Section 9.6.8 is updated to include IP 
exposure summaries. 
 
Section 10 is updated to clarify that 
unplanned interim analysis was 
performed and it fulfilled the 
requirement for second interim 
analysis. 
 


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Table of Contents 
Table of Contents ................................................................................................... 9 
1. 
Introduction ........................................................................................................... 14 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 14 
2.1 
Objectives and Endpoints .......................................................................... 14 
2.2 
Hypotheses and/or Estimations ................................................................. 15 
3. 
Study Overview .................................................................................................... 15 
3.1 
Study Design ............................................................................................. 15 
3.2 
Sample Size .............................................................................................. 18 
3.3 
Adaptive Design ........................................................................................ 18 
4. 
Covariates and Subgroups ................................................................................... 18 
4.1 
Planned Covariates ................................................................................... 18 
4.2 
Subgroups ................................................................................................. 18 
5. 
Definitions ............................................................................................................. 19 
5.1 
Definition of Terms Included in Study Endpoints ....................................... 19 
5.2 
Study Dates .............................................................................................. 19 
5.3 
Study Points of Reference ......................................................................... 20 
5.4 
Study Time Interval ................................................................................... 21 
5.4.1 
Study Periods ............................................................................ 21 
5.5 
Subject Disposition .................................................................................... 22 
5.6 
Arithmetic Calculations .............................................................................. 23 
6. 
Analysis Sets ........................................................................................................ 24 
6.1 
Full Analysis Set........................................................................................ 24 
6.2 
Safety Analysis Set ................................................................................... 24 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 24 
6.4 
Interim Analyses Set(s) ............................................................................. 24 
6.5 
Extension Analysis Set .............................................................................. 25 
7. 
Planned Analyses ................................................................................................. 25 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 25 
7.2 
Primary Analysis ....................................................................................... 26 
7.3 
Final Analysis ............................................................................................ 26 
8. 
Data Screening and Acceptance ........................................................................... 26 
8.1 
General Principles ..................................................................................... 26 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 26 
8.3 
Handling of Missing and Incomplete Data ................................................. 26 
8.4 
Detection of Bias ....................................................................................... 27 
8.5 
Outliers ..................................................................................................... 27 
8.6 
Distributional Characteristics ..................................................................... 27 


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8.7 
Validation of Statistical Analyses ............................................................... 27 
9. 
Statistical Methods of Analysis.............................................................................. 28 
9.1 
General Considerations ............................................................................. 28 
9.2 
Subject Accountability ............................................................................... 28 
9.3 
Important Protocol Deviations ................................................................... 29 
9.4 
Demographic and Baseline Characteristics ............................................... 29 
9.5 
Efficacy Analyses ...................................................................................... 30 
9.6 
Safety Analyses ........................................................................................ 30 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 30 
9.6.2 
Adverse Events ......................................................................... 30 
9.6.3 
Laboratory Test Results ............................................................ 31 
9.6.4 
Vital Signs ................................................................................. 31 
9.6.5 
Physical Measurements ............................................................ 31 
9.6.6 
Electrocardiogram ..................................................................... 31 
........................................................... 32 
9.6.8 
Exposure to Investigational Product .......................................... 32 
9.6.9 
Exposure to Concomitant Medication ........................................ 32 
................. 32 
9.7 
Other Analyses ......................................................................................... 32 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 32 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 33 
9.7.3 
Neurological Assessment .......................................................... 33 
10. 
Changes From Protocol-specified Analyses.......................................................... 33 
11. 
Literature Citations / References ........................................................................... 34 
12. 
Prioritization of Analyses....................................................................................... 34 
13. 
Data Not Covered by This Plan............................................................................. 34 
14. 
Appendices ........................................................................................................... 35 
Appendix A.  Reference Values/Toxicity Grades ................................................... 35 
Appendix B.  Clinical Outcome Assessment Forms/Instruments ........................... 36 
 
List of Table 
Table 9-1.  Safety Endpoint Summary Table ................................................................. 30 
 
 
 


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List of Abbreviations 
 
Abbreviation 
Explanation 
AE 
Adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-28day 
Area under the concentration-time curve from time 0 to 28 Days 
BMI 
Body Mass Index 
CI 
Confidence interval 
CL 
Clearance 
Cmax 
maximum concentration 
CPMS 
Clinical pharmacology modeling and simulation 
C-SSRS 
Columbia suicide severity rating scale 
CTCAE 
Common terminology criteria for adverse events 
Ctrough 
trough concentration 
DARS 
Data acquisition requirements specification 
DMC 
Data Monitoring Committee 
DMP 
data management plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
end of study 
GBS 
Global Biostatistical Science 
GSO-DM 
Global study operations-Data management 
ITP 
Initial Treatment Phase 
IP 
investigational product 
IPD 
important protocol deviation 
IVRS 
Interactive voice response system 
kg 
Kilogram 
m 
Meter 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram 
NCI 
National Cancer Institute 
OEP 
Optional Extension Phase 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic(s) 


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Abbreviation 
Explanation 
PT 
preferred term 
Q4W 
every 4 weeks 
QTc 
QT interval corrected 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SOC 
system organ class 
TBL 
total bilirubin 
TFL 
Tables, Figures, and Listings 
tmax 
time to maximum concentration 
ULN 
Upper limit of normal 
Vc 
Central volume of distribution 
WHO Drug 
World Health Organization Drug 
 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the Protocol Amendment 5 for study 20160172, 
AMG 334 dated 03 November 2021.  The scope of this plan includes the interim 
analyses, the primary analysis and the final analysis that are planned and will be 
executed by the Amgen Global Biostatistical Science (GBS) department unless 
otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the safety, tolerability, 
and pharmacokinetic (PK) profile of 
multiple subcutaneous (SC) doses of 
AMG 334 in children and adolescent 
subjects with migraine, respectively 
 
Serum PK parameters of AMG 334 
(eg, time to maximum concentration 
[tmax], maximum observed 
concentration [Cmax], trough 
concentration [Ctrough], and area under 
the concentration time curve [AUC] 
from 0 to 28 days [AUC0-28day]) 
 
Subject incidence of 
treatment-emergent adverse events 
(AEs) 
 
Changes in vital signs, 12-lead 
electrocardiograms (ECGs), clinical 
laboratory safety tests, and 
neurological assessments 
Key Secondary 
 
Not applicable 
 
Not applicable 
Secondary 
 
Not applicable 
 
Not applicable 
 
a 
 
Exploratory 


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2.2 
Hypotheses and/or Estimations 
Multiple subcutaneous doses of AMG 334 will be safe and well-tolerated, and the PK 
profiles will support further development of AMG 334 in children and adolescents with 
migraine, respectively.  There will be no formal hypothesis testing; any comparisons 
made will be descriptive only. 
3. 
Study Overview 
3.1 
Study Design 
This is a Phase 1b, multicenter, randomized, open-label, multiple-dose study evaluating 
AMG 334 in male and female children (6 to < 12 years of age) and adolescents (12 to 
< 18 years of age) with migraine.  The study population will consist of 2 cohorts based 
on body weight at baseline enrolling a total of at least 52 subjects and up to 
approximately 60 subjects in the study.   
Cohort 1 will enroll at least 12 subjects and up to approximately 22 subjects in total with 
body weight of < 40 kg.  At least 9 subjects in Cohort 1 must be aged 6 to < 12 years old 
including at least 2 subjects aged 6 to < 10 years old, at the time of consent.   
Cohort 2 will enroll at least 35 subjects and up to approximately 38 subjects in total with 
a body weight of ≥ 40 kg at baseline.  It is anticipated that most subjects in this cohort 
will be 12 to < 18 years of age. Enrollment requirements for subjects in Cohort 1 and 
Cohort 2 will be tracked and administered via Interactive Voice Response System 
(IVRS) to ensure that the minimum number of subjects in each cohort is achieved. 
Enrollment will be staggered by age category with adolescents (ie, subjects 12 to 
< 18 years of age) starting enrollment first. 
Children 6 to < 12 years of age at the time of consent will participate in the initial 
treatment phase, for a total of 12 weeks of treatment. Adolescents 12 to < 18 years of 
age at the time of consent will participate in the initial treatment phase for a total of 12 
weeks of treatment after which they will have the option of continuing treatment in an 
optional 40-week extension phase, for a total of 52 weeks of treatment. A safety follow-
up visit will take place 16 weeks after the last dose to complete end of study (EOS) 
assessments either (i) after completion of the initial 12-week treatment phase, (ii) after 
completion of the optional 40-week extension phase for those adolescents who choose 


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to continue treatment or (iii) after the last dose received before discontinuation of 
treatment during the study.  
Subjects weighing < 40 kg (Cohort 1) will be randomized in a 1:2 allocation ratio to low 
dose (35 mg) or high dose (70 mg) for a total of at least 12 and up to approximately 15 
subjects completing Week 12 assessments.  Subjects weighing ≥ 40 kg (Cohort 2) will 
be randomized in a 1:4 allocation ratio to low dose (70 mg) or high dose (140 mg) for a 
total of at least 26 and up to approximately 30 subjects completing Week 12 
assessments.  Treatments will be allocated to qualifying subjects in a randomized order 
within either cohort through IVRS.  Study drug (low-dose or high-dose AMG 334) will be 
administered in either cohort in an open-label fashion against a background of allowed 
concomitant medications, including agents for migraine prevention. 
It is anticipated that at least 52 and up to approximately 60 subjects will be enrolled in 
the study to ensure that at least 38 and up to approximately 45 subjects complete 
Week 12 assessments.   
During the initial treatment phase, each subject will receive a total of 3 SC doses of AMG 
334 administered every 4 weeks (Q4W) on Days 1, 29 (± 3 days), and 57 (± 3 days), 
respectively.  The study is expected to confirm a PK profile in pediatric subjects that is 
similar to that in adults, based on population PK analysis, and to provide preliminary 
safety data in each body weight cohort supportive of the initiation of the AMG 334 Phase 
3 studies in the pediatric population.  All subjects will be administered AMG 334. 
Concomitant use of agents for migraine prevention (up to 2 treatments on a stable dose) 
and for the acute treatment of migraine are permitted during the study.  All subjects will 
be followed for 16 weeks following the last dose of AMG 334.   
The overall study design is described in the study schema below: 
 


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a 
3.2 
Sample Size 
The study population will consist of 2 cohorts based on body weight enrolling a total of at 
least 52 subjects up to approximately 60 subjects in the study.  Cohort 1 will enroll at 
least 12 subjects and up to approximately 22 subjects in total with body weight of 
< 40 kg at baseline.  It is anticipated that most subjects in this cohort will be  
6 to < 12 years of age.  Cohort 2 will enrol at least 35 subjects and up to approximately 
38 subjects with a body weight of ≥ 40 kg at baseline. It is anticipated that most subjects 
in this cohort will be 12 to < 18 years of age. 
Subjects weighing < 40 kg (Cohort 1) will receive a dose of 35 mg or 70 mg for a total of 
at least 12 and up to approximately 15 subjects completing Week 12 assessments. 
Subjects weighing ≥ 40 kg (Cohort 2) will receive a dose of 70 mg or 140 mg for a total 
of at least 26 and up to approximately 30 subjects completing Week 12 assessments. 
The rate of early discontinuation up to Week 12 assessments is assumed to be 20% and 
similar across the two cohorts. 
All subjects in this study will be administered AMG 334.  The sample size for this study is 
based on clinical and practical considerations to adequately fulfil its objectives and to 
inform on planned phase 3 pediatric studies.  Assuming clearance (CL) and central 
volume of distribution (Vc) on body weight basis is similar between pediatric subjects 
and adults, and assuming the percentage coefficient of variation for CL and Vc are 
43% and 53%, respectively (based on total between-subject-variability from adult 
population PK), the proposed sample size provides > 80% power to estimate 
95% confidence interval (CI) of CL and Vc within 60-140% of the true parameters for 
both weight cohorts combined and across the two age categories (Wang Y et al, 2012). 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Covariates are not applicable in this study as no formal statistical modeling will be 
performed. 
4.2 
Subgroups 
Selected safety analyses based on age group (6 to < 12 years and 12 to < 18 years) 
may be performed. 


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5. 
Definitions 
5.1 
Definition of Terms Included in Study Endpoints 
Treatment-emergent AE 
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by “Did event start before first dose of 
investigational product” equal to “No” or missing on the Events electronic case report 
form (eCRF) and up to the End of Study date.  
Treatment-emergent Serious Adverse Events (SAEs) 
Treatment-emergent adverse events indicated as serious on the Events eCRF.  
Device-related Treatment-emergent Adverse Event 
A treatment-emergent adverse event with the indicator flag “Is there a reasonable 
possibility that the event may have been caused by the investigational device” equal to 
“Yes” on the Events eCRF. 
5.2 
Study Dates 
Enrollment Date  
Enrollment Date is defined as the date collected on the eCRF. 
Randomization Date 
Randomization Date is defined as the date subject was allocated to a treatment group. 
First Investigational Product (IP) Dose Date 
First IP Dose Date is the date on which a subject is administered the first dose of IP 
following randomization, which may be the same day or after the randomization date, as 
recorded on IP Administration eCRF.  For subjects who are randomized but not dosed 
with IP after randomization, First IP Dose Date is considered missing. 
First Initial Treatment Phase (ITP) IP Dose Date 
First ITP IP Dose Date is the date on which a subject is administered the first dose 
of IP in the initial treatment phase, as recorded on IP Administration eCRF. 
First Optional Extension Phase (OEP) IP Dose Date 
First OEP IP Dose Date is the date on which a subject is administered the first dose of 
IP in the optional extension phase following completion of initial treatment phase, as 
recorded on IP Administration eCRF. 


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Last IP Dose Date 
Last IP Dose Date for each subject is defined as the latest date IP is administered, as 
recorded on IP Administration eCRF. 
Last ITP IP Dose Date 
Last ITP IP Dose Date for each subject is defined as the latest date IP is 
administered during the initial treatment phase, as recorded on IP Administration 
eCRF. 
Last OEP IP Dose Date 
Last OEP IP Dose Date for each subject is defined as the latest date IP is 
administered during the optional extension phase, as recorded on IP 
Administration eCRF. 
End of IP Admin Date  
End of IP Admin date for each subject is defined as the date the decision was made to 
end IP as recorded on the End of IP eCRF.  
End of ITP Date  
End of ITP date for each subject is defined as the date recorded on the End of Initial 
Treatment Phase eCRF. 
End of OEP Date  
End of OEP date for each subject is defined as the date recorded on the End of Optional 
Extension Treatment Phase eCRF. 
Subject-level End of Study (EOS) Date  
EOS for each subject is defined as the date the subject last completed a protocol-
specified procedure, as recorded on the EOS eCRF page. 
5.3 
Study Points of Reference 
Baseline 
Unless otherwise stated, baseline will be defined as the last assessment taken prior to 
the first AMG 334 administration (ie, Day 1 pre-dose or Screening if Day 1 pre-dose is 
not available) of the ITP.  For subjects continuing treatment in an OEP after completion 
of the ITP, their baseline will be the same as the ITP. 


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For ECG and Neurological Evaluation, the entire set of data from the Day 1 visit will be 
used as baseline.  If the data is missing on Day 1, the entire set of data from the 
Screening visit will be used as baseline. 
Study Day 1 
Day 1 is defined as the first day that IP is administered to the subject.  For subjects who 
are randomized but not dosed after randomization, the Study Day 1 is defined as the 
date of randomization.  The day before Day 1 is referenced as Day -1. 
Study Day 
 
On or after Study Day 1: Study Day = (Study Date - Date of Study Day 1) + 1 
 
Before Study Day 1: Study Day = (Study Date - Date of Study Day 1) 
5.4 
Study Time Interval 
5.4.1 
Study Periods 
The following data will be categorized into treatment periods, if applicable.  Any data 
occurred after EOS date will not be included in the analysis 
 
Study Phase 
Start Time Point 
End Time Point 
Initial 
Treatment 
Phase 
Study Day 1 
 
For Treatment-emergent Adverse 
Event: 
 
Min (First OEP Dose Date – 1, 
EOS date) for subjects who 
received OEP dose; 
 
EOS Date, for subjects who did not 
receive any OEP dose 
For lab, ECG, 
, Neurological 
Evaluation and Vital Signs: 
 
Min (First OEP Dose Date, EOS 
date) for subjects who received 
OEP dose; 
 
EOS Date, for subjects who did not 
receive any OEP dose 
 


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Study Phase 
Start Time Point 
End Time Point 
Optional 
Extension 
Phase 
For Treatment-emergent 
Adverse Event: 
 
First OEP Dose Date 
For 
 lab, ECG, 
 Neurological 
Evaluation and Vital Signs: 
 
First OEP Dose Date + 
1 
For Treatment-emergent Adverse 
Event, lab, ECG, 
 
Neurological Evaluation and Vital 
Signs: 
 
EOS Date 
Entire Study  
Study day 1 
EOS 
5.5 
Subject Disposition 
Randomized 
Individuals are considered randomized if they have been assigned a randomization 
number.  Randomized individuals are referred to as “subjects”. 
Exposed to Investigational Product 
Subjects are defined as exposed if they receive at least one dose of investigational 
product. 
Completing the Initial Treatment Phase 
Subjects are defined as completing the ITP if they complete the Week 12 assessment.  It 
will be derived from the End of Initial Treatment Phase eCRF with “Completed” as the 
primary reason for ending study phase. 
Completing the Optional Extension Phase 
Subjects are defined as completing the OEP if they complete the Week 52 assessment.  
It will be derived from the End of Optional Extension Treatment Phase eCRF with 
“Completed” as the primary reason for ending study phase. 
Completing Study 


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Subjects are defined as completing study if they complete the entire study duration, as 
applicable.  It will be derived from the End of Study eCRF with “Completed” as the 
primary reason for ending study. 
5.6 
Arithmetic Calculations 
Change from Baseline:  
The arithmetic difference between a post-baseline value and the baseline value: 
 
Change from Baseline = (Post-baseline Value – Baseline Value) 
 
Percent change from Baseline = [(Post-baseline Value – Baseline Value) / Baseline 
Value] x 100 
Duration of IP Exposure During ITP 
If subject enters into OEP, 
Minimum (Last ITP IP Dose Date + 27, First OEP Dose Date - 1, EOS Date) – First 
ITP IP Dose Date + 1 
Otherwise, 
Minimum (Last ITP IP Dose Date + 27, EOS Date) – First ITP IP Dose Date + 1 
Duration of IP Exposure During OEP 
Minimum (Last OEP IP Dose Date + 27, EOS Date) – First OEP IP Dose Date + 1 
Duration of IP Exposure During Entire Study 
Minimum (Last IP Dose Date + 27, EOS Date) – First IP Dose Date + 1 
Subject Incidence 
The subject incidence for a given event in a given period is defined as the number of 
subjects with at least one reported occurrence of the event divided by the number of 
subjects who enter that period (ie, number of at-risk subjects).  For subjects with multiple 
occurrences of the same event in a given period, the event will only be counted once per 
subject in that period. 
Exposure-adjusted Incidence Rate 
The exposure-adjusted incidence rate for a given event in a given period is defined as 
the number of subjects with at least one reported occurrence of the event in a given 
period divided by total exposure time of all subjects who are at risk for the event.  For 
subjects with a given event, only the time until the onset of each subject’s first event 
contributes to the exposure time.  For subjects without a given event, the exposure time 


Product:  AMG 334 [OR] Enter Established Name 
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is the entire duration of the period.  This incidence rate will be presented as number of 
subjects per 100 subject-years.  
6. 
Analysis Sets 
The following subsections define the analysis sets for this study. 
6.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects.  Subjects will be analyzed 
according to their randomized treatment, regardless of the treatment received.  
Tabulations of demographic and baseline characteristics, disposition, important protocol 
deviations (IPD) and protocol deviations related to COVID-19 control measures will 
utilize this analysis set.  
6.2 
Safety Analysis Set 
The safety analysis set will consist of all randomized subjects who received at least 
one dose of AMG 334 during ITP.  Subjects will be analyzed according to the 
randomized treatment unless a subject has received the incorrect dose during the entire 
ITP.  Analyses for safety endpoints and summary of IP administration in ITP and for 
entire study duration will utilize this analysis set. 
6.3 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
The Pharmacokinetic (PK) analysis set will contain all randomized subjects who receive 
at least one dose of AMG 334 and have at least one PK concentration result. 
Pharmacodynamic (PD) analysis set is not applicable for this study. 
6.4 
Interim Analyses Set(s) 
The interim analysis set will be defined separately for each interim analysis.  For the 
first interim analysis, the analysis set will include a subset of the safety analysis set 
consisting of at least 6 adolescents (12 to < 18 years of age) who have completed study 
Week 8 assessments and all available data collected for all subjects up to and including 
the corresponding data cutoff date.  For the second interim analysis, the analysis set will 
include a subset of the safety analysis set consisting of at least 8 children (6 to < 12 
years of age) who have completed study Week 12 assessments and will include all 
available data collected for all children up to and including the corresponding data cutoff 
date. 


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6.5 
Extension Analysis Set 
The Extension Analysis Set will consist of all adolescent subjects receiving at least one 
dose of AMG 334 in the OEP.  This analysis set will be used when summarizing data 
collected during the OEP. 
7. 
Planned Analyses 
There are two planned interim analyses, one primary analysis, and one final safety 
analysis. 
7.1 
Interim Analysis and Early Stopping Guidelines 
There are 2 interim analyses of PK and safety planned for this study.  The first interim 
analysis will occur when at least 6 adolescents (12 to < 18 years of age) have completed 
study Week 8 assessments. The second interim analysis will occur when at least  
8 children (6 to < 12 years of age) have completed study Week 12 assessments. All data 
collected up to and including the corresponding data cutoff date will be available but only 
AEs, vital sign data and laboratory data will be summarized by GBS group, and PK data 
will be analyzed by Clinical Pharmacology Modeling and Simulation (CPMS) group.  The 
purpose of the first and second interim analyses is to inform the selection of AMG 334 
doses to be evaluated in the AMG 334 Phase 3 pediatric studies.   
Results from the interim analyses will be presented to the independent Data Monitoring 
Committee (DMC) responsible for reviewing and making recommendations regarding the 
AMG 334 Phase 3 pediatric studies. The DMC will not review individual patient level 
data from this study or make recommendations regarding this study. 
Impact of any changes in data during any analysis as compared to previous analysis will 
be assessed separately.   
Interim Data Review Team 
The interim data review team will consist of the Sponsor study team, including at least 
one medical monitor, safety representative, PK representative, biostatistician, and 
one representative from Novartis, which is partner in the development of AMG 334.   
At each interim analysis, this team will review the PK and safety data. 
Early Stopping Guidelines 
No early stopping rules are planned 


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7.2 
Primary Analysis 
The primary analysis for the study will be performed at the End of the Study 
milestone described in the protocol Section 3.5.2. All data will be cleaned and a 
database lock will occur. 
No formal hypothesis testing will be performed; all analyses will be descriptive.  PK and 
safety data will include summaries by body weight cohort and AMG 334 treatment 
dosage group.  Primary analysis will include safety summaries for ITP only. Safety 
data will be analyzed by GBS and PK data will be analyzed by CPMS. The review of 
the results of this primary analysis will inform on further pediatric studies utilizing 
AMG 334. 
7.3 
Final Analysis 
The final analysis will utilize the same database as the primary analysis. 
No formal hypothesis testing will be performed; all analyses will be descriptive.  PK and 
safety data will include summaries by body weight cohort and AMG 334 treatment 
dosage group.  Final analysis will include safety summaries for the entire study 
and separately for OEP only, as appropriate. Safety data will be analyzed by GBS 
and PK data will be analyzed by CPMS.  
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
Details of PK, 
, and external lab data transfer to the database is 
provided in the corresponding study data transfer plans.  See Data Management Plan 
(DMP) and Data Acquisition Requirements Specification (DARS). 
8.3 
Handling of Missing and Incomplete Data 
In general, missing data will not be imputed.  However, missing and incomplete dates for 
AEs and concomitant medications will be handled using the methods described below. 
Imputation Rules for Partial or Missing Start Dates 


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Missing 
Imputation 
Exception on Adverse Event Start Date 
Start date 
(AE, 
concomitant 
medication) 
Day 
01 
Default to Study Day 1 if an adverse 
event starts the same year and month as 
Study Day 1 and the flag indicates that 
the adverse event started on or after the 
first dose on the Events eCRF 
Day/Month 
01JAN 
Default to Study Day 1 if an adverse 
event started the same year as 
Study Day 1 and the flag indicates that 
the adverse event started on or after the 
first dose on the Events eCRF 
Day/Month/Year 
No imputation 
 
 
8.4 
Detection of Bias 
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations (IPD) in each 
age group.  The clinical study team will identify and document the criteria for IPD. 
8.5 
Outliers 
All confirmed outlier data will be included in the analyses presented in this SAP unless 
there is sufficient scientific justification (eg, IPD leading to invalid data) to exclude them.  
PK concentration data will be evaluated for outliers by visual inspection, and decisions to 
re-assay individual samples will be made in accordance with standard CPMS evaluation 
practice.  All excluded observations will be detailed by CPMS along with reasons for 
exclusion, in accordance with standard CPMS practices. 
8.6 
Distributional Characteristics 
Not applicable for this study. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, Figures and Listings (TFL) will be produced with validated standard macro 
programs where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 


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9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Unless otherwise stated, descriptive statistics will be provided for demographic and 
baseline characteristic by body weight cohort (< 40 kg and ≥ 40 kg), treatment dosage 
(35 mg, 70 mg and 140 mg), and all subjects combined. 
Safety summaries during the entire study, ITP or OEP, as applicable, will be provided 
by body weight cohort (< 40 kg and ≥ 40 kg), treatment dosage (35 mg, 70 mg and 
140 mg), and all subjects combined. 
Where appropriate, safety summaries will be provided by each age group 
(adolescents and children) separately. 
PK data will be summarized by body weight cohort and treatment dosage.   
Descriptive statistics on continuous measurements will include number of subjects (n), 
means, medians, standard deviations (and standard errors for post-baseline data), first 
and third quartiles, and minimum and maximum, while categorical data will be 
summarized using frequency counts and percentages.  No formal statistical hypothesis 
testing will be performed. 
When data are summarized by visit, the values recorded against the scheduled visits, 
including any time windows specified in the protocol will be used.  
When assessing post-baseline minimum/ maximum increases or decreases over the 
study (eg, shift in lab toxicity grade), all assessments, including unscheduled 
assessments will be used. 
9.2 
Subject Accountability 
The number and percent of subjects randomized, those who received AMG 334, 
completed ITP, discontinued the ITP (including reasons for discontinuing), entered the 
OEP, completed OEP, discontinued the OEP (including reasons for discontinuing), 
completed investigational product and discontinued investigational product (including 
reasons for discontinuation) will be summarized.  Subjects who withdraw early, reason 
for withdrawal, and timing of the withdrawal will be reviewed. 
Key study dates for the first subject enrolled, last subject enrolled, last subject's end of 
investigational product and last subject's end of study will be presented. 
The number and percent of subjects randomized will be tabulated by study site. 
The number and percent of subjects for each analysis set will also be summarized. 


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9.3 
Important Protocol Deviations 
IPD categories are defined by the study team before the first subject’s initial visit and 
updated during the IPD reviews throughout the study prior to database lock.  These 
definitions of IPD categories, subcategory codes, and descriptions will be used during 
the course of the study.  Eligibility deviations are defined in the protocol. 
The final IPD list will be used to produce the Summary of IPDs table and the list of 
subjects with IPDs.  In addition, a separate listing of all inclusion and exclusion 
deviations will be provided. 
Protocol deviations related to COVID-19 controlled measures will be summarized.   
9.4 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized. 
Demographics: 
 
Age (years) at consent (continuous summary statistics)  
 
Sex (number and percentage of males and females) 
 
Ethnicity (number and percentage in each ethnicity category) 
 
Race (number and percentage of subjects in each race, or mixed-race 
combination). If multiple races have been reported for a subject, the subject will 
be categorized as multiple race (as well as by combination of races). 
Baseline Characteristics: 
 
Height, weight and BMI (continuous summary statistics)  


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9.5 
Efficacy Analyses 
Not applicable for this study. 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Primary and exploratory safety endpoints are summarized in the table below. 
Table 9-1.  Safety Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method 
Primary Safety Endpoint 
 
Subject incidence of treatment-emergent adverse 
events (AEs) 
 
Changes in vital signs, 12-lead electrocardiograms 
(ECGs), clinical laboratory safety tests, and 
neurological assessments 
Exploratory Safety Endpoint 
Summary statistics will be provided 
by body weight cohort and 
treatment dosage group 
 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.1 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. 
The subject incidence and exposure-adjusted subject incidence of all treatment-
emergent adverse events, treatment-emergent serious adverse events, device-related 
treatment-emergent adverse events, treatment-emergent adverse events leading to 
discontinuation of investigational product, and fatal adverse events will be 
summarized.   
Treatment-emergent adverse events, treatment-emergent serious adverse events, 
device-related treatment-emergent adverse events, treatment-emergent adverse events 
leading to discontinuation of AMG 334, and fatal adverse events will be tabulated by 
system organ class (SOC) in alphabetical order and preferred term (PT) in descending 
order of frequency.  Summaries of treatment-emergent AEs and treatment-emergent 
serious adverse events will be tabulated by system organ class, preferred term, and 


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grade.  The severity of each AE will be graded using Common Terminology Criteria for 
AE (CTCAE) version 4.03 criteria. 
9.6.3 
Laboratory Test Results 
The following analyses will be provided for chemistry, hematology and urinalysis 
laboratory data: 
 
Shifts tables of the laboratory toxicity for all laboratory parameters based on 
CTCAE grade (version 4.03) relative to baseline will be tabulated by body weight 
cohort and treatment group.  In the cases when CTCAE grading scales include 
numeric ranges in combination with clinical assessment (eg, Potassium 
[Hypokalemia]), laboratory test results may be summarized based on standard 
normal ranges or by CTCAE grade utilizing investigator’s input. 
 
Descriptive statistics of change from baseline by visit for all laboratory 
parameters 
 
Subject listing of grades ≥ 3 laboratory toxicities for all laboratory parameters as 
applicable 
 
Subject incidence of suspected Hy’s Law cases  
 
Summary of liver function abnormalities for alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin 
(TBL) or the following categories:  
 
ALT (> 3x upper limit of normal (ULN); > 5x ULN; > 10x ULN; > 20x ULN 
respectively)  
 
AST (> 3x ULN; > 5x ULN; > 10x ULN; > 20x ULN respectively) 
 
AST or ALT (> 3x ULN; > 5x ULN; > 10x ULN; > 20x ULN respectively)  
 
Total Bilirubin (> 1x ULN; > 1.5x ULN; > 2x ULN respectively) and 
ALP (> 1.5 ULN)  
Unscheduled assessments will be incorporated in the laboratory analyses where 
possible. 
9.6.4 
Vital Signs 
Vital signs will be reviewed for each subject.  Summaries of heart rate, temperature, and 
blood pressure (systolic and diastolic) data over time and change from baseline will be 
provided. 
9.6.5 
Physical Measurements 
Height, weight, and BMI will be summarized by visit and change from baseline will be 
provided, as applicable. 
9.6.6 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 


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assessment of potential QT interval corrected (QTc) effect.  Because these evaluations 
may not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data; neither summaries nor statistical analyses will be 
provided for QTc data, and these data would not be expected to be useful for meta-
analysis with data from other studies. 
Shift in pre- and post-baseline ECG diagnosis will be summarized. 
9.6.8 
Exposure to Investigational Product 
Number of IP doses received and duration of exposure to IP will be summarized. 
Subject listings of manufacturing lot numbers and a separate listing of unique 
manufacturing lot numbers used in this study will be provided. 
9.6.9 
Exposure to Concomitant Medication 
All medication will be coded using the World Health Organization Drug (WHO DRUG) 
dictionary and a subject listing will be provided.   
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Serum AMG 334 concentrations will be determined using a validated assay.  Individual 
serum concentration-time plots for AMG 334 will be presented for each subject as well 
as mean concentration-time plots for each dose.  PK parameters will be estimated using 
either compartmental (eg, PK modeling) or non-compartmental methods.  Actual dosing 
and sampling times will be used for calculation of PK parameters.  Summary statistics 
will be generated for each PK parameter (eg, time to maximum concentration [tmax], 


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maximum observed concentration [Cmax], trough concentration [Ctrough], and area under 
the concentration time curve [AUC] from 0 to 28 days [AUC0-28day]). 
Clearance (CL) and central volume of distribution (Vc) on body weight basis may be 
summarized. 
Summary statistics will be generated for each PK parameter for each treatment group. 
All PK-related tables, figures, listings and other deliverables will be generated by CPMS.  
9.7.2 
Analyses of Clinical Outcome Assessments 
9.7.3 
Neurological Assessment 
Neurological assessment will be completed as per standard of care and subject 
incidence of abnormalities will be summarized. 
10. 
Changes From Protocol-specified Analyses 
As a change from protocol-specified analysis per protocol amendment 4 dated 
20 March 2020, an unplanned interim analysis was conducted in May 2021, when 
at least 8 children (aged 6 to < 12 years) had completed study Week 12 
assessments, to facilitate engagement with health authorities regarding 
modifications to the AMG 334 Pediatric Investigational Plan (PIP) and 
commencement of enrollment of children in AMG 334 Pediatric Phase 3 studies. 
An as-is database snapshot occurred and included all data up to and including 
corresponding data cutoff date. Safety analyses including AEs, vital sign, 
laboratory, ECG, 
 was summarized by GBS group. PK 
data was analyzed by CPMS group based on all available PK data including all 
adolescent and children subjects from both Cohort 1 (< 40 kg) and Cohort 2 (≥ 40 
kg). 
The unplanned interim analysis fulfilled the requirement of second interim 
analysis (as described in Section 7.1), as reflected in Protocol Amendment 5 dated 
03 November 2021. All TFLs generated during the unplanned interim analysis will 
be considered as second interim analysis outputs for the purpose of study 
documentation. 


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There is a change in timing of the primary analysis (as described in Section 7.2) 
compared to the Protocol Amendment 5 dated 03 November 2021. 
11. 
Literature Citations / References 
Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol.  
2012;52(10):1601-6. 
12. 
Prioritization of Analyses 
Prioritization of analyses has not been identified at this time. 
13. 
Data Not Covered by This Plan 
There are no plans to specifically analyze or summarize the following data: 
 
ECG QTc data 
 
Data for biomarker development 
 
Pharmacogenetic data 


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14. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
Adverse event severity and laboratory toxicity are graded based on National Cancer 
Institute (NCI) Common Toxicity Criteria version 4.03 or higher, which is available at the 
following: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf   


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Appendix B.  Clinical Outcome Assessment Forms/Instruments