Clinical trial NCT02174861
Conditions: Treatment for Prevention of Chronic Migraine
Keywords: Chronic Migraine
Sponsor: Amgen
Start date: 2014-06-30; Completion date: 2017-05-26
Enrollment: 609 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess the long-term safety and efficacy of erenumab.

Detailed description:
This was a multicenter, 52-week, open-label study designed to assess the long-term safety and efficacy of erenumab in adults with chronic migraine. Participants who completed the 12-week double-blind treatment of the parent Study 20120295 (NCT02066415) and met all Study 20130255 eligibility criteria were eligible for enrollment into this study. Enrollment occurred within 14 days after the parent study's week 12 visit.

The initial dose used in the study was erenumab 70 mg every month (QM). The protocol was subsequently amended to increase the dose to erenumab 140 mg QM (Protocol Amendment 2). Participants who had already completed the week 28 visit (ie, midpoint of the study) at the time of Protocol Amendment 2 continued to receive open-label erenumab 70 mg QM for the remainder of the study. Participants who enrolled but had not completed the week 28 visit at the time of Protocol Amendment 2 increased the open-label erenumab dose from 70 mg QM to 140 mg QM at the next visit. All participants who enrolled after Protocol Amendment 2 received open-label erenumab 140 mg QM throughout the study.

Participants may elect to participate in a separate clinical home use (CHU) substudy to assess subjects' ability to self-administer 140 mg of erenumab for in-home use using either two prefilled syringes (PFS) or two prefilled autoinjector/pens (AI/pens). Enrollment in the 12-week substudy occurred at either week 12 or week 40 of study 20130255. Participants were randomized to self-administer erenumab using either the PFS or AI/pen on CHU days 29 and 57 at home.

Arms: arm 1: Participants received erenumab 70 mg once a month (QM) or 140 mg QM by subcutaneous injection for up to 52 weeks.
Interventions: intervention 1: Erenumab
Intervention descriptions: intervention 1: Administered by subcutaneous injection once a month

Protocol documents:
Prot_000.pdf: 
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PPD


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 2 of 84 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled An Open-label Extension (OLE) Study to 
Assess the Long-term Safety and Efficacy of AMG 334, dated 31 March 2016, and 
agree to abide by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) 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:  20130255 
Date:  31 March 2016 
Page 3 of 84 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  An Open-label Extension (OLE) Study to Assess the Long-term Safety and Efficacy of 
AMG 334 
Study Phase:  Open-label extension 
Indication:  Prevention of chronic migraine 
Primary Objective:  To characterize the safety and tolerability of long-term administration of 
AMG 334    
• 
Primary Objective of Clinical Home Use (CHU) Substudy:  To assess users’ ability to 
administer a full dose of AMG 334 in home-use, using either two prefilled syringes (PFS) or 
two prefilled autoinjector/pens (AI/pen). 
Secondary Objectives:   
• 
To characterize the efficacy of long-term administration of AMG 334 as assessed by: 
• 
Change from baseline in monthly migraine days 
• 
Proportion of subjects with at least 50% reduction from baseline in monthly migraine days 
• 
Change from baseline in monthly acute migraine-specific medication treatment days 
• 
Change from baseline in monthly cumulative hours of headache  
• 
Secondary Objective of CHU Substudy:  To assess the safety and tolerability of AMG 334 
administered using two 1-mL PFS or two 1-mL AI/pens 
For the purpose of primary analysis for secondary and exploratory endpoints in the 20130255 
open-label extension (OLE) study, baseline is defined as baseline of the AMG 334 20120295 
parent study (from the first day subject used eDiary in baseline at week -4 study visit through the 
day prior to study day 1).  However, change from week 8 through 12 data of the parent study 
(hereafter referred to as parent study Month 3 data) will also be evaluated. 
Hypotheses:  The clinical hypothesis is that long-term exposure of AMG 334 will be safe and 
well tolerated in subjects with chronic migraine 
Primary Endpoint:  Subject incidence of adverse events 
Secondary Endpoints: 
• 
Change from baseline in monthly migraine days at assessment timepoints 
• 
Achievement of at least a 50% reduction from baseline in monthly migraine days at 
assessment timepoints 
• 
Change from baseline in monthly migraine-specific medication treatment days at assessment 
timepoints 
• 
Change from baseline in cumulative monthly headache hours at assessment timepoints 
Study Design:  This is a multicenter, open-label study designed to assess the long-term safety 
and efficacy of AMG 334.  Subjects who complete the 12-week double-blind treatment phase of 
the AMG 334 20120295 parent study and meet all AMG 334 20130255 eligibility criteria will be 
enrolled into the study.  Enrollment should occur within 14 days of the week 12 visit of the 
AMG 334 20120295 parent study.  Subjects who enroll in the AMG 334 20130255 study will end 
the AMG 334 20120295 study and will not participate in the parent study safety follow-up visit.  
Subjects may also elect to participate in a Novel Patient-reported Outcome Substudy in addition 
to a CHU substudy. 
All subjects who have not yet enrolled in the study will receive open-label AMG 334 140 mg every 
month (QM) subcutaneous (SC) for 13 months.  Subjects who are already enrolled in the 
20130255 study will increase the open-label dose from 70 mg QM to 140 mg QM at the first 
available opportunity at either week 4, 8, 12, 16, 20, 24, or 28 visits.  Subjects who have already 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 4 of 84 
CONFIDENTIAL 
 
 
completed the week 28 visit will continue to receive 70 mg QM.  Subjects will not have the option 
to decrease open-label AMG 334 from 140 mg QM to 70 mg QM.  The 13-month open-label 
AMG 334 treatment phase will be followed by a 12-week safety follow-up visit (16 weeks after last 
dose of investigational product).   
Sample Size:  All subjects who completed the 12-week double-blind treatment phase of the 
AMG 334 20120295 parent study, meet the inclusion and exclusion criteria for the AMG 334 
20130255 OLE study will be eligible to be enrolled.  Up to 651 subjects may participate in the 
study. 
Summary of Subject Eligibility Criteria:  Adults with history of chronic migraine and who 
completed the 12-week double-blind treatment phase of the parent study.  For a full list of 
eligibility criteria, please refer to Section 4.1.  
Amgen Investigational Product Dosage and Administration:  Investigational product (IP) 
(ie, AMG 334 70 mg or 140 mg) will be dosed QM by SC injection.  For subjects participating in 
the CHU substudy, IP is AMG 334 140 mg in either a PFS or prefilled AI/Pen. 
Procedures:  Prior to enrolling in this study, subjects will need to undergo week-12 procedures 
for the parent study.  In addition, subjects will need to meet eligibility criteria requirements, which 
includes review by the investigator of the parent study week-12 labs and electrocardiogram 
(ECG) central reader report.  Subject numbers will be the same as those in the parent study.   
After signing informed consent, subjects will have monthly in-clinic study visits throughout the 
13-month treatment phase.  During these visits, IP will be administered and study-related 
procedures will be completed.   
All subjects will receive open-label AMG 334 QM SC for 13 months followed by a 12-week safety 
follow up visit (16 weeks after the last dose of IP). 
Subjects will use an electronic diary (eDiary) every day between the Day 1 and month 3 visit, 
between the month 5 and 6 visit, between the month 9 and 10 visit, and between the 
month 12 and 13 visit to report information about their migraine and non-migraine headaches and 
acute medication use.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 1).   
Statistical Considerations:   
For the purpose of primary analysis for secondary and exploratory endpoints in the 20130255 
OLE study, baseline is defined as baseline of the AMG 334 20120295 parent study (from the first 
day subject used eDiary in baseline at week -4 study visit through the day prior to study day 1).  
However, change from parent study Month 3 data will also be evaluated. 
Descriptive statistics will be provided for all endpoints, including efficacy endpoints. 
The exposure-adjusted subject incidence of all treatment-emergent adverse events will be 
tabulated by system organ class and preferred term.  Tables of fatal adverse events, serious 
adverse events, and adverse events leading to withdrawal from investigational product will be 
provided.    
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version/Date:  
Version 4.0 – 01 November 2013 
 


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Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 7 of 84 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADL 
Activities of daily living 
ADE 
Adverse Device Effects 
AE 
Adverse event 
AI/pen 
Autoinjector/pen 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
Baseline 
For the purpose of primary analysis for secondary and exploratory 
endpoints in the 20130255 OLE study, baseline is defined as 
baseline of the AMG 334 20120295 parent study (from the first day 
subject used eDiary in baseline at week -4 study visit through the 
day prior to study day 1).   
Change from week 8 through 12 data of the parent study (referred to 
as parent study Month 3 data) will also be evaluated. 
BIL 
Bilirubin 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CGRP 
Calcitonin gene-related peptide 
CHU 
Clinical Home Use  
Cmax 
Peak concentration 
COAs 
Clinical Outcomes Assessments 
Combination-analgesic 
combination formulations of simple analgesics with opiates or 
butalbital 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
C-SSRS  
Columbia-Suicide Severity Rating Scale 
CTCAE   
Common Terminology Criteria for Adverse Events 
Day 1 / Study Day 1 
The first day that protocol-specified investigational product is 
administered to the subject 
DBF 
Dermal blood flow 
DILI 
Drug-induced liver injury 
EC90 
90% effective concentration 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 8 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
eDiary(ies) 
Electronic diary(ies) 
End of study for individual 
subject 
The last day at which protocol-specified procedures are conducted 
for an individual subject. 
End of Trial 
The time when the last subject is assessed for evaluation in the 
study (ie, when the last subject completes the study, which includes 
the safety follow-up visit after the last dose of investigational product, 
or is discontinued from the study). 
Enrollment 
Timepoint at which a subject meets all screening eligibility criteria 
and enrolls into the baseline phase of the study.   
ET 
Early termination 
ETO System 
Electronic Trial Operations System; an electronic system that is used 
to facilitate the operations of a clinical trial through the collection of 
study-related data.  The most common applications of an ETO 
system within a clinical trial are subject randomization and 
investigational product management.  The term is synonymous with 
the industry term Interactive Voice Response (IVR) / Interactive Web 
Response (IWR) System.   
FAS 
Full analysis set 
FDA 
Food and Drug Administration  
FSH 
Follicle-stimulating hormone 
HDL 
High-density lipoprotein 
Headache 
A migraine or non-migraine headache 
Headache Day 
Any calendar day in which the subject experiences a qualified 
migraine or non-migraine headache (initial onset, continuation or 
recurrence of the headache) lasting ≥ 4 continuous hours, or a 
headache of any duration for which acute medication (simple 
analgesics, combination analgesics, triptans, ergot-derivatives, 
opiates) was administered for treatment of headache pain. 
Headache Day with 
moderate or severe 
intensity 
Any calendar day in which the subject experiences a headache,  
with headache pain lasting ≥ 4 continuous hours, and a peak 
severity of moderate to severe, or of any severity or duration if the 
subject takes a triptan or ergot-derivative for headache pain 
ICF 
Informed consent form 
ICH GCP 
International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice  
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
INR 
International normalized ratio 
IP 
Investigational product (ie, AMG 334 or if participating in CHU 
substudy, AMG 334 in either a PFS or prefilled AI/Pen) 
IPIM 
Investigational Product Instructional Manual 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 9 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
IRB 
Institutional Review Board 
IVR/IWR System 
Interactive Voice Response (IVR) / Interactive Web Response (IWR) 
System; telecommunication / internet technology that is linked to a 
central computer in real time as an interface to collect and process 
information. 
Kd 
The equilibrium dissociation constant 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
M 
Month 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MIDAS 
Migraine Disability Assessment 
Migraine Attack 
An episode of any qualified migraine headache or episode for which 
the subject took a triptan or ergot-derivative to treat headache or 
aura.  The following rules will be used for distinguishing an attack of 
long duration from two attacks, or for distinguishing between attacks 
and relapses: 
a) A migraine attack which is interrupted by sleep or temporarily 
remits, and then recurs within 48 hours after onset of the attack 
will be considered as one attack, and not two. 
b) An attack primarily treated successfully with medication but with 
relapse within 48 hours will be considered as one attack. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 10 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
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 either 
as a migraine without aura or a migraine with aura as outlined below: 
1. A migraine without aura, lasting for ≥ 4 continuous hours, and 
meeting criteria a and/or b: 
a) 
≥ 2 of the following pain features:   
• 
Unilateral 
• 
Throbbing 
• 
Moderate to severe 
• 
Exacerbated with  exercise/physical activity  
b) 
≥ 1 of the associated symptoms:   
• 
Nausea and/or vomiting  
• 
Photophobia and phonophobia 
OR 
2. A migraine with aura and meeting criteria a and b: 
a) 
Meeting ≥ 1 of the following fully reversible aura symptoms: 
• 
Visual 
• 
Sensory 
• 
Speech and/or language 
• 
Retinal 
• 
Brainstem 
b) 
Aura is accompanied, or followed within 60 minutes, by 
headache lasting for ≥ 4 continuous hours. 
If the subject took a triptan or ergot-derivative on a calendar day, 
then it will be counted as a migraine day regardless of the duration 
and pain features/associated symptoms. 
Monthly Headache Days 
Number of headache days in any 28-consecutive day interval 
relative to study day 1.   
Monthly Migraine Days 
Number of migraine days in any 28-consecutive day interval relative 
to study day 1.   
MPFID 
Migraine Physical Function Impact Diary 
MSQ 
Migraine-specific Quality of Life Questionnaire 
MWt 
molecular weight 
NOAEL 
No observed adverse effect level 
OLE 
Open-label extension 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 11 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Parent study 
AMG 334 20120295 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of AMG 334 in Chronic Migraine 
Prevention 
Parent study Month 3 
data 
Week 8 through 12 data of the parent study 
PD 
Pharmacodynamic 
PE 
Physical examination 
PET 
Positron emission tomography 
PFS 
Prefilled syringe 
PG 
Pharmacogenetic 
PK 
Pharmacokinetic 
Primary Completion 
The time when the last subject is assessed for evaluation in the 
study (ie, when the last subject completes the study, which includes 
the safety follow-up visit after the last dose of investigational product, 
or is discontinued from the study). 
PRO 
Patient-reported outcome 
PROMIS 
Patient Reported Outcomes Measurement Information System Pain 
Interference Scale short form 
QM 
Every month / Monthly 
RBC 
Red blood cell 
RDW 
Red blood cell distribution width 
RG 
Reference Guide 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SC 
Subcutaneous 
SEC 
Self-evident corrections 
SGOT 
serum glutamic-oxaloacetic transaminase; see AST 
SGPT 
serum glutamic-pyruvic transaminase; see ALT 
Simple analgesic 
Includes non-narcotic analgesics such as acetaminophen or NSAIDs 
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).  Examples of source data include subject 
identification and randomization identification. 
TBL 
Total bilirubin 
tmax 
time to peak concentration 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 12 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
True abstinence 
To refrain from any sort of sexual activity that could involve the spill 
of an ejaculate, even if the spill does not occur. 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
Wk 
Week 
WOCBP 
Woman/women of childbearing potential; any female who has 
experienced menarche and does not meet the criteria for “Women 
not of childbearing potential” 
Women not
Any female who: 
 of 
childbearing potential 
• 
Is post-menopausal by history defined as  
o 
Age ≥ 55 years with cessation of menses for 12 or 
more months, OR  
o 
Age < 55 years but no spontaneous menses for at 
least 2 years, OR  
o 
Age < 55 years and spontaneous menses within the 
past 1 year, but currently amenorrheic (eg, 
spontaneous or secondary to hysterectomy), AND 
with postmenopausal gonadotropin levels 
(luteinizing hormone and follicle-stimulating 
hormone levels > 40 IU/L) or postmenopausal 
estradiol levels (< 5 ng/dL) or according to the 
definition of "postmenopausal range" for the 
laboratory involved. 
OR 
• 
Underwent bilateral oophorectomy OR 
• 
Underwent hysterectomy OR 
• 
Underwent bilateral salpingectomy. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 13 of 84 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 5 
Study Glossary .................................................................................................................. 7 
1. 
OBJECTIVES ......................................................................................................... 17 
1.1 
Primary ....................................................................................................... 17 
1.2 
Secondary .................................................................................................. 17 
1.3 
Exploratory ................................................................................................. 17 
2. 
BACKGROUND AND RATIONALE ........................................................................ 18 
2.1 
Disease ....................................................................................................... 18 
2.2 
AMG 334 Background ................................................................................ 20 
2.3 
Rationale .................................................................................................... 22 
2.4 
Clinical Hypotheses .................................................................................... 24 
3. 
EXPERIMENTAL PLAN ......................................................................................... 24 
3.1 
Study Design .............................................................................................. 24 
3.2 
Number of Sites .......................................................................................... 25 
3.3 
Number of Subjects .................................................................................... 25 
3.4 
Replacement of Subjects ............................................................................ 25 
3.5 
Estimated Study Duration ........................................................................... 25 
3.5.1 
Study Duration for Subjects ........................................................ 25 
3.5.2 
End of Study ............................................................................... 25 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 26 
4.1 
Inclusion and Exclusion Criteria ................................................................. 26 
4.1.1 
Inclusion Criteria ......................................................................... 26 
4.1.2 
Exclusion Criteria ........................................................................ 26 
5. 
SUBJECT ENROLLMENT ..................................................................................... 27 
6. 
TREATMENT PROCEDURES ............................................................................... 28 
6.1 
Classification of Product and Medical Devices ........................................... 28 
6.2 
Investigational Product ............................................................................... 28 
6.2.1 
Amgen Investigational Product - AMG 334 ................................ 29 
6.2.1.1 
Dosage, Administration, and Schedule .................... 29 
6.2.1.2 
Rules for Withholding or Restarting 
Investigational Product ............................................. 30 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 30 
6.3.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product due to Potential Hepatotoxicity ............. 30 
6.3.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product due to Potential Hepatotoxicity ............. 31 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 14 of 84 
CONFIDENTIAL 
 
 
6.3.3 
Criteria for Rechallenge of Amgen Investigational 
Product After Potential Hepatotoxicity ........................................ 32 
6.4 
Concomitant Therapy ................................................................................. 32 
6.5 
Excluded Treatments During Study Period ................................................ 33 
6.6 
Medical Devices ......................................................................................... 33 
6.7 
Product Complaints .................................................................................... 34 
7. 
STUDY PROCEDURES ......................................................................................... 34 
7.1 
Schedule of Assessments .......................................................................... 34 
7.2 
General Study Procedures ......................................................................... 40 
7.2.1 
Study Specific Assessments ...................................................... 40 
7.2.1.1 
Informed Consent .................................................... 40 
7.2.1.2 
Calls to Interactive Voice Response (IVR) / 
Interactive Web Response (IWR) System ............... 40 
7.2.1.3 
Physical Examination ............................................... 40 
7.2.1.4 
Weight Measurements ............................................. 40 
7.2.1.5 
Vital Signs ................................................................ 40 
7.2.1.6 
Urine Drug Screening .............................................. 41 
7.2.1.7 
Pregnancy Testing for Women of 
Childbearing Potential .............................................. 41 
7.2.1.8 
Electrocardiogram (ECG) ......................................... 41 
7.2.1.9 
Pharmacokinetic (PK) Sampling .............................. 42 
7.2.1.10 
Clinical Outcomes Assessments (COAs) 
and Electronic Diaries (eDiaries) ............................. 42 
7.2.1.11 
Migraine Symptom Interference Items ..................... 43 
7.2.1.12 
Patient Reported Outcomes Measurement 
Information System (PROMIS) Pain 
Interference Scale Short Form ................................. 43 
7.2.1.13 
Migraine-specific Quality of Life 
Questionnaire (MSQ) ............................................... 43 
7.2.1.14 
Migraine Disability Assessment 
Questionnaire (MIDAS) ............................................ 44 
7.2.1.15 
Novel PRO Instrument Substudy 
(Optional) ................................................................. 44 
7.2.1.16 
Clinical Home Use Substudy (Optional; 
Limited to Subjects in US, Germany and 
Sweden) ................................................................... 45 
7.2.1.17 
Columbia-Suicide Severity Rating Scale 
(C-SSRS) ................................................................. 46 
7.2.1.18 
Concomitant Medications Recording ....................... 47 
7.2.1.19 
Adverse Event Reporting ......................................... 47 
7.2.1.20 
Laboratory Assessments ......................................... 47 
7.2.2 
Screening ................................................................................... 49 
7.2.3 
Day 1 .......................................................................................... 49 
7.2.4 
Open-label Treatment Phase ..................................................... 49 


 
 
 
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7.2.5 
Safety Follow-up ......................................................................... 51 
7.3 
Antibody Testing Procedures ..................................................................... 52 
7.4 
Biomarker Development ............................................................................. 52 
7.5 
Sample Storage and Destruction ................................................................ 53 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 54 
8.1 
Subjects’ Decision to Withdraw .................................................................. 54 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 55 
8.3 
Reasons for Removal From Treatment and Study ..................................... 55 
8.3.1 
Reasons for Removal From Treatment ...................................... 55 
8.3.2 
Reasons for Removal From Study ............................................. 55 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 55 
9.1 
Adverse Events .......................................................................................... 55 
9.1.1 
Definition of Adverse Events ...................................................... 55 
9.1.2 
Definition of Serious Adverse Events ......................................... 56 
9.2 
Reporting of Adverse Events ...................................................................... 57 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria .................................................................. 57 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 58 
9.3 
Adverse Event Adjudication ........................................................................ 59 
9.4 
Pregnancy and Lactation Reporting ........................................................... 60 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 61 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 61 
10.1.1 
Study Endpoints ......................................................................... 61 
10.1.1.1 
Primary Endpoint ..................................................... 61 
10.1.1.2 
Secondary Endpoints ............................................... 61 
10.1.1.3 
Exploratory Endpoints .............................................. 61 
10.1.1.4 
Clinical Outcome Assessments - Definition 
of Terms Included in Endpoints ............................... 62 
10.1.2 
Analysis Sets .............................................................................. 63 
10.1.3 
Covariates and Subgroups ......................................................... 63 
10.2 
Sample Size Considerations ...................................................................... 63 
10.3 
Planned Analyses ....................................................................................... 64 
10.3.1 
Interim Analyses ......................................................................... 64 
10.3.2 
Final Analysis ............................................................................. 64 
10.4 
Planned Methods of Analysis ..................................................................... 64 
10.4.1 
General Considerations .............................................................. 64 
10.4.2 
Efficacy Endpoint ........................................................................ 65 
10.4.3 
Safety Endpoints ........................................................................ 65 
10.4.4 
Others ......................................................................................... 66 
11. 
REGULATORY OBLIGATIONS ............................................................................. 66 


 
 
 
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11.1 
Informed Consent ....................................................................................... 66 
11.2 
Institutional Review Board/Independent Ethics 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 ........................................ 71 
12.5 
Language.................................................................................................... 72 
12.6 
Publication Policy ....................................................................................... 72 
12.7 
Compensation ............................................................................................ 73 
13. 
REFERENCES ....................................................................................................... 74 
14. 
APPENDICES ........................................................................................................ 77 
List of Tables 
Table 1.  Schedule of Assessments
 
 ................................................................................ 36
List of Figures 
Figure 1.  Predicted Capsaicin-induced Dermal Blood Flow (DBF) Inhibition 
(Left) and AMG 334 Exposure (Right) for the Phase 2 Doses
 
 ................. 24
List of Appendices 
Appendix A.  Additional Safety Assessment Information
 
 ................................................ 78
Appendix B.  Sample Serious Adverse Event Report Form
 
 ............................................ 81
Appendix C.  Pregnancy Notification Worksheet
 
 ............................................................ 83
Appendix D.  Lactation Notification Worksheet
 
 ............................................................... 84


 
 
 
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1. 
OBJECTIVES 
1.1 
Primary 
To characterize the safety and tolerability of long-term administration of AMG 334 
• 
Primary Objective of Clinical Home Use (CHU) Substudy:  To assess users’ ability to 
administer a full dose of AMG 334 in home-use, using either two prefilled syringes 
(PFS) or two prefilled autoinjector/pens (AI/pen) 
1.2 
Secondary 
To characterize the efficacy of long-term administration of AMG 334 as assessed by: 
• 
Change from baseline in monthly migraine days 
• 
Proportion of subjects with at least 50% reduction from baseline in monthly migraine 
days 
• 
Change from baseline in monthly acute migraine-specific medication treatment days   
• 
Change from baseline in monthly cumulative hours of headache  
For the purpose of primary analysis for secondary and exploratory endpoints in the 
20130255 open-label extension (OLE) study, baseline is defined as baseline of the 
AMG 334 20120295 parent study (from the first day subject used eDiary in baseline at 
week -4 study visit through the day prior to study day 1).  However, change from week 8 
through 12 data of the parent study (hereafter referred to as parent study Month 3 data) 
will also be evaluated. 
• 
Secondary Objective of CHU Substudy:  To assess the safety and tolerability of 
AMG 334 administered using two 1-mL PFS or two 1-mL AI/pens 
1.3 
Exploratory 
• 
To evaluate the effect of AMG 334 as measured by reduction from baseline in 
monthly migraine attacks, in subjects with chronic migraine  
• 
To evaluate the effect of AMG 334 as measured by the reduction from baseline in 
monthly headache (migraine and non-migraine headache) days, headache days with 
moderate or severe intensity, monthly average severity of migraine pain  
• 
To evaluate the effect of AMG 334 as measured by the change from baseline on 
monthly average severity of migraine related symptoms (nausea, vomiting, 
phonophobia, photophobia) for qualified migraine headaches  
• 
To evaluate the effect of AMG 334 on migraine-specific quality of life (as measured 
by the Migraine-Specific Quality of Life Questionnaire [MSQ], version 2.1), 
migraine-related disability (as measured by the Migraine Disability Assessment 
[MIDAS]), pain interference with daily activities and migraine-specific impact (as 
measured by the Patient-Reported Outcomes Measurement Information System 
[PROMIS] Pain Interference Scale short form and single pain and migraine symptom 
interference questions) 
• 
To evaluate effect of AMG 334 on change in physical impairment over time as 
measured by the Migraine Physical Function Impact Diary (MPFID)  


 
 
 
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• 
To evaluate the effect of AMG 334 on change in impact on everyday activities over 
time as measured by the MPFID 
• 
To evaluate AMG 334 pharmacokinetic (PK) in subjects with migraine    
• 
To investigate potential biomarker development by analysis of blood samples 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Migraine 
Migraine is a disabling disorder characterized by primary recurrent headaches with or 
without aura lasting 4 to 72 hours with at least two of the following pain characteristics:  
unilateral, pulsating, moderate or severe intensity, or aggravated by routine physical 
activity.  In addition, the migraine attacks are often accompanied by nausea, vomiting, 
and sensitivity to light (photophobia) and sound (phonophobia).  The pathophysiology of 
aura may differ from that of migraine pain (Eikermann-Haerter and Ayata, 2010).  
Migraine is a highly prevalent disease worldwide.  The prevalence of migraine is 
approximately 11.7% in the USA, 14.6% in Canada, and 14.7% in Europe 
(Lipton et al, 2007; Stovner and Andree, 2010).  The disease is more common in women 
than in men and presents most often during the period of an individual’s peak economic 
productivity between the ages of 30 and 50 years of age (Lipton et al, 2007; 
Stovner et al, 2007; Stovner and Andree, 2010).  Depending on the headache 
frequency, migraine is divided into two broad forms:  episodic migraine and chronic 
migraine [ICHD-3].  Episodic migraine is characterized by migraine with fewer than 
15 headache days per month, while chronic migraine is characterized by 15 or more 
headache days per month (where at least 8 of those days are migraine days).  Episodic 
and chronic migraine share many common features in terms of the clinical presentation, 
which include the headache pain features and associated symptoms.  However, there 
are also differences between patients with episodic and those with chronic migraine 
including epidemiologic profiles, risk factors and co-morbidities.  In general, patients with 
chronic migraine experience more severe and disabling migraine attacks, and have 
more co-morbidities (eg, depression and anxiety, chronic pain and cardiovascular 
disorders) than patients with episodic migraine.  Individuals with chronic migraine are 
typically older, have lower levels of overall education, lower household incomes and are 
less likely to be working full time than individuals diagnosed with episodic migraines 
(Diener et al, 2012; Katsarava et al, 2012).   


 
 
 
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Migraine headaches are commonly treated acutely.  The most frequently used acute 
migraine medications include analgesics and a class of drugs called triptans (Houston 
and Vanhoutte, 1986; Humphrey et al, 1990).  It has been demonstrated the triptans are 
effective in both episodic and chronic migraine, although those with chronic migraine 
tend to have less robust response to triptans than those with episodic migraine (Lipton 
and Chu, 2009).  Based on published treatment guidelines, up to 40% of the migraine 
patient population (including all patients with chronic migraine) would benefit from 
preventive therapy (Lipton et al, 2001).  The available migraine preventive therapies are 
associated with modest efficacy and significant tolerability and safety issues.  Migraine 
prophylaxis is an area of large unmet medical need.  While recommendations exist for 
the preventive treatment of migraine headache in the U.S. and Europe, most of the 
medications were evaluated in episodic migraine (Silberstein et al, 2012; Evers et al, 
2009).  Topiramate is the only migraine prophylactic agent with demonstrated efficacy in 
both episodic and chronic migraine patients through randomized placebo-controlled trials 
(Diener et al, 2007; Silberstein et al, 2007).  However, topiramate is poorly tolerated due 
to common adverse events such as paresthesias, anorexia, psychomotor slowing, 
somnolence, language difficulties, and difficulties with memory and concentration 
(Adelman et al, 2008; Brandes et al, 2004).  Additionally, onabotulinumtoxinA was 
recently approved by United States Food and Drug Administration (FDA), several EU 
countries, and Canada for prophylaxis of chronic migraine, based on 2 randomized, 
placebo-controlled, double-blind studies (Aurora et al, 2010; Diener et al, 2010).     
Calcitonin Gene-related Peptide (CGRP)  
Migraine was historically considered to be due to vasodilatation of cranial blood vessels.  
More recent understanding of the pathophysiology of migraine indicates that the 
vasodilatation of the cranial blood vessels is secondary to activation of the trigeminal 
nociceptive pathway (Goadsby et al, 2002).  CGRP is a 37 amino acid peptide 
expressed in both the central and peripheral nervous systems including the trigeminal 
ganglion and nucleus, and is believed to be a key mediator of migraine based on several 
lines of evidence.  CGRP was elevated in jugular venous blood  in migraine attacks 
(Goadsby et al, 1990) and was also elevated interictally in migraine patients (Ashina et 
al, 2000), and trials with antagonists to the CGRP receptor demonstrated efficacy in 
acute migraine with aura and migraine without aura (Connor et al 2009; Ho et al, 2008; 
Ho et al, 2010; Olesen et al, 2004).  It is expected that mechanistically antagonism of the 


 
 
 
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CGRP pathway could be a potentially effective treatment for prophylaxis of episodic as 
well as chronic migraine. 
2.2 
AMG 334 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) and 
competitively and reversibly blocks the binding of the native ligand, CGRP.  AMG 334 
functions as a CGRP receptor antagonist.   
The potential mechanisms of action of CGRP receptor antagonists involve components 
of the trigeminal-vascular system and include normalization of CGRP-induced 
vasodilation, reduction of CGRP-induced neurogenic inflammation, and inhibition of pain 
transmission at the trigeminal ganglion and trigeminal nucleus (Durham, 2004; Poyner, 
1992; Wang et al, 1995; Zimmermann et al, 1996).  The site of action for AMG 334 will 
be predominantly restricted to the periphery due to AMG 334’s physical size and 
structure (antibody).  While it is not definitively known whether the CGRP receptors that 
are relevant for migraine lie within or outside of the blood brain barrier, the following 
scientific evidence argues strongly for a predominant role for peripheral CGRP in the 
generation of migraine: 
1) 
CGRP-induced migraine headaches via intravenous (IV) infusion are most 
likely initiated through peripheral CGRP receptor signaling systems. 
a. Migraine can be initiated by IV infusion of peripherally restricted 
CGRP peptides in migraine patients (Lassen et al, 2002). 
b. CGRP is a 37-amino acid peptide (molecular weight [MWt] 
>3700 daltons).  It most likely has limited brain penetration across the 
blood brain barrier (MWt cut off for brain penetration is ~ 500 daltons). 
c. CGRP peptide has a short plasma half -life [mean plasma 
T½~11 min in man (Kraenzlin et al, 1985)].   
2) 
The physical and chemical properties of the CGRP-receptor antagonists 
olcegepant and telcagepant suggest that their site of action is likely to be in 
the periphery. 
a. Olcegepant is a peptidic IV CGRP-receptor antagonist that has a 
molecular weight (MWt 870 daltons)  that is greater than the upper 
limit for blood brain barrier penetration with low oral bioavailability 
(Rudolf et al, 2005).  
b. A positron emission tomography (PET) study showed minimal brain 
penetration of telcagepant and low central receptor occupancy 
(4-10%) at the clinically efficacious dose of 140 mg (Connor et al, 
2009; Ho et al, 2010; Hostetler et al, 2013).  This degree of receptor 
occupancy would be unlikely to produce a functional effect.  


 
 
 
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Furthermore, in a large clinical study, a higher dose of 300 mg was 
not more efficacious than the 150 mg dose, suggesting that the 
treatment effect was saturated at a lower dose of 150 mg, which has 
little to no evidence of brain receptor occupancy (Connor et al, 2009). 
3) 
Antagonist mechanisms typically require much higher receptor occupancy 
(>60%) to produce a pharmacodynamic (PD) effect resulting in efficacy 
(Grimwood and Hartig, 2009). 
Given the likely peripheral activity of AMG 334 and its mechanism of action, it is unlikely 
that it will impact the treatment of aura, which is considered a central phenomenon 
(Eikermann-Haerter et al, 2012).   
The preclinical toxicology data were generated in cynomolgus monkey as it is the only 
laboratory species in which AMG 334 had suitable binding and functional activity.  There 
were no significant findings in the toxicology studies that would predict a risk to human 
subjects.  The no-observed adverse effect level (NOAEL) was the maximum dose 
evaluated in the 6-month Good Laboratory Practice (GLP) toxicology study, 
150 mg/kg subcutaneous (SC).  There were no significant effects on electrocardiogram 
(ECG) parameters, blood pressure (BP) or respiration rate in the single dose 
cardiovascular study in cynomolgus monkeys. 
The safety and PK of AMG 334 have been evaluated in three phase 1 studies that 
administered a single SC dose up to 210 mg, multiple doses up to 140 mg in healthy 
male subjects, and multiple dose studies of 21 mg and 140 mg in male and female 
migraine subjects.     
Preliminary PK data are available from all subjects in the single dose first-in-human 
study.  AMG 334 exposure increased more than dose proportionally at doses from 
1 to 70 mg SC and increased approximately dose proportionally from 70 to 210 mg SC 
in healthy subjects.  The median time of maximum observed concentration (tmax) ranged 
from 4 to 11 days within the dose range of 1 to 210 mg SC.  There was no apparent 
difference in PK results between the healthy subject cohorts and the migraineur cohort. 
In preliminary PK results from healthy subjects in the multiple-dose study, the observed 
mean area under the curve (AUC)0-28d accumulation ratio at all 3 dose levels (21, 70, and 
140 mg) after 3 monthly SC administrations was < 2, which is consistent with the dosing 
frequency and half-life of monoclonal antibodies.  
Refer to the AMG 334 Investigator’s Brochure for additional information. 


 
 
 
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2.3 
Rationale 
Migraine prophylaxis in chronic migraine is an area of large unmet medical need, with 
existing therapies not fully efficacious or poorly tolerated.  While a variety of medications 
are used off-label for prophylaxis of chronic migraine, only onabotulinumtoxinA is 
approved for this indication.  CGRP receptor antagonism represents a novel approach to 
migraine therapies.  Results from the AMG 334 phase 2 study (Study 20120178) in 
subjects with episodic migraine demonstrated that the 70 mg dose resulted in 
statistically significant and clinically meaningful reductions in monthly migraine days at 
week 12 compared with placebo (70 mg: -3.40 vs Placebo: -2.28; Difference: -1.12; 
p = 0.02).  Neither the 7 mg nor the 21 mg dose was associated with statistically 
significant reductions in monthly migraine days.  The 70 mg dose produced statistically 
significant improvements in multiple secondary and exploratory outcome measures, 
including the 50% responder rate, monthly headache days, and monthly 
migraine-specific medication treatment days, while neither the 7 mg nor the 21 mg dose 
resulted in improvements in these measures.  Exposure-response analyses over a large 
range of PK exposures indicate that 70 mg is the lowest dose that results in efficacious 
concentrations (Lenz et al, 2015; Sun et al, 2015).  This study is designed to assess 
whether a CGRP receptor antagonist is safe and well tolerated in subjects with chronic 
migraine.   
Rationale for AMG 334 Open-label Treatment Dose  
A dose of AMG 334 70 mg was originally chosen for this phase 2 study based on the 
demonstration that this dose and higher doses have been generally well tolerated in 
phase 1 studies and that this dose is predicted to result in near complete inhibition of the 
peripheral CGRP receptor for a month.  To ensure optimal efficacy is achieved with 
AMG 334, a higher dose, 140 mg, is currently being evaluated in the double-blind 
placebo-controlled parent study in chronic migraine (Study 20120295) as well as in a 
phase 3 study in Episodic Migraine (Study 20120296) and efficacy data are being 
collected.  Based on the AMG 334 phase 2 data in Episodic Migraine, the open-label 
dose of AMG 334 is being increased in this study to 140 mg to provide additional 
6-month and one-year safety data. 
The no observed adverse effect level from preclinical toxicology studies was determined 
to be the high dose, 150 mg/kg SC twice weekly, corresponding to a maximum 
concentration (Cmax) of 2620 μg/mL, and AUC0-7d of 15300 μg•day/mL.  This is 275-fold 
and 296-fold higher than the observed mean Cmax and AUC0-28d,  in humans after the third 


 
 
 
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dose of the repeated monthly SC administration of 70 mg and 111-fold and 129-fold 
higher than the observed mean Cmax and AUC0-28 day after the third monthly subcutaneous 
administration in humans of 140 mg, after correcting the different dosing frequency in 
cynomolgus monkeys and humans. 
Based on the clinical data generated to date, it is expected that multiple doses of 
AMG 334 up to 140 mg will be well tolerated in subjects with migraine.  AMG 334 has 
been administered at single doses up to 210 mg SC and 140 mg IV and at doses up to 
140 mg SC administered monthly for 3 months in migraine subjects, and in healthy 
subjects at doses of 280 mg SC administered on day 1 followed by 210 mg SC 
administered on days 29 and 57.  Refer to the AMG 334 Investigator’s Brochure for 
details.   
The ability of AMG 334 to inhibit CGRP receptors in humans was evaluated by inhibition 
of the DBF increase induced by topical application of capsaicin.  This capsaicin-induced 
DBF model has been used to demonstrate proof of pharmacological activity for CGRP 
antagonists (eg, telcagepant, olcegepant) (Sinclair et al, 2010).  Based on the results of 
the study with AMG 334, a dose of 70 mg is predicted to result in near complete 
inhibition of the peripheral CGRP receptor for a month.  The plasma concentration 
achieved at 70 mg is approximately 10 fold higher than the 90% effective concentration 
(EC90) from the DBF model and is sustained for greater than 28 days (Figure 1).  The 
correlation between the DBF model and clinical efficacy in migraine prophylaxis has not 
been established with AMG 334 although clinical efficacy has been demonstrated in 
acute migraine treatment for telcagepant (a small molecule CGRP antagonist) at doses 
with concentrations approximately 2 - 4 fold higher than EC90 from the DBF model 
studies (Connor et al, 2009; Ho et al, 2008; Sinclair et al, 2010). 


 
 
 
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Figure 1.  Predicted Capsaicin-induced Dermal Blood Flow (DBF) Inhibition (Left) 
and AMG 334 Exposure (Right) for the Phase 2 Doses  
 
Figure legends:  Lines in figures are median predicted DBF inhibition as percent of maximum inhibition (Left) 
and time courses by dose for AMG 334 concentration (Right). Estimated mean maximum inhibition in DBF 
response from phase 1 study is approximately 93%. 
2.4 
Clinical Hypotheses 
The clinical hypothesis is that long-term exposure of AMG 334 will be safe and well 
tolerated in subjects with chronic migraine.  In the CHU substudy, it is hypothesized that 
users will be able to administer a full dose of AMG 334 comparably using either the PFS 
or prefilled AI/pen.  No formal hypotheses will be tested. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multicenter, open-label study designed to assess the long-term safety and 
efficacy of AMG 334.  Subjects who complete the 12-week double-blind treatment phase 
of the AMG 334 20120295 parent study and meet all AMG 334 20130255 eligibility 
criteria will be enrolled into the study.  Enrollment should occur within 14 days after the 
parent study’s week 12 visit.  Subjects who enroll in the AMG 334 20130255 study will 
end the AMG 334 20120295 study and will not participate in the parent study safety 
follow-up visit. 


 
 
 
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All subjects who have not yet enrolled in the study will receive open-label AMG 334 
140 mg every month (QM) SC for 13 months.  Subjects who are already enrolled in the 
20130255 study will increase the open-label dose from 70 mg QM to 140 mg QM at the 
first available opportunity at either week 4, 8, 12, 16, 20, 24, or 28 visits.  Subjects who 
have already completed the week 28 visit will continue to receive 70 mg QM.   
All subjects will receive open-label AMG 334 QM SC for 13 months followed by a 
12-week safety follow up visit (16 weeks after the last dose of investigational product 
[IP]).  
Investigational product (ie, AMG 334 70 mg or 140 mg) will be dosed QM, SC.  
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
It is anticipated that approximately 60 sites across North America and Europe will 
participate in the study.  The same sites that participate in the parent study will be 
utilized for the study.  All sites in the US, Sweden, and Germany may participate in the 
CHU substudy. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  Up to 
651 subjects may participate in the study.  Up to 80 subjects may participate in the CHU 
substudy. 
The sample size justification is described in Section 10.2. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced.   
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The planned length of participation in the study for an individual subject is up to 
16 months, which includes the 13-month open-label treatment phase and 3 month 
(12 weeks) safety follow-up after treatment phase. 
3.5.2 
End of Study 
Primary Completion and End of Trial:  The time when the last subject is assessed for 
evaluation in the study (ie, when the last subject completes the study, which includes the 


 
 
 
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safety follow-up visit after the last dose of investigational product, or is discontinued from 
the study). 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).     
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion and Exclusion Criteria  
4.1.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures 
102 
Completed the 12-week study visit and did not end IP early during the 
double-blind treatment period of the AMG 334 20120295 parent study, and is 
appropriate for continued treatment     
4.1.2 
Exclusion Criteria 
201 
Development of any unstable or clinically significant medical condition, laboratory 
or ECG abnormality following randomization into the parent study, that in the 
opinion of the investigator, would pose a risk to subject safety or interfere with 
the study evaluation, procedures or completion 
Note:  Any ECG abnormality noted by the central reader must be evaluated by 
the investigator to determine if the ECG finding is representative of an unstable 
or clinically significant medical condition. 
202 
Any subject who experienced an SAE in the parent study (AMG 334 20120295) 
for whom the investigator determined that there was a reasonable possibility that 
the event may have been caused by investigational medicinal product 
203 
In the opinion of the investigator, subject demonstrated poorly controlled 
hypertension following randomization into the parent study 
204 
Systolic blood pressure (BP) 160 mm Hg and/or diastolic BP 100 mm Hg or 
greater at screening/Day 1 
If the systolic BP is > 160 mm Hg or diastolic BP is > 100 mm Hg when initially 
assessed, BP may be repeated 30 minutes after the initial measurement.  BP 
measurements may only be repeated once after the initial measurement 
205 
Subject is currently or plans to participate in another clinical study during 
participation in this study 
206 
Subject who used excluded concomitant medications between week 8 and 
week 12 of the parent study 
207 
Pregnant (as confirmed by the week 12 urine pregnancy test of parent study) or 
breastfeeding, or is a female expecting to conceive during the study, including 
through 16 weeks after the last dose of investigational product   


 
 
 
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208 
Female subject of childbearing potential who is unwilling to use an acceptable 
method of effective contraception during treatment with AMG 334 through 
16 weeks after the last dose of investigational product.  Acceptable methods of 
effective birth control include not having intercourse (true abstinence, when this 
is in line with the preferred and usual lifestyle of the subject), hormonal birth 
control methods (pills, shots/injections, implants or patches), intrauterine devices, 
surgical contraceptive methods (vasectomy with medical assessment of the 
surgical success of this procedure or bilateral tubal ligation), or two barrier 
methods (each partner must use one barrier method) with spermicide - males 
must use a condom with spermicide; females must choose either a Diaphragm 
with spermicide, OR Cervical cap with spermicide, OR Contraceptive sponge 
with spermicide   
Female subjects not of childbearing potential are defined as any female who: 
• 
Is post-menopausal by history, defined as  
o Age ≥ 55 years with cessation of menses for 12 or more 
months, OR 
o Age < 55 years but no spontaneous menses for at least 
2 years, OR  
o Age < 55 years and spontaneous menses within the past 
1 year, but currently amenorrheic (eg, spontaneous or 
secondary to hysterectomy), AND with postmenopausal 
gonadotropin levels (luteinizing hormone and 
follicle-stimulating hormone levels > 40 IU/L) or 
postmenopausal estradiol levels (< 5 ng/dL) or according to 
the definition of "postmenopausal range" for the laboratory 
involved. 
OR  
• 
Underwent bilateral oophorectomy OR 
• 
Underwent hysterectomy OR 
• 
Underwent bilateral salpingectomy 
209 
Likely to not be able or available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures (eg, independent 
completion of electronic diary [eDiary] items) to the best of the subject’s and 
investigator’s knowledge 
5. 
SUBJECT ENROLLMENT 
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 (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the IRB/IEC and Amgen-approved ICF before 
commencement of study-specific procedures.   


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 28 of 84 
CONFIDENTIAL 
 
 
The screening phase starts when the subject signs and dates the ICF and ends when 
the subject is enrolled or screen failed (does not meet all screening eligibility criteria, 
refer to Section 4).  The screening phase must not begin prior to the completion of all 
week 12 procedures in the AMG 334 20120295 parent study and must be completed 
within 14 days following the week 12 procedures in the parent study.  Amgen may grant 
approval in cases for which additional time is required to confirm eligibility. 
Subjects are considered eligible for participation once they have completed week 12 
procedures in the parent study and meet all OLE study eligibility criteria.  Subjects will be 
considered enrolled once they have received at least one dose of IP.  The investigator is 
to document  the date of enrollment in the subject’s medical record and on the 
enrollment CRF. 
Investigators may re-test laboratory values within the allowed screening window (within 
14 days after the week 12 visit of the parent study).  Reasons for a re-test may include: 
• 
Laboratory value(s) out of range for unclear reasons 
• 
The subject has a medical condition that can be resolved prior to the re-test 
attempt. 
Subject numbers for this study will be an 11 digit number; the first 3 digits will be 
255 and the remaining 8 digits will match the last 8 digits of the 11 digit number assigned 
by IVR System in the parent study.  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.    
A subject who is determined to be ineligible must be registered as a screen fail in the 
IVR/IWR System. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product and Medical Devices 
The Amgen investigational product used in this study is AMG 334.   
For subjects participating in the CHU substudy, Amgen investigational product used is 
AMG 334 either in a PFS or prefilled AI/pen. 
6.2 
Investigational Product 
The double-blind treatment assignments from the parent study will remain blinded after 
subjects are enrolled into the OLE study until the primary analysis of the 20120295 study 
is conducted.  


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Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 30 of 84 
CONFIDENTIAL 
 
 
Please refer to specific instructions provided in the IPIM for additional information.   
6.2.1.2 
Rules for Withholding or Restarting Investigational Product  
Investigational product doses are fixed and will not be adjusted for individual subjects 
during the study.   
At any time during the study, the investigator may discontinue investigational product 
administration for any subject who experiences a severe or life-threatening adverse 
event reported by the investigator to be related to investigational product.  Refer to 
Section 9 for details regarding adverse event reporting.   
End of investigational product and early discontinuation from investigational product are 
to be registered in the IVR/IWR System. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransaminase [ALT], total bilirubin 
[TBL]) and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation 
(US FDA, 2009). 
6.3.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product due to Potential Hepatotoxicity 
Amgen investigational product will be discontinued permanently and the subject should 
be followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met:  
• 
TBL > 2x upper limit of normal (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 
> 3x ULN 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL 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:  20130255 
Date:  31 March 2016 
Page 31 of 84 
CONFIDENTIAL 
 
 
• 
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,  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 (NASH)  
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if Amgen investigational product should be 
withheld or permanently discontinued, as deemed appropriate for the safety of the 
subject.  
6.3.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product due to Potential Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational product outlined above and have no underlying liver disease, the 
following rules are recommended for withholding of Amgen investigational product and 
other protocol-required therapies:  
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).   
• 
OR: TBL > 3x ULN at any time 
• 
OR: ALP > 8x ULN at any time 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 32 of 84 
CONFIDENTIAL 
 
 
Amgen investigational product should be withheld pending investigation into alternative 
causes of DILI.  If investigational product(s) is withheld, the subject is to be followed 
according to recommendations in Appendix A for possible DILI.  Rechallenge may be 
considered if an alternative cause for impaired liver tests (ALT, AST, ALP) and/or 
elevated TBL, is discovered and the laboratory abnormalities resolve to normal or 
baseline (Section 6.3.3).   
6.3.3 
Criteria for Rechallenge of Amgen Investigational Product After 
Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product will be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.3.1) should never be rechallenged. 
6.4 
Concomitant Therapy  
Throughout the study and while the subject is receiving investigational product, 
investigators may prescribe any concomitant medications or treatments deemed 
necessary to provide adequate supportive care except as noted in Section 6.5.  For a 
subject who prematurely discontinues investigational product, concomitant therapy may 
be adjusted as needed. 
Concomitant therapies are to be collected from enrollment through the end of study.  
The therapy name, indication, dose, unit, frequency, route, start date, and stop date are 
to be recorded on each subject’s CRF or eDiary. 
During the parent study, the subject and investigator are to agree on the medications for 
the acute treatment of migraine pain and the appropriate dose(s) that the subject may 
take on an as-needed basis throughout the parent and open-label extension study.  
Medications for acute treatment of migraine pain include: simple analgesics, combination 
analgesics, triptans, ergot derivatives, opiates.  To avoid confounding the study results, 
new acute medications for treatment of headache pain should not be introduced and 
addition of daily medications that fall into the categories of simple analgesics, 
combination analgesics, triptans, and ergot-derivatives should be avoided, even if the 
medication is used for indications other than headache. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 33 of 84 
CONFIDENTIAL 
 
 
6.5 
Excluded Treatments During Study Period 
1. The following medications are excluded between screening and 4 weeks after last 
dose of IP: 
• 
Divalproex sodium, sodium valproate, topiramate, carbamazepine or 
gabapentin, 
• 
All beta blockers (for example: metoprolol, propranolol, timolol, atenolol, 
nadolol, nebivolol, pindolol, bisoprolol), 
• 
All tricyclic antidepressants (for example: amitriptyline, nortriptyline, 
protriptyline), 
• 
Flunarizine or verapamil, 
• 
Venlafaxine, desvenlafaxine, duloxetine or milnacipran, 
• 
Botulinum toxin (injected in the head and/or neck region), 
• 
Lisinopril,  
• 
Candesartan, 
• 
Butterbur, feverfew, magnesium (≥ 600 mg/day), riboflavin (≥ 100 mg/day), 
• 
Clonidine or guanfacine, 
• 
Cyproheptadine, 
• 
Methysergide, 
• 
Pizotifen 
2. The following medications are excluded only if used daily throughout the month for 
migraine prophylaxis between screening and 4 weeks after last dose of IP: 
• 
Fluoxetine, fluvoxamine, 
• 
Acetazolamide, 
• 
Picotamide, 
• 
Cyclandelate, 
• 
Ergot-derivatives, steroids, triptans, 
• 
Nicardipine, nifedipine, nimodipine 
If the above medications are used daily, but not for migraine prophylaxis, the doses 
should remain stable between screening and 4 weeks after last dose of IP.   
3. Investigational drugs, devices or procedures (eg, acupuncture, occipital stimulator, 
transcranial magnetic stimulation) between screening and 4 weeks after last dose 
of IP. 
6.6 
Medical Devices 
The AMG 334 70 mg/mL SureClick AI/pen is a single-use, disposable, handheld 
mechanical injection device that administers a fixed dose of AMG 334 70 mg/mL into 
subcutaneous tissue.  The AMG 334 prefilled AI/pen uses the same components as the 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 34 of 84 
CONFIDENTIAL 
 
 
commercially available Enbrel SureClick autoinjector but assembled with a HyFlow 
syringe. 
The AMG 334 PFS is a single-use, disposable, manual injection device that administers 
a single dose of AMG 334 into subcutaneous tissue.  Amgen has developed the 
AMG 334 PFS presentation using the commercially available sterile 1-mL long glass 
syringe components procured from Becton Dickinson Pharmaceutical Systems (BD). 
In addition, tuberculin syringes will be used in this study.  Authorized study staff will use 
the syringes to pull out investigational product from the vials in the subject’s assigned kit 
and administer the investigational product to the subject.   
Subjects participating in the CHU substudy will return the AI/pens or PFS back to the 
clinic for reconciliation and disposal by the site staff using a plastic box provided by 
Amgen to the clinical sites.  Medical devices that are not considered test articles may be 
used in the conduct of the study as part of standard of care (except for AI/pen or PFS).  
These devices, such as alcohol prep pads, are commercially available and 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.   
Detailed information regarding the medical devices will be provided separately in the 
IPIM. 
6.7 
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 any product(s) or device(s) after it is released to the clinic by Amgen or 
by distributors, and partners with whom Amgen manufactures the material.  This 
includes any products, devices, or combination products provisioned and/or 
repackaged/modified by Amgen.  Product(s) or device(s) includes IP.  Any product 
complaint(s) associated with an investigational product or device supplied by Amgen are 
to be reported according to the instructions provided in the IPIM. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
Refer to the Schedule of Assessments (Table 1) for an outline of the procedures 
required at each study visit.  Each study visit during the open-label treatment phase and 
the safety follow-up phase has a window of ± 4 consecutive calendar days.  The day 1 
visit should occur once a subject has completed all 12-week procedures of the parent 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 35 of 84 
CONFIDENTIAL 
 
 
study and within 14 days of the 12-week visit of the parent study.  The subject may not 
enroll in this study on the same day as the week 12 visit of the parent study as the 
investigator must review the week 12 laboratory data and the central read of the week 
12 ECG prior to enrolling the subject in order to assess clinical significance of this data 
as per exclusion criteria.  
All study procedures for a given study visit are to be completed on the same day. 
Investigators are responsible for ensuring that all study procedures are performed as 
specified in the protocol.   
Study visits should be conducted without additional non-protocol therapies and subjects 
should be reminded about the investigational nature of the study drug. 
Refer to the applicable supplemental (eg, laboratory) manuals for detailed collection and 
handling procedures.


 
 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 36 of 84 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
General Assessments and Administrative Procedures 
Screening 
Day 1
a 
Wk 
4 / 
M1 
Wk 
8 / 
M2 
Wk 
12 / 
M3 
Wk 
16 / 
M4 
Wk 
20 / 
M5 
Wk 24 / 
M6 
Wk 28 / 
M7 
Wk 
32 / 
M8 
Wk 36 / 
M9 
Wk 
40 / 
M10 
Wk 
44 / 
M11 
Wk 
48 / 
M12 
Wk 52 / 
M13 / 
ET 
Wk 64/M16 
(16 Wks/4M 
After Last 
Dose of IP) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital Signs  
X
b 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
 
 
X 
 
X 
 
 
X
c 
 
 
X
d 
 
 
 
X 
 
Concomitant 
Medications 
Recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IP Administration  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SAE/AE Recording  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calls to IVR/IWR 
System
e   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Brings 
eDiary to Site 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
Page 1 of 3 
Footnote defined on last page of the table 


 
 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 37 of 84 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
Laboratory Procedures and Clinical Outcome Assessments 
Screening 
Day 
1
a 
Wk 4 
/ M1 
Wk 8 
/ M2  
Wk 
12 / 
M3 
Wk 
16 / 
M4 
Wk 20 
/ M5 
Wk 
24 / 
M6 
Wk 
28 / 
M7 
Wk 
32 / 
M8 
Wk 
36 / 
M9 
Wk 
40 / 
M10 
Wk 
44 / 
M11 
Wk 
48 / 
M12 
Wk 52 / 
M13 / ET 
Wk 64/M16 
(16 Wks/4M 
After Last Dose 
of IP) 
UDS 
Testing as needed throughout study based on investigator’s clinical suspicion 
Pregnancy Test-
Urine  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test-
Serum 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry, 
Hematology 
 
 
X 
 
X 
 
 
X
c 
 
 
X
d 
 
 
 
X 
X 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biomarker 
Development 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PK Sampling  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Anti-AMG 334 
Antibodies 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
COAs 
 
Daily
f 
 
Daily
f 
 
 
Daily
f 
 
Daily
f 
 
Migraine Symptom  
Interference Items 
 
Daily
f 
 
Daily
f 
 
 
Daily
f 
 
Daily
f 
 
PROMIS 
 
Weekly
f 
 
Weekly
f 
 
 
Weekly
f 
 
Weekly
f 
 
MSQ 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MIDAS 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Novel PRO 
Substudy: The 
Migraine Physical 
Function Impact 
Diary (MPFID) 
 
Daily
f 
 
Daily
f 
 
 
Daily
f 
 
Daily
f 
 
C-SSRS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 2 of 3 
Footnote defined on last page of the table 


 
 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 38 of 84 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
Clinical Home Use Substudy Assessments 
Screening
 g 
Day 1
h 
Day 28 visit
i 
Day 29 Telephone 
visit 
Day 56 visit
j 
Day 57 Telephone 
visit 
Day 85 visit
 k/ ET
l 
Informed Consent  
X 
 
 
 
 
 
 
Randomization to PFS or AI/pen IP self-
administration arm 
 
X 
 
 
 
 
 
PFS or AI/pen Instruction
m 
X 
X 
 
 
 
 
 
Physical Examination 
 
X 
 
 
 
 
 
Self-administration IP on-site 
 
X 
 
 
 
 
 
Self-administration IP at non-clinic setting 
 
 
 
X 
 
X 
 
Study coordinator IP dispense 
 
 
X 
 
X 
 
 
Study coordinator IP reconcile 
 
X 
 
 
X 
 
X 
Inquiry re: administration of IP 
 
 
 
 
X 
 
 
X 
 
Review for ADEs 
 
X 
X 
X 
X 
X 
X 
Review for AEs/SAEs 
 
 
 
X 
 
X 
 
Product Complaints Recording (if applicable) 
 
X 
X 
X 
X 
X 
X 
Page 3 of 3 
Footnote defined on last page of the table 


 
 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 39 of 84 
CONFIDENTIAL 
 
 
a Day 1 visit should occur once a subject has completed all 12-week procedures of the parent study and within 14 days of the 12-week visit of the parent study. 
b BP should be measured as part of the screening criteria to determine eligibility (no later than at day 1 as long as BP is taken before subject is enrolled via IVR).  Note:  
BP taken at week 12 of the parent study (AMG 334 20120295) should not be used as screening BP. 
c Only for subjects who increased IP to 140 mg at week 12, 16, or 20 
d Only for subjects who increased IP to 140 mg at week 24 or 28 
e Additional steps during IVR/IWR call to accommodate IP dose increase from 70 mg to 140 mg (between week 4 and week 28). 
f Collection will start at the end of the applicable scheduled visit and finish at the beginning of the applicable scheduled visit. 
g Screening must occur 4 weeks prior to the planned start of the CHU substudy (week 8 or week 36 of the 20130255 study).  IVR System will be adjusted to 
accommodate CHU screening and randomization information as required. 
h Day 1 of the CHU is equivalent to either week 12 or week 40 of the 20130255 study. 
i Day 28 of the CHU is equivalent to either week 16 or week 44 of the 20130255 study. 
j Day 56 of the CHU is equivalent to either week 20 or week 48 of the 20130255 study. 
k Day 85 of the CHU is equivalent to either week 24 or week 52 of the 20130255 study; subject will receive AMG 334 140mg SC administered by site staff using vial 
formulation and will continue scheduled procedures and assessments as per 20130255 study. 
l ET:  If a subject early terminates the CHU substudy, he/she may receive administration of AMG 334 140 mg SC at site as per 20130255 protocol and will continue 
20130255 scheduled procedures and assessments as per 20130255 protocol. 
m Study coordinator will review PFS or AI/pen training materials (Reference Guide and Instructions for Use) with subject. 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 40 of 84 
CONFIDENTIAL 
 
 
7.2 
General Study Procedures  
7.2.1 
Study Specific Assessments 
7.2.1.1 
Informed Consent 
All subjects or legally authorized representatives must personally sign and date the 
Amgen/IRB/IEC approved ICF before any study-specific procedures are performed. 
7.2.1.2 
Calls to Interactive Voice Response (IVR) / Interactive Web 
Response (IWR) System 
Sites are to call the Interactive Voice Response (IVR) / Interactive Web Response (IWR) 
System for the following:  to enroll an eligible subject, to obtain the investigational 
product assignment, to register the end of investigational product, and to register study 
early termination (ET) or completion.  Subject data will be collected in the IVR/IWR 
system. 
7.2.1.3 
Physical Examination 
A complete physical examination (PE) per standard of care (including neurological 
exam) will be performed on all subjects.   
7.2.1.4 
Weight Measurements 
Weight is to be measured without shoes and is to be recorded on the Physical 
Measurements CRF. 
7.2.1.5 
Vital Signs 
The following measurements are to be performed: Systolic/diastolic blood pressure, 
heart rate, and body temperature.   
Blood pressure will be measured in the following manner: 
• 
Subjects should be lying in a supine position quietly and comfortably for at least 
5 minutes.  The upper arm should be bare without constrictive clothing and 
supported at heart level (such as with a pillow approximately 13 centimeters tall). 
• 
Caffeine, exercise, and smoking should be avoided for at least 30 minutes prior 
to measurement. 
• 
An appropriately-sized cuff (cuff bladder encircling at least 80 percent of the arm) 
should be used to ensure accuracy.  At least two measurements (separated by at 
least 5 minutes) should be made and the average recorded.  If there is a high 
value, it is acceptable to wait approximately 30 minutes before the next two blood 
pressure measurements are taken for the purpose of averaging and recording in 
the CRF. 
• 
Neither the subject nor the observer (measurer) should talk during measurement. 
The position selected for a subject should be the same that is used throughout the study 
and documented on the Vital Signs CRF.   


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 41 of 84 
CONFIDENTIAL 
 
 
If the screening systolic BP is > 160 mm Hg or diastolic BP is > 100 mm Hg when initially 
assessed, BP may be repeated 30 minutes after the initial measurement.  BP 
measurements may only be repeated once after the initial measurement. 
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the Vital Signs CRF. 
All measurements are to be recorded on the Vital Signs CRF. 
7.2.1.6 
Urine Drug Screening 
During the study, urine drug tests may be performed at the investigator’s discretion 
based on clinical suspicion.  Urine samples will be analyzed by the central laboratory.  
For a subject with a positive urine drug screen during the study (except for certain 
prescribed medications), the investigator should consider discontinuing the subject from 
investigational product. 
7.2.1.7 
Pregnancy Testing for Women of Childbearing Potential 
Female subjects of childbearing potential will have urine pregnancy tests throughout the 
treatment phase and a serum pregnancy test at the safety follow-up visit.  All urine 
pregnancy testing will be performed by the local laboratory. 
7.2.1.8 
Electrocardiogram (ECG) 
The subject must be in a supine position in a rested and calm state for at least 5 minutes 
before the 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.  The ECG must 
include the following measurements: Heart Rate, QRS, QT, QTc, and PR intervals.  
Sites will use ECG equipment supplied by Amgen.  It is the responsibility of the 
investigator to determine if the ECG tracings are consistent with a subject’s safe 
participation in the study.   The investigator will review and sign the original ECG tracing 
and retain the signed tracing with the subject’s source documents.  The central reader 
will review all ECGs.  At the request of Amgen, a copy of the original ECG will be made 
available to Amgen.   
Any ECG abnormality noted by the central reader must be evaluated by the investigator 
and discussed with the Amgen Medical Monitor as deemed necessary to determine if the 
ECG finding is representative of an unstable or clinically significant medical condition. 
Please refer to the central ECG reader manual for details. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 42 of 84 
CONFIDENTIAL 
 
 
7.2.1.9 
Pharmacokinetic (PK) Sampling 
Blood samples will be collected and assayed for AMG 334 serum concentration.  During 
the study visits at which investigational product is administered, the investigator will 
administer the investigational product to the subject after the PK sample has been 
collected. 
Please refer to the central laboratory manual for instructions on sample collection, 
processing, and shipping of PK samples. 
7.2.1.10 
Clinical Outcomes Assessments (COAs) and Electronic Diaries 
(eDiaries) 
Clinical Outcomes Assessments (COAs) will be collected by subjects using a handheld 
electronic diary (eDiary).  The eDiary will collect the following COAs: 
• 
Incidence of headache (ie, migraine with or without aura or non-migraine 
headache) 
• 
Time of onset of headache 
• 
Time of resolution of headache 
• 
Pain severity per headache 
• 
Pain features (eg, one-sided, throbbing, pain severity, worsens with 
exercise/physical activity)  
• 
Symptoms (eg, nausea, vomiting, photophobia, phonophobia) and related 
severity 
• 
Presence of aura  
• 
Use of acute medication  
Subjects will use an eDiary every day between the Day 1 and month 3 visit, between the 
month 5 and 6 visit, between the month 9 and 10 visit, and between the month 12 and 
13 visit to report information about their migraine and non-migraine headaches and 
acute medication use.  Subjects will be instructed to bring their eDiary to every study 
visit during the visits they interact with the eDiary.   
The subject’s eDiary will also be used for the completion of the following patient-reported 
outcomes (PROs) measures: Migraine symptom interference items (daily between the 
Day 1 and month 3 visit, between the month 5 and 6 visit, between the month 9 and 
10 visit, and between the month 12 and 13 visit), Patient Reported Outcomes 
Measurement Information System (PROMIS) Pain Interference Scale short form (weekly 
between the Day 1 and month 3 visit, between the month 5 and 6 visit, between the 
month 9 and 10 visit, and between the month 12 and 13 visit), Migraine-specific Quality 


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CCI


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 46 of 84 
CONFIDENTIAL 
 
 
event, serious adverse event, and concomitant medication assessment, vital signs 
measurement, ECGs, urinalysis, and blood draw for serum chemistry and hematology 
analytes and anti-AMG 334 antibody assay will be performed as described in the 
20130255 study.  Subjects will be randomized to self-administer either 2x70mg AMG 
334 via PFS or 2x70mg AMG 334 via prefilled AI/pen.  On the CHU day 1 visit (week 12 
or week 40 of AMG 334 20130255 study) the site should review the IFU and RG for 
AI/pen or PFS with the subject prior to administration of IP (depending upon device 
subject has been randomized to use).  On day 1 of the substudy, subjects will 
self-administer IP, AMG 334 140 mg SC with either two x 70 mg prefilled AI/pen or two 
x 70 mg PFS, under clinical site supervision.  Subjects will be provided a box containing 
either 2x70 mg PFS or 2x70 mg prefilled AI/pen at the CHU day 28 (week 16 or week 
44 of AMG 334 20130255 study) and day 56 (week 20 or week 48 of AMG 334 
20130255 study) visits and will self-administer IP individually without supervision at 
home on days 29 and 57 of the CHU substudy.  On CHU day 29 and day 57, site staff 
will call the subject at a previously scheduled time and will ask the subject which 
injection site was used, if the subject administered a full, partial, or no dose of AMG 334 
(after explaining that a full dose means that the entire volume of both PFS or AI/pens 
were injected) and will document the subject’s response in the CRF.  If the subject was 
not able to administer a full dose of AMG 334, the site staff will inquire further to 
determine if the subject experienced a device failure or use error that prevented the 
full-dose administration.  Safety will be monitored as adverse events, serious adverse 
events, and ADEs.  Day 85 is the end of the CHU substudy and sites will inquire about 
ADEs.  Day 85 of the CHU substudy is equivalent to either week 24 or week 52 of the 
20130255 study; site will administer AMG 334 140 mg SC and will continue 20130255 
scheduled procedures and assessments as per the 20130255 protocol.  If a subject 
early terminates the CHU substudy, he/she may receive administration of AMG 334 
140 mg SC at site as per the 20130255 protocol and will continue 20130255 scheduled 
procedures and assessments as per the 20130255 protocol.  Subjects who elect to early 
terminate the CHU substudy will not be replaced.   
7.2.1.17 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a clinical rating of suicide behavior and ideation, which consists of a 
maximum of 20 items and which defines 5 subtypes of suicidal ideation and behavior in 
addition to self-injurious behavior with no suicidal intent.  C-SSRS will be administered to 
study subjects at each study visit to assess possible suicide ideation and behavior.  
Reports of suicidal ideation with intent to act (severity of 4 or 5) and reports of actual, 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 47 of 84 
CONFIDENTIAL 
 
 
aborted, or interrupted suicide attempts or a behavior preparatory for making an attempt 
indicate subjects at high risk for suicide.  If such reports are identified, the investigator is 
to appropriately manage the subject in accordance with standard of care. 
7.2.1.18 
Concomitant Medications Recording 
Data on all concomitant therapies being taken by the subject should be collected 
throughout the study.  Acute medications taken during aura or to treat headache will be 
collected in the eDiary during the periods of daily diary collection, and data will include 
the medication name, date of administration, time of administration, dose, and route of 
administration.  Acute medications ongoing at the time of enrollment will be collected in 
the CRF.  Any new or change to dose regimen for an ongoing acute medication will also 
be collected in the CRF. 
Other concomitant therapies will be collected from the time of enrollment and throughout 
the end of study or ET in the CRF, and data will include the generic drug 
name/treatment, indication, and dates of administration.   
Refer to Section 6.4 regarding concomitant therapy and Section 6.5 for the list of 
treatments excluded during the study. 
7.2.1.19 
Adverse Event Reporting 
Adverse event information should be collected throughout the study and recorded at 
each study visit.  Refer to Section 9 for details.   
7.2.1.20 
Laboratory Assessments 
Sites must utilize the central laboratory for subject eligibility and assessments during the 
study, unless stated otherwise.  Laboratory samples will be processed and sent to the 
central laboratory which is responsible for either completing the assessment or shipping 
the samples to Amgen for assay, depending on the assessment.  The central laboratory 
will be utilized for parameters such as complete blood count (CBC) with differential, 
serum chemistry, urine drug screening and urinalysis.  Samples for PK testing, 
biomarker development, and anti-AMG 334 antibody testing will be sent to the central 
laboratory and the central laboratory will forward the samples to Amgen (or designee) for 
analysis.  Sites will use their local laboratory for urine pregnancy testing (for WOCBP).   
Please refer to the central laboratory manual for instructions on the collection, 
processing, and shipping of samples. 
Any sample collected according to the Schedule of Assessments (Table 1) may be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 48 of 84 
CONFIDENTIAL 
 
 
ensure subject safety.  This includes testing to ensure analytical methods produce 
reliable and valid data throughout the course of the study.  This may also include, but is 
not limited to, investigation of unexpected results, incurred sample reanalysis, and 
analyses for method transfer and comparability. 
Analyte Listing (all run by central laboratory, unless otherwise noted as 
“Amgen/designee” or “local” laboratory.  Please refer to the central laboratory manual for 
the complete listing of analytes run by the central laboratory):   
Chemistry  
Urinalysis 
Hematology 
Sodium 
Other Labs 
Specific gravity 
RBC 
Pregnancy testing-urine 
(local) 
Potassium 
pH 
Hemoglobin 
Pregnancy testing-serum 
Chloride 
Blood 
Hematocrit 
Urine drug screening 
Bicarbonate 
Protein  
MCV 
PK (Amgen/designee) 
Total protein 
Glucose 
MCH 
Anti-AMG 334 antibodies 
(Amgen/designee) 
Albumin 
Bilirubin 
MCHC 
Biomarker development 
(Amgen/designee) 
Calcium 
WBC 
RDW 
 
Magnesium  
RBC 
Reticulocytes 
Phosphorus  
Epithelial cells 
Platelets 
WBC 
Glucose  
Bacteria 
WBC Differential 
BUN or Urea  
Casts 
• 
Bands/stabs 
Creatinine 
eGFR MDRD 
Uric acid  
Crystals 
• 
Eosinophils 
• 
Basophils 
Total bilirubin 
CPK  
 
• 
Lymphocytes 
• 
Neutrophils  
Direct bilirubin  
 
• 
Monocytes  
Alk phos  
 
Myeloblasts  
AST (SGOT) 
 
• 
Promyelocytes  
ALT (SGPT) 
 
• 
Myelocytes  
Cholesterol  
 
• 
Metamyelocytes  
HDL  
 
• 
Atypical 
lymphocytes  
LDL 
Triglycerides  
TSH 
 
Nucleated RBC  


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 49 of 84 
CONFIDENTIAL 
 
 
7.2.2 
Screening 
After confirming the ICF has been signed, the following procedures are to be completed: 
• 
Vital signs 
• 
Subject brings eDiary to site 
• 
Screening call to IVR/IWR System 
7.2.3 
Day 1 
Review laboratory and central reader ECG report from week 12 visit of AMG 334 
20120295 study 
Vital signs (if not measured at Screening visit) 
After confirming subject eligibility, the following procedures are to be completed: 
• 
Enrollment of the subject using the IVR/IWR System 
• 
Concomitant medications recording 
• 
Serious and non-serious adverse event recording 
• 
Subject brings eDiary to site 
• 
Novel PRO Substudy:  The MPFID (optional) 
• 
Administration of AMG 334 140 mg SC.  Administration of AMG 334 should be the 
last procedure performed at each study visit. 
7.2.4 
Open-label Treatment Phase 
The following procedures are to be completed during the open-label treatment phase at 
time points designated in the Schedule of Assessments (Table 1). 
• 
Physical examination (including neurological examination) as per standard of care  
• 
Weight  
• 
Vital signs 
• 
ECG 
• 
Laboratory assessments using the central laboratory: urine drug screen (based upon 
the investigator’s clinical suspicion), chemistry and hematology panels  
• 
Urine pregnancy test 
• 
PK sampling 
• 
AMG 334 antibody collection 
• 
COAs, migraine symptom interference items and PROMIS 
• 
C-SSRS 
• 
MSQ and MIDAS.  The subject will complete these PROs while in the clinic, using 
the eDiary.  For each study visit, these PROs should be completed prior to invasive 
procedures (eg, blood draws).    


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 50 of 84 
CONFIDENTIAL 
 
 
• 
Novel PRO Substudy: The MPFID (optional) 
• 
Concomitant medications recording 
• 
Serious and non-serious adverse event recording 
• 
Subject brings eDiary to site 
• 
Administration of AMG 334 70 mg or 140 mg SC QM.  Administration of AMG 334 
should be the last procedure performed at each study visit. 
• 
Increase IP to 140 mg for subjects enrolled on 70 mg at first available opportunity at 
either week 4, 8, 12, 16, 20, 24 or 28 (during regular IP Assignment IVRS/IWRS call) 
• 
CHU Substudy in US, Germany, and Sweden (optional) 
• 
After confirming the ICF has been signed, the following procedures are to be 
completed:   
• 
Screening (20130255 week 8 or 36):  Review of IFU and RG for both PFS and 
prefilled AI/pen with subject 
• 
After confirming subject eligibility, the following procedures are to be completed: 
• 
Day 1 (20130255 week 12 or 40):   
• 
Randomization of the subject to PFS or prefilled AI/pen self-
administration using the IVR/IWR System 
• 
Site to instruct subject on how to self-administer AMG 334 with either 
PFS or prefilled AI/pen by reviewing entire IFU and RG 
• 
Physical examination of subject with particular attention to any skin 
abnormalities in areas that might be used for IP self-administration 
• 
Subject self-administration using either PFS or prefilled AI/pen under site 
supervision 
• 
Review for ADEs, adverse events, and serious adverse events 
• 
Study Coordinator to reconcile IP (PFS or prefilled AI/pen) 
• 
Product Complaint Recording (if applicable)  
• 
Day 28 (20130255 week 16 or 44):   
• 
Study coordinator dispenses PFS or prefilled AI/pen to subject for 
self-administration on day 29 
• 
Telephone call time scheduled for day 29 (Note, telephone visit must 
occur after subject has self-administered IP) 
• 
Product Complaint Recording (if applicable)  
• 
Day 29:   
• 
Subject self-administers AMG 334 using either PFS or prefilled AI/pen in 
non-clinic setting 
• 
Telephone visit with study coordinator to inquire of subject if he/she 
administered a full, partial, or no dose of AMG 334 
• 
If the subject was not able to administer a full dose of AMG 334, the site 
staff will inquire further to determine if the subject experienced a device 
failure or use error that prevented the full-dose administration 


 
 
 
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• 
Review adverse events/ADEs/serious adverse events 
• 
Product Complaint Recording (if applicable)   
• 
Day 56 (20130255 week 20 or 48):   
• 
Study coordinator dispenses PFS or prefilled AI/pen to subject for 
self-administration on day 57 
• 
Telephone call time scheduled for day 57 (Note, telephone visit must 
occur after subject has self-administered IP) 
• 
Product Complaint Recording (if applicable)  
• 
Day 57:   
• 
Subject self-administers AMG 334 using either PFS or prefilled AI/pen in 
non-clinic setting 
• 
Telephone visit with study coordinator to inquire of subject if he/she 
administered a full, partial, or no dose of AMG 334 
• 
If the subject was not able to administer a full dose of AMG 334, the site 
staff will inquire further to determine if the subject experienced a device 
failure or use error that prevented the full-dose administration 
• 
Review adverse events/ADEs/serious adverse events 
• 
Product Complaint Recording (if applicable)   
• 
Day 85 (20130255 week 24 or 52): End of CHU substudy   
• 
Study coordinator inquires about any ADEs, product complaint recording 
(if applicable)  
• 
Subject continues all 20130255 study assessments and IP is 
administered at site as per 20130255 protocol using vial formulation 
7.2.5 
Safety Follow-up 
The following procedures are to be completed for the safety follow-up as designated in 
the Schedule of Assessments (Table 1): 
• 
Register subject’s end of study using the IVR/IWR System   
• 
Weight 
• 
Vital signs 
• 
Laboratory assessments using the central laboratory: urine drug screen (based upon 
the investigator’s clinical suspicion), urinalysis, pregnancy testing (serum), chemistry 
and hematology panels 
• 
PK sampling 
• 
Biomarker development collection 
• 
AMG 334 antibody serum sampling 
• 
C-SSRS  


 
 
 
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• 
Concomitant medications recording 
• 
Serious and non-serious adverse event recording.  (Note: Serious and non-serious 
adverse events are to be collected through 16 weeks after the last dose of 
investigational product).   
7.3 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected at timepoints outlined in the 
Schedule of Assessments for the measurement of anti-AMG 334 binding antibodies.  
Samples testing positive for binding antibodies will also be tested for neutralizing 
antibodies and may be further characterized for quantity/titer, isotype, affinity and 
presence of immune complexes.  Additional blood samples may be obtained to rule out 
anti-AMG 334 antibodies during the study.   
Sites will be notified of any positive neutralizing antibody results to the investigational 
product at the end of the study for each subject.  If results are not provided, no 
neutralizing antibodies to the investigational product have been detected. 
Subjects who test positive for neutralizing antibodies to the investigational product at the 
final scheduled study visit will be asked to return for additional follow-up testing.  This 
testing is to occur approximately every 3 months starting from when the site has been 
notified of the positive result, until:  (1) neutralizing antibodies are no longer detectable 
or (2) the subject has been followed for a period of at least 1 year (± 4 weeks) post 
administration of investigational product.  All follow-up results, both positive and negative 
will be communicated to the sites.  More frequent testing (eg, every month) or testing for 
a longer period of time may be requested in the event of safety-related concerns.  
Follow-up testing is not required where it is established that the subject did not receive 
AMG 334. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-AMG 334 antibody response 
may also be asked to return for additional follow-up testing.   
7.4 
Biomarker Development 
Blood samples are to be collected for biomarker development, and samples collected for 
other testing could be utilized for 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 identifying disease subtypes, guiding therapy, and/or predicting disease 
severity.   


 
 
 
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Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to AMG 334.    
7.5 
Sample Storage and Destruction  
Any sample collected according to the Schedule of Assessments (Table 1) 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, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
migraine, the dose response and/or prediction of response to AMG 334, characterize 
antibody response, 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 pharmacogenetic, biomarker development, 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 retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
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. 


 
 
 
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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.   
Refer to Section 11.3 regarding 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 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 or other 
protocol-required therapies and must discuss with the subject the options for 
continuation of the Schedule of Assessments (Table 1) and collection of data, including 
endpoints and adverse events.  The investigator must document the change to the 
Schedule of Assessments (Table 1) and the level of follow-up that is agreed to by the 
subject (eg, in person, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, from review of the medical 
records).   
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 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   


 
 
 
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8.2 
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 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. 
8.3 
Reasons for Removal From Treatment and Study  
8.3.1 
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, failure to follow contraception, breast 
feeding, requirement for treatment not allowed in the protocol, and/or protocol 
requirements) 
• 
Death 
• 
Lost to follow-up 
• 
Decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• 
Lack of efficacy 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
Decision by sponsor  
• 
Withdrawal of consent from study 
• 
Death 
• 
Lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of 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.   


 
 
 
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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 (ie, 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.   
An adverse device effect (ADE) is any adverse event related to the use of 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. 
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.   
9.1.2 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
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 
• 
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 


 
 
 
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include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2 
Reporting of Adverse Events 
9.2.1 
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 first dose of investigational 
product through the end of study are reported using the applicable CRF (eg, Adverse 
Event Summary), including events that are reported to the Event Adjudication 
Committee for adjudication. 
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, 
• 
Assessment of relatedness to investigational product and/or any study-mandated 
activity or procedure, 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.  The criteria for grade 4 in the CTCAE grading scale differs from the 
regulatory criteria for serious adverse events.  It is left to the investigator’s judgment to 
report these grade 4 abnormalities as serious adverse events.   
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a new event on the Adverse Event Summary CRF. 
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?”   
During the CHU, the investigator must assess whether the adverse event is possibly 
related to the IP and/or device.  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 IP.  The investigator must assess whether the adverse event is possibly related to 
the PFS or prefilled AI/pen used to administer IP.  The relationship is indicated by a 


 
 
 
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“yes” or “no” response to the question:  Is there a reasonable possibility that the event 
may have been caused by the device? 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity or procedure (eg, administration of investigational product, 
device(s) [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/procedure (eg, administration of 
investigational product, device[s])?”  
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.  For example, hematuria caused by menstruation should 
generally not be considered an adverse event.  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. 
9.2.2 
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 ICF through end 
of study 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 applicable CRF, including events that are 
reported to the Event Adjudication Committee for adjudication. 
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event 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.  


 
 
 
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In addition to the attributes listed in Section 9.1.2, the investigator must also complete 
the Serious Adverse Events section of the Adverse Event Summary CRF. 
See Appendix B for a sample of the Serious Adverse Event Worksheet. 
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, Adverse 
Event Summary 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 IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice.  
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. 
9.3 
Adverse Event Adjudication 
In order to carefully evaluate cardiovascular and cerebrovascular events during the trial, 
all adverse events that are deemed to be of potential cardiovascular or cerebrovascular 
etiology will be submitted to an independent committee for adjudication.  Detailed 
definitions of these events to be adjudicated, including mapping of pre-defined preferred 
terms potentially indicative of cardiovascular or cerebrovascular etiology, will be 
provided in the Event Adjudication Committee Charter.  Adjudication of these adverse 


 
 
 
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events will be based on clinical, laboratory, and/or imaging data ordered at the treating 
physician’s discretion to assess and treat the event. 
The Event Adjudication Committee will be comprised of a group of experienced 
clinicians with expertise in cardiology and neurology.  The Event Adjudication Committee 
will be responsible for the review and adjudication of the selected adverse events in a 
blinded manner.  The responsibilities and procedures of the Event Adjudication 
Committee will be described in the Event Adjudication Committee Charter. 
9.4 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject while the 
subject is taking investigational product through 16 weeks after the last dose of 
investigational product, report the pregnancy to Amgen as specified below. 
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen’s 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 a male subject's female partner becomes pregnant, the investigator should 
discuss obtaining information regarding the birth outcome and health of the infant 
from the pregnant partner. 
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, neonatal death, or there is a fetal or neonatal congenital anomaly), the 
investigator will report the event as a serious adverse event. 
If a lactation case occurs while the female subject is taking investigational product 
through 16 weeks after the last dose of investigational product, report the lactation case 
to Amgen as specified below.  
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up 
with the investigator regarding additional information that may be requested. 


 
 
 
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10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
The primary endpoint for the study is subject incidence of adverse events. 
• 
Subject-reported outcome of attempted full-dose administration at each of day 29 
and day 57  
CHU Substudy 
10.1.1.2 
Secondary Endpoints 
• 
Change from baseline in monthly migraine days at assessment timepoints 
• 
Achievement of at least a 50% reduction from baseline in monthly migraine days at 
assessment timepoints 
• 
Change from baseline in monthly acute migraine-specific medication treatment days 
at assessment timepoints 
• 
Change from baseline in cumulative monthly headache hours at assessment 
timepoints 
• 
Subject incidence of adverse events, serious adverse events, and adverse device 
effects 
CHU Substudy 
10.1.1.3 
Exploratory Endpoints 
• 
Change from baseline in monthly migraine attacks at assessment timepoints  
• 
Change from baseline in monthly headache (migraine and non-migraine headache) 
days at assessment timepoints 
• 
Change from baseline in monthly moderate and severe headache (migraine and 
non-migraine headache) days at assessment timepoints 
• 
Reduction from baseline in monthly average severity of migraine pain at assessment 
timepoints 
• 
Change from baseline in monthly average severity of migraine related symptoms 
(nausea, vomiting, phonophobia, photophobia) for qualified migraine headaches at 
assessment timepoints 
• 
Change from baseline in migraine-specific quality of life, as measured by the MSQ, 
version 2.1 at assessment timepoints 
• 
Change from baseline in migraine-related disability, as measured by the MIDAS at 
assessment timepoints 
• 
Change from baseline in pain interference with daily activities and migraine-specific 
impact, as measured by the PROMIS Pain Interference Scale short form and single 
pain and migraine symptom interference questions at assessment timepoints 
• 
Change in physical impairment over time as measured by the MPFID  


 
 
 
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• 
Change in impact on everyday activities over time as measured by the MPFID 
• 
AMG 334 exposure 
10.1.1.4 
Clinical Outcome Assessments - Definition of Terms Included in 
Endpoints 
Clinical outcome assessments will be determined via diary data. 
• 
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 either as a migraine without aura or a 
migraine with aura as outlined below: 
1. A migraine without aura, lasting for ≥ 4 continuous hours, and meeting criteria a 
and/or b: 
a) 
≥ 2 of the following pain features:   
• Unilateral 
• Throbbing 
• Moderate to severe 
• Exacerbated with exercise/physical activity  
b) 
≥ 1 of the associated symptoms:   
• Nausea and/or vomiting  
• Photophobia and phonophobia  
OR 
2. A migraine with aura and meeting criteria a and b: 
a) 
Meeting ≥ 1 of the following fully reversible aura symptoms: 
• Visual 
• Sensory 
• Speech and/or language 
• Retinal 
• Brainstem 
b) 
Aura is accompanied, or followed within 60 minutes, by headache lasting for 
≥ 4 continuous hours 
If the subject took a triptan or ergot-derivative on a calendar day, then it will be 
counted as a migraine day regardless of the duration and pain features/associated 
symptoms. 
• 
Headache Day:  Any calendar day in which the subject experiences a qualified 
migraine or non-migraine headache (initial onset, continuation or recurrence of the 
headache lasting ≥ 4 continuous hours, or a headache of any duration for which 
acute medication was administered (Refer to Section 6.4) for treatment of headache 
pain. 


 
 
 
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• 
Headache Day with moderate or severe intensity: Any calendar day in which the 
subject experiences a headache, with headache pain lasting ≥ 4 continuous hours, 
and a peak severity of moderate to severe, or of any severity or duration if the 
subject takes a triptan or ergot-derivative for headache pain 
• 
Monthly Migraine Days:  Number of migraine days in any 28-consecutive day interval 
relative to study day 1.  See above for the definition of a migraine day. 
• 
Monthly Headache Days:  Number of headache days in any 28-consecutive day 
interval relative to study day 1.  See above for the definition of a headache day.   
• 
Migraine Attack:  An episode of any qualified migraine headache or episode for 
which the subject took a triptan or ergot-derivative to treat headache or aura.  The 
following rules will be used for distinguishing an attack of long duration from two 
attacks, or for distinguishing between attacks and relapses: 
a) A migraine attack which is interrupted by sleep or temporarily remits, and then 
recurs within 48 hours after onset of the attack will be considered as one attack, 
and not two. 
b) An attack primarily treated successfully with medication but with relapse within 
48 hours will be considered as one attack. 
10.1.2 
Analysis Sets 
The full analysis set (FAS) includes all subjects who were enrolled in the study and 
received at least one dose of investigational product.  All subjects participating in the 
PRO substudy and have at least one monthly score for the MPFID will be included in the 
PRO analysis set.  All subjects enrolled in the CHU substudy will be included in the CHU 
analysis set.   
10.1.3 
Covariates and Subgroups 
Since no formal statistical testing is planned for either safety or efficacy endpoint, no 
covariate analysis will be performed.  
Subgroups: 
• 
Region (North America vs. other) 
• 
Medication overuse (Yes vs. no) 
10.2 
Sample Size Considerations 
All subjects who completed the 12-week double-blind treatment phase of the parent 
study, meet the inclusion and exclusion criteria for the 20130255 OLE study, and 
consent to receive IP will be eligible to be enrolled.  Up to 651 subjects may participate 
in the study.     
In the CHU Substudy:  Assuming 5% of subjects per treatment group discontinue IP and 
90% of the remaining subjects respond that they administered a full dose, then the 
anticipated distribution of responses per treatment group at a planned visit would be 


 
 
 
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5% categorized as not attempting due to discontinuing IP, 85.5% responding that they 
administered a full dose, and 9.5% responding that they did not administer a full dose.  
The associated 95% confidence interval halfwidths with 40 subjects per group are 
6.8%, 10.9%, and 9.1%, respectively.  The anticipated 95% confidence interval halfwidth 
for the difference between treatment groups in the proportion of subjects administering a 
full dose is 15.4%.  The discontinuation rate is expected to be less than 5% and the rate 
of administering a full dose is expected to be greater than 90%, and therefore these 
calculations are anticipated to be lower bounds.  Calculations were performed using 
nQuery Advisor 7.0. 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
On an annual basis or until an administrative decision is made to close the study, 
descriptive statistics of safety and efficacy will be produced for use in the annual report 
and/or to support publications, if warranted. 
An analysis of the data collected as part of the CHU substudy will be performed once the 
substudy has been completed.  In addition, an additional interim analysis may be 
performed as deemed necessary.  However, there are no stopping rules applied based 
on any interim analysis. 
10.3.2 
Final Analysis  
The final analysis for the study will be performed at the end of study. 
10.4 
Planned Methods of Analysis  
10.4.1 
General Considerations 
All subjects who have received at least one dose of AMG 334 in the study will be 
included in the data analysis according to their allocated treatment groups in the parent 
study, as well as an overall analysis (of all subjects in the OLE study). 
For the purpose of primary analysis for secondary and exploratory endpoints in the 
20130255 OLE study, baseline is defined as baseline of the AMG 334 20120295 parent 
study (from the first day subject used eDiary in baseline at week -4 study visit through 
the day prior to study day 1).  However, change from the parent study Month 3 data will 
also be evaluated. 
Descriptive statistics will be presented for all endpoints.  Summary statistics for 
continuous variables will include number of subjects, mean, median, standard deviation, 


 
 
 
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standard error, lower and upper quartiles, minimum, and maximum.  For categorical 
variables, frequency and percentage will be given. 
No formal statistical tests will be performed.  Missing values for safety endpoints will not 
be imputed. 
Subject disposition, demographics, and baseline characteristics will be summarized.  
The full analysis set will be utilized to tabulate subject disposition of all enrolled subjects, 
the demographic data, baseline disease characteristics, efficacy, and safety endpoints. 
10.4.2 
Efficacy Endpoint 
Descriptive summaries on efficacy endpoints will be provided by treatment group of the 
AMG 334 20120295 parent study (ie, AMG 334 70 mg, AMG 334 140 mg), treatment 
group of the AMG 334 20130255 study (AMG 334 70 mg if the max dose for a subject is 
70 mg, AMG 334 140 mg if the max dose for a subject is 140 mg), and study visit using 
the efficacy analysis set. 
10.4.3 
Safety Endpoints 
For safety endpoints, all enrolled subjects who received at least one dose of 
investigational product (ie, safety analysis set) will be analyzed based on the maximum 
actual treatment dose received using safety analysis set. 
The Medical Dictionary for Regulatory Activities (MedDRA) version 16 or later will be 
used to code all adverse events. 
The exposure-adjusted subject incidence of all treatment-emergent adverse events 
will be tabulated by system organ class and preferred term. 
Overall summary table of all treatment-emergent adverse events, serious, fatal, leading 
to withdrawal from investigational products, and treatment-related adverse events will be 
provided.  Tables of fatal adverse events, serious adverse events, and adverse events 
leading to withdrawal from investigational product will also be provided by system organ 
class and preferred term. 
Treatment-emergent adverse events and serious adverse events will be tabulated by 
preferred term in descending order of frequency.   
Subject incidence of adverse events, serious adverse events, and ADEs will be 
summarized by system organ class and preferred term for subjects enrolled in the CHU 
substudy. 


 
 
 
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Shift tables based on CTCAE grade relative to baseline will be tabulated by treatment 
group for selected laboratory analytes. 
The analyses of vital signs (systolic blood pressure, diastolic blood pressure, heart rate, 
temperature, weight) will include summary statistics of change from baseline measure 
over time by treatment group. 
The ECG measurements from this clinical study will be performed as per standard of 
care for routine safety monitoring, rather than for purposes of assessment of potential 
QTc effect.  Since these evaluations may not necessarily be performed under the 
rigorous conditions expected to lead to meaningful evaluation of QTc data, summaries 
and statistical analyses of ECG measurements are not planned, and these data would 
not be expected to be useful for meta-analysis with data from other studies. 
The incidence and percentage of subjects who develop anti-AMG 334 antibodies 
(binding and if positive, neutralizing) at any time will be tabulated by treatment group. 
The analysis of subject-reported outcome of attempted full-dose administration at each 
of day 29 and day 57 as collected in the CHU substudy will include calculating the 
proportion of each of the subject reported outcomes of attempted full-dose 
administration at each of weeks 4 and 8.  For all subjects who have not discontinued IP, 
a subject report of full dose administration will be considered a “yes” response, and a 
subject report of partial or no dose administered will be considered a “no” response.  The 
proportion of each possible pattern of responses across the two visits will also be 
estimated.  Ninety-five percent confidence intervals will be provided for each group and 
the difference in proportions between the groups. 
10.4.4 
Others 
Descriptive summaries of the primary and secondary endpoints may be provided by 
subgroups stated in Section 10.1.3. 
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 Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 


 
 
 
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Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject 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 products are administered.     
The investigator is also responsible for asking the subject 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 and 
the subject’s agreement or refusal of his/her notification of the primary care physician 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 and by the person who conducted the 
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. 
11.2 
Institutional Review Board/Independent Ethics 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/renewal 
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 for 
documents submitted to Amgen.   
• 
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 CRF demographics page, in addition to the unique subject identification 
number, include the age at 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 confidence by the investigator, except as described below. 
In compliance with Federal regulations/ International Conference on Harmonisation 
Tripartite Guideline on Good Clinical Practice (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 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, 
Investigator is to return the signed Investigator’s Signature page confirming 
agreement to continue participation in the study according to the amendment.  


 
 
 
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The IRB/IEC must be informed of all amendments and give approval.  The investigator 
must send a copy of the approval letter from the IRB/IEC to Amgen. 
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 ET 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, and by what mechanism, after 
termination of the study and before the product 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 CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF 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. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data).  In this study, the 
MSQ and MIDAS CRFs can be used as source documents.  
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 CRFs, 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 


 
 
 
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• 
Investigational product-related correspondence including proof of receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
Medical devices (ie, syringes) documentation, as applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
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, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen clinical monitor is responsible for verifying the CRFs 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 CRFs. 
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 CRFs, 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. 
All paper CRFs are to be typed or filled out with a black ballpoint pen and must be 
legible. 
• 
Corrections to paper forms are to be made by a single line stroke through the error 
and insertion of the correction above or beside the error.  The change must be 
initialed and dated by the investigator or a member of the study staff authorized by 
the investigator on the Amgen Delegation of Authority Form.  No erasures, correction 
fluid, or tape are to be used.   


 
 
 
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• 
Corrections to electronic forms are 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 and/or site notifications are sent to the site for completion and 
returned to Amgen. 
• 
The investigator signs (or inscribes and seals, if applicable) and dates the indicated 
places on the CRF.  These signatures indicate that the investigator inspected or 
reviewed the data on the CRF the data queries, and the site notifications, and agrees 
with the content. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
• 
Updates to CRFs 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 and/or site notifications are created in the EDC system 
database for site resolution and closed by Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that investigator inspected or reviewed the 
data on the CRF, the data queries, and the site notifications, and agrees with the 
content. 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the eCRF instructions 
available in the EDC system.  Examples of obvious data errors that may be corrected 
by Amgen (or designee) include deletion of obvious duplicate data (eg, same results 
sent twice with the same date with different visit-week 4 and ET) and clarifying “other, 
specify” if data are provided (eg, race, physical examination).  Each investigative site will 
be provided a list of the types of corrections applied to study data at the initiation of the 
trial and at study closeout.   
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 
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 


 
 
 
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Schedule of Assessments (Table 1), the investigator can search publicly available 
records [where permitted]) to ascertain survival status.  This ensures that the data sets 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
CRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 
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 
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 Publications 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; (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, 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 review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 


 
 
 
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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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AMG 334 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
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14. 
APPENDICES 


 
 
 
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Appendix A.  Additional Safety Assessment Information 
The Common Terminology Criteria for Adverse Events Version 4 (CTCAE v4) is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Adverse Event Grading Scale 
Grade 
Clinical Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL* 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self 
care ADL** 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
A semi-colon indicates ‘or’ within the description of the grade. 
Activities of Daily Living (ADL): 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
Drug-induced Liver Injury Reporting and Additional Assessments  
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 
Reporting 
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 CRF (eg, Adverse Event CRF) 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 9.2.2. 
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 
Additional Clinical Assessments and Observation 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 79 of 84 
CONFIDENTIAL 
 
 
Sections 6.3.1 and 6.3.2 or who experience AST or ALT elevations >3 x ULN 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 
bilirubin), 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 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
o Obtain complete blood count (CBC) with differential to assess for eosinophilia 
o Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
o Obtain serum acetaminophen (paracetamol) levels 
o Obtain a more detailed history of:  
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
• 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
o Obtain viral serologies 
o Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
o Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for PK analysis if this has not already been 
collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 80 of 84 
CONFIDENTIAL 
 
 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  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 CRFs. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 81 of 84 
CONFIDENTIAL 
 
 
Appendix B.  Sample Serious Adverse Event Report Form 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 82 of 84 
CONFIDENTIAL 
 
 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 83 of 84 
CONFIDENTIAL 
 
 
Appendix C.  Pregnancy Notification Worksheet 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 84 of 84 
CONFIDENTIAL 
 
 
Appendix D.  Lactation Notification Worksheet 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 1 of 11 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  An Open-label Extension (OLE) Study to Assess the Long-term 
Safety and Efficacy of AMG 334 
 
Amgen Protocol Number AMG 334 20130255 
EudraCT number 2013-005311-27 
 
Amendment Date: 
31 March 2016 
 
Rationale: 
This protocol is being amended to: 
• clarify language regarding length of time surrounding excluded treatments 
• align with current protocol template language (Sections 9 and 12) 
• update pregnancy and lactation notification worksheets 
• clarifications made to product complaints section 
• review of adverse events and serious adverse events added to Open-label 
treatment phase 
• serious adverse events collection added for Clinical Home Use Substudy 
• correct typographical, grammatical, and formatting errors throughout the protocol 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 2 of 11 
CONFIDENTIAL 
 
 
Description of Changes: 
Section: Global 
Change: Updated version date from 14 October 2015 to 31 March 2016 throughout 
the protocol. 
Section: Global 
Change: Added “prefilled” before all instances of “AI/Pen” to maintain consistency 
throughout the document. 
Section: Global 
Change: Typographical, grammatical, and formatting errors were corrected throughout 
the protocol. 
Section: Title Page 
Add: 
Amendment 3 
31 March 2016 
Section: Protocol Synopsis, Amgen Investigational Product Dosage and 
Administration 
Add: 
Investigational product (IP) (ie, AMG 334 70 mg or 140 mg) will be dosed QM by SC 
injection.  For subjects participating in the CHU substudy, IP is AMG 334 140 mg in 
either a PFS or prefilled AI/Pen. 
Section: Study Glossary 
Add: 
eCRF 
Electronic case report form 
ICMJE 
International Committee of Medical Journal Editors 
IP 
Investigational product (ie, AMG 334 or if participating in CHU 
substudy, AMG 334 in either a PFS or prefilled AI/Pen) 
SEC 
Self-evident corrections 
Section: 6.3 Hepatotoxicity Stopping and Rechallenge Rules 
Add: 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransaminase [ALT], total bilirubin 
[TBL]) and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis (as 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 3 of 11 
CONFIDENTIAL 
 
 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies as specified in the 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(US FDA, 2009). 
Section: 6.4 Concomitant Therapy, Paragraph 1 
Replace: 
Throughout the study and while the subject is receiving investigational product, 
investigators may prescribe any concomitant medications or treatments deemed 
necessary to provide adequate supportive care except for those listed in Section 6.5. 
With: 
Throughout the study and while the subject is receiving investigational product, 
investigators may prescribe any concomitant medications or treatments deemed 
necessary to provide adequate supportive care except as noted in Section 6.5. 
Section: 6.5 Excluded Treatments During Study Period, Bullet 1 
Replace: 
1. The following medications are excluded throughout the study: 
With: 
1. The following medications are excluded between screening and 4 weeks after 
last dose of IP: 
Section: 6.5 Excluded Treatments During Study Period, Bullet 2 
Add: 
2. The following medications are excluded only if used daily throughout the month 
for migraine prophylaxis between screening and 4 weeks after last dose of IP: 
Section: 6.5 Excluded Treatments During Study Period, Bullet 2, Paragraph 2 
Add: 
If the above medications are used daily, but not for migraine prophylaxis, the doses 
should remain stable between screening and 4 weeks after last dose of IP. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 4 of 11 
CONFIDENTIAL 
 
 
Section: 6.5 Excluded Treatments During Study Period, Bullet 3 
Replace: 
3. Investigational drugs, devices or procedures (eg, acupuncture, occipital 
stimulator, transcranial magnetic stimulation) throughout the study. 
With: 
3. Investigational drugs, devices or procedures (eg, acupuncture, occipital 
stimulator, transcranial magnetic stimulation) between screening and 4 weeks 
after last dose of IP. 
Section: 6.7 Product Complaints 
Add: 
This includes any products, devices, or combination products provisioned and/or 
repackaged/modified by Amgen.  Product(s) or device(s) includes IP.   
Section: 7.2.1.16 Clinical Home Use Substudy (Optional; Limited to Subjects in US, 
Germany and Sweden), Paragraph 4 
Add: 
Adverse event, serious adverse event, and concomitant medication assessment, vital 
signs measurement, ECGs, urinalysis, and blood draw for serum chemistry and 
hematology analytes and anti-AMG 334 antibody assay will be performed as described 
in the 20130255 study. 
Section: 7.2.4 Open-label Treatment Phase, Day 1 (20130255 week 12 or 40), Bullet 5 
Add: 
• 
Review for ADEs, adverse events, and serious adverse events 
Section: 9.1.1 Definition of Adverse Events, Paragraphs 2 and 3 
Add: 
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 (ie, 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.   


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 5 of 11 
CONFIDENTIAL 
 
 
An adverse device effect (ADE) is any adverse event related to the use of 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. 
Section: 9.2.1 Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria, Paragraph 2, Bullet 4 
Add: 
• 
Assessment of relatedness to investigational product and/or any 
study-mandated activity or procedure, and 
Section: 9.2.1 Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria, Paragraph 7 
Add: 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity or procedure (eg, administration of investigational product, 
device(s) [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/procedure (eg, administration of 
investigational product, device[s])?” 
Section: 9.4 Pregnancy and Lactation Reporting, Paragraph 2 
Replace: 
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen’s Global Patient Safety will 
seek to follow the pregnant woman throughout her pregnancy and her baby up to 
12 months after birth. 
With: 
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen’s Global Patient Safety will 
follow-up with the investigator regarding additional information that may be 
requested. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 6 of 11 
CONFIDENTIAL 
 
 
Section: 9.4 Pregnancy and Lactation Reporting, Paragraphs 3 and 4 
Add: 
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 a male subject's female partner becomes pregnant, the investigator should 
discuss obtaining information regarding the birth outcome and health of the infant 
from the pregnant partner. 
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, neonatal death, or there is a fetal or neonatal congenital anomaly), the 
investigator will report the event as a serious adverse event. 
Section: 9.4 Pregnancy and Lactation Reporting, Paragraph 6 
Add: 
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up 
with the investigator regarding additional information that may be requested. 
Section: 12.1 Protocol Amendments and Study Termination, Paragraph 1 
Replace: 
If Amgen amends the protocol, agreement from the investigator must be obtained. 
With: 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, 
Investigator is to return the signed Investigator’s Signature page confirming 
agreement to continue participation in the study according to the amendment. 
Section: 12.1 Protocol Amendments and Study Termination, Paragraph 2 
Replace: 
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the study contract. 
With: 
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the Clinical Trial Agreement. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 7 of 11 
CONFIDENTIAL 
 
 
Section: 12.3 Study Monitoring and Data Collection, Paragraph 7 
Replace: 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan. 
With: 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the eCRF instructions 
available in the EDC system. 
 
Section: 12.6 Publication Policy, Paragraph 1 
Replace: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors, 2013), which states: 
With: 
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 Publications of 
Scholarly Work in Medical Journals, which states: 
Section: 13. References 
Add: 
United States Food Drug Administration. Guidance for Industry Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation.  
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf.  Accessed 05 
April 2016. 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 8 of 11 
CONFIDENTIAL 
 
 
Section: Appendix C.  Pregnancy Notification Worksheet 
Replace: 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 9 of 11 
CONFIDENTIAL 
 
 
With: 
 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 10 of 11 
CONFIDENTIAL 
 
 
Section: Appendix D.  Lactation Notification Worksheet 
Replace: 
 


 
 
 
Product:  AMG 334 
Protocol Number:  20130255 
Date:  31 March 2016 
Page 11 of 11 
CONFIDENTIAL 
 
 
With: 
 
 

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Product:  AMG 334 
Statistical Analysis Plan:  20130255 
Date:  07 October 2016 
Page 21 
 
140 mg duration = minimum (last 140 mg dose date + 27, EOS date, date of data 
cut off) – first 140 mg dose date + 1. 
Change from Baseline in Monthly Efficacy Measurement 
The change from baseline in monthly efficacy measurement is the monthly efficacy 
measurement in between consecutive exposures to IP prior to the given time point 
minus the baseline monthly efficacy measurement (see Interval Based on Dose Dates 
for OLE Phase table presented in Section 6.4).  For example, the change from baseline 
in monthly migraine days at week 12 will be calculated as: 
(Monthly migraine days between week 12 interval start date and week 12 interval 
end date) – Baseline monthly migraine days  
If the baseline or post-baseline value is missing, then the change from baseline is set to 
be missing.  
Following efficacy endpoints will be calculated as above: 
Secondary endpoints 
 
change from baseline in monthly migraine days 
 
change from baseline in monthly acute migraine-specific medication treatment in 
days 
 
change from baseline in cumulative monthly headache hours 
Exploratory endpoints 
 
change from baseline in monthly migraine attacks 
 
change from baseline in monthly headache (migraine and non-migraine 
headache) days 
 
change from baseline in monthly moderate and severe headache (migraine and 
non-migraine headache) days 
 
change from baseline in monthly average severity of migraine pain 
 
change from baseline in monthly average severity of migraine related symptoms 
(nausea, vomiting, phonophobia, photophobia) for qualified migraine headaches 
 
Change from baseline in migraine-specific quality of life, as measured by 
the MSQ, version 2.1 
 
Change from baseline in migraine-related disability, as measured by the 
MIDAS 
 
Change from baseline in pain interference with daily activities and 
migraine-specific impact, as measured by the PROMIS Pain Interference 
Scale short form and single pain and migraine symptom interference 
questions 
 
Change in physical impairment over time as measured by the MPFID 


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