Clinical trial NCT02630459
Conditions: Migraine
Keywords: Migraine Prevention Headache Prophylaxis
Sponsor: Amgen
Start date: 2016-01-06; Completion date: 2019-06-05
Enrollment: 475 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized, double-blind, placebo-controlled, parallel-group, multicenter study followed by an open-label treatment phase (OLTP). To evaluate the effect of erenumab (AMG 334) compared to placebo on the change from baseline in monthly migraine days.

Detailed description:
This is a Phase 2, randomized, double-blind, placebo-controlled study in participants with episodic migraine. The study's double blind treatment phase (DBTP) is designed to evaluate if treatment with erenumab once a month for 6 months compared with placebo is effective in reducing the mean monthly migraine days. Additionally, this study will continue to evaluate the efficacy and safety of erenumab during the OLTP where participants will continue to receive active treatment monthly.

The study also includes a clinical home use (CHU) sub-study to assess a participant's ability to self-administer 140 mg of erenumab. Participants will be randomized 1:1 to use either 2 pre-filled 70 mg/mL autoinjector (AI)/pens or 1 pre-filled 140 mg/mL AI/pen. Participation in the substudy is optional, and no additional samples will be collected for the sub-study.

After implementation of Protocol Amendment 2, the dose of erenumab in the OLTP increased from 70 mg to 140 mg QM. Participants who had already completed week 48 remain on 70 mg QM, participants not yet starting the OLTP, or not yet completing the week 48 visit receive erenumab 140 mg QM for the remainder of the OLTP.

Arms: arm 1: Participants received placebo by subcutaneous injection on day 1 and at weeks 4, 8, 12, 16, and 20 in the double-blind treatment phase. arm 2: Participants received erenumab 28 mg by subcutaneous injection on day 1 and at weeks 4, 8, 12, 16, and 20 in the double-blind treatment phase. arm 3: Participants received erenumab 70 mg by subcutaneous injection on day 1 and at weeks 4, 8, 12, 16, and 20 in the double-blind treatment phase. arm 4: Participants received erenumab 140 mg by subcutaneous injection on day 1 and at weeks 4, 8, 12, 16, and 20 in the double-blind treatment phase. arm 5: Participants received an erenumab dose of 70 and/or 140 mg QM SC (depending on the participant's visit completion status after Institutional Review Board \[IRB\] approval of Protocol Amendment 2) in the OLTP for a total of 76 weeks. arm 6: A subset of participants in the OLTP randomized to self administer erenumab via two 70 mg/mL autoinjector (AI)/pens on day 29 and day 57 of the CHU Sub-Study arm 7: A subset of participants in the OLTP randomized to self administer erenumab via one 140 mg/mL AI/pen on day 29 and day 57 of the CHU Sub-Study
Interventions: intervention 1: Placebo intervention 2: Erenumab intervention 3: Erenumab
Intervention descriptions: intervention 1: placebo via subcutaneous injection intervention 2: erenumab via subcutaneous injection intervention 3: erenumab via autoinjector (AI)/pen

Protocol documents:
Prot_000.pdf: 
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Eletriptan hydrobromide 
Relpax (tablet) 
Rizatriptan benzoate 
Maxalt (tablet, RPD tablet) 
Naratriptan hydrochloride 
Amerge (tablet) 
NSAIDS 
 
Acetaminophen 
Calonal etc  
Aspirin 
Aspirin etc 
Ibupurofen 
Brufen etc 
Diclofenac sodium 
Voltaren etc 
Naproxen 
Naixan (tablet) 
Etodolac 
Hypen/ Osteluc (tablet) 
Celecoxib 
Celecox (tablet) 
Mefenamic acid 
Pontal (powder, fine granule, tablet capsule, syrup)  
Zaltoprofen  
Soleton/ Peon (tablet) 
Pranoprofen 
Niflan (tablet, syrup)/ Pransus (syrup) 
Loxoprofen 
Loxonin (fine granule, tablet) 
Lornoxicam 
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Cleamine combination tablet A, S 
Dihydroergotamine mesilate 
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Steroids 
Dexamethasone sodium phosphate 
Orgadrone/ Decadron (injection) 
Hydrocortisone  
Cortril (tablet) 
Others 
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Tramal (capsule, injection) 
Tramadol hydrochloride, acetaminophen 
Tramcet (combination tablet) 
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Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 1 of 80 
Amendment 2 
Protocol Title:  A Phase 2, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention 
 
Amgen Protocol Number AMG 334 20120309 
 
Amendment Date: 
05 June 2017 
 
Rationale: 
This is Amendment 2 for AMG 334 Study 20120309.  Amendment 1 for this protocol was 
not implemented and therefore, the changes captured in this document reflect changes 
made in both Amendment 1 and Amendment 2. 
The primary change to the protocol is to include a Clinical Home Use (CHU) substudy 
during the open-label phase.  The purpose of the CHU substudy is to assess subject’s 
ability to administer a full dose of AMG 334 in home use, using either 2 pre-filled 
70 mg/mL autoinjectors/pens (Als/pens) or 1 pre-filled 140 mg/mL Al/pen. 
In addition, the following were clarified to ensure alignment with study procedures: 
• 
Updated the open-label treatment phase to include AMG 334 dose increase to 
140 mg/mL. 
• 
Update the number of subjects that have received at least 1 dose of AMG 334 to 
date. 
• 
Update pregnancy, lactation, and contraception requirements in alignment with Core 
Risk & Discomforts language. 
• 
To align Section 6 (Treatment Procedures), Section 7 (Study Procedures), and 
Section 10 (Statistical Considerations) with changes made in the pivotal 20120296 
study. 
• 
To align Section 9 (Safety Data Collection, Recording, and Reporting), Section 12.6 
(Publication Policy), and End of Study language with new Amgen protocol template 
language. 
• 
Administration, typographical, and formatting changes were made throughout the 
protocol. 
CONFIDENTIAL 
 
 
 
 


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Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 3 of 80 
Section:  Protocol Synopsis, Clinical Home Use Substudy (During the Open-label 
Treatment Phase [OLTP]) Objectives 
Add: 
Clinical Home Use Substudy (During the Open-label Treatment Phase [OLTP]) 
Objectives: 
• 
Primary Objective:  To assess users’ ability to administer a full dose (140 mg) 
of AMG 334 in home-use, using either 2 pre-filled 70 mg/mL autoinjectors/pens 
(Als/pens) or 1 pre-filled 140 mg/mL AI/pen 
• 
Secondary Objective:  To assess the safety and tolerability of AMG 334 
administered using either 2 pre-filled 70 mg/mL AIs/pens or 1 pre-filled 
140 mg/mL AI/pen 
Section:  Protocol Synopsis, Hypothesis 
Add: 
In subjects with episodic migraine, AMG 334 reduces the mean monthly migraine days 
from baseline, compared to placebo.  In the clinical home use (CHU) substudy, it is 
hypothesized that users will be able to administer a full dose of AMG 334 
comparably using 2 pre-filled 70 mg/mL AIs/pens or 1 pre-filled 140 mg/mL AI/pen.  
No formal hypotheses will be tested in the CHU substudy. 
Section:  Protocol Synopsis, Clinical Home Use Substudy (During the OLTP) Endpoints 
Add: 
Clinical Home Use Substudy (During the OLTP) Endpoints: 
Primary Endpoint:  Subject-reported outcome of attempted full-dose 
administration at day 29 and day 57. 
Secondary Endpoint:  Subject incidence of adverse events, serious adverse 
events, and adverse device effects 
Section:  Protocol Synopsis, Study Design, Paragraph 2 
Add: 
Approximately 50 subjects will be enrolled in the AMG 334 20120309 CHU 
substudy to assess the subject’s ability to self-administer 140 mg of AMG 334 for 
in-home use.  Subjects will be randomized 1:1 to use either 2 pre-filled 70 mg/mL 
AIs/pens or 1 pre-filled 140 mg/mL AI/pen.  Participation in the substudy is 
optional, and no additional samples will be collected for the substudy. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 4 of 80 
Section:  Protocol Synopsis, Amgen Investigational Product Dosage and Administration, 
Paragraph 1 
Replace: 
Double-blind AMG 334 140 mg, AMG 334 70 mg, AMG 334 28 mg, or placebo will be 
administered during the 24-week double-blind treatment phase (ie, at day 1 and weeks 
4, 8, 12, 16, and 20) and AMG 334 70 mg will be administered during the 52-week 
open-label treatment phase (ie, at weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 
and 72). 
With: 
Double-blind AMG 334 140 mg, AMG 334 70 mg, AMG 334 28 mg, or placebo will be 
administered during the 24-week double-blind treatment phase (ie, at day 1 and weeks 
4, 8, 12, 16, and 20).  During the OLTP, AMG 334 70 mg or 140 mg QM SC will be 
administered, depending on the subject’s visit completion status after institutional 
review board (IRB) approval of Protocol Amendment 2. 
Section:  Protocol Synopsis, Procedures, Paragraph 1 
Replace: 
At the week 24 visit, subjects will be entered into the 52-week open-label treatment 
phase and will begin to receive open-label AMG 334 70 mg QM SC.  A safety follow-up 
visit occurs 16 weeks after the last dose of investigational product.  Subjects will use an 
electronic diary (eDiary) every day throughout the baseline phase, double-blind 
treatment phase and for the first 6 months and last month of the open-label treatment 
phase to report information about their migraine and non-migraine headaches and acute 
headache medication use.  Subjects will have in-clinic study visits monthly after the 
week 4 visit.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2). 
With: 
At the week 24 visit, subjects will be entered into the 76-week OLTP and will begin to 
receive open-label AMG 334. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 5 of 80 
After IRB approval of Protocol Amendment 2, the 24-week double-blind treatment 
phase is followed by a 76- week OLTP with the dose determined by the subject’s 
week 48 status: 
(1) Subjects who have already completed the week 48 visit will continue to 
receive open-label AMG 334 70 mg QM SC (OL70) for a total of 76 weeks.  
(2) Subjects who have not yet completed the double-blind treatment phase and 
are not yet in the open-label phase will receive AMG 334 140 mg QM SC 
(OL140) upon entering the open-label phase and continue receiving 
open-label AMG 334 140 mg QM SC for 76 weeks. 
(3) Subjects who have not yet completed the week 48 visit but are in the 
open-label phase receiving AMG 334 70 mg QM SC must increase their 
dose to AMG 334 140 mg QM SC and continue receiving open-label 
AMG 334 140 mg QM SC until the week 100 visit (OL70-140 ) for a total open 
label phase duration of 76 weeks.  The dose increase should be done at the 
first available opportunity, defined as the first visit after IRB approval of 
Protocol Amendment 2.  Refer to Table 3 for assessments to be collected at 
the visit of the dose increase and 12 weeks after the dose increase.  At the 
time of the dose increase, the End of Open-label 70 mg electronic case 
report form (eCRF) page will need to be completed as subjects will be 
transitioning from 70 mg to 140 mg. 
As a result of Protocol Amendment 2, there will be 3 possible dose sequences in 
the open-label phase, depending on completion of week 48 visit as noted above:  
(1) subjects receiving only AMG 334 70 mg QM SC in the open-label phase (OL70),  
(2) subjects receiving only AMG 334 140 mg QM SC in the open-label phase 
(OL140), (3) subjects receiving both AMG 334 70 mg (for up to 24 weeks) and 
140 mg QM SC (OL70-OL140).   
Subjects assigned to receive AMG 334 140 mg QM SC during the open-label phase 
will not have the option to decrease open-label AMG 334 from 140 mg QM to 
70 mg QM.  A safety follow-up visit occurs 16 weeks after the last dose of investigational 
product.  Subjects will use an electronic diary (eDiary) every day throughout the baseline 
phase and double-blind treatment phase and for the first 6 months and between the 
week 72 and week 76 study visits and between the week 96 and week 100/early 
termination (ET) study visits of the OLTP to report information about their migraine 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 6 of 80 
and non-migraine headaches and acute headache medication use.  Subjects will have 
in-clinic study visits monthly after the week 4 visit.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2-Table 3, and Table 4 for CHU 
substudy). 
Section: Protocol Synopsis, Statistical Considerations, Paragraph 1 
Replace: 
The final analysis for the study will occur after all subjects have completed safety 
follow-up through week 88 or discontinued from the study. 
With: 
The final analysis for the study will occur after all subjects have completed safety 
follow-up through week 112 or discontinued from the study. 
Section: Protocol Synopsis, Statistical Considerations, Paragraph 3 
Replace: 
For the open-label treatment phase, follow-up time adjusted subject incidence rate of 
treatment-emergent adverse events will be tabulated overall. 
With: 
For the OLTP, exposure-adjusted subject incidence rate of treatment-emergent adverse 
events will be tabulated overall. 
Section: Protocol Synopsis, Statistical Considerations, Paragraph 4 
Add: 
The proportion of subjects who administer a full dose of AMG 334 in home-use 
will be summarized by treatment group at CHU day 29 and day 57.  Subject 
incidence of adverse events, serious adverse events, and adverse device effects 
will be summarized by system organ class and preferred term for subjects 
enrolled in the CHU substudies. 
 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 7 of 80 
Section: Protocol Synopsis, Study Design and Treatment Schema,  
Replace: 
Study Design and Treatment Schema 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 8 of 80 
With: 
Study Design and Treatment Schema for Subjects That Completed Week 48 under Protocol Amendment 2 (OL70 subjects) 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 9 of 80 
Section: Protocol Synopsis, Study Design and Treatment Schema 
Add: 
Study Design and Treatment Schema for Subjects Still in the Double-blind Treatment Phase Protocol Amendment 2 
(OL140 Subjects) 
 
IP = investigational product; QM = monthly; SC = subcutaneous  
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 10 of 80 
Section: Protocol Synopsis, Study Design and Treatment Schema 
Add: 
Study Design and Treatment Schema for Subjects in the Open-label Phase AND Not Yet Completed W48 Under Protocol 
Amendment 2 (OL70-140 Subjects) 
 
IP = investigational product; QM = monthly; SC = subcutaneous 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 11 of 80 
Section:  Study Glossary 
Add: 
AI/Pen 
Autoinjector/pen 
ANCOVA 
Analysis of covariance 
CHU 
Clinical home use 
CMH 
Cochran-Mantel-Haenszel 
eCRF 
Electronic case report form 
IFU 
Instructions for use 
MAR 
Missing at random 
MI 
Multiple imputation 
MNAR 
Missing not at random 
Section:  Study Glossary 
Delete: 
AE 
Adverse event 
Section:  Study Glossary 
Replace: 
End of Trial 
The time when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, when the last 
subject completes the study, which includes the safety 
follow-up visit 16 weeks after the last dose of investigational 
product, or is discontinued from the study) 
Primary Completion 
The time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the 
primary analysis (ie, when the last subject completes the 
week 24 assessment or is discontinued from the study)    
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 12 of 80 
Women not of 
childbearing potential 
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.   
With: 
End of Study 
The end of study date is defined as the date when the last 
subject across all sites is assessed or receives an intervention 
for evaluation in the study (ie, the last subject last visit), 
following any additional parts in the study (eg, long-term 
follow-up), as applicable. 
Primary Completion 
The primary completion date is defined as the time when 
the last subject is assessed or receives an intervention for the 
final collection of data for the primary endpoint(s), for the 
purpose of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was 
terminated early. 
The primary completion date is the date when the last 
subject has completed the assessments for week 24 or is 
discontinued from the study.    
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 13 of 80 
Women not of 
childbearing potential 
• 
Any female who:  
o 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 a follicle-stimulating hormone level 
> 40 IU/L or according to the definition of 
"postmenopausal range" for the laboratory 
involved. 
OR 
• 
Underwent bilateral oophorectomy OR 
• 
Underwent hysterectomy OR 
• 
Underwent bilateral salpingectomy.   
Section:  1.3 Exploratory, Bullet 18 
Replace: 
• 
To evaluate the long-term safety, tolerability and maintenance of effect of AMG 334 
after 76 weeks of treatment 
With: 
• 
To evaluate the long-term safety, tolerability and maintenance of effect of AMG 334 
after 100 weeks of treatment  
Section:  1.4 Clinical Home Use Substudy 
Add: 
1.4 
Clinical Home Use Substudy 
1.4.1 Primary 
The primary objective of the clinical home use (CHU) substudy (during the 
open-label treatment phase [OLTP]) is to assess users’ ability to administer a full 
dose (140 mg) of AMG 334 in home-use, using either 2 pre-filled 70 mg/mL 
autoinjectors/pens (Als/pens) or 1 pre-filled 140 mg/mL AI/pen. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 14 of 80 
1.4.2 Secondary 
Secondary objective of the CHU substudy (OLTP):  To assess the safety and 
tolerability of AMG 334 administered using either 2 pre-filled 70 mg/mL Als/pens 
or 1 pre-filled 140 mg/mL AI/pen. 
Section:  2.2 Amgen Investigational Product AMG 334 Background, Paragraph 5 
Replace: 
As of November 2014, approximately 100 subjects (healthy subjects and migraineurs) 
had participated in Phase 1 studies, and 103 subjects with hot flashes associated with 
menopause participated in a Phase 2a study.  Approximately 152 subjects had received 
single or multiple doses of AMG 334 in the Phase 1 and Phase 2a studies.  AMG 334 
has demonstrated a favorable safety and tolerability profile similar to placebo in these 
studies.  Refer to the AMG 334 Investigator’s Brochure for details. 
With: 
As of January 2017, approximately 3623 subjects (2786.43 subject years) have 
received at least 1 dose of AMG 334.  This includes 613 healthy volunteers and 
2917 migraine subjects.  AMG 334 has to date, demonstrated a favorable safety and 
tolerability profile similar to placebo in these studies.  Refer to the AMG 334 
Investigator’s Brochure for details.  
Section:  2.3 Rationale, Paragraph 1 
Replace: 
Migraine prophylaxis is an area of a large unmet medical need, with existing therapies 
having modest efficacy and being poorly tolerated.   
With: 
Migraine prophylaxis is an area of a large unmet medical need, with existing therapies 
having modest efficacy and poor tolerability.   
Section:  2.3 Rationale, Rationale for AMG 334 Doses, Paragraph 1 
Add: 
In the open-label phase, the dose of AMG 334 is being increased to 140 mg in a 
subset of subjects to provide continuous 1-year safety data for subjects receiving 
either AMG 334 70 mg or 140 mg. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 15 of 80 
Section:  2.3 Rationale, Rationale for AMG 334 Doses, Paragraph 3 
Delete: 
AMG 334 140 mg currently is being evaluated in the ongoing chronic migraine study 
(Study 20120295) and efficacy data are being collected. 
Section:  2.3 Rationale, Rationale for AMG 334 Doses, Paragraph 5 
Replace: 
In the global Phase 2 episodic migraine study (Study 20120178), treatment-emergent 
adverse events (AEs) were reported by 165 (51.7%) subjects across all AMG 334 arms, 
and 82 (53.6%) subjects in the placebo arm. 
With: 
In the double blind treatment phase of the global Phase 2 episodic migraine study 
(Study 20120178), treatment-emergent adverse events were reported by 
165 (51.7%) subjects across all AMG 334 arms, and 82 (53.6%) subjects in the placebo 
arm. 
Section:  2.3 Rationale, Rationale for AMG 334 Doses, Paragraph 5 
Replace: 
The safety and tolerability data generated to date support further evaluation of the 70-mg 
dose in the Phase 3 studies. The study 20120178 open-label treatment phase is 
ongoing. 
With: 
The safety and tolerability data generated to date supported further evaluation of the 
70-mg dose in the Phase 3 studies. The study 20120178 OLTP is ongoing and the 
protocol has been amended to increase the open-label dose from 70 mg to 
140 mg. 
Section:  2.3 Rationale, Rationale for AMG 334 Doses, Paragraph 6 and 7 
Replace: 
The 140 mg of AMG 334 is included in the ongoing chronic migraine study 
(Study 20120295). As of 13 November 2014, 165 subjects had been randomized 
3:2:2 to placebo, AMG 334 70 mg, or AMG 334 140 mg, respectively.  Approximately 
47 subjects had been randomized to the 140 mg group. Blinded interim safety review did 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 16 of 80 
not reveal any safety signal. Among all subjects who were randomized in study 
20120295, four (4) subjects had discontinued investigational product, with 
two (2) subjects who discontinued investigational product due to adverse event 
(constipation, gastroesophageal reflux disease). Most commonly reported adverse 
events (≥ 2% in any group) included fatigue, muscle spasms, and nasopharyngitis. Five 
serious adverse events (cholecystectomy, non-cardiac chest pain, pancreatitis, parotitis, 
vomiting) had been reported and all were deemed by the investigator as not related to 
investigational product. 
Overall, the safety data generated to date for both 70 mg and 140 mg of AMG 334 
support further evaluation in Phase 3. 
With: 
AMG 334 140 mg has been evaluated for the prevention of episodic migraine in a 
global Phase 3 study (20120296) with a 24-week double-blind treatment phase.  
The study randomized 955 subjects (AMG 334 70 mg [n = 317], AMG 334 140 mg 
[n = 319], and placebo [n = 319], QM SC) with a history of migraine with or without 
aura for ≥ 12 months and a monthly migraine frequency of ≥ 4 to 
< 15 migraine days.  For the primary endpoint of change in monthly migraine days 
from baseline to the last 3 months (months 4, 5, and 6) of the 24-week 
double-blind treatment phase, the 70 mg and 140 mg doses were significantly 
different from placebo (-3.23 days and -3.67 days vs. -1.83 days, p < 0.001).  Both 
doses produced statistically significant improvements in the secondary outcome 
measures of 50% responder rate and monthly migraine-specific medication 
treatment days.  The results of the other secondary endpoints were consistent 
with those of the primary endpoint.  Across the primary and all secondary 
endpoints, AMG 334 140 mg showed numerically greater efficacy than 70 mg.  At 
the end of the double-blind treatment phase, subjects in each treatment group are 
re-randomized 1:1 in a blinded fashion to AMG 334 70 mg or AMG 334 140 mg for 
the 28-week active treatment phase, which is ongoing. 
During the placebo-controlled double-blind treatment phase of the 
20120296 study, treatment-emergent adverse events were reported in 57.3%, 
55.5%, and 63.0% of subjects in the AMG 334 70 mg, AMG 334 140 mg, and 
placebo groups, respectively, and most were Common Terminology Criteria for 
Adverse Events [CTCAE] grade 1 or 2 (mild to moderate in severity).  Study drug 
discontinuations due to adverse events were reported in 7 subjects (2.2%), 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 17 of 80 
6 subjects (1.9%), and 7 subjects (2.2%) in the AMG 334 70 mg, AMG 334 140 mg, 
and placebo groups, respectively.  The most frequent adverse events occurring in 
≥ 2% of all AMG 334 treated subjects were nasopharyngitis, upper respiratory tract 
infection, sinusitis, constipation, arthralgia, fatigue, and nausea. Serious adverse 
events were reported in 2.5%, 1.9%, and 2.2% of subjects in the AMG 334 70 mg, 
AMG 334 140 mg, and placebo groups, respectively.  No serious adverse event 
occurred in more than 1 subject, except cholelithiasis which was reported by 
2 subjects in the AMG 334 70 mg group (one of whom had clear risk factors).  
Study 20120296 and Study 20120309 are being monitored by the same 
independent DMC. 
In the global 12-week study 20120295, 667 subjects with chronic migraine 
(≥ 15 headache days per month, with ≥ 8 migraine days) were randomized to 
AMG 334 70 mg (n = 191), AMG 334 140 mg (n = 190), or placebo (n = 286), QM SC.  
For the primary endpoint of change in monthly migraine days from baseline to the 
last 4 weeks of the 12-week double-blind treatment phase, the 70 mg and 140 mg 
doses were significantly different from placebo (-6.64 days and -6.63 days vs. 
-4.18 days, p < 0.001).  Treatment-emergent adverse events were reported in 
39.0%, 43.7%, and 46.8% of subjects in the placebo, AMG 334 70 mg, and AMG 334 
140 mg groups, respectively.  No apparent dose-response pattern was observed 
across the most common treatment-emergent adverse events.  The most 
commonly reported adverse events occurring in ≥ 2% of all AMG 334 treated 
subjects were injection site pain, upper respiratory tract infection, nausea, 
nasopharyngitis, constipation, muscle spasms, and migraine.  Serious adverse 
events were reported in 2.5%, 3.2%, and 1.1% of subjects in the placebo, AMG 334 
70 mg, and AMG 334 140 mg groups, respectively.  No individual serious adverse 
event was reported in more than 1 subject in the placebo, AMG 334 70 mg, or 
AMG 334 140 mg groups.  Subjects from 20120295 were eligible to enroll in an 
ongoing 52-week open-label extension study (20130255), in which the original 
dose was 70 mg QM SC, but subsequently the dose was increased to 140 mg QM 
SC.  Of the 609 subjects enrolled, 259 subjects received at least one dose of 
AMG 334 140 mg.  Based on the interim analysis data cut-off of 01 September 2016 
with a mean (SD) duration of exposure to AMG 334 140 mg of 176.4 (70.9) days, 
the reported adverse events were consistent with the known safety profile of 
AMG 334. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 18 of 80 
The global Phase 2 study (20120178) in episodic migraine has an ongoing 
open-label phase of up to 256 weeks.  The original dose was 70 mg but a protocol 
amendment dated 07 April 2016 increased the dose to 140 mg for all subjects.  
Thus 140 mg has been investigated in the double-blind portions of studies 
20120296 and 20120295, as well in open-label or active treatment extension 
phases (studies 20120296, 20130255, 20120178), and no new safety signal has 
been detected.   
Section:  2.3 Rationale, Rationale for AMG 334 Doses, Figure 2 and Table 1 
Delete: 
Figure 2.  Predicted AMG 334 Exposure and Capsaicin-induced Dermal Blood Flow 
(DBF) Inhibition for the Phase 2 Doses Up to 52 Weeks of Dosing in the Japan Phase 2 
Study 
 
Figure legends: 50th (solid lines), 5th and 95th (lower and upper dashed lines) percentiles of predictions.  
Estimated mean maximum inhibition in DBF response from Phase 1 study is approximately 93%.     
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 19 of 80 
Table 1.  Predicted Safety Margins as Ratios of Exposure After SC Dosing of 70 mg 
Q4W Compared to Exposure Following the Highest Tested Safe Dose in Studies 
20101267 and 20101268 
Weight 
(kg)$ 
Predicted Exposure After 
Third Dose of  
70 mg Q4W SC 
Highest Observed Single 
Dose Exposure: 
Predicted Exposure at  
70 mg SC Q4W* 
Observed Multiple Dose 
Exposure at 140 mg SC 
Q4W: Predicted 
Exposure at 70 mg SC 
Q4W# 
Mean AUC0-
28D 
Mean Cmax 
AUC 
Cmax 
AUC 
Cmax 
(µg•day/mL) 
(µg/mL) 
72 
201 
9.4 
2.0 
5.1 
2.4 
2.5 
53 
284 
13 
1.4 
3.7 
1.7 
1.8 
SC = subcutaneous; Q4W = once every 4 weeks; AUC = area under the curve; Cmax = maximum 
concentration. 
$: 72 -kg reference weight for non-Japanese subjects and 53 -kg as typical body weight for a Japanese 
female subject 
*:  Ratios of observed 140 mg IV single dose PK to predicted 70 mg SC Q4W PK after third dose; observed 
mean (%CV) AUC0-28D and Cmax in Study 20101267 at 140 mg IV SD are 403 µg⋅day/mL (12.8) and 
47.8 µg/mL (8.55), N=6, respectively   
#: Ratios of observed 140 mg SC Q4W PK to predicted 70 mg SC Q4W PK after third dose; observed 
preliminary mean (%CV) AUC0-28D and Cmax for 140 mg SC Q4W after third dose in Study 20101268 are 
475 µg⋅day/mL(33.8) and 23.7 µg/mL (33.3), respectively. 
Section:  2.4 Clinical Hypothesis, Paragraph 1 
Add: 
In subjects with episodic migraine, AMG 334 reduces the mean monthly migraine days 
from baseline, compared to placebo.  In the CHU substudy, it is hypothesized that 
users will be able to administer a full dose of AMG 334 comparably using 
2 pre-filled 70 mg/mL AIs/pens or 1 pre-filled 140 mg/mL AI/pen.  No formal 
hypotheses will be tested in the CHU substudy. 
Section:  3.1 Study Design, Paragraph 1 
Replace: 
The study is composed of an initial screening phase (up to 3 weeks), a 4-week baseline 
phase, a 24-week double blind treatment phase, a 52-week open-label treatment phase, 
and an 12-week safety follow-up phase (16 weeks after the last dose of investigational 
product). 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 20 of 80 
With: 
The study is composed of an initial screening phase (up to 3 weeks), a 4-week baseline 
phase, a 24-week double-blind treatment phase, a 76-week OLTP, and a 12-week 
safety follow-up phase (16 weeks after the last dose of investigational product). 
Section:  3.2 Clinical Home Use Study Design (Optional) (new section) 
Add: 
3.2 
Clinical Home Use Study Design (Optional) 
Approximately 50 subjects will be enrolled in this AMG 334 20120309 CHU 
substudy to assess subjects’ ability to self-administer 140 mg of AMG 334 for 
in-home use.  Subjects will be randomized 1:1 to use either 2 pre-filled 70 mg/mL 
AIs/pens (for a total dose of 140 mg) or 1 pre-filled 140 mg/mL AI/pen.  It is 
hypothesized that users will be able to self-administer a full dose of AMG 334 
comparably using either dosage.  No formal hypotheses will be tested.   
Safety and tolerability of AMG 334 self-administered using two 70 mg/mL AIs/pens 
or one 140 mg/mL AI/pen will also be assessed.  Participation in the substudy is 
optional and no additional samples are collected for the substudy.  Subjects who 
elect to participate in this CHU substudy will be required to provide separate 
informed consent and must meet the eligibility criteria. 
CHU substudy screening (day -28) should occur during or after a subject has 
received at least 1 dose of open-label AMG 334 140 mg.  Subjects should also 
review the AI/pen instructions for use (IFU) at day -28 of the CHU substudy to 
determine if they wish to enroll in the substudy at day 1.  Subjects must have 
received at least 1 dose of AMG 334 140 mg by day 1 of the CHU substudy. 
Day 1 of the CHU substudy should correspond with any 20120309 study visit up 
through week 88.  At day 1, subjects who meet all eligibility criteria will be 
randomized via IVR System to self-administer AMG 334 using either two 70 mg/mL 
AIs/pens or one 140 mg/mL AI/pen (approximately 25 subjects in each arm).   
At CHU substudy day 1, areas that may be injected (upper arm, abdomen, or upper 
thigh) should be examined for any skin abnormalities; adverse events, serious 
adverse events, and adverse device effects will be collected during the CHU 
substudy, and will be assessed on CHU screening, day 1, day 28 (at site), and day 
56 (at site) and on CHU substudy days 29 and 57 (assessed by telephone visit).  
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 21 of 80 
Adverse event, serious adverse event, adverse device effect, concomitant 
medication therapies, 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 main study.  On the CHU substudy day 1 
visit, the site should review the IFU with the subject before administration of IP.  
On day 1 of the substudy, subjects will self-administer IP (two 70 mg/mL AIs/pens 
or one 140 mg/mL AI/pen) under clinical site supervision.   
Subjects will be provided a box containing either two 70 mg/mL AI/pens or one 
dose of 140 mg AI/pen at the CHU substudy day 28 and day 56 visits and will 
self-administer IP individually without supervision at home on substudy 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 the AI/pen was 
injected) and will document the subject’s response in the eCRF.  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 adverse device effects.   
Day 85 (clinic visit) is the end of the CHU substudy and sites will inquire about 
adverse events, serious adverse events, and adverse device effects.  At day 85 of 
the CHU substudy, site staff will administer AMG 334 140 mg SC and will continue 
the scheduled procedures and assessments as per the 20120309 protocol.  If a 
subject terminates the CHU substudy early, the subject may receive 
administration of AMG 334 140 mg SC at the site as per the 20120309 protocol and 
will continue 20120309 scheduled procedures and assessments as per the 
20120309 protocol. 
Section:  3.4 Number of Subjects, Paragraph 4 
Add: 
Approximately 50 subjects may participate in the CHU substudy. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 22 of 80 
Section:  3.6.1 Study Duration for Subjects, Paragraph 1 
Replace: 
The planned length of participation in the study for an individual subject is up to 
95 weeks, which includes the following: 
With: 
The planned length of participation in the study for an individual subject is up to 
119 weeks, which includes the following: 
Section:  3.6.1 Study Duration for Subjects, Bullet 4 
Replace: 
• 
52-week open-label treatment phase 
With: 
• 
76-week OLTP 
Section:  3.6.2 End of Study 
Replace: 
Primary Completion:  The time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis (such as 
when the last subject completes the week 24 assessment or is discontinued from the 
study).  
End of Trial:  The time when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, when the last subject completes the study, which includes the 
safety follow-up visit 16 weeks after the last dose of investigational product, or is 
discontinued from the study). 
With: 
Primary Completion:  The primary completion date is defined as the time when the 
last subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purpose of conducting the primary analysis, whether 
the study concluded as planned in the protocol or was terminated early.  
The primary completion date is the date when the last subject has completed the 
assessments for week 24 or is discontinued from the study).  
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 23 of 80 
If the study concludes prior to the primary completion date originally planned in 
the protocol (ie, early termination of the study), then the primary completion will 
be the date when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the study (eg, long-term 
follow-up), as applicable. 
Section:  4.1 Inclusion Criteria, Criterion 109 
Add: 
CHU Substudy: 
• 
Subjects must have provided informed consent for the substudy.  Subjects 
enrolling in the CHU substudy must have received open-label 140 mg 
AMG 334 for at least 1 dose. 
Section:  4.2 Exclusion Criteria, Criterion 221, Bullet 6 Sub-bullet 3 
Replace: 
 
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. 
With: 
 
Age < 55 years and spontaneous menses within the past 1 year, but currently 
amenorrheic (eg, spontaneous or secondary to hysterectomy), AND with a 
follicle-stimulating hormone level > 40 IU/L or according to the definition of 
"postmenopausal range" for the laboratory involved. 
Section:  4.2 Exclusion Criteria, Criterion 227 
Add: 
CHU Substudy 
227 
Unreliability as a study participant based on the investigator’s (or 
designee’s) knowledge of the subject (eg, unwillingness to adhere to the 
protocol, unwilling to self-inject using an AI/pen after review of the IFU).  
Subjects receiving AMG 334 70 mg in the open-label phase are not eligible. 
CONFIDENTIAL 
 
 
 
 


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Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 26 of 80 
should be separated by no more than approximately 1 minute.  During the open-label 
treatment phase, only 1 SC injection is to be given for each investigational product 
administration (ie, at weeks 24, 28, etc.).  The anatomical sites for administration of 
investigational product are the upper arm, upper thigh, or abdomen.  Please see the 
IPIM for investigational product details. 
With: 
During the double-blind treatment phase, 3 SC injections are to be given for each 
investigational product administration (ie, at day 1 and weeks 4, 8, 12, 16, and 20) to 
maintain the dose-level blinding.  The 3 SC injections should be separated by no more 
than approximately 1 minute.  During the OLTP, 1 SC injection is to be given for 
AMG 334 70 mg and 2 SC injections for AMG 334 140 mg.  If and when 140 mg/mL 
pre-filled syringes become available during the open-label phase, the 140 mg dose 
may be administered by a single 140 mg/mL SC injection. 
After IRB approval of Protocol Amendment 2, after the 24-week double-blind 
treatment phase, there is a 76-week OLTP with the dose determined by the 
subject’s week 48 status: 
(1) Subjects who have already completed the week 48 visit will continue to 
receive open-label AMG 334 70 mg QM SC (OL70) for a total of 76 weeks. 
(2) Subjects who have not yet completed the double-blind treatment phase and 
are not yet in the open-label phase will receive AMG 334 140 mg QM SC 
(OL140) upon entering the open-label phase and continue receiving 
open-label 140 mg QM SC for 76 weeks. 
(3) Subjects who have not yet completed the week 48 visit but are in the 
open-label phase receiving AMG 334 70 mg QM SC must increase their 
dose to AMG 334 140 mg QM SC and continue receiving open-label 
AMG 334 140 mg QM SC until the week 100 visit (OL70-140 ) for a total 
open-label phase duration of 76 weeks.  The dose increase to 140 mg 
should be done at the first available opportunity, defined as the first visit 
after IRB approval of Protocol Amendment 2.  At the time of the dose 
increase, the End of Open-label 70 mg eCRF page will need to be 
completed as subjects will be transitioning from 70 mg to 140 mg. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 27 of 80 
As a result of Protocol Amendment 2, there will be 3 possible dose sequences in 
the open-label phase, depending on completion of week 48 visit as noted above:  
(1) subjects receiving only AMG 334 70 mg QM SC in the open-label phase (OL70), 
(2) subjects receiving only AMG 334 140 mg QM SC in the open-label phase 
(OL140), and (3) subjects receiving both AMG 334 70 mg (for up to 24 weeks) and 
140 mg QM SC (OL70-140).  Subjects assigned to receive AMG 334 140 mg QM SC 
during the open-label phase will not have the option to decrease open-label 
AMG 334 from 140 mg QM to 70 mg QM. 
The anatomical sites for administration of investigational product are the upper arm, 
upper thigh, or abdomen.  Please see the IPIM for investigational product details. 
Section:  6.2.1.1 Dosage, Administration, and Schedule, Paragraph 7 
Add: 
During the CHU substudy, the subject will self-administer IP (1 or 2 injections 
using AI/pen) under site supervision on day 1.  On day 28 and day 56 during the 
CHU substudy, the site will provide IP to the subject to self-administer (1 or 
2 injections using AI/pen) on the next day.  The anatomical sites for 
self-administration are the upper thigh or abdomen.  The upper arm should only 
be used if administered by a care-giver.  During the CHU substudy the injection 
site location should be the same for all injections but do not use the same spot on 
the injection site you used for a previous injection.  For further details regarding 
self-administration procedures, the IFU should be consulted. 
Section:  6.2.1.1 Dosage, Administration, and Schedule, Paragraph 11 
Add: 
If a subject is enrolled in the CHU substudy, the box number provided to the 
subject and information obtained at telephone visits should be recorded by the 
site on each subject’s CRF, as described in Section 7.2.25.  
Section:  6.2.1.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation, Paragraph 5 
Replace: 
Subjects who permanently discontinue investigational product during the open-label 
treatment phase are to complete the study procedures for the week 76/early termination 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 28 of 80 
(ET) visit and the safety follow-up visit 16 weeks after the last dose of investigational 
product. 
With: 
Subjects who permanently discontinue investigational product during the OLTP are to 
complete the study procedures for the week 100/early termination (ET) visit and the 
safety follow-up visit 16 weeks after the last dose of investigational product. 
Section:  6.3 Hepatoxicity Stopping and Rechallenge Rules 
Replace: 
6.3 
Hepatoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [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 (as specified in the Guidance for Industry Drug-Induced 
Liver Injury:  Premarketing Clinical Evaluation, July 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) 
− 
Right sided heart failure, hypotension, or any cause of hypoxia to the liver 
causing ischemia   
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 29 of 80 
− 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms   
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, 
indinavir, atazanavir) 
− 
Alpha-one antitrypsin deficiency 
− 
Alcoholic hepatitis 
− 
Autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
Nonalcoholic Fatty Liver Disease including Nonalcoholic Steatohepatitis (NASH)  
− 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
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, and 
eligibility criteria requiring normal transaminases and TBL at baseline or subjects with 
underlying liver disease and baseline abnormal transaminases, the following rules are 
recommended for withholding of Amgen investigational product:  
• 
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 
Amgen investigational product should be withheld pending investigation into alternative 
causes of DILI.  If investigational product 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). 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 30 of 80 
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 should 
be permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.3.1) should never be rechallenged. 
With: 
6.3 
Hepatotoxicity Stopping Rules 
Refer to Appendix A for details regarding drug-induced liver injury (DILI) 
guidelines, as specified in the Guidance for Industry Drug-Induced Liver Injury:  
Premarketing Clinical Evaluation, July 2009. 
Section:  6.4 Concomitant Therapy, Paragraph 4 
Add: 
During the initial screening phase, the subject and investigator are to agree on the acute 
headache medications shown below (Table 1) and the appropriate dose(s) that the 
subject may take on an as-needed basis (PRN) throughout the study. 
Section:  6.4 Concomitant Therapy, Table Header 
Add: 
Table 1.  List of Acute Headache Medications 
Section:  6.5 Medical Devices, Paragraph 3 
Add: 
In the CHU substudy, the AMG 334 SureClick AI/pen is a single-use, disposable, 
handheld mechanical injection device that administers a fixed-dose of AMG 334 
into SC tissue.  The AMG 334 AI/pen uses the same components as the 
commercially available Repatha SureClick autoinjector. 
Subjects participating in the CHU substudy will return the AIs/pens 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 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 31 of 80 
AI/pen).  The investigator will be responsible for obtaining supplies of these 
devices. 
Detailed information regarding the medical devices will be provided separately in 
the IPIM. 
Section:  6.6 Product Complaints, Paragraph 1 
Replace: 
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 or devices provisioned and/or repackaged/modified by Amgen. 
With: 
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 for distribution to market 
or clinic by either Amgen or by distributors, and partners with whom Amgen 
manufactures the material.  This includes any products, devices, combination 
product(s) provisioned and/or repackaged/modified by Amgen.  Drug(s) or device(s) 
includes investigational product. 
Section:  6.7 Excluded Therapies Prior to the Start of the Baseline Phase and 
Throughout the Study, Number 5 
Replace: 
5. 
Investigational medications, devices, and procedures are excluded throughout 
the study.  Subjects also must not have used investigational medications, devices or 
procedures for at least 90 days prior to screening (refer to Exclusion Criterion 222). 
With: 
5 
Investigational medications and devices are excluded throughout the study.  
Subjects also must not have used investigational medications, devices or procedures for 
at least 90 days prior to screening (refer to Exclusion Criterion 222). 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 32 of 80 
Section:  7 Study Procedures, Paragraph 1 
Add: 
Refer to the Schedule of Assessments (Table 2-Table 4) for an outline of the procedures 
required at each study visit. 
Section:  7 Study Procedures, Paragraph 3, Bullet 3 
Replace: 
• 
Each study visit during the 52-week open-label treatment phase has a window of 
± 4 consecutive calendar days. 
With: 
• 
Each study visit during the 76-week OLTP has a window of ± 4 consecutive calendar 
days. 
Section:  7 Study Procedures, Paragraph 4 
Add: 
Refer to the Schedule of Assessments (Table 4) for an outline of the procedures 
required at each study visit in the CHU substudy.
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 33 of 80 
Section:  7.1 Schedule of Assessments, Table 2 
Add: 
Procedures 
Screening Phase  
(up to 7 wks) 
Double-blind Treatment Phase (24 wks) 1 
Initial 
Screening 
(up to  
3 wks) 2 
Baseline 
Phase  
(4 wks) 1 
D 1 
(post-
rand.) 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 / 
ET 3 
Wk 
-4 
D 1 
(pre-
rand.) 
Medical and Medication History 
X 
 
 
 
 
 
 
X 
 
 
Employment Status 15 
 
 
 
X 
 
 
X 
 
 
X 
Adverse Event/Serious Adverse Event 
Collection/Recording/Reporting 16 
X (SAEs only) 
X 
X 
X 
X 
X 
X 
X 
Section: 7.1 Schedule of Assessments, Table 2, Footnotes 
Replace: 
Footnotes defined on last page of the second table 
With: 
Footnotes defined on last page of Table 4. 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 34 of 80 
Section:  7.1 Schedule of Assessments, Table 3 
Replace: 
Procedures 
Open-label Treatment Phase (OLTP) (52 wks) 1 
Safety 
F/U 1 
Wk 
24 
(cont) 
Wk 
28 
Wk 32 
Wk 
36 
Wk 
40 
Wk 
44 
Wk 
48 
Wk 
52 
Wk 
56 
Wk 
60 
Wk 64 
Wk 
68 
Wk 72 
Wk 
76 
/ET 
16 Wks 
After Last 
Dose of 
IP 
Study Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calls to IVR/IWR System 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Entry into the OLTP 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Body Weight Measurement 7 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital Signs 8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UDS 
 
Testing as needed throughout study based on investigator’s clinical suspicion 
Pregnancy Testing- Serum 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testing- Urine 9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry, Hematology 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
ECG 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
PK Sampling 10 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Anti-AMG 334 Antibodies; 
Serum  
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
COAs 14 
X (Daily) 
 
 
 
 
X (Daily) 
 
Subject Brings eDiary to Site 
for Use during Study Visit 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
Migraine Symptom  
Interference Items 14 
X (Daily) 
 
 
 
 
X (Daily) 
 
Migraine Physical Function 
Impact Stand-alone Item 14 
X (Daily) 
 
 
 
 
X (Daily) 
 
HIT-6 14  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
Recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IP Administration 15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event Recording 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Product Complaints 
Recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 35 of 80 
With: 
Procedures 
Open-label Treatment Phase (OLTP) (76 wks) 1 
Safety 
F/U 1 
Wk 24 
(cont) 
Wk 
28 
Wk 
32 
Wk 
36 
Wk
40 Wk 44 Wk 48 Wk 52 Wk 56 Wk 60 Wk 64 Wk 68 Wk 72 
Wk 
76 
Wk
80 
Wk 
84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 100 
/ET3 
Dose 
increase to 
140 mg 
visit18 
12 wk 
post 
increase
18 
16 Wks 
After Last 
Dose of IP
Study Visit 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
Calls to IVR/IWR 
System 2 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
Entry into the OLTP 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PE 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
X 
X 
X 
X 
Body Weight 
Measurement 7 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X  
 
 
 
 
X 
X 
 
X 
Vital Signs 8 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
UDS 
Testing as needed throughout study based on investigator’s clinical suspicion 
Pregnancy Testing- 
Serum 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testing- 
Urine 9 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
 
Chemistry, 
Hematology 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
X 
X 
X 
X 
ECG 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X  
 
X 
 
 
X 
X 
X 
 
PK Sampling 10 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
X 
X 
X 
X 
Anti-AMG 334 
Antibodies; Serum  
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
X 
X 
X 
X 
Page 1 of 2 
Footnotes defined on last page of Table 4. 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 36 of 80 
Procedures 
Open-label Treatment Phase (OLTP) (76 wks) 1 
Safety 
F/U 1 
Wk 24 
(cont) 
Wk 
28 
Wk 
32 
Wk 
36 
Wk
40 Wk 44 Wk 48 Wk 52 Wk 56 Wk 60 Wk 64 Wk 68 Wk 72 
Wk 
76 
Wk
80 
Wk 
84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 100 
/ET3 
Dose 
increase to 
140 mg 
visit18 
12 wk 
post 
increase
18 
16 Wks 
After Last 
Dose of IP
COAs 14 
X (Daily) 
 
 
 
 
X 
(Daily) 
 
 
 
 
X (Daily) 
 
 
 
Subject Brings eDiary 
to Site for Use during 
Study Visit 
 
X X 
X 
X 
X 
X 
X 
 
 
 
 
 
X  
 
 
 
 
X 
 
 
 
Migraine Symptom  
Interference Items 14 
X (Daily) 
 
 
 
 
X 
(Daily) 
 
 
 
 
X (Daily) 
 
 
 
Migraine Physical 
Function Impact 
Stand-alone Item 14 
X (Daily) 
 
 
 
 
X 
(Daily) 
 
 
 
 
X (Daily) 
 
 
 
HIT-6 14  
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
Employment Status 
17 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Concomitant 
Medications Recording 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
IP Administration 15 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
X 
X 
 
Adverse 
Event/Adverse 
Device 
Effects/Serious 
Adverse Event 
Collection 
/Recording/Reporting 
16 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
Product Complaints 
Recording 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X 
X 
X 
X 
 
X 
X 
 
Page 2 of 2 
Footnotes defined on last page of Table 4. 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 37 of 80 
Section:  7.1 Schedule of Assessments, Table 4 
Add: 
Table 4.  Clinical Home Use Substudy Assessments  
 
Screening19 
Day 120 
Day 28 visit 
Day 29 
Telephone 
visit 
Day 56 visit 
Day 57 
Telephone 
visit 
Day 85 visit21/ 
ET22 
Informed Consent  
X 
 
 
 
 
 
 
Randomization to AMG 334 70 mg/ml 
AI/pen x2 or AMG 334 140 mg/ml 
AI/pen IP self-administration arm 
 
X 
 
 
 
 
 
AI/pen Instruction23 
X 
X 
 
 
 
 
 
Examination of areas for injection 
 
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 Adverse Device Effects 
X 
X 
X 
X 
X 
X 
X 
Review for adverse events/serious 
adverse events 
X 
X 
X 
X 
X 
X 
X 
Product Complaints Recording (if 
applicable) 
 
X 
X 
X 
X 
X 
X 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 38 of 80 
Section:  7.1 Schedule of Assessments, Table 4 Footnotes (moved from Table 3 to Table 4) 
Replace: 
AE = adverse event; BDI-II = Beck Depression Inventory-II; CGRP = Calcitonin gene-related peptide; COAs = Clinical Outcomes Assessments; cont = continued; C 
SSRS = Columbia-Suicide Severity Rating Scale; D = day; DBTP = Double-blind Treatment Phase; ECG = electrocardiogram; eDiary = electronic diary; EOS = end 
of study; EOT = end of treatment; ET = early termination; F/U = follow-up; HIT-6 = Headache Impact Test; IP = investigational product; IVR = interactive voice 
response; IWR = interactive web response; M = month (end of month x); OLTP = open-label treatment phase; PE = physical exam; per. = period; PK = 
pharmacokinetics; QM = monthly; rand. = randomized / randomization; SAE = serious adverse event; SC = subcutaneous; UDS = urine drug screen; Wk = week (end 
of week x); Wkly = weekly  
1  Each study visit during the double-blind treatment phase and safety follow-up has a window of ± 3 consecutive calendar days.  The day 1 visit (randomization day) 
has a window of 0, +7 consecutive calendar days; the day 1 visit must occur 28 to 35 days after the week -4 visit date.  Each study visit during the open-label 
treatment phase has a window of ± 4 consecutive calendar days.  All study visit target dates are to be calculated from the day 1 visit date.  All study procedures for a 
given study visit are to be completed on the same day. 
2   
Sites to access the Interactive Voice Response (IVR) / Interactive Web Response (IWR) System for the following: to enter the subject into the initial screening  
 phase, to randomize an eligible subject, to obtain the investigational product assignment, to enter the subject into the open-label treatment phase, to register the end 
of investigational product, and to register study early termination or completion.  Subject data will be collected in the IVR/IWR System including, but not limited to 
reason for screen fail (if applicable).  
   Sites to access the IVR/IWR System to obtain the investigational product assignment at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72.  
The IVR/IWR System will automatically assign investigational product when a subject is randomized at day 1 and when a subject is entered into the open-label 
treatment phase at week 24.  Investigational product is dosed QM, SC. 
3 A subject who discontinues the study during the double-blind treatment phase will complete the week 24/early termination (ET) visit.  A subject who discontinues 
open-label investigational product or the study during the open-label treatment phase will complete the week 76/early termination (ET) visit.  Subjects also will 
complete the safety follow-up visit 16 weeks after the last dose of investigational product.    
4 Entry into the baseline phase must occur only after completion of initial screening phase procedures 
6  Enrollment (ie, randomization) into the double-blind treatment phase using the IVR/IWR System must occur only after completion of all baseline phase procedures 
  and prior to the first dose of double-blind investigational product (randomization and administration of the first dose of investigational product should occur on day 1) 
6   
Entry into the open-label treatment phase using the IVR/IWR System must occur only after completion of all double-blind treatment phase procedures and 
prior to 
 the first dose of open-label AMG 334 70 mg QM SC 
7  Height and weight, measured without shoes.  Height to be collected at the initial screening phase visit only.  
8  Systolic/diastolic blood pressure, heart rate and body temperature.  Blood pressure to be obtained after the subject has been in a semi-recumbent position (partial 
semi- Fowler’s position) or supine position in a rested and calm state for at least 5 minutes.  At least 2 measurements (separated by at least 5 min) should be made 
and the average recorded.  The position selected for a subject should be used for all blood pressure measurements throughout the study. 
9 Pregnancy testing for women of childbearing potential (WOCBP) 
10 Samples for PK assessment will be serum   
11 PK samples collected at a study visit during which investigational product will be administered should be collected before dosing with investigational product (trough)   
12 Only subjects participating in the optional PK substudy (must have provided informed consent for the PK substudy) will have blood samples collected on 
 day 8 and day 64.  The PK substudy sampling window is ± 3 consecutive calendar days.     
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 39 of 80 
13 For subjects who provided informed consent for the pharmacogenetic studies, DNA will be obtained from the cell pellet collected in the plasma tube used for the 
biomarker development sample.  Therefore, additional sampling is not required.  
14 Clinical Outcomes Assessments (COAs) and Patient-reported Outcomes (PROs) to be collected by subjects using eDiaries. The HIT-6 is to be completed during 
applicable study visits before invasive procedures (eg, blood draws) and investigational product administration.  
15 Site study staff to administer investigational product to subjects on day 1 (only after randomization and completion of all day 1 procedures) and at weeks 4, 8, 12, 16, 
20, 24 (only after entering the open-label treatment phase and completion of all week 24 procedures), 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72.  
Investigational product administration should occur after any trough PK sampling.  Sites are to record the time of investigational product administration.  Following the 
first 3 doses of investigational product in the double-blind treatment phase (ie, day 1, week 4, week 8), subjects are to remain in the clinic for approximately 1 hour for 
observation. 
16  
SAEs are to be collected after signing of the informed consent through end of study (16 weeks after the last dose of investigational product).  Non-serious AEs 
are to be collected after the first dose of investigational product through end of study (16 weeks after the last dose of investigational product). 
With: 
ADE = adverse device effect; AE = adverse event; AI = autoinjector; BDI-II = Beck Depression Inventory-II; CGRP = Calcitonin gene-related peptide; CHU = clinical 
home use; COAs = Clinical Outcomes Assessments; cont = continued; C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; DBTP = Double-blind 
Treatment Phase; ECG = electrocardiogram; eDiary = electronic diary; EOS = end of study; EOT = end of treatment; ET = early termination; F/U = follow-up; HIT-6 = 
Headache Impact Test; IP = investigational product; IVR = interactive voice response; IWR = interactive web response; M = month (end of month x); OLTP = open-
label treatment phase; PE = physical exam; per. = period; PK = pharmacokinetics; PROs = Patient-reported Outcomes; QM = monthly; rand. = randomized / 
randomization; SAE = serious adverse event; SC = subcutaneous; UDS = urine drug screen; Wk = week (end of week x); Wkly = weekly; WOCBP = women of 
childbearing potential 
1  Each study visit during the double-blind treatment phase and safety follow-up has a window of ± 3 consecutive calendar days.  The day 1 visit (randomization day) 
has a window of 0, +7 consecutive calendar days; the day 1 visit must occur 28 to 35 days after the week -4 visit date.  Each study visit during the open-label 
treatment phase has a window of ± 4 consecutive calendar days.  All study visit target dates are to be calculated from the day 1 visit date.  All study procedures for a 
given study visit are to be completed on the same day. 
2   Sites to access the Interactive Voice Response (IVR) / Interactive Web Response (IWR) System for the following: to enter the subject into the initial screening phase, 
to randomize an eligible subject, to obtain the investigational product assignment, to enter the subject into the open-label treatment phase, to register the end of 
investigational product, and to register study early termination or completion.  Subject data will be collected in the IVR/IWR System including, but not limited to reason 
for screen fail (if applicable).  
   Sites to access the IVR/IWR System to obtain the investigational product assignment at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72.  
The IVR/IWR System will automatically assign investigational product when a subject is randomized at day 1 and when a subject is entered into the open-label 
treatment phase at week 24.  Investigational product is dosed QM, SC. 
3 A subject who discontinues the study during the double-blind treatment phase will complete the week 24/early termination (ET) visit.  A subject who discontinues 
open-label investigational product or the study during the open-label treatment phase will complete the week 100/early termination (ET) visit.  Subjects also will 
complete the safety follow-up visit 16 weeks after the last dose of investigational product.    
4 Entry into the baseline phase must occur only after completion of initial screening phase procedures 
5Enrollment (ie, randomization) into the double-blind treatment phase using the IVR/IWR System must occur only after completion of all baseline phase procedures and 
prior to the first dose of double-blind investigational product (randomization and administration of the first dose of investigational product should occur on day 1) 
6   Entry into the open-label treatment phase using the IVR/IWR System must occur only after completion of all double-blind treatment phase procedures and prior to the 
first dose of open-label AMG 334  
7  Height and weight, measured without shoes.  Height to be collected at the initial screening phase visit only.  
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 40 of 80 
8  Systolic/diastolic blood pressure, heart rate and body temperature.  Blood pressure to be obtained after the subject has been in a semi-recumbent position (partial 
semi- Fowler’s position) or supine position in a rested and calm state for at least 5 minutes.  At least 2 measurements (separated by at least 5 min) should be made 
and the average recorded.  The position selected for a subject should be used for all blood pressure measurements throughout the study. 
9 Pregnancy testing for women of childbearing potential (WOCBP)  Note:  Additional on treatment pregnancy testing may be performed at the investigator’s 
discretion or per local laws and regulation. 
10 Samples for PK assessment will be serum.   
11 PK samples collected at a study visit during which investigational product will be administered should be collected before dosing with investigational product (trough)   
12 Only subjects participating in the optional PK substudy (must have provided informed consent for the PK substudy) will have blood samples collected on 
 day 8 and day 64.  The PK substudy sampling window is ± 3 consecutive calendar days.     
13 For subjects who provided informed consent for the pharmacogenetic studies, DNA will be obtained from the cell pellet collected in the plasma tube used for the 
biomarker development sample.  Therefore, additional sampling is not required.  
14 Clinical Outcomes Assessments (COAs) and Patient-reported Outcomes (PROs) to be collected by subjects using eDiaries. The HIT-6 is to be completed during 
applicable study visits before invasive procedures (eg, blood draws) and investigational product administration.  
15 Site study staff to administer investigational product to subjects on day 1 (only after randomization and completion of all day 1 procedures) and at weeks 4, 8, 12, 16, 
20, 24 (only after entering the open-label treatment phase and completion of all week 24 procedures), 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 
92, and 96.  Investigational product administration should occur after any trough PK sampling.  Sites are to record the time of investigational product administration.  
Following the first 3 doses of investigational product in the double-blind treatment phase (ie, day 1, week 4, week 8), subjects are to remain in the clinic for 
approximately 1 hour for observation. 
16 Serious adverse events are to be collected after signing of the informed consent through end of study (16 weeks after the last dose of investigational product).  
Non-serious adverse events and adverse device effects (for OLTP only) are to be collected after the first dose of investigational product through end of study (16 
weeks after the last dose of investigational product). 
17 Current employment status will be collected at D1 (pre-rand.), week 12, week 24, and during the open label phase; the status should be collected 
retrospectively if needed. 
18Visit for Dose Increase to 140 mg and 12Wk Post Increase to 140 mg apply only to subjects in the open-label phase who have not completed W48 after 
IRB approval of Protocol Amendment 2. 
19 Screening must occur 4 weeks prior to the planned start of the CHU substudy (day 1).  IVR System will be adjusted to accommodate CHU substudy 
screening and randomization information as required. 
20 Day 1 of the CHU substudy may occur at any visit as long as subject has received at least 1 open-label dose of AMG 334 140 mg in the 20120309 main 
study. 
21 At day 85 of the CHU substudy, subject will receive AMG 334 140 mg SC administered by site staff using PFS formulation and will continue scheduled 
procedures and assessments as per 20120309 main study. 
22 ET:  If a subject early terminates the CHU substudy, he/she may receive administration of AMG 334 140 mg SC at the site as per 20120309 main study and 
will continue 20120309 scheduled procedures and assessments as per 20120309 main study. 
23Study coordinator will review AI/pen training materials (Instructions for Use) with subject at screening and will review AI/pen training materials at day 1 of 
the CHU substudy. 
 
CONFIDENTIAL 
 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 41 of 80 
Section:  7.2.3 Medical and Medication History, Paragraph 1 
Add: 
A review of medical and medication history will be performed at initial screening to 
confirm subject eligibility and at week 16. 
Section:  7.2.13 Clinical Outcomes Assessments (COAs) and Electronic Diaries 
(eDiaries), Paragraph 4 
Replace: 
The subject will be instructed to interact with the eDiary every day during the baseline 
phase and between the day 1 and week 52 study visits and between the week 72 and 
week 76/early termination (ET) study visits, and to bring the eDiary to every study visit 
during these periods.  At the day 1 study visit the investigator will use the subject’s 
eDiary to review all data entered during the baseline phase and confirm the relevant 
inclusion and exclusion criteria. 
With: 
The subject will be instructed to interact with the eDiary every day during the baseline 
phase and between the day 1 and week 52 study visits, between the week 72 and 
week 76/ study visits, between the week 96 and week 100/early termination (ET) 
study visits, and to bring the eDiary to every study visit during these periods.  At the 
day 1 study visit the investigator will use the subject’s eDiary to review all data entered 
during the baseline phase and confirm the relevant inclusion and exclusion criteria.  
During these periods the subject will bring the eDiary to every study visit. 
Section:  7.2.17 Adverse Event, Serious Adverse Event, Adverse Device Effect 
Collection/Recording/Reporting 
Add: 
7.2.17 Adverse Event, Serious Adverse Event, Adverse Device Effect 
Collection/Recording/Reporting 
Adverse event, serious adverse event, and adverse device effect information should 
be collected throughout the study and recorded at each study visit.  Refer to Section 9 
for details.   
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 42 of 80 
Section:  7.2.19 Laboratory Assessments, Paragraph 3 
Add: 
Any sample collected according to the Schedule of Assessments (Table 2-Table 4) may 
be analyzed for any of the tests outlined in the protocol and for any tests necessary to 
ensure subject safety. 
Section:  7.2.19 Laboratory Assessments, Paragraph 4 
Add: 
See Table 5 for 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): 
Section:  7.2.19 Laboratory Assessments, Table 5 Header 
Add: 
Table 5.  Analyte Listing 
Section:  7.2.20 Initial Screening Phase, Bullet 13 
Add: 
Serious adverse event collection/recording/reporting (Note:  Serious adverse events 
are to be collected after signing of the informed consent through 16 weeks after the last 
dose of investigational product.) 
Section:  7.2.21.1 Week -4 Visit, Bullet 7 
Add: 
Serious adverse event collection/recording/reporting 
Section:  7.2.22 Day 1 Visit (Prior to Randomization), Bullet 6 
Add: 
• 
Employment status 
Section:  7.2.22 Day 1 Visit (Prior to Randomization), Bullet 8 
Add: 
• 
Serious adverse event collection/recording/reporting 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 43 of 80 
Section:  7.2.23 Day 1 (After Randomization) and the Double-blind Treatment Phase, 
Bullet 3 
Add: 
• 
Medical and Medication History 
Section:  7.2.23 Day 1 (After Randomization) and the Double-blind Treatment Phase, 
Bullet 17 
Add: 
• 
Employment status (weeks 12 and 24/end of double-blind treatment phase) 
Section:  7.2.23 Day 1 (After Randomization) and the Double-blind Treatment Phase, 
Bullet 20 
Add: 
• 
Serious and non-serious adverse event collection/recording/reporting.  (Note: 
Serious adverse events are to be collected after signing of the informed consent 
through 16 weeks after the last dose of investigational product.  Non-serious adverse 
events are to be collected after the first dose of investigational product through 
16 weeks after the last dose of investigational product.)  
Section:  7.2.24 Open-label Treatment Phase, Bullet 15 
Add: 
• 
Employment status 
Section:  7.2.24 Open-label Treatment Phase, Bullets 17, 18, 19, and 20 
Add: 
• 
Administration of open-label AMG 334 70 mg QM SC or 140 mg QM SC.  The first 
dose of open-label investigational product is to be administered only after completion 
of all week 24 procedures.  In general, administration of investigational product 
should be the last procedure performed at each study visit. 
• 
After IRB approval of Protocol Amendment 2, the 24-week double-blind 
treatment phase is followed by a 76-week OLTP with dose determined by the 
subject’s week 48 status: 
• 
(1)  Subjects who have already completed the week 48 visit will continue to 
receive AMG 334 70 mg QM SC (OL70) for a total of 76 weeks, following the 
open label assessments in Table 3. 
• 
(2)  Subjects who have not yet completed the double-blind treatment phase 
and are not yet in the open-label phase will receive AMG 334 140 mg QM SC 
(OL140) upon entering the open-label phase and continue receiving 
open-label AMG 334 140 mg QM SC for 76 weeks. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 44 of 80 
• 
(3)  Subjects who have not yet completed the week 48 visit but are in the 
open-label phase receiving AMG 334 70 mg QM SC must increase their 
dose to AMG 334 140 mg QM SC and continue receiving open-label 
AMG 334 140 mg QM SC until the week 100 visit (OL70-140) for a total open 
label phase duration of 76 weeks.  The dose increase should be done at the 
first available opportunity, defined as the first visit after IRB approval of 
Protocol Amendment 2.  Refer to Table 3 for assessments to be collected at 
the visit of the dose increase and 12 weeks after the dose increase.  At the 
time of the dose increase, the End of Open Label 70 mg eCRF page will 
need to be completed as subjects will be transitioning from 70 mg to 
140 mg. 
• 
Serious and non-serious adverse event collection/recording/reporting.  (Note: 
Serious and non-serious adverse events are to be collected through 16 weeks after 
the last dose of investigational product) 
• 
Adverse device effects collection/recording/reporting 
Section:  7.2.24 Open-label Treatment Phase, Paragraph 2 
Replace: 
A subject who discontinues open-label investigational product or the study during the 
open-label treatment phase will complete the week 76/early termination (ET) visit and 
the safety follow-up visit 16 weeks after the last dose of investigational product. 
With: 
A subject who discontinues open-label investigational product or the study during the 
OLTP will complete the week 100/early termination (ET) visit and the safety follow-up 
visit 16 weeks after the last dose of investigational product. 
Section:  7.2.25 Clinical Home Use Substudy (Optional) 
Add: 
7.2.25 Clinical Home Use Substudy (Optional) 
The following procedures are to be completed during the OLTP at time points 
designated in the Schedule of Assessments (Table 4).  At each CHU substudy 
visit, any assessments scheduled for the main 20120309 study visit should also 
be completed. 
Screening: 
• 
Obtain consent to CHU substudy 
• 
Review of IFU for AI/pen with subject 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 45 of 80 
• 
Register CHU consent date using the IVR/IWR System (via Additional Product 
Dispensing activity)  
• 
Review for adverse events/adverse device effects/serious adverse events 
Day 1: 
• 
After confirming subject eligibility, the following procedures are to be 
completed: 
• 
Register CHU randomization to randomize the subject to two 70 mg/mL 
AIs/pens or one 140 mg/mL AI/pen self-administration using the IVR/IWR 
System (via Additional Product Dispensing activity) 
− 
Site to instruct subject on how to self-administer AMG 334 with the AI/pen 
by reviewing entire IFU 
− 
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 the AI/pen under site supervision 
− 
Review for adverse events/adverse device effects/serious adverse events 
− 
Product complaint recording (if applicable)  
− 
Study coordinator to reconcile IP (AI/pen) 
Day 28:   
• 
Study coordinator dispenses AI/pen to subject for self-administration on 
day 29 (IP device assigned using the IVR/IWR system via Additional Product 
Dispensing activity) 
• 
Review for adverse events/adverse device effects/serious adverse events 
• 
Product complaint recording (if applicable)  
• 
Telephone call time scheduled for day 29 (Note, telephone visit must occur 
after subject has self-administered IP) 
Day 29: 
• 
Subject self-administers AMG 334 using AI/pen in non-clinic setting 
• 
Telephone visit with study coordinator to inquire of subject if the subject 
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/adverse device effects/serious adverse events  
• 
Product complaint recording (if applicable)  
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 46 of 80 
Day 56: 
• 
Subject returns IP for Study Coordinator to reconcile IP (AI/pen) 
• 
Study coordinator dispenses AI/pen to subject for self-administration on 
day 57 (IP device assigned using the IVR/IWR system via Additional Product 
Dispensing activity) 
• 
Review for adverse events/adverse device effects/serious adverse events 
• 
Product complaint recording (if applicable)  
• 
Telephone call time scheduled for day 57 (Note, telephone visit must occur 
after subject has self-administered IP) 
Day 57: 
• 
Subject self-administers AMG 334 using AI/pen in the non-clinical setting 
• 
Telephone visit with study coordinator to inquire of subject if the subject 
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/adverse device effects/serious adverse events  
• 
Product complaint recording (if applicable)  
Day 85:  End of CHU substudy   
• 
Subject returns IP for study coordinator to reconcile IP (AI/pen) 
• 
Review adverse events/adverse device effects/serious adverse events  
• 
Product complaint recording (if applicable)  
• 
Subject continues all 20120309 study assessments and IP is administered at 
site as per the 20120309 protocol  
Section:  7.2.26 Safety Follow-up / End of Study Visit, Bullet 11 and 12 
Add: 
• 
Serious and non-serious adverse event collecting/recording/reporting.  (Note: 
Serious and non-serious adverse events are to be collected through 16 weeks after 
the last dose of investigational product) 
• 
Adverse device effect/recording/reporting 
• 
Product complaint recording 
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Protocol Number:  20120309 
Date:  05 June 2017 
Page 47 of 80 
Section:  7.6 Sample Storage and Destruction, Paragraph 1 
Add: 
Any sample collected according to the Schedule of Assessments (Table 2-Table 3) can 
be analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects. 
Section:  8.1 Subjects’ Decision to Withdraw, Paragraph 1 
Replace: 
If this occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from investigational product and must discuss with the subject the 
options for continuation of the Schedule of Assessments (Table 3) and collection of data, 
including endpoints and adverse events.  The investigator must document the change to 
the Schedule of Assessments (Table 3) 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). 
With: 
If this occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from investigational product and must discuss with the subject the 
options for continuation of the Schedule of Assessments (Table 2-Table 4) and 
collection of data, including endpoints, adverse events, adverse device effects 
(if applicable), and serious adverse events.  The investigator must document the 
change to the Schedule of Assessments (Table 2-Table 4) 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). 
Section:  9.2.1 Reporting Procedures for Adverse Events and Adverse Device Effects 
That do not Meet Serious Criteria, Header and Paragraph 1 
Replace: 
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 the first dose of investigational 
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Product:  AMG 334 
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Page 48 of 80 
product through the end of the safety follow-up visit (16 weeks after the last dose of 
investigational product) are reported using the Event CRF (eg, Adverse Event 
Summary), including events that are reported to the Event Adjudication Committee for 
adjudication. 
With: 
9.2.1 Reporting Procedures for Adverse Events and Adverse Device Effects That do 
not Meet Serious Criteria 
The investigator is responsible for ensuring that all adverse events and adverse device 
effects (including the OLTP and CHU substudy) observed by the investigator or 
reported by the subject that occur after the first dose of investigational product through 
the end of the safety follow-up visit (16 weeks after the last dose of investigational 
product) are reported using the Event CRF (eg, Adverse Event Summary), including 
events that are reported to the Event Adjudication Committee for adjudication. 
Section:  9.2.1 Reporting Procedures for Adverse Events and Adverse Device Effects 
That do not Meet Serious Criteria, Paragraph 2, Bullet 4 
• 
Replace: 
• 
assessment of relatedness to investigational product (medicine and/or pre-filled 
syringe), and 
With: 
• 
assessment of relatedness to investigational product (AMG 334 / placebo), and/or 
the Amgen medical devices (pre-filled syringe or the AI/Pen), and/or 
study-mandated procedure/study activity, and 
Section:  9.2.1 Reporting Procedures for Adverse Events and Adverse Device Effects 
That do not Meet Serious Criteria, Paragraph 3 
Replace: 
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 investigator must assess whether the adverse event is possibly related 
to the investigational product (medicine and/or pre-filled syringe).  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 (medicine and/or 
pre-filled syringe)?”   
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Protocol Number:  20120309 
Date:  05 June 2017 
Page 49 of 80 
With: 
The adverse event grading scale used will be the CTCAE.  The grading scale used in 
this study is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
During the double-blind treatment period, the investigator must assess whether the 
adverse event is possibly related to the investigational medicinal product 
(AMG 334/placebo).  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 medicinal product (AMG 334/placebo)?”   
During the OLTP and the CHU substudy, the investigator must assess whether the 
adverse event is possibly related to AMG 334.  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 AMG 334?”   
During the OLTP and the CHU substudy, the investigator must assess whether the 
adverse event is possibly related to the prefilled syringe or AI/Pen (investigational 
medical devices used to administer AMG 334).  The 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 medical devices? 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, 
protocol-required therapies, device(s) and/or procedure (including any screening 
procedure(s)).  This relationship is indicated by a “yes” or “no” response to the 
question:  “Is there a reasonable possibility that the event may have been caused 
by a study activity (eg, administration of investigational product, 
protocol-required therapies, device(s)), and/or procedure”? 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
Add: 
The investigator is responsible for ensuring that all serious adverse events (this 
includes the CHU substudy) observed by the investigator or reported by the subject 
that occur after signing of the informed consent through the end of the safety follow-up 
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Product:  AMG 334 
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Page 50 of 80 
visit (16 weeks after the last dose of investigational product) are recorded in the 
subject’s medical record and are submitted to Amgen, including serious adverse events 
that are reported to the Event Adjudication Committee for adjudication. 
If the electronic data capture (EDC) system is unavailable to the site staff to report 
the serious adverse event, the information is to be reported to Amgen via an 
electronic Serious Adverse Event (eSAE) Contingency Report Form within 
24 hours of the investigator’s knowledge of the event.  See Appendix B for a 
sample of the Serious Adverse Event Worksheet/electronic Serious Adverse Event 
Contingency Report Form.  For EDC studies where the first notification of a 
Serious Adverse Event is reported to Amgen via the eSerious Adverse Event 
Contingency Report Form, the data must be entered into the EDC system when 
the system is again available. 
During the double-blind treatment period, the investigator must assess whether 
the serious adverse event is possibly related to the investigational medicinal 
product (AMG 334 / placebo).  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 medicinal product (AMG 334 / placebo)?”   
During the OLTP and the CHU substudy, the investigator must assess whether the 
serious adverse event is possibly related to AMG 334.  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 AMG 334?”   
During the OLTP and the CHU substudy, the investigator must assess whether the 
serious adverse event is possibly related to the prefilled syringe or AI/Pen 
(investigational medical devices used to administer AMG 334).  The 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 medical 
devices? 
The investigator must assess whether the serious adverse event is possibly 
related to any study-mandated activity (eg, administration of investigational 
product, protocol-required therapies, device(s) and/or procedure (including any 
screening procedure(s)).  This relationship is indicated by a “yes” or “no” 
response to the question:  “Is there a reasonable possibility that the event may 
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Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 51 of 80 
have been caused by a study activity (eg, administration of investigational 
product, protocol-required therapies, device(s)), and/or procedure”? 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events (unamended text was 
moved from Section 9.2.3 to the end of Section 9.2.2) 
Add: 
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. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs in 
compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB of serious adverse events occurring at 
the site and other adverse event reports received from Amgen, in accordance with local 
procedures and statutes. 
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Protocol Number:  20120309 
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Page 52 of 80 
Section:  9.2.3 Reporting Serious Adverse Events After the Protocol-required Reporting 
Period, Paragraph 2 and 3 
Delete: 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form.  
For EDC studies where the first notification of a Serious Adverse Event is reported to 
Amgen via the eSerious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
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?”  
Section:  9.4 Pregnancy and Lactation Reporting 
Replace: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking investigational product, report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur through 16 weeks after the last dose of 
investigational product.  
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix C).  The Pregnancy 
Surveillance Program (PSP) will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required therapies, 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur 16 weeks after the last dose of investigational product.  
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Product:  AMG 334 
Protocol Number:  20120309 
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Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
(LSP) within 24 hours of the investigator’s knowledge of event.  Report a lactation case 
on the Lactation Notification Worksheet (Appendix D). 
With: 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking investigational product/product-required therapies, report the 
pregnancy to Amgen Global Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur through 16 weeks after the last dose of investigational 
product/protocol-required therapies.  
The pregnancy should be reported to Amgen 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 Global Patient Safety will 
follow-up with the investigator regarding additional information that may be 
requested. 
If a female subject becomes pregnant during the study, the investigator should 
attempt to obtain information regarding the birth outcome and health of the infant.  
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event.  
If a female breastfeeds while taking investigational product/protocol-required 
therapies report the lactation case to Amgen as specified below.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix D).  Amgen Global Patient Safety will follow-up 
with the investigator regarding additional information that may be requested. 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur 16 weeks after the last dose of investigational 
product/protocol-required therapies. 
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Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 54 of 80 
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. 
Section:  10.1.1.4 Clinical Home Use Substudy 
Add: 
10.1.1.4 
Clinical Home Use Substudy 
10.1.1.4.1 
Primary Endpoint 
• 
Subject-reported outcome of attempted full-dose administration on day 29 and 
day 57 
10.1.1.4.2 
Secondary Endpoint 
• 
Subject incidence of adverse events, serious adverse events, and adverse 
device effects 
Section:  10.1.1.5 Definitions of Terms Included in Endpoints, Acute Headache 
Medication Treatment Day 
Add: 
Acute Headache Medication Treatment Day:  Any calendar day during which the 
subject took an acute headache medication (migraine-specific or 
non-migraine-specific). 
Section:  10.1.1.5 Definitions of Terms Included in Endpoints, Monthly eDiary Data 
Replace: 
Data collected by the eDiary in any 28-consecutive day interval relative to study day 1 
when more than 14 days of eDiary data are collected within that 28-consecutive day 
interval. 
With: 
Data collected by the eDiary in any 28-consecutive day interval relative to study day 1 
when at least 14 days of eDiary data are collected within that 28-consecutive day 
interval.  Monthly frequency measurements will be prorated to 28-day equivalents.   
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Section:  10.1.2 Analysis Sets, Paragraph 1 
Replace: 
The efficacy analysis set includes subjects in the FAS and who received at least one 
dose of investigational product and completed at least one post-baseline monthly 
migraine day measurement in the double-blind treatment phase.   
With: 
The efficacy analysis set includes subjects in the FAS and who received at least one 
dose of investigational product and had at least one change from baseline 
measurement in monthly migraine days during the double-blind treatment phase.   
Section:  10.1.2 Analysis Sets, Paragraph 1 
Replace: 
For safety endpoints, all randomized subjects who received at least one dose of 
investigational product (ie, safety analysis set) will be analyzed based on actual 
treatment received.   
With: 
For safety endpoints, all randomized subjects who received at least one dose of 
investigational product (ie, safety analysis set) will be analyzed according to the 
randomized treatment unless a subject has received the incorrect dose during the 
entire double-blind treatment phase.   
Section:  10.1.2 Analysis Sets, Paragraph 2 
Add: 
All subjects enrolled in the CHU substudy will be included in the CHU substudy 
analysis set. 
Section:  10.1.3 Covariates and Subgroups 
Replace: 
The primary, secondary efficacy, and selected safety endpoints will be analyzed in the 
subgroups defined by the stratification factor as well as age (< median vs ≥ median), 
sex, race, body mass index (BMI; < median vs ≥ median), and duration of disease 
(< median vs ≥ median). 
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Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 56 of 80 
With: 
The primary, secondary efficacy, and selected safety endpoints will be analyzed in the 
subgroups defined by the stratification factor as well as baseline monthly migraine 
days (< 8 days vs ≥ 8 days), prior prophylactic failure status (failed any vs not 
failed any), and BMI (< median vs ≥ median).  
Section:  10.2 Sample Size Considerations, Paragraph 2 
Add: 
Clinical Home Use Substudy 
Approximately 50 subjects will be enrolled in to the CHU substudy.  The following 
assumptions are made based on the minimum sample size of 50 subjects:  5% of 
subjects per treatment group discontinue IP and 90% of the remaining subjects 
respond that they administered a full dose.  As such, the anticipated distribution 
of responses per treatment group at a planned visit would be 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 25 subjects per group are 
8.5%, 13.8%, and 11.5%, respectively.  The anticipated 95% confidence interval 
half width for the difference between treatment groups in the proportion of 
subjects administering a full dose is 19.5%.  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. 
Section:  10.4.2 Interim Analysis, Paragraph 1 
Replace: 
During the open-label treatment phase of the study, an interim analysis is planned after 
at least 100 subjects randomized to 70 mg of AMG 334 have completed 52 weeks of 
treatment with investigational product. 
With: 
During the OLTP of the study, an interim analysis is planned after at least 100 subjects 
randomized to 140 mg of AMG 334 have completed 26 and 52 weeks of treatment with 
investigational product. 
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Section:  10.4.4 Final Analysis, Paragraph 1 
Replace: 
The objective of the final analysis is to evaluate the long-term profile of migraine days 
and adverse events of AMG 334 in subjects with migraine after the 24-week double-blind 
treatment phase, 52-week open-label treatment phase, and safety follow up. 
With: 
The objective of the final analysis is to evaluate the long-term profile of migraine days 
and adverse events of AMG 334 in subjects with migraine after the 24-week double-blind 
treatment phase, OLTP, and safety follow-up.  
Section:  10.4.4 Final Analysis, Paragraph 2 
Replace: 
Final Analysis activities are commenced based on achieving the End of Trial milestone 
described in Section 3.5.2. 
With: 
Final Analysis activities are commenced based on achieving the End of Trial milestone 
described in Section 3.6.2.  
Section:  10.5.1 General Considerations, Paragraph 7 
Add: 
The proportion of subjects who administer a full dose of AMG 334 in home-use 
will be summarized by treatment group at CHU day 29 and day 57.  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 2 visits will also be estimated.  
Ninety-five percent confidence intervals will be provided for each group and the 
difference in proportions between the groups.  Subject incidence of adverse 
events, serious adverse events, and adverse device effects will be summarized by 
system organ class and preferred term for subjects enrolled in the CHU 
substudies.  Details of the analysis of the CHU substudy will be described in a 
separate Statistical Analysis Plan. 
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Product:  AMG 334 
Protocol Number:  20120309 
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Section:  10.5.2 Primary Efficacy Endpoint, Paragraph 2 
Replace: 
Sensitivity analyses for the primary endpoint include: (1) the same analysis using the 
per-protocol analysis set, (2) the last observation carried forward (LOCF) to handle 
missing data, and (3) the inverse probability weighted (IPW) method using generalized 
estimate equation (GEE) to handle missing data. 
With: 
Sensitivity analyses for the primary endpoint include: (1) the same analysis using the 
per-protocol analysis set, (2) the last observation carried forward (LOCF) to handle 
missing data with analysis of covariance (ANCOVA) model, and (3) multiple 
imputation (MI) with assumptions of missing at random (MAR) and missing not at 
random (MNAR) to handle missing data.  
Section:  10.5.3 Secondary Efficacy Endpoints, Paragraph 1 
Replace: 
The odds ratio for each AMG 334 treatment group vs placebo group and associated 
95% confidence intervals will be reported. Sensitivity analyses for response include: 
(1) the same analysis using the per-protocol analysis set, and (2) the logistic regression 
model adjusting for baseline values where missing values will be imputed as 
non-responders. 
With: 
The odds ratio for each AMG 334 treatment group vs placebo group and associated 
95% confidence intervals will be reported.  Sensitivity analyses for the binary endpoint 
include: (1) CHM test using the per-protocol analysis set, and (2) generalized linear 
mixed model without imputation of missing data, and (3) logistic regression model 
for each visit after the missing data are imputed as non-responders.  
Section:  10.5.5 Safety Endpoints, Paragraph 1 
Replace: 
For safety endpoints, all randomized subjects who received at least one dose of 
investigational product (ie, safety analysis set) will be analyzed based on the actual 
treatment received. 
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Page 59 of 80 
With: 
For safety endpoints, all randomized subjects who received at least one dose of 
investigational product (ie, safety analysis set) will be analyzed according to the 
randomized treatment unless a subject has received the incorrect dose during the 
entire double-blind treatment phase.  
Section:  10.5.5 Safety Endpoints, Paragraph 3 
Replace: 
Subject incidence rates (double-blind treatment phase) and subject incidence rates 
adjusted for follow-up time (open-label treatment phase) of all treatment-emergent 
adverse events will be tabulated by treatment groups and by system organ class and 
preferred term. 
With: 
Subject incidence rates (double-blind treatment phase) and exposure-adjusted subject 
incidence rates (OLTP) of all treatment-emergent adverse events will be tabulated by 
treatment groups and by system organ class and preferred term.  
Section:  10.5.5 Safety Endpoints, Paragraph 4 
Replace: 
The analyses of safety laboratory endpoints will include summary statistics over time by 
treatment group.  Shift tables of the worst on-study safety laboratory toxicity based on 
grade relative to baseline will be tabulated by treatment group.  Subject listing of grades 
≥ 3 laboratory toxicities will be provided. 
Add: 
The analyses of safety laboratory endpoints will include summary statistics over time by 
treatment group for selected analytes.  Shift tables of the worst on-study safety 
laboratory toxicity based on grade relative to baseline will be tabulated by treatment 
group. 
Section:  12.4 Investigator Responsibilities for Data Collection 
Add: 
For subjects who withdraw prior to completion of all protocol-required visits and are 
unable or unwilling to continue the Schedule of Assessments (Table 2-Table 4), the 
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Product:  AMG 334 
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investigator can search publically available records (where permitted) to ascertain 
survival status. 
Section:  12.6 Publication Policy, Paragraph 1 
Replace: 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter. 
With: 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter. 
Section:  12.6 Publication Policy, Paragraph 2 
Add: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals (International Committee of Medical Journal Editors, 
2013, updated 2014), which states: 
Section:  13 References, Reference 19 
Add: 
International Committee of Medical Journal Editors.  Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals. 2013, 
updated 2014.  http://www.icmje.org/.  Accessed 19 September 2013.  
Section:  14 Appendices, Appendix A  
Replace: 
Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
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 
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Product:  AMG 334 
Protocol Number:  20120309 
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Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.3 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate 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 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. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product is withheld (either permanently or 
conditionally) due to potential DILI as specified in 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), 
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 has been discontinued AND the subject is 
asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
− 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− 
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 
− 
Obtain serum acetaminophen (paracetamol) levels 
− 
Obtain a more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
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Date:  05 June 2017 
Page 62 of 80 
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of investigational product. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
With: 
Appendix A.  Hepatoxicity Stopping Rules:  Suggested Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [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, July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product Therapies Due to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom 
another cause of their changes in liver biomarkers (TBL, INR, and transaminases) 
has not been identified. 
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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) 
• 
Right sided heart failure, hypotension, or any cause of hypoxia to the liver 
causing ischemia   
• 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms   
• 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
• 
Alpha-one antitrypsin deficiency 
• 
Alcoholic hepatitis 
• 
Autoimmune hepatitis  
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic fatty liver disease including steatohepatitis (NASH)  
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product is withheld, the subject is to be followed according for 
possible DILI according to recommendations in the last section of this appendix. 
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 (see next section in this appendix). 
CONFIDENTIAL 
 
 
 
 


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Protocol Number:  20120309 
Date:  05 June 2017 
Page 64 of 80 
Table 6.  Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 
weeks 
> 5x ULN but < 8x ULN and unable 
to adhere to enhanced monitoring 
schedule 
> 3x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was 
< ULN) 
 
OR 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product Therapies 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 
is to be permanently discontinued.  Subjects who clearly meet the criteria for 
permanent discontinuation (as described in Table 6) are never to be rechallenged. 
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 65 of 80 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified above, 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 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. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product is withheld (either permanently or 
conditionally) due to potential DILI as specified in Table 6 or who experience AST or 
ALT elevations > 3 x upper limit of normal (ULN) or 2-fold increases above baseline 
values for subjects with elevated values before drug are to undergo a period of 
“close observation” until abnormalities return to normal or to the subject’s baseline 
levels.   
Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve. 
• 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have 
been discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL.  The following are to be considered depending on the clinical situation: 
• 
Complete blood count (CBC) with differential to assess for eosinophilia 
• 
Serum total immunoglobulin IgG, anti-nuclear antibody (ANA), anti smooth 
muscle antibody, and liver kidney microsomal antibody -1 (LKM1) to assess for 
autoimmune hepatitis 
• 
Serum acetaminophen (paracetamol) levels 
• 
A more detailed history of:  
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
CONFIDENTIAL 
 
 
 
 


Product:  AMG 334 
Protocol Number:  20120309 
Date:  05 June 2017 
Page 66 of 80 
• 
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 
• 
Viral serologies 
• 
Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), 
and peripheral blood smear 
• 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
• 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the 
investigator.  The “close observation period” is to continue for a minimum of 
4 weeks after discontinuation of all investigational product(s) and protocol-required 
therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs 
CONFIDENTIAL 
 
 
 
 


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Date:  05 June 2017 
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Section:  14 Appendices, Appendix B 
Replace: 
Appendix B.  Sample Serious Adverse Event Report 
Form
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With: 
Appendix B.  Sample Serious Adverse Event Contingency Report 
Form
 
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Section:  14 Appendices, Appendix C 
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With: 
 
 
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Date:  05 June 2017 
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Section:  14 Appendices, Appendix D 
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SAP_001.pdf: 
Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 1
STATISTICAL ANALYSIS PLAN
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of AMG 334 in Migraine Prevention
Protocol Number:
20120309
Version:
Version 1.0
Date:
February 14, 2016
Author:
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IRUSXUSRVHVRISRVWLQJRQFOLQLFDOWULDOVJRY
PPD


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 2
Table of Contents
Table of Abbreviations.....................................................................................................5
1.
Introduction.............................................................................................................6
2.
Objectives...............................................................................................................6
2.1
Primary .......................................................................................................6
2.2
Secondary...................................................................................................6
2.3
Exploratory..................................................................................................6
3.
Study Overview ......................................................................................................8
3.1
Study Design...............................................................................................8
3.1.1
Double-blind Treatment Phase ....................................................8
3.1.2
Open-Label Treatment Phase .....................................................9
3.1.3
Safety Follow-up Phase...............................................................9
3.2
Sample Size................................................................................................9
4.
Study Endpoints and Covariates...........................................................................10
4.1
Study Endpoints........................................................................................10
4.1.1
Primary Endpoint.......................................................................10
4.1.2
Secondary Endpoints ................................................................10
4.1.3
Exploratory Endpoints ...............................................................10
4.2
Planned Covariates...................................................................................12
5.
Hypotheses...........................................................................................................12
6.
Definitions.............................................................................................................13
6.1
Definition of Terms Included in Study Endpoints .......................................13
6.1.1
Efficacy Endpoints.....................................................................13
Migraine Physical Function Impact Stand-alone Item ................17
6.1.2
Safety Endpoints .......................................................................18
6.2
Study Dates ..............................................................................................19
6.3
Study Points of Reference.........................................................................20
6.4
Study Time Intervals .................................................................................21
6.5
Subject Disposition....................................................................................25
6.6
Arithmetic Calculations..............................................................................26
6.7
Disease Characteristics.............................................................................28
7.
Analysis Subsets ..................................................................................................29
7.1
Full Analysis Set........................................................................................29
7.2
Efficacy Analysis Set.................................................................................29
7.3
Safety Analysis Set ...................................................................................29
7.4
Open-Label Treatment Phase Set.............................................................29
7.5
Per Protocol Set........................................................................................29
7.6
Patient Reported Outcomes Analysis Set..................................................31


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 3
7.7
Interim Analysis Set ..................................................................................31
7.8
Subgroup Analyses...................................................................................31
8.
Interim Analysis and Early Stopping Guidelines....................................................31
9.
Data Screening and Acceptance...........................................................................31
9.1
General Principles.....................................................................................31
9.2
Data Handling and Electronic Transfer of Data .........................................32
9.3
Handling of Missing and Incomplete Data .................................................32
9.3.1
Missing and Incomplete Dates...................................................33
9.3.2
Missing Baseline Evaluation......................................................33
9.3.3
Missing Post-baseline Evaluation in Double-Blind 
Treatment Phase.......................................................................34
9.4
Detection of Bias.......................................................................................35
9.5
Outliers .....................................................................................................35
9.6
Distributional Characteristics.....................................................................35
9.7
Validation of Statistical Analyses...............................................................36
10.
Statistical Methods of Analysis..............................................................................36
10.1
General Principles.....................................................................................36
10.2
Subject Accountability ...............................................................................37
10.3
Important Protocol Deviations ...................................................................37
10.4
Demographic and Baseline Characteristics...............................................37
10.5
Efficacy Analyses......................................................................................38
10.5.1
Analyses of Primary and Secondary Efficacy 
Endpoints..................................................................................42
10.5.2
Analyses of Exploratory Efficacy Endpoints...............................43
10.5.3
Analyses of Efficacy Endpoints in Open-Label 
Treatment Phase.......................................................................44
10.5.4
Analyses of Patient Reported Outcomes (PROs) ......................44
10.5.5
Pharmacokinetic Endpoints .......................................................44
10.6
Safety Analyses ........................................................................................44
10.6.1
Adverse Events .........................................................................45
10.6.2
Laboratory Test Results ............................................................45
10.6.3
Vital Signs .................................................................................46
10.6.4
Columbia-Suicide Severity Rating Scale (C-SSRS)...................46
10.6.5
Electrocardiogram (ECG) ..........................................................46
10.6.6
Antibody Formation ...................................................................46
10.6.7
Exposure to Investigational Product ..........................................47
10.6.8
Summary Concomitant Medication Use.....................................47
10.7
Pharmacokinetic Analysis .........................................................................47
10.7.1
Exposure-Response Analysis....................................................47
11.
Changes from Protocol-specified Analyses...........................................................47
12.
Literature Citations / References...........................................................................48


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 4
13.
Prioritization of Analyses.......................................................................................48
14.
Data not Covered by This Plan .............................................................................48
15.
Appendices...........................................................................................................49
List of Tables
Table 1.  Summary of Efficacy Endpoints and Analysis Methods...................................39
List of Appendices
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures and Programs......................................................50
Appendix B.  Code Fragments.......................................................................................56
Appendix C.  Reference Values/Toxicity Grades ...........................................................63
Appendix D.  Patient-reported Outcome Forms/Instruments..........................................64


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 5
Table of Abbreviations
In addition to the study glossaries and abbreviations defined in the protocol, here is a 
table of abbreviations used in this document:
Abbreviation
Definition
ANCOVA
Analysis of Covariance
CMH
Cochran-Mantel-Haenszel
CPMS
Clinical Pharmacology Modeling and Simulation
CTCAE
Common Toxicity Criteria for Adverse Events
DMP
Data Management Plan
DTP
Data Transfer Plan
EDC
Electronic Data Capture
EOS
End of Study
ET
Early Termination
GEE
Generalized Estimating Equations
GLMM
Generalized Linear Mixed Model
GSO-DM
Global Study Operations-Data Management
IPW
Inverse Probability Weighting
IVRS
Interactive Voice Response System
LOCF
Last Observation Carried Forward
MAR
Missing at Random
MCMC
Markov Chain Monte Carlo
MCP-Mod
Multiple Comparison Procedure – Modelling
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
NRI
Non-responder Imputation
SAP
Statistical Analysis Plan
SSAP
Supplemental Statistical Analysis Plan
WHODRUG
World Health Organization Drug Dictionary


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 6
1.
Introduction
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the Protocol 1.0 for AMG 334 Study 20120309
dated June 16, 2015. The study is being conducted in migraine patients in Japan. The 
scope of this plan includes the primary analysis and the final analysis, and will be 
executed by the Biostatistics Department. The analysis plan for the exposure–response 
analysis and additional exploratory efficacy endpoints from eDiary and bridging analysis 
will be provided in separate Supplement Statistical Analysis Plans (SSAPs).
2.
Objectives
2.1
Primary
To evaluate the effect of AMG 334 compared to placebo on the change from baseline in 
mean monthly migraine days, in subjects with episodic migraine
2.2
Secondary
Efficacy:

To evaluate the effect of AMG 334 compared to placebo on the proportion of 
subjects with at least 50% reduction from baseline in mean monthly migraine 
days

To evaluate the effect of AMG 334 compared to placebo on the change from 
baseline in mean monthly acute migraine-specific medication treatment days  
Safety:
To evaluate the safety and tolerability of AMG 334
2.3
Exploratory

To evaluate the effect of AMG 334 compared to placebo on change from 
baseline in headache impact scores as measured by the Headache Impact Test 
(HIT-6)

To evaluate the month of onset of action of AMG 334 compared to placebo as 
assessed by monthly migraine days 

To evaluate the effect of AMG 334 compared to placebo on the change from 
baseline in mean monthly migraine attacks 

To evaluate the effect of AMG 334 compared to placebo on change from 
baseline in mean monthly headache (migraine and non-migraine headache) days   


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 7
!
To evaluate the effect of AMG 334 compared to placebo on the proportion of 
subjects with at least 75% reduction from baseline in mean monthly migraine 
days
!
To evaluate the effect of AMG 334 compared to placebo on the proportion of 
subjects with 100% reduction from baseline in mean monthly migraine days 
!
To evaluate the effect of AMG 334 compared to placebo on change from 
baseline in monthly acute headache medication treatment days 
!
To evaluate the effect of AMG 334 compared to placebo on change from 
baseline in monthly hours of migraine headache
!
To evaluate the effect of AMG 334 compared to placebo on change from 
baseline in monthly average severity of migraine pain 
!
To evaluate the effect of AMG 334 compared to placebo on change from 
baseline in mean monthly migraine days with severe pain 
!
To evaluate the effect of AMG 334 compared to placebo on change from 
baseline in mean monthly hours of severe migraine pain
!
To evaluate the effect of AMG 334 compared to placebo on migraine pain 
interference with daily activities as measured by the migraine symptom 
interference items 
!
To evaluate the effect of AMG 334 compared to placebo on the change from 
baseline in the overall impact on everyday activities score as measured by the 
Migraine Physical Function stand-alone item
!
To evaluate AMG 334 pharmacokinetics (PK) in subjects with migraine and 
characterize the exposure-response (E-R) relationships for efficacy and safety 
endpoints
!
To investigate the dose-response relationship of AMG 334 for efficacy
!
 
 
!
To evaluate the long-term safety, tolerability and maintenance of effect of 
AMG 334 after 76 weeks of treatment 
CCI


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 8
3.
Study Overview
3.1
Study Design
This is a Phase 2, multicenter, randomized, stratified, double-blind, placebo-controlled, 
parallel-group study of subjects in Japan with episodic migraine.  The study is composed 
of an initial screening phase (up to 3 weeks), a 4-week baseline phase, a 24-week 
double-blind treatment phase (DBTP), a 52-week open-label treatment phase (OLTP),
and a 12-week safety follow-up phase (16 weeks after the last dose of investigational 
product).
The overall study design is described by a study schema at the end of the protocol 
synopsis section.
3.1.1
Double-blind Treatment Phase
Approximately 459 eligible subjects will be randomized in a 2:1:2:2 ratio to 1 of 4 
treatment groups: placebo, AMG 334 28 mg, AMG 334 70 mg, or AMG 334 140 mg, with 
approximately 131 subjects assigned to placebo, approximately 66 subjects assigned to 
AMG 334 28 mg, approximately 131 subjects assigned to AMG 334 70 mg, and 
approximately 131 subjects assigned to AMG 334 140 mg.  The randomization will be 
stratified by prior/current treatment with migraine prophylactic medication (current 
migraine prophylactic medication treatment vs prior migraine prophylactic medication 
treatment only vs no prior or current migraine prophylactic medication treatment).  There 
will be a limit on the percentage of subjects on current migraine prophylactic medication 
treatment.
Amgen investigational product (ie, AMG 334 28 mg, AMG 334 70 mg, AMG 334 140 mg, 
or placebo) will be dosed monthly (QM) by subcutaneous (SC) injections.  Double-blind 
AMG 334 140 mg, AMG 334 70 mg, AMG 334 28 mg, or placebo will be administered 
during the 24-week DBTP (ie, at day 1 and weeks 4, 8, 12, 16, and 20).
Migraine and non-migraine headache outcomes and other efficacy measures will be 
assessed based on eDiary data. Subjects will also have in-clinic study visits at Day 1 
and monthly visits thereafter.
Subjects who permanently discontinue investigational product during the DBTP are to 
continue to return for all other study procedures until the end of the DBTP and study 
procedures for the safety follow-up visit 16 weeks after the last dose of investigational 
product.  


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 9
3.1.2
Open-Label Treatment Phase
At the week 24 visit, subjects will be entered into the 52-week OLTP and will begin to 
receive open-label AMG 334 70 mg QM SC. 
A subject who discontinues open-label investigational product or the study during OLTP
will complete the week 76/early termination (ET) visit and the safety follow-up visit 16
weeks after the last dose of investigational product.
Subjects will use eDiary every day for the first 6 months and last month of the OLTP to 
report information about their migraine and non-migraine headaches and acute 
headache medication use. Subjects will participate in monthly in-clinic study visits.
3.1.3
Safety Follow-up Phase
Subjects who complete the OLTP or who discontinue investigational product would 
complete the safety follow-up visit 16 weeks after the last dose of investigational 
product.
3.2
Sample Size
The primary endpoint is the change from baseline in mean monthly migraine days over 
the last three months (months 4, 5, and 6) of the DBTP.  Using the treatment effect 
compared to placebo of -1.12 and -1.30 for the AMG 334 70 mg and 140 mg dose 
groups, respectively and a common standard deviation of 2.8 based on a placebo-
controlled dose-finding study of JNS019 (topiramate) in migraine patients
(www.clinicaltrials.gov), the planned sample size of 131 subjects in the placebo, 70 mg 
and 140 mg dose groups will provide 90% and 96% power for a two-sided test with 
significance level of 0.05 to show the difference of AMG 334 70 mg and 140 mg 
compared to placebo, respectively. The proposed number of subjects in the 28 mg 
(n=66) dose group with the placebo (n=131), the 70 mg (n=131) and the 140 mg (n=131) 
dose groups is sufficient to demonstrate a dose-response using Multiple Comparison 
Procedure – Modelling (MCP-Mod) analysis with minimum power of 95% and provide 
estimates of response in a Japanese population, using an assumed treatment effect of -
0.55 for the AMG 334 28 mg dose group.
Power calculations are derived through nQuery 7.0.


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 10
4.
Study Endpoints and Covariates
4.1
Study Endpoints
4.1.1
Primary Endpoint
Change from baseline in mean monthly migraine days. The mean monthly migraine days 
will be calculated using the monthly migraine days from each of the last three months 
(months 4, 5, and 6) of the DBTP.
Change from baseline in mean monthly migraine days is calculated based on the 
following: mean monthly migraine days – number of migraine days during the 4-week 
baseline phase.
4.1.2
Secondary Endpoints
Efficacy:

Achievement of at least a 50% reduction from baseline in mean monthly 
migraine days over the last three months (months 4, 5, and 6) of the DBTP

Change from baseline in mean monthly acute migraine-specific medication 
treatment days over the last three months (months 4, 5, and 6) of the DBTP
Safety:

Adverse events

Clinical laboratory values and vital signs

Anti-AMG 334 antibodies
4.1.3
Exploratory Endpoints 

Change from baseline in mean headache impact scores as measured by the 
Headache Impact Test (HIT-6) over the last three months (months 4, 5, and 6) of 
the DBTP

Change from baseline in monthly migraine days at assessment timepoints

Change from baseline in mean monthly migraine attacks over the last three 
months (months 4, 5, and 6) of the DBTP

Change from baseline in monthly migraine attacks at assessment timepoints

Change from baseline in mean monthly headache (migraine and non-migraine 
headache) days over the last three months (months 4, 5, and 6) of the DBTP


Product:  AMG 334
Statistical Analysis Plan:  20120309
Dated:  February 14, 2016
Page 11

Change from baseline in monthly headache (migraine and non-migraine 
headache) days at assessment timepoints

Achievement of at least 50% reduction from baseline in monthly migraine days at 
assessment timepoints  

Achievement of at least 75% reduction from baseline in mean monthly migraine 
days over the last three months (months 4, 5, and 6) of the DBTP

Achievement of at least 75% reduction from baseline in monthly migraine days at 
assessment timepoints  

Achievement of 100% reduction from baseline in mean monthly migraine days 
over the last three months (months 4, 5, and 6) of the DBTP

Achievement of 100% reduction from baseline in monthly migraine days at 
assessment timepoints  

Change from baseline in mean monthly acute headache medication treatment 
days over the last three months (months 4, 5, and 6) of the DBTP

Change from baseline in monthly acute headache medication treatment days at 
assessment timepoints

Change from baseline in monthly acute migraine-specific medication treatment 
days at assessment timepoints

Change from baseline in mean monthly hours of migraine headache over the last 
three months (months 4, 5, and 6) of the DBTP

Change from baseline in monthly hours of migraine headache at assessment 
timepoints

Change from baseline in mean monthly average severity of migraine pain over 
the last three months (months 4, 5, and 6) of the DBTP

Change from baseline in monthly average severity of migraine pain at 
assessment timepoints

Change from baseline in mean monthly migraine days with severe pain over the 
last three months (months 4, 5, and 6) of the DBTP

Change from baseline in monthly migraine days with severe pain at assessment 
timepoints 


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!
Change from baseline in mean monthly hours of severe migraine pain over the 
last three months (months 4, 5, and 6) of the DBTP
!
Change from baseline in monthly hours of severe migraine pain at assessment 
timepoints 
!
Change from baseline in migraine pain interference with daily activities as
measured by the migraine symptom interference items over the last three months 
(months 4, 5, and 6) of the DBTP at assessment timepoints
!
Change from baseline in the overall impact on everyday activities score as 
measured by the Migraine Physical Function stand-alone item over the last three 
months (months 4, 5, and 6) of the DBTP
!
AMG 334 exposure and PK-PD relationships
  
4.2
Planned Covariates
The following covariates will be included in the primary analysis of the efficacy 
endpoints:
!
Stratification factor: prior/current treatment with migraine prophylactic medication 
(current migraine prophylactic medication treatment vs prior migraine 
prophylactic medication treatment only vs no prior or current migraine 
prophylactic medication treatment)
!
Baseline value for corresponding endpoint (eg, baseline monthly migraine days 
will be added in the model as a covariate for the endpoint of change from 
baseline in monthly migraine days)
Stratification factor will use the values used for randomization unless otherwise noted.
5.
Hypotheses
The primary endpoint will be tested for each AMG 334 treatment group compared to the 
placebo group sequentially at a 2-sided significance level of 0.05 in the order of AMG 
334 140 mg vs. placebo, 70 mg vs. placebo and 28 mg vs. placebo. The lower dose 
group will be tested only when the higher dose group is considered statistically 
significant.
C
C
I


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
Null Hypothesis: In subject with episodic migraine, the AMG 334 treatment group
is same as placebo, in terms of the change in the mean monthly migraine days
from baseline

Alternative Hypothesis : In subject with episodic migraine, the AMG 334 
treatment group is different from placebo, in terms of the change in the mean 
monthly migraine days from baseline
6.
Definitions
6.1
Definition of Terms Included in Study Endpoints
6.1.1
Efficacy Endpoints
The baseline period for efficacy analysis is defined as the period between week -4 visit 
(when eDiary device is set up or eDiary device assignment date) and the day prior to 
study day 1 (study day 1 is not included).
Migraine Day
Any calendar day in which the subject experiences a qualified migraine headache
(onset, continuation or recurrence of the migraine headache).  A qualified migraine 
headache is defined as a migraine with or without aura, lasting for ≥ 30 minutes, and 
meeting at least one of the following criteria (a and/or b):
a) ≥ 2 of the following pain features: 

Unilateral

Throbbing

Moderate to severe

Exacerbated with exercise/physical activity
b) ≥ 1 of the following associated symptoms:

Nausea and/or vomiting 

Photophobia and phonophobia
If the subject took a migraine-specific medication (ie, triptan or ergotamine) during aura 
or to treat headache on a calendar day, then it will be counted as a migraine day 
regardless of the duration and pain features/associated symptoms.
Monthly Migraine Days


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Number of migraine days between each monthly IP dose. Monthly migraine days at 
baseline is the number of migraine days in the baseline period. Days without eDiary data
in each monthly interval are handled by proration according to Section 9.3.
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).  A qualified 
headache is defined as:

a qualified migraine headache (including an aura-only event that is treated with 
acute migraine-specific medication), or

a qualified non-migraine headache, which is a headache that lasts ≥ 30 minutes 
and is not a qualified migraine headache, or

a headache of any duration for which acute headache treatment is administered.
Monthly Headache Days
Number of headache days between each monthly IP dose. Monthly headache days at 
baseline is the number of headache days in baseline period.  Days without eDiary data
in each monthly interval are handled by proration according to Section 9.3.
Migraine Attack
An episode of any qualified migraine headache or migraine specific medication intakes 
for aura only. The following rules will be used to distinguish an attack of long duration 
from two attacks, or to distinguish between attacks and relapses:
a) A migraine attack that is interrupted by sleep, or temporarily remits, and then 
recurs within 48 hours will be considered as one attack and not two.
b) An attack treated successfully with medication but with relapse within 48 hours 
will be considered as one attack.
A migraine attack lasting more than 48 hours will be counted as one attack.
Monthly Migraine Attacks
Number of migraine attacks between each monthly IP dose. Monthly migraine attacks at 
baseline is the number of migraine attacks in baseline period. Days without eDiary data
are handled by proration according to Section 9.3.
Response
At least 50% (or 75%, 100%) reduction from baseline in monthly migraine days.


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Monthly Migraine Days with Severe Pain
Number of migraine days with severe pain between each monthly IP dose. Monthly rate 
at baseline is the number of migraine days with severe pain in baseline period. Days 
without eDiary data in each monthly interval are handled by proration according to 
Section 9.3. 
Monthly Cumulative Hours of Severe Migraine Pain
Cumulative duration of any qualified migraine headache with severe pain between each 
monthly IP dose regardless of acute treatment use. Monthly cumulative hours of 
migraine pain at baseline is the cumulative duration of any qualified migraine headache
with severe pain in baseline period.  Days without eDiary data are handled by proration 
according to Section 9.3.
Monthly Cumulative Hours of Migraine Headache 
Cumulative duration of any qualified migraine headache between each monthly IP dose
regardless of acute treatment use. Monthly cumulative hours of migraine headache at 
baseline is the cumulative duration of any qualified migraine headache in baseline 
period. Days without eDiary data are handled by proration according to Section 9.3.
Monthly Acute Medication Use in Days
Number of days on which acute medications are used as recorded in eDiary between 
each monthly IP dose. Monthly acute treatment use at baseline is the number of acute 
treatment days in the baseline period. Days without eDiary data are handled by proration 
according to Section 9.3.
Monthly Migraine-Specific Medication Use in Days
Number of days on which migraine-specific medications are used between each monthly 
IP dose. Migraine-Specific Medications including two categories of medications: triptan-
based migraine medications and ergotamine-based migraine medications. Monthly 
migraine-specific medication use at baseline is the number of migraine-specific 
medication days in the baseline period. Days without eDiary data are handled by 
proration according to Section 9.3.
Monthly Average Severity of Migraine Pain
Severity of migraine pain is graded as 1=mild, 2=moderate or 3=severe and is rated as 
its worst or peak intensity per migraine headache. Monthly average severity of migraine 
pain is defined as the sum of the severity of each observed qualified migraine headache 


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between each monthly IP dose divided by the total number of observed qualified 
migraine headaches (as one record in eDiary with start and end time) in that interval. If 
less than 14 days of eDiary data in each interval is recorded, then the monthly average 
severity of migraine pain will be set as missing. Monthly average severity of migraine 
pain at baseline is the average severity of migraine pain in the baseline period.
Migraine Symptom Interference Items
A single item will assess the extent to which the migraine-related symptoms interfered 
with the subject’s daily activities within the past 24 hours. The scale is from 0 to 10 with 
higher score indicating more severe interference. This question is answered whether or 
not the subject reported headache. Data will be collected from eDiary.
Monthly average scale of migraine symptom interference is defined as the sum of 
observed scales divided by the number of days when this question is answered between 
each monthly IP dose. If less than 14 days of eDiary out of the interval is recorded, then 
the monthly average scale of migraine symptom interference will be set as missing. For 
monthly average scale of migraine symptom interference at baseline, data collected from 
end of initial screening phase (week -4 study visit) through the day that the 
investigational site runs the eligibility report will be utilized. 
Bed Days due to Migraine Symptoms
A single item will assess if the subject spends the day or part of the day in bed due to 
migraine-related symptoms in the past 24 hours. Data will be collected from eDiary.
Monthly Bed Days is defined as the number of days during which the subject spends the 
day or part of the day in bed between each monthly IP dose. For monthly bed days at 
baseline, data collected from end of initial screening phase (week -4 study visit) through 
the day that the investigational site runs the eligibility report will be utilized. Days without 
eDiary data are handled by proration according to Section 9.3.
Missed Work/School Days due to Migraine Symptoms
A single item will assess if the subject misses work or school due to migraine-related 
symptoms in the past 24 hours. Data will be collected from eDiary.
Monthly Missed Work/School Days is defined as the number of Days on which subject 
missed work/school between each monthly IP dose. For monthly Missed Work/School 
Days at baseline, data collected from end of initial screening phase (week -4 study visit) 
through the day that the investigational site runs the eligibility report will be utilized. Data 


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will be treated as missing if subject answered this question as “I do not work or attend 
school”. Days without eDiary data are handled by proration according to Section 9.3.
Migraine Physical Function Impact Stand-alone Item 
The Migraine Physical Function Impact stand-alone item is a global question which 
provides an assessment of overall impact of migraine on everyday activities. Subjects 
respond to the item using a 5-point scale, with difficulty items ranging from “Not difficult” 
to “Extremely difficult.”  These are assigned scores from 1 to 5, with 5 representing the 
greatest burden. The score will be rescaled to a 0 - 100 scale, with higher scores 
representing greater impact of migraine (ie, higher burden).
The recall period is the past 24 hours.
Subjects will complete the Migraine Physical Function Impact stand-alone item using the 
eDiary.
Headache Impact Test (HIT-6)
The Headache Impact Test (HIT-6) is a short-form self-administered questionnaire 
based on the Internet-HIT question pool.  The HIT-6 was developed as a global measure 
of adverse headache impact to assess headache severity in the previous month and 
change in a patient’s clinical status over a short period of time.  Six questions cover:

severe pain, 

limitation of daily activity (household, work, school and social), 

wanting to lie down when headache is experienced, 

feeling too tired to work or do daily activities because of headache, 

feeling fed up or irritated because of headache, 

headache limiting ability to concentrate or work on daily activities. 
Each of the 6 questions is responded using 1 of 5 response categories: “never,” “rarely,” 
“sometimes,” “very often,” or “always.” Besides, 6, 8, 10, 11, or 13 points, respectively, 
are assigned to the response provided for each HIT-6 item. These points are summed to 
produce a total HIT-6 score that ranges from 36 to 78.  HIT-6 score are categorized into 
4 grades, representing little or no impact (49 or less), some impact (50-55), substantial 
impact (56-59), and severe impact (60-78) due to headache. No recall period is 
specified for the first 3 items. The recall period is the past 4 weeks for the last 3 items.
Please refer to Appendix D for scoring algorithm.


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Achievement of at least a 50% reduction from baseline in mean monthly 
migraine days over the last three months (months 4, 5, and 6) of the double-blind 
treatment phase
Calculated based on the following: if (mean monthly migraine days over the last three 
months of the DBTP - baseline monthly migraine days)*100/baseline monthly migraine 
days is less than or equal to - 50%
Change from baseline in mean monthly acute migraine-specific medication 
treatment days over the last three months (months 4, 5, and 6) of the double-blind 
treatment phase
Calculated based on the following: (mean monthly acute migraine-specific medication 
treatment days over the last three months of the DBTP) – (baseline monthly acute 
migraine-specific medication treatment days)
6.1.2
Safety Endpoints
Serious Adverse Event (SAE)
SAEs determined by the flag indicating if the adverse event is serious on the Adverse 
Events eCRF page will include those that occur after signing of the informed consent 
and up to and including end of study.
Treatment-Emergent Adverse Event
Adverse Events (AEs) recorded on the Adverse Events eCRF page that occurs on or 
after first dose of investigational product as determined by the flag indicating if the 
adverse event started prior to the first dose on the Adverse Events eCRF and up to and 
including 112 days after the end of investigational product (16 weeks after the last dose 
of IP) or end of study, whichever comes earlier. 
Serious Treatment-Emergent Adverse Event
A serious treatment-emergent adverse event is an SAE considered to be treatment-
emergent.
Treatment-Related Adverse Event
A treatment-related AE is defined as a treatment-emergent adverse event that is 
considered by investigators to have reasonable possibility that it may have been caused 
by IP as determined by the flag indicating if the event is caused by investigational 
product on the Adverse Events eCRF page.


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Serious Treatment-Related Adverse Event
A serious treatment-related adverse event is an SAE considered to be treatment-related.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a clinician rating of suicidal behavior and ideation. Two versions 
depending on the type of visits will be used in this study: Screening and Since Last Visit. 
The C-SSRS consists of a maximum of 20 items to evaluate suicidal behavior and 
suicidal ideation. 
Beck Depression Inventory (BDI)-II
The Beck Depression Inventory (BDI)-II is a 21-item questionnaire that assesses 
severity of depression.  Each item is scored from 0 to 3.  The total score is categorized 
into 4 severity grades: minimal depression (0-13), mild depression (14-19), moderate 
depression (20-28), and severe depression (29-63).  
6.2
Study Dates
Informed Consent Date
The date on which subject signs the informed consent form.
eDiary Device Assignment Date
The date on which an eDiary device is assigned to a subject for the first time after 
completion of initial screening at week -4 visit. 
Randomization (Enrollment) Date in DBTP
Randomization (Enrollment) Date in DBTP is the date on which a subject is assigned to 
one of the treatments through Interactive Voice Response System (IVRS) in DBTP.
First IP Dose Date
First IP Dose Date is the date on which a subject is administered the first dose of 
investigational product following randomization, which may be the same day or after the 
randomization date. For subjects who are randomized but not dosed with double-blind IP 
after randomization, First IP Dose Date is considered missing.
First OLTP IP Dose Date
First OLTP IP Dose Date is the date on which a subject is administered the first dose of 
investigational product in the open-label treatment phase following completion of DBTP.
Last IP Dose Date


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Last IP Dose Date for each subject is defined as the latest date IP is administered.
End of IP Admin Date
End of IP Admin for each subject is defined as the date the decision was made to end IP 
as recorded on the End of IP eCRF page.
Subject-level End of Study (EOS) Date
End of study (EOS) date for each subject is defined as the last date on which the subject 
participated in the study. The date will be recorded on the End of Study eCRF page.
Primary Completion Date
The Primary Completion Date is the date of the End of Double-Blind Treatment Phase 
page for the last subject who completes DBTP.
Study Completion Date
The Study Completion Date is the EOS date of the last subject in the study.
6.3
Study Points of Reference
Baseline Assessment 
Baseline assessment is defined as the last non-missing measurement for the endpoint of 
interest taken before the first dose of investigational product. In cases where baseline 
measurements are taken on the same day as IP, it will be assumed that these 
measurements are taken prior to IP being administered. For subjects who are 
randomized but not dosed after the randomization, the baseline of the study is defined 
as the last non-missing measurement prior to or on the date of randomization.
For C-SSRS, if subject completes C-SSRS form on Day 1 then all individual items from 
Day 1 visit will be used as baseline. If subject does not complete C-SSRS form on Day 1 
then all individual items from Week -4 visit will be used as baseline.
Baseline assessment of data collected from eDiary will be summarized as monthly 
measurements using data collected during baseline period. See Section 6.1.1 for detail.
Study Day 1
Study Day 1 is defined as the first IP dose date. For subjects who are randomized but 
not dosed after randomization, the Study Day 1 is defined as the date of randomization.
Study Day
Study Day is defined as the number of days from Study Day 1.


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Before Study Day 1:
Study Day = (Date of Interest – Date of Study Day 1)
On or after Study Day 1:
Study Day = (Date of Interest – Date of Study Day 1) + 1
Therefore the day prior to Study Day 1 is -1.
6.4
Study Time Intervals
Monthly Interval for Efficacy Endpoints
Monthly efficacy measurements will be calculated based on the subject’s monthly IP 
dosing schedule defined below using eDiary data collected from beginning of the 
baseline phase (week -4 visit) up to week 76 (end of eDiary use). Any eDiary data 
occurring after EOS date will not be included in the analysis.
Study Phase
Assessment 
Timepoint
Start Date
End Date
Baseline Phase
Baseline
LogPad 
assignment date 
(Week -4 study 
visit)
Day prior to study day 1
Double-blind 
Treatment 
Phase
Week 4

Study Day 1 

Week 4 dose date-1

Study day 28 if Week 4 dose 
is not received (either missed 
or IP discontinued prior to 
Week 4)
Week 8

Week 4 dose 
date

Study day 29 if 
Week 4 dose is 
not received 
(either missed 
or IP 
discontinued 
prior to Week 
4)

Week 8 dose date-1

Study day 56 if Week 8 dose 
is not received (either missed 
or IP discontinued prior to 
Week 8)
Week 12

Week 8 dose 
date

Week 12 IP dose date-1

Study day 84 if Week 12 


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
Study day 57 if 
Week 8 dose is 
not received 
(either missed 
or IP 
discontinued 
prior to Week 
8)
dose is not received (either 
missed or IP discontinued 
prior to Week 12)
Week 16

Week 12 dose 
date

Study day 85 if 
Week 12 dose 
is not received 
(either missed 
or IP 
discontinued 
prior to Week 
12)

Week 16 dose date-1

Study day 112 if Week 16
dose is not received (either 
missed or IP discontinued 
prior to Week 16)
Week 20

Week 16 dose 
date

Study day 113 
if Week 16 
dose is not
received (either 
missed or IP 
discontinued 
prior to Week 
16)

Week 20 IP dose date-1

Study day 140 if Week 20
dose is not received (either 
missed or IP discontinued 
prior to Week 20)
Week 24

Week 20 dose 
date

Study day 141 
if Week 20
dose is not 
received (either 
missed or IP 
discontinued 
prior to Week 
20)

Week 24 IP dose date-1

Study day 168 if Week 24
dose is not received (either 
missed or IP discontinued 
prior to Week 24)
Open-label 
Treatment 
Phase
Week 28

The 1st OL 
dose day  

Week 28 dose date-1

OLTP day 28 if Week 28 
dose is not received (either 
missed or IP discontinued 
prior to Week 28)


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Week 32 or 
later when 
eDiary is 
used

Same rule as 
above
Study Visit
Since the actual visit for a subject may not exactly coincide with their targeted visit date, 
the actual visit date is mapped to the study visit as follows.
Study Visit
Target Day
Study Day
Baseline
Please refer to Section 6.3 Baseline Assessment of the 
Study
Day 1
1
1
Week 4
29
16-43
Week 8
57
44-71
Week 12
85
72-99
Week 16
113
100-127
Week 20
141
128-155
Week 24
169
•
156 to (week 24 OLTP dose date – 1) 
for subjects who receive OLTP dose 
at week 24
•
156-183 for subjects who did not 
receive OLTP dose at week 24
Week 28
197

Week 24 OLTP dose date to 211 for 
subjects who receive OLTP dose at 
week 24

184-211 for subjects who received at 
least one OLTP dose and did not 


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receive OLTP dose at week 24 (e.g., 
first OLTP dose was postponed)
Week 32
225
212-239
Week 36 to 
Week 72
Following same monthly windowing as Week 32
Safety follow-up 
Based on visit name from RAVE or other source data
Note:
If more than one visit (including the unscheduled visits, ie, CPEVENT = ‘UNSCHED’) fall 
within the same defined window, scheduled visit will be used regardless of the distance 
from the target day. Unscheduled visit will only be used when there is no scheduled visit 
in the defined window. The closest visit to the target day among the same type of visit 
(scheduled vs. unscheduled) will be considered for analysis. If two assessment dates 
are equidistant from the target date, the latter visit will be considered for analysis.
For safety analyses which are summarized by study phase, analysis windows will be set 
up based on study phase:
Study Phase
Start Time Point
End Time Point
Double-Blind Treatment Phase
Study Day 1 after the 1st DB IP 
Dose

First OL Dose Date for subjects 
who receive OL IP dose;

Min(EOS Date, last IP dose 
date + 112 days) for subjects 
who do not receive any OL IP 
dose
Open-Label Treatment Phase
1st OL IP Dose Date
Min(EOS Date, last OL IP dose 
date + 112 days)
Entire Study
Study Day 1 after the 1st DB IP 
Dose
Min(EOS Date, last IP dose date + 
112 days)
Note: all antibody data will be included in antibody analysis.


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6.5
Subject Disposition
Randomized
Individuals are considered randomized if they have been assigned a randomization 
number. Randomized individuals are referred to as “subjects”.
Completing the Double-Blind Treatment Phase
Subjects are defined as completing the DBTP if they complete week 24 assessment. It 
will be derived from the End of Double-Blind Treatment Phase CRF page with 
“Completed” as the reason for ending study phase.
Completing the Open-Label Treatment Phase
Subjects are defined as completing the OLTP if they complete the week 76 assessment.
It will be derived from the End of Open-Label Treatment Phase CRF page with 
“Completed” as the reason for ending study phase.
Completing Study
Subjects are defined as completing study if they complete the whole 88 weeks of study 
evaluation. It will be derived from the End of Study CRF page with “Completed” as the 
primary reason for ending study.
Exposed to Investigational Product
Subjects are defined as exposed if they receive at least one dose of investigational 
product.
Completing the Double-Blind Investigational Product
Subjects are defined as completing double-blind investigational product if they complete 
week 20 IP dose or temporarily withhold IP at week 20 and continue to receive IP during 
OLTP. It will be derived from the End of IP DBTP CRF page with “Completed” as the 
reason for ending IP.
Completing the Open-Label Investigational Product
Subjects are defined as completing open-label investigational product if they complete 
week 72 IP dose. It will be derived from the End of IP OLTP CRF page with “Completed” 
as the reason for ending IP.
On-study


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Subjects are considered on-study if they have been randomized and have not yet had 
their end of study visit.
6.6
Arithmetic Calculations
Duration of Migraine
The number of years from the diagnosis date (DXDT) of migraine (migraine with aura or 
migraine without aura, whichever is earlier) to the date informed consent is signed.
If month or day of the diagnosis date is missing, follow the formula below to calculate the 
duration:
Observed portion 
Missing 
portion 
Formula to Calculate Duration 
Year, Month, Day
(Informed Consent Day – DXDT)/365.25
Year, Month 
Day 
[Year(Informed Consent Day)-Year(DXDT)]+ 
[Month(Informed Consent Day)-Month(DXDT)]/12
*if it equals 0, add 1 month or 1/12 years (this is to 
avoid a disease duration of 0)
Year
Month, Day
[Year(Informed Consent Day)-Year(DXDT)] 
*if it equals 0, add 1 month or 1/12 years (this is to 
avoid a disease duration of 0)
Duration of DB IP Exposure
If subject enter into OL treatment phase, 
Duration = Minimum (Last DB Dose Date + 27, First OL Dose Date - 1, EOS 
Date) – First DB Dose Date + 1
Otherwise, 
Minimum (Last DB Dose Date + 27, EOS Date) – First DB Dose Date + 1
Duration of OLTP IP Exposure
Minimum (Last OLTP Dose Date + 27, EOS Date, Date of Data Cut-off ) – First OLTP
Dose Date + 1


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Change from Baseline in Monthly Efficacy Measurement
The change from baseline in monthly efficacy measurement is the monthly efficacy 
measurement prior to the given time point minus the baseline monthly efficacy 
measurement. Please refer to the Monthly Intervals defined in Section 6.4. For example, 
change from baseline in monthly migraine days at Week 24 will be calculated based on 
the following:
(Monthly migraine days during the week 24 interval) – (monthly migraine days 
during the baseline phase) 
If the baseline or post-baseline value is missing, then the change from baseline is set to 
missing.
Following Efficacy endpoints will be calculated as above:

Change from baseline in monthly migraine days

Change from baseline in monthly migraine attacks

Change from baseline in monthly headache days

Change from baseline in monthly migraine days with severe pain

Change from baseline in monthly cumulative migraine hours

Change from baseline in monthly cumulative migraine hours with severe pain

Change from baseline in monthly acute medication use in days

Change from baseline in monthly migraine-specific medication use in days

Change from baseline in monthly average severity of migraine pain

Change from baseline in monthly average migraine symptoms interference scale

Change from baseline in monthly bed days due to migraine related symptoms

Change from baseline in monthly missed work/school days due to migraine 
related symptoms

Change from baseline in monthly headache impact scores as measured by HIT-6
Mean Change from Baseline in Monthly Efficacy Measurement over multiple 
months


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The Mean Change from Baseline in Monthly Efficacy Measurement is the Arithmetic 
mean of each change from baseline value for the months considered
Percent Change from Baseline
The change from baseline divided by baseline and multiplied by 100: 
(Post-baseline – Baseline) * 100 / Baseline 
If the baseline value is 0 and the post-baseline value is also 0, then the percent change 
from baseline is set to 0. If the baseline value is 0 and the post-baseline value is non-
zero, then the percent change from baseline is set to missing.
Percent change from baseline in (mean) monthly migraine days which is used to 
determine 50%, 75%, and 100% responder will be calculated as above.
Subject Incidence
The subject incidence for a given event in a given period is defined as the number of 
subjects with at least one reported occurrence of the event divided by the number of 
subjects who entered that period. For subjects with multiple occurrences of the same 
event, the event will only be counted once per subject.
Exposure-Adjusted Incidence Rate
The exposure-adjusted incidence rate for a given event in a given period is defined as 
the number of subjects with at least one reported occurrence of the event in a given time 
period at risk divided by total exposure time of all subjects who are at risk for the event. 
For subjects with events, only the time until the first event contributes to the total 
exposure time. For subjects with no event, the exposure time is the time from the first IP 
dose to the last follow-up assessment. This rate will be presented per 100 subject years.
For subjects with multiple occurrences of the same event, the first occurrence of an 
event will be counted for each subject.
6.7
Disease Characteristics
Migraine-Specific Medications
Migraine-specific medications include two categories of medications: triptan-based and 
ergotamine-based migraine medications collected from subject’s eDiary. 
Treatment Failure of Prior Migraine Prophylactic Medications


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Treatment failure of prior migraine prophylactic medications is determined by “Reason 
for ending medication” as “Lack of efficacy” or “Adverse Reaction” in the Prior Migraine 
Prophylactic Medication eCRF page.
7.
Analysis Subsets
7.1
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized in the study. 
Subjects will be analyzed according to their randomized treatment, regardless of the 
treatment received.  Tabulations of demographic and baseline characteristics, 
disposition, and important protocol deviations (IPD) will utilize this analysis set.
7.2
Efficacy Analysis Set
The Efficacy Analysis Set (EAS) will be used to carry out the primary analyses of
efficacy endpoints, which is a subset of the Full Analysis Set consisting of subjects who 
received at least one dose of IP and completed at least one post-baseline monthly 
migraine day measurement in the DBTP. Subjects will be analyzed according to their 
randomized treatment, regardless of the treatment received. Analyses for efficacy
endpoints and patient reported outcomes (PROs) will utilize this analysis set.
7.3
Safety Analysis Set
The Safety Analysis Set will consist of all randomized subjects who received at least one 
dose of IP. Subjects will be analyzed according to the randomized treatment unless a 
subject has received the incorrect dose during the entire DBTP. Analyses for safety 
endpoints and summary of IP administration in DBTP will utilize this analysis set.
7.4
Open-Label Treatment Phase Set
The Open-Label Treatment Phase Set (OLTPS) will consist of all subjects receiving at 
least one dose of AMG 334 in the OLTP.  This analysis set will be used when 
summarizing data collected during the OLTP.
7.5
Per Protocol Set
The Per Protocol Set is a subset of the Efficacy Analysis Set which consists of subjects 
who received IP at Week 12, 16, and 20 and do not satisfy any of the following 
conditions:
1) Important protocol deviations that will potentially impact primary analysis of 
efficacy endpoints from week 16 to week 24 or violate GCP at site as specified in 
the IPD List (Cabinets/AMG 334/TMF/20120309 - Episodic Migraine Prophylaxis 


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Japan/Study Protocol Compliance/Protocol Deviation Listing) to be applied in per
protocol analysis:

Informed Consent was not provided

Monthly migraine days at baseline is < 4 or ≥15

Monthly headache days at baseline is ≥15

No therapeutic response with > 2 of the 7 medication categories for 
prophylactic treatment of migraine after an adequate therapeutic trial

Received botulinum toxin in the head and/or neck region within 4 months 
prior to the start of the baseline phase and throughout the study

Ergotamine-derivatives, steroids, and triptans used for migraine prophylaxis 
are excluded within 2 months prior to the start of the baseline phase and 
throughout the study

Devices and procedures used for migraine prophylaxis are excluded within 2 
months prior to the start of the baseline phase and throughout the study

Using opioid- or butalbital-containing analgesics on ≥ 4 days in any month 
during the 2 months prior to the start of the baseline phase

History of chronic pain syndromes (eg, fibromyalgia, chronic back pain, 
chronic pelvic pain)

Received current migraine prophylaxis medication prior to the start of the 
baseline phase after closure of the stratum

Received less than 75% or more than 125% of planned total dose of AMG 
334 at any of the weeks 12, 16, 20 (based on unblinded information) 
(Example: subject who was randomized to AMG 334 70 mg treatment group 
received 140 mg, not 70 mg at week 20) 

Important GCP violation resulting in that data can’t be used for analysis
2) In addition to above protocol deviations, subjects who did not have an observed 
monthly migraine day value at any of the weeks 16, 20, 24 will also be excluded
from Per Protocol Set
The Per Protocol Set will be used to perform the sensitivity analysis on the primary and 
secondary efficacy endpoints.


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7.6
Patient Reported Outcomes Analysis Set 
The Efficacy Analysis Set will be used to carry out analyses for patient reported 
outcomes.
7.7
Interim Analysis Set 
The Interim Analysis Set will include all subjects at the time when 100 subjects have 
completed 52 weeks of treatment with investigational product. The purpose of this 
interim analysis is to evaluate the long-term efficacy and safety of AMG 334 in subjects 
with episodic migraine after the 24-week DBTP.
7.8
Subgroup Analyses
The primary and secondary efficacy will be analyzed in the subgroups defined by the 
stratification factor, BMI (< median vs ≥ median), baseline monthly migraine days (< 8 vs 
≥8) and treatment failure of prior migraine prophylactic medications.
8.
Interim Analysis and Early Stopping Guidelines
An independent Date Monitoring Committee (DMC) will review and make 
recommendations regarding the safety of the study participants throughout the DBTP of 
the study, and until treatment assignment information is available to the study team for 
the primary analysis.  The DMC will be composed of external advisors, including at least 
2 clinicians and a biostatistician. Summaries of data at the treatment group level will be 
prepared and presented by an independent biostatistician at the DMC meeting.
Additionally the DMC will review pharmacokinetic data and compare the results against 
pre-defined criteria for observed and predicted data to potentially recommend 
discontinuation of enrollment into one or more of the AMG 334 treatment groups, in 
which case randomization of the remaining subjects would continue for the remaining 
treatment groups.
During the OLTP of the study, an interim analysis is planned after at least 100 subjects 
randomized to 70 mg of AMG 334 have completed 52 weeks of treatment with 
investigational product. The purpose of this interim analysis is to evaluate the long-term 
efficacy and safety of AMG 334 in subjects with episodic migraine after the 24-week 
DBTP.
9.
Data Screening and Acceptance
9.1
General Principles
The objective of the data screening is to assess the quantity, quality and statistical 
characteristics of the data relative to the requirements of the planned analyses.


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9.2
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database.  The database will be subjected to edit check outlined in the Data 
Management Plan (DMP). eDiary data, PK, antibody, biomarkers, and ECG data are
outside of RAVE database. All the datasets to be used for planned analyses will be
received from GSO-DM department. Additional details will be provided in the DMP and 
Data Transfer Plan (DTP).
9.3
Handling of Missing and Incomplete Data
Subjects may miss specific data points for a variety of causes.  In general, data could be 
missing due to a subject’s early withdrawal from study, a missed visit, or inability to 
evaluate an endpoint at a particular point in time.  For this study, most of the efficacy 
endpoint will be collected via eDiary and subjects could miss entering several days of 
data in each monthly interval. The general procedures outlined below describe what will 
be performed when a data point is missing.
Missing eDiary data in the calculation of monthly measurements about subjects’ 
migraine and non-migraine headaches will be handled using the following method.
1. For monthly intervals with ≥14 days of eDiary days (including retrospective 
eDiary days) in each interval:
a) Monthly frequency measurements (including migraine days, headache days, 
migraine attacks, cumulative hours of migraine headaches, acute medication 
use, bed days due to migraine and missed work/school days due to migraine) 
will be prorated to 28-day equivalents. Prorated result does not need to be 
rounded.
b) Monthly average severity of migraine pain, migraine related symptoms and 
monthly average scale of migraine interference with daily activity will 
calculated as the average of observed scores
2. For monthly intervals with < 14 days of eDiary use (including retrospective eDiary 
days), all monthly measurement will be set as missing and will be handled as 
described in Section 9.3.3
Missing eDiary data in the calculation of cumulative average monthly measurements 
about subjects’ migraine and non-migraine headaches is treated as if subjects do not 
have headache or medication use to report.


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Missing PROs (HIT-6) scheduled to be collected at office visit at certain assessment will 
not be imputed.
Missing safety endpoints will not be imputed. Missing day portion of AE start time will be 
imputed based on Section 9.3.1.
Missing pharmacogenetic and antibody data will not be imputed.
Handling of missing or incomplete data for exposure-response analysis will be described 
in the E-R SSAP or associated documents to support population PK/PD dataset 
generation and E-R analysis.
9.3.1
Missing and Incomplete Dates
Missing or incomplete dates will be listed as it is in any listings.
Incomplete start date of an adverse event or concomitant medication taken will be 
handled by following rule:
Missing
Imputation
Exception
Start date
(AE, concomitant 
medication)
Day
01
Default to Study Day 1 if 
an adverse event starts the 
same year and month as 
Study Day 1 and the flag 
indicates that the adverse 
event started on or after
the first dose on the 
Adverse Events eCRF
Day/Month
01JAN
Default to Study Day 1 if 
an event started the same 
year as Study Day 1 and 
the flag indicates that the 
adverse event started on 
or after the first dose on 
the Adverse Events eCRF
Day/Month/Year
No imputation
9.3.2
Missing Baseline Evaluation
Baseline values are defined in Section 6.3 “Baseline Assessment of the Study”. Missing 
baseline evaluations will not be imputed.
All subjects included in the efficacy analysis set will have baseline monthly rate or 
monthly average of migraine and non-migraine headaches related measurements after 
applying proration rule defined in Section 9.3 since only subject with ≥80% compliance 
of eDiary use during baseline will be eligible for randomization.


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9.3.3
Missing Post-baseline Evaluation in Double-Blind Treatment Phase
Primary analysis of efficacy endpoints during the 24-week randomized DBTP will be 
conducted using the repeated measures linear mixed effects model on observed data 
without imputation.
For the descriptive summary of mean monthly value calculated using the monthly value 
from each of the last three months (months 4, 5, and 6) of the DBTP, if a subject has at 
least one month’s value in months 4, 5, and 6, then the subject contributes to the
summary statistics. 
In the sensitivity analysis on primary and secondary efficacy endpoints during the 24-
week DBTP, missing continuous efficacy endpoints will be handled using last 
observation carried forward (LOCF) method, inverse probability weighting (IPW) 
generalized estimation equations (GEE) method, and multiple imputation (MI) with 
assumption of missing at random (MAR), respectively. 
In LOCF method, post-baseline missing continuous efficacy endpoints during DBTP will 
be imputed using the last observed value including baseline value. For example, if 
subject has all of the post-baseline values as missing, then all of the post-baseline 
values will be imputed using the observed baseline value.
In non-responder imputation (NRI) method, post-baseline missing dichotomous 
secondary efficacy endpoint (responder (Yes/No) based on ≥50% reduction from 
baseline in monthly migraine days) during DBTP will be imputed as non-responder at 
each corresponding time point. 
IPW GEE method will be used to handle monotone missing data during DBTP. 
Intermittent missing data during DBTP will be handled by LOCF or NRI method before 
applying IPW GEE method.
If the proportion of missing data in primary endpoint is high (eg, > 20% for primary 
analysis at week 24), further analysis will be performed to 

examine the frequency and reason of missing data

determine if there are any patterns in the missing data

distinguish true missing values from other unknown values (eg, due to 
measurement or sample processing error)


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9.4
Detection of Bias
This study has been designed to minimize potential bias by allocating treatment groups 
randomly, assessing endpoints and handling withdrawals without knowledge of the 
treatment. Other factors that may bias the results of the study include:

important protocol deviations likely to impact the analysis and interpretation of 
the efficacy endpoints 

inadvertent breaking of the blind before formal unblinding 

investigational product dosing non-compliance 

the timing of and reasons for early withdrawal from treatment and from study 
The incidence of these factors may be assessed. Important protocol deviations will be 
listed and/or tabulated in the clinical study report (CSR). If necessary, the incidence of 
other factors will be tabulated. 
Any breaking of the blind for individual subjects prior to formal unblinding of the study will 
be documented in the CSR. 
The timing of and reasons for early withdrawal from treatment and from study will be 
tabulated and/or listed.
9.5
Outliers
Histograms will be examined to identify outliers in any of the continuous variables used 
in the analyses. Unexpected and/or unexplained values in categorical data will be 
identified by utilizing frequency tables. 
Outliers due to data entry errors will be corrected by the study team before final 
database lock. The validity of any questionable values or outliers will be confirmed. 
Outliers or any questionable values with confirmed validity will be included in the 
analyses. However, ad-hoc sensitivity analyses may be conducted to evaluate the 
influence of extreme values in the data.
9.6
Distributional Characteristics
Continuous endpoints of change from baseline value will be analyzed under normality 
assumption. If they deviate appreciably from normality, appropriate transformations or 
the non-parametric alternatives such as Quade test (Quade D, 1966) may additionally be 
considered. For repeated measure analysis, GEE model which is less sensitive to 
normality violation may be used in addition to the mixed effect model.


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9.7
Validation of Statistical Analyses
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System and S-plus.  
For the exposure–response analysis, refer to the E-R SSAP for the software used.
10.
Statistical Methods of Analysis
10.1
General Principles
The primary objective of this study is to evaluate the effect of AMG 334 compared to 
placebo on the change from baseline in mean monthly migraine days, in subjects with 
episodic migraine.
The primary analysis will be performed when the last randomized subject completes the 
week 24 assessment or is discontinued from the study. The final analysis for the study 
including DBTP, OLTP and safety follow-up phase will be performed at the end of the 
study.
Subjects will be analyzed based on their randomized treatment group assignment.
Summary descriptive statistics by each treatment group will be tabulated at each visit.  
For continuous endpoints, the descriptive statistics include: number of observations, 
mean, median, standard deviation, first and third quartiles, minimum and maximum.  For 
categorical and ordinal endpoints, frequency and percentage will be given.
Change from baseline for efficacy endpoints will be summarized using both the study 
baseline and the pre-OLTP baseline for efficacy endpoint, respectively.
Primary analyses for efficacy endpoints are based on a linear mixed effects model 
including appropriate terms and covariates in the model (See Section 4.2). Nominal p-
values will be provided for the comparisons between each AMG 334 treatment group vs. 
the placebo group for efficacy endpoints. To maintain a family-wise type I error at 0.05, 
the pair-wise comparison will be tested in a sequential testing procedure in the order of 
AMG 334 140 mg vs. placebo, 70 mg vs. placebo and 28 mg vs. placebo. The lower 
dose group will be tested only when the higher dose group is considered statistically 
significant. For continuous efficacy endpoints, the adjusted mean change from baseline 


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for each treatment group, and the adjusted treatment difference compared to placebo, 
associated 95% confidence intervals, and p-values for pairwise comparison will be 
reported. For dichotomous efficacy endpoints, adjusted odds ratios compared to 
placebo, associated 95% confidence intervals, and p-values will be reported.
Randomized stratum (stratification group) will be included in the statistical models for the 
efficacy endpoints. However, the actual data collected will be used for the analysis of 
baseline characteristics and subgroup analyses.
10.2
Subject Accountability
For the primary analysis at week 24, the disposition of all enrolled subjects will be 
tabulated by the randomized treatment group. The summary will include the number of 
subjects who are randomized, the number and percent of subjects who receive the
double-blind IP, who complete double-blind IP, discontinue double-blind IP and reasons 
for discontinuing, who complete the 24-week DBTP, and who withdraw prematurely from 
the study before completion of the 24-week DBTP and their reasons for withdrawal.
For the final analysis, disposition of the OLTP and safety follow-up phases will be added, 
which include the number and percent of subjects who enter the OLTP, who receive
AMG 334, who complete AMG 334, discontinue AMG 334 and reasons for discontinuing, 
who complete the OLTP, who complete the study, and who withdraw prematurely from 
the study and their reasons for withdrawal.
A footnote on the subject disposition tables will include the number of subjects screened, 
date first subject enrolled, date last subject enrolled, the date of study primary 
completion, the date of study completion (eg, last subject completed the safety follow-up 
visit or drop out from the study) and corresponding data cutoff date.
10.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, sub-category codes and descriptions 
will be used during the course of the study. Eligibility deviations are defined in the 
protocol. IPDs will be summarized by randomized treatment group and listed for DBTP 
and OLTP, respectively. 
10.4
Demographic and Baseline Characteristics
Subject demographic and baseline characteristics will be summarized using descriptive
statistics by randomized treatment group and overall study population using FAS. If 


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multiple races have been reported for a subject, the subject will be categorized as 
multiple race.
The following demographic and baseline characteristics will be summarized: 

Age

Sex

Ethnicity

Race

Height (cm)

Weight (kg)

Body Mass Index (BMI, kg/m2)

Targeted neurological disease diagnosis at baseline

Disease duration of migraine with or without aura

Age at onset of migraine

Migraine specific-medications subjects used during baseline phase: 
a. Triptan-based
b. Ergotamine-based

Monthly acute migraine-specific medication use in days during baseline phase

Prior/current treatment with migraine prophylactic medication (current migraine 
prophylactic medication treatment vs prior migraine prophylactic medication 
treatment only vs no prior or current migraine prophylactic medication treatment)

Monthly migraine days during baseline phase

Monthly migraine attacks during baseline phase

Monthly headache days during baseline phase

Prior prophylactic treatment failure (Yes vs. No)
10.5
Efficacy Analyses 
Primary analysis of efficacy endpoints will utilize the efficacy analysis set. Subjects will 
be analyzed according to their randomized treatment group regardless of the actual 


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treatment received during the study. Per protocol analysis of the primary and secondary 
endpoints will utilize the Per Protocol Set.
For primary analysis at week 24, the continuous change from baseline efficacy 
endpoints as specified in Section 9.3 will be analyzed using linear mixed effect models 
adjusted by stratification factor and baseline value on observed data as the primary 
analysis method. The dichotomous efficacy endpoints will be analyzed using the 
stratified Cochran-Mantel-Haenszel (CMH) test after the missing data are imputed as 
non-response.
Detailed primary analysis methods, sensitivity analyses, and covariates included in the 
models are summarized in the table below.
Table 1.  Summary of Efficacy Endpoints and Analysis Methods
Endpoint
Primary Summary and 
Analysis Method
Sensitivity Analysis
Primary Endpoint
Change from 
baseline in 
monthly 
migraine days
(Note: Results 
from time points 
during DB 
treatment phase 
will also be 
generated in the 
same model.)
1.
Summary statistics by 
visit using observed data, 
and using mean monthly 
migraine days at month 
4,5,6
2.
Least squares mean at 
each timepoint from a 
linear mixed effect model 
adjusted by stratification 
variable and baseline 
value using observed 
data
3.
Test pairwise treatment 
difference between active 
and placebo for the 
primary endpoint –
change from baseline in 
mean monthly migraine 
days, using a contrast 
from the model in #2.
1.
LOCF: Summary statistics by visit and 
analyze using an ANCOVA model for 
the mean monthly migraine days.
2.
Per-Protocol subset: Same as primary 
summary and analysis method.
3.
IPW GEE model for change from 
baseline in monthly migraine days
4.
MI with assumption of MAR
Secondary Endpoints
Response 
defined as at 
least a 50% 
reduction from 
baseline in 
mean monthly 
migraine days
(Note: Results 
1.
Summary statistics by 
visit using observed data, 
and responder rate 
calculated using mean 
monthly migraine days at 
month 4,5,6
2.
A stratified Cochran-
Mantel-Haenszel (CMH) 
1.
Without imputation, adjusted odds 
ratios from a generalized linear mixed 
model adjusted by stratification 
variable and baseline migraine days by 
visit using observed data, and using 
responder rate calculated using mean 
monthly migraine days at month 4,5,6
2.
NRI: Summary statistics by visit and 


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Endpoint
Primary Summary and 
Analysis Method
Sensitivity Analysis
from time points 
during DB 
treatment phase 
will also be 
generated in the 
same model.)
test will be used after the 
missing data are imputed 
as non-response
analyze using a logistic regression 
model, and using responder rate 
calculated using mean monthly 
migraine days at month 4,5,6
3.
Per-Protocol subset: Same as primary 
summary and analysis method.


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Endpoint
Primary Summary and 
Analysis Method
Sensitivity Analysis
Change from 
baseline in 
monthly acute 
migraine-specific 
medication 
treatment days 
(Note: Results 
from time points 
during DB 
treatment phase 
will also be 
generated in the 
same model.)
1.
Summary statistics by 
visit using observed data
and using mean monthly 
acute migraine-specific 
medication treatment 
days
2.
Least squares mean at 
each timepoint from a 
linear mixed effect model 
adjusted by stratification 
variable and baseline 
value using observed 
data
3.
Test pairwise treatment 
difference between active 
and placebo for the 
endpoint of change from 
baseline in mean monthly 
acute migraine-specific 
medication treatment 
days, using a contrast 
from the model in #2.
1.
LOCF: Summary statistics by visit and 
analyze using an ANCOVA model.
2.
Per-Protocol subset: Same as primary 
summary and analysis method.
3.
IPW GEE model for change from 
baseline in monthly acute migraine-
specific medication treatment days
4.
MI with assumption of MAR
Exploratory Endpoints
Change from 
baseline in 
monthly 
headache 
(migraine and 
non-migraine 
headache) days 
at assessment 
time points a
1.
Summary statistics by 
visit using observed data
and mean monthly 
headache
2.
Least squares mean at 
each timepoint from a 
linear mixed effect model 
adjusted by stratification 
variable and baseline 
value using observed 
data
3.
Test pairwise treatment 
difference between active 
and placebo for the 
corresponding endpoint 
of change from baseline 
in mean monthly values, 
using a contrast from the 
model in #2.
Response 
defined as at 
least a 75% 
reduction from 
baseline in 
mean monthly 
1.
Summary statistics by 
visit using observed data
and responder rate 
calculated using mean 
monthly migraine days at 
month 4,5,6


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Endpoint
Primary Summary and 
Analysis Method
Sensitivity Analysis
migraine days
(Note: Results 
from time points 
during DB 
treatment phase 
will also be 
generated in the 
same model.) b
2.
Adjusted odds ratios from 
a generalized linear 
mixed model adjusted by 
stratification variable and 
baseline migraine days 
by visit using observed 
data, and using 
responder rate calculated 
using mean monthly 
migraine days at month 
4,5,6
a: The same analyses methods will be applied to the endpoints:
Change from baseline in mean headache impact scores as measured by HIT-6 (HIT-6 total score), 
Change from baseline in monthly migraine attack,
Change from baseline in monthly cumulative migraine hours, 
Change from baseline in monthly average severity of migraine pain,
Change from baseline in monthly migraine days with severe pain,
Change from baseline in monthly cumulative hours of migraine with severe pain,
Change from baseline in monthly acute medication use in days,
Change from baseline in monthly average migraine symptoms interference scale,
Change from baseline in monthly bed days due to migraine related symptoms,
Change from baseline in monthly missed work/school days due to migraine related symptoms.
b: The same analyses methods will be applied to the endpoints: 
Response defined as at least a 100% reduction from baseline in mean monthly migraine days.
10.5.1
Analyses of Primary and Secondary Efficacy Endpoints
For the primary analyses at the end of DBTP, the continuous primary and secondary 
endpoints will be tested using a linear mixed model based on observed monthly data 
from 24-week DBTP with appropriate contrasts provided in Appendix B for pairwise 
comparisons for the corresponding efficacy endpoints: change from baseline in mean 
monthly values. 
The model will include treatment, visit, treatment by visit interaction, stratification 
variable and baseline value as covariates. If applicable, the first-order autoregressive 
covariance structure is assumed. Least squares means (LSMs) for each treatment 
group, standard errors, associated 95% confidence intervals, difference of LSMs 
compared to placebo group, associated 95% confidence intervals and nominal two-sided 
p-values will be tabulated by visit and treatment, as well as for the mean monthly values 
over the last 3 months in DBTP.


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For binary endpoints, adjusted odds ratios compared to placebo group, associated 95% 
confidence intervals and nominal two-sided p-values will be tabulated by visit and 
treatment.
Sensitivity analysis described below will be performed for the primary and secondary 
endpoints:
1. Summary statistics and ANCOVA model for continuous endpoints (logistic 
regression model for binary endpoints) by visit using imputed data by LOCF (NRI 
for binary endpoint). Factor of treatment, baseline covariate and stratification 
variable will be included in the model.
2. Inverse probability weighted generalized estimation equation (IPW GEE) model
on the primary and secondary endpoints.
3. MI with assumption of MAR
4. Primary summary and analysis method based on per protocol analysis set.
5. Primary summary and analysis by the subgroup of 

Prior/current treatment with migraine prophylactic medication (current 
migraine prophylactic medication treatment vs prior migraine prophylactic 
medication treatment only vs no prior or current migraine prophylactic 
medication treatment)

BMI (< median vs. ≥ median)

Baseline monthly migraine days (< 8 vs ≥8) 

Treatment failure of prior migraine prophylactic medications
6. Primary summary and analysis method with interaction: If the inclusion criterion 
at the 0.15 level is met, the interaction of treatment group by stratification 
variable will be included in the model as sensitivity analysis for the primary 
analysis method.
The purpose of the subgroup analyses is to explore if the treatment effect varies across 
subgroups of interest. Subgroup analyses are performed for primary and secondary 
efficacy endpoints using the same method as Primary Summary and Analysis Method 
but performed within each described subgroup.
10.5.2
Analyses of Exploratory Efficacy Endpoints
For exploratory efficacy endpoints as specified in Section 9.3, summary statistics and 
primary analysis method will be conduct in the same way as that for the primary 
endpoint.


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The exploratory efficacy endpoints at each assessment time will be analyzed using the 
repeated measures linear mixed effects model (a generalized linear mixed model for 
dichotomized variables) that includes treatment group, baseline values, stratification 
factor, scheduled visit, and the interaction of treatment and scheduled visit without any 
imputation for missing data.  The least squares mean (or odds ratio) of treatment group 
and placebo with associated 95% confidence intervals and p-values will be reported.
10.5.3
Analyses of Efficacy Endpoints in Open-Label Treatment Phase
For the OLTP of the study, descriptive summaries of efficacy endpoints will be tabulated 
by randomized treatment group and visit based on observed data without imputation.
10.5.4
Analyses of Patient Reported Outcomes (PROs)
PROs include migraine symptom interference items and HIT-6. Change from baseline in
total score (or subscale if applicable) of each PRO will be analyzed similarly as the 
primary analysis of primary and secondary efficacy endpoints described in the Section 
10.5.1 above during DBTP.
For HIT-6, in addition to the analysis of continuous change from baseline value, 
proportions of subject with a ≥5 point reduction from baseline and proportions of subject 
with HIT-6 ≥60 (severe impact) will be analyzed similarly as the primary analysis 
method for dichotomous efficacy endpoints described in the in the Section 10.5.1 above.
No sensitivity analysis will be conducted for PROs.
For the OLTP of the study, descriptive summaries of PRO endpoints will be tabulated by 
randomized treatment group and visit based on observed data without imputation.
10.5.5
Pharmacokinetic Endpoints
The pharmacokinetic concentration of all subjects will be summarized with descriptive 
statistics by treatment groups and visits using PK analyses set. 
For the population PK analysis, please refer to the separate population PK/PD analysis 
plan for details.
10.6
Safety Analyses
For safety endpoints, all randomized subjects who received at least one dose of 
investigational product (ie, Safety Analysis Set) will be analyzed based on the 
randomized treatment unless a subject has received the incorrect dose the entire period 
of interest (phase or study).


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No statistical testing comparing treatment groups will be performed in the safety 
analyses. 
10.6.1
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 18 or later will be 
used to code all adverse events (AE) to a system organ class and a preferred term.  All 
adverse events will be graded using the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4. All adverse event tables will be summarized by treatment 
group.  Refer to Section 6.1.2 for the definition of treatment-emergent adverse event.
The subject incidence of AEs will be summarized for all treatment-emergent AEs 
(TEAEs), serious AEs, AEs leading to withdrawal of investigational product, fatal AEs, 
and device-related AEs for DBTP and OLTP, respectively. 
Subject incidence of all treatment-emergent AEs, serious AEs, AEs leading to 
withdrawal of investigational product, serious AEs leading to withdrawal of 
investigational product, fatal AEs and device-related AEs will be tabulated by system 
organ class in alphabetical order and preferred term in descending order of frequency, 
for DBTP and OLTP, respectively. 
In addition, subject incidence of all treatment-emergent AEs and serious AEs will be 
tabulated by system organ class in alphabetical order, preferred term and CTCAE grade 
in descending order of frequency, for DBTP and OLTP, respectively. Subject incidence 
of all treatment-emergent AEs and serious AEs will also be tabulated by preferred term 
in descending order of frequency.
Treatment-related treatment-emergent AEs will be summarized for OLTP by system 
organ class, preferred term and CTCAE grade. 
In addition, exposure-adjusted incidence rate will be produced for DBTP and OLTP, 
respectively. All treatment-emergent AEs and serious AEs will be tabulated by preferred 
term in descending order of frequency.
10.6.2
Laboratory Test Results
Shifts tables of the laboratory toxicity for absolute neutrophil count (ANC) based on 
CTCAE grade relative to baseline will be tabulated by treatment group for each study 
phase. 
Summary of change from baseline for ANC, alanine transaminase (ALT) and aspartate 
aminotransferase (AST) will also be provided by visit for each study phase.


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Subject incidence of liver function test abnormalities (including AST, ALT, Total Bilirubin
(TBL) and Alkaline Phosphatase (ALP)) will also be summarized by treatment group and 
study phase.
10.6.3
Vital Signs
The analyses of vital signs (systolic/diastolic blood pressure and weight) will include 
summary statistics of change from baseline over time by treatment group.
Systolic blood pressure and diastolic blood pressure may be analyzed by change from 
baseline in categories: 10-20 mmHg and ≥20 mmHg and analyzed for SBP >140 mmHg 
(Yes vs. No) and DBP > 90 mmHg (Yes vs. No) at each time point.
10.6.4
Columbia-Suicide Severity Rating Scale (C-SSRS)
No statistical testing will be performed on C-SSRS. The number and percentage of 
subjects reporting any suicidal ideation and any suicidal behavior will be summarized 
descriptively by treatment group separately for the DBTP and OLTP. Shift table of C-
SSRS maximum severity of suicidal ideation/behavior compared to baseline will be 
provided by treatment group separately for the DBTP and OLTP.
10.6.5
Electrocardiogram (ECG)
The ECG measurements from this clinical study were 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 in a thorough QT study, neither summaries nor statistical analyses 
for QTc will be provided, and these data are not expected to be useful for meta-analysis 
with data from other trials.
Subject incidence of ECG diagnosis will be summarized by treatment group separately 
for the DBTP and OLTP.
10.6.6
Antibody Formation
The number and percentage of subjects who develop anti-AMG 334 antibodies (binding 
and, if positive, neutralizing) will be tabulated by treatment group for the entire study. 
The list of subjects with positive antibodies at any time will be provided.
In addition, a listing of treatment-emergent AEs will be provided for subjects with   
positive binding or neutralizing antibodies.


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10.6.7
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group and by phases.  The number and percentage of subjects with dose 
change, reason for dose change and duration of exposure to investigational product in 
days will be summarized by treatment group.
10.6.8
Summary Concomitant Medication Use
The number and proportion of subjects receiving headache-related medications will be 
summarized by acute medication category for each treatment group. 
10.7
Pharmacokinetic Analysis
All PK-related tables, figures, listings and other deliverables will be generated by Clinical 
Pharmacology Modeling and Simulation (CPMS).
10.7.1
Exposure-Response Analysis
Exposure-Response (E-R) analysis will be performed. Please refer to the E-R SSAP for 
additional details.
11.
Changes from Protocol-specified Analyses
N/A


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12.
Literature Citations / References
!
Fitzmaurice GM, Laird NM and Ware JH. (2004). Applied Longitudinal 
Analysis. New York: John Wiley and Sons.
!
Breslow, N. E. and Clayton, D. G. (1993), Approximate Inference in 
Generalized Linear Mixed Models, Journal of the American Statistical 
Association, 88, 9–25.
!
Wolfinger, R. and O’Connell, M. (1993), Generalized Linear Mixed Models: A 
Pseudo Likelihood Approach, Journal of Statistical Computation and 
Simulation, 4, 233–243.
!
Rubin, D. B. (1987), Multiple Imputation for Nonresponse in Surveys, New 
York: John Wiley & Sons, Inc. 
!
Heinze, G. and Schemper, M. (2002), A Solution to the Problem of 
Separation in Logistic Regression, Statistics in Medicine, 2002; 21:2409–
2419. 
!
Quade, D. (1966), Rank analysis of covariance, University of North Carolina, 
Institute of Statistics Mimeo Series. No. 483 
!
Gould AL, Shih WJ. Sample size re-estimation without unblinding for normally 
distributed outcomes with unknown variance. Commun Stats-theory Meth. 
1992;21(10):2833-2853.
!
Fairclough DL1, Cella DF. Functional Assessment of Cancer Therapy (FACT-
G): non-response to individual questions. Qual Life Res. 1996 Jun;5(3):321-9.
13.
Prioritization of Analyses
The tables, listings and figures for Flash Memo of primary analysis at week 24 will be 
prioritized.
14.
Data not Covered by This Plan
There are no plans to specifically analyze or summarize the following data points. 
!
ECG interval data
!
PK
!
!
CCI
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15.
Appendices


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Appendix A. Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs
A1
Generalized Linear Mixed Model
Generalized mixed effects repeated measure model fits data with correlations or nonconstant 
variability and where the response is not necessarily normally distributed, which is also known as 
generalized linear mixed models (GLMM). The correlations can arise from repeated observation 
of the same sampling units, shared random effects in an experimental design, spatial (temporal) 
proximity, multivariate observations, and so on.
GLMMs, like linear mixed models, assume normal (Gaussian) random effects. Conditional on 
these random effects, data can have any distribution in the exponential family. The exponential 
family comprises many of the elementary discrete and continuous distributions. The binary, 
binomial, Poisson, and negative binomial distributions, for example, are discrete members of this 
family. The normal, beta, gamma, and chi-square distributions are representatives of the 
continuous distributions in this family.
Suppose Y represents the 
vector of observed data and γ is a 
vector of random 
effects. GLMM Models assume that
where 
is a differentiable monotonic link function and 
is its inverse. The matrix 
is 
an 
matrix of rank k, and Z is an 
design matrix for the random effects. The random 
effects are assumed to be normally distributed with mean 0 and variance matrix G.
The GLMM contains a linear mixed model inside the inverse link function. This model component 
is referred to as the linear predictor,
The variance of the observations, conditional on the random effects, is
The matrix A is a diagonal matrix and contains the variance functions of the model. The variance 
function expresses the variance of a response as a function of the mean. 
The GLIMMIX procedure in SAS fits Generalized linear mixed model. Sample SAS code is 
provided in Appendix B.
The GLIMMIX procedure distinguishes two types of random effects. Depending on whether the 
parameters of the covariance structure for random components in your model are contained in G 
or in R, the procedure distinguishes between “G-side” and “R-side” random effects. The 
associated covariance structures of G and R are similarly termed the G-side and R-side 


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covariance structure, respectively. R-side effects are also called “residual” effects. Simply put, if a 
random effect is an element of
, it is a G-side effect and you are modeling the G-side 
covariance structure; otherwise, you are modeling the R-side covariance structure of the model. 
Models without G-side effects are also known as marginal (or population-averaged) models. 
Models fit with the GLIMMIX procedure can have none, one, or more of each type of effect.
For a model containing random effects, the GLIMMIX procedure, by default, estimates the 
parameters by applying pseudo-likelihood techniques as in Wolfinger and O’Connell (1993) and 
Breslow and Clayton (1993). You can also fit generalized linear mixed models by maximum 
likelihood where the marginal distribution is numerically approximated by the Laplace method 
(METHOD=LAPLACE) or by adaptive Gaussian quadrature (METHOD=QUAD).
Once the parameters have been estimated, you can perform statistical inferences for the fixed 
effects and covariance parameters of the model. Tests of hypotheses for the fixed effects are 
based on Wald type tests and the estimated variance-covariance matrix.
A2
Marginal Model and Inverse Probability Weighted Generalized Estimating 
Equation (IPW GEE)
Marginal model (Fitzmaurice et.al. 2004) refers to a method for extending generalized linear 
models to longitudinal data. The term “marginal” in this context indicates that the model for mean 
responses depends only on the covariates of interest, and not on any random effects or previous 
responses. That is, the term marginal is used to emphasize that the model for the mean response 
at each occasion does not incorporate dependence on any random effects or previous 
responses. This is in contrast to mixed effect models, where the mean response depends not 
only on covariates but also on a vector of random effects. Marginal models do not require 
distributional assumptions for the observations, only a regression model for the mean response. 
That is, marginal models provide a unified method for analyzing diverse types of longitudinal 
responses, which avoids making assumptions about the distribution of the vector of responses; 
the method replies solely on assumptions about the mean responses. Marginal models are 
primarily used to make inferences about population means. As a result, marginal models for 
longitudinal data separately model the mean response and within-subject association among the 
repeated responses. In a marginal model, the goal is to make inferences about the former, 
whereas the latter is regarded as a nuisance characteristic of the data that must be accounted for 
to make correct inferences about the changes in the population mean responses.
Assume that there are  repeated measurements of the response on the  subject and that 
each 	
 is observed at time 
, with associated covaraites 
, which can be time-stationary or 
time-varying.  A marginal model for longitudinal data has the following three-part specification:
1.
The conditional expectation or mean of each response, 	

 = 
 , is assumed to 
depend on the covariates through a known link function


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
 = 
 = 
′ . 
2.
The conditional variance of 	
, given the covariates, is assumed to depend on the mean 
according to
Var	
 = (
),
where (
) is a known “variance function” (ie a known function of the mean, 
) and 
is a scale parameter that may be known or may need to be estimated. 
3.
The conditional within-subject association among the vector of repeated responses, given 
the covariates, is assumed to be a function of an additional set of association 
parameters,  (and also depends upon the means, 
). For example, the components of 
 might represent the pairwise correlations or log odds ratios among the repeated 
responses. 
The avidance of distributional assumptions leads to a method of estimation known as generalized 
estimating equations (GEE). The GEE estimator of  for marginal models can be thought of as 
arising from minimizing the following objective function:

y! −μ!(β)#
′$!
%&
'
(&
y! −μ!(β)#  ,
With respect to  , where ) is treated as known (by ignoring its dependence on  through ) and 
 is the vector of mean responses, with elements 

 = 
() = %&(*
′ )
Using calculus, it can be shown that if a minimum of the above function exists, it must solve the 
following generalized estimating equations:
+
D′$!
%&
'
(&
y! −μ!# = 0 ,
where . = // / is the derivative matrix and ) is the so called working covariance matrix, 
which approximates the true underlying covariance matric for 	, that is, ) ≅Cov(	),  
recognizing that ) ≠Cov(	) unless the models for the variance and he within-subject 
associations are correct. Parameter estimates from the GEE are precise or efficient as the MLE 
and are consistent even when the variance structure is misspecified, under mild regularity 
conditions.
The solution to standard Generalized Estimating Equation yields consistent estimator of
coefficients provided the data are MCAR (missing completely at random) or provided that 
missingness depends only on the covariates included in the model for the mean response. 
However, when dropout is MAR (missing at random), the standard GEE can yield badly biased 
estimates of coefficients. The inverse probability weighted GEE (IPW-GEE) approach was 


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developed to circumvent this specific problem. In the IPW-GEE the idea is to base the estimation 
on the observed responses but weight them to account for the probability of remaining on the 
study. Assume random variable . is recorded for all individuals and . = 6 if an individual drops 
out between (6 −1) and 6 occasion, that is, only the first . −1 responses are observed. 
Then we estimate 89 = Pr (. = 6 + 1), the probability that the  subject is still in the study at 
6 occasion, then it is representated by 
89 = (1 −<&) × (1 −<>) × ⋯× (1 −<9)
where <9 = Pr (. = 6 |. ≥6), which can be estimated from those still remaining at the 
(6 −1) occasion, given the record history of all available data up to (6 −1) occasion. Then 
the available data at the 6 occasion are weighted by 
&
BCD in the analysis. The intuition behind 
the inverse probability weighted methods is that each subject’s contribution to the weighted 
complete case analysis is replicated 
&
BCD times, in order to count once for herself, and E
&
BCD −1F
times for those who do not complete the study. In general, the weight methods are valid provided 
that the model that produces the estimated 89 is correctly specified.
A3     Multiple Imputation (MI) and MCMC Method
The multiple imputation assume that the missing data are missing at random (MAR), that is, the 
probability that an observation is missing may depend on the observed values but not the missing 
values. It also assumes that the parameters q of the data model and the parameters f of the 
missing data indicators are distinct. That is, knowing the values of q does not provide any 
additional information about f, and vice versa. If both MAR and the distinctness assumptions are 
satisfied, the missing data mechanism is said to be ignorable. The MI procedure provides three 
methods for imputing missing values and the method of choice depends on the type of missing 
data pattern. For monotone missing data patterns, either a parametric regression method that 
assumes multivariate normality or a nonparametric method that uses propensity scores is 
appropriate. For an arbitrary missing data pattern, a Markov chain Monte Carlo (MCMC) method 
that assumes multivariate normality can be used. 
In MCMC, one constructs a Markov chain long enough for the distribution of the elements to 
stabilize to a common, stationary distribution. By repeatedly simulating steps of the chain, it 
simulates draws from the distribution of interest. 
In Bayesian inference, information about unknown parameters is expressed in the form of a 
posterior distribution. MCMC has been applied as a method for exploring posterior distributions in 
Bayesian inference. That is, through MCMC, one can simulate the entire joint distribution of the 
unknown quantities and obtain simulation-based estimates of posterior parameters that are of 
interest. 


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Assuming that the data are from a multivariate normal distribution, data augmentation is applied 
to Bayesian inference with missing data by repeating a series of imputation and posterior steps. 
These two steps are iterated long enough for the results to be reliable for a multiply imputed data 
set (Schafer 1997). The goal is to have the iterations converge to their stationary distribution and 
then to simulate an approximately independent draw of the missing values. 
Sample SAS code for MI using MCMC method is provided in Appendix B.
A4
Quade Test for Continuous Response Variable with Covariates
When assumption of normality in analysis of covariance model is violated, 
nonparametric methods, eg rank test, can then be used. Quade (1966) proposed the use 
of rank analysis of covariance. This technique can be combined with the extended 
Mantel-Haenszel statistics to carry out nonparametric comparisons between treatment 
groups, after adjusting for the effects of one or more covariates. 
Suppose that from each of m treatment groups, we have observations (	G, G), where 
	G is the univariate response of the  observation in the I group (1 ≤ ≤G, 1 ≤I ≤
K), and G is the corresponding value of covariates, possibly multivariate, whose 
marginal probability distribution is the same in each treatment group. Assume, in order to 
make ranking possible, that each variate has been measured on at least an ordinal 
scale; continuity is not required, however, and even a dichotomy is permitted as extreme 
case. So let the rank of 	G among all the L = ∑G observed values of Y be NG −
(L + 1)/ 2, where the term (L + 1)/ 2 has been inserted for the convenience so that 
∑∑NG = 0 , thus correcting the ranks for their mean; use “average ranks” in case of ties, 
and (for definiteness) rank from the smallest first. Similarly, if X is actually a p-variate 
variable((&), (>), … , (Q) ), let RG
(9) −(L + 1)/2 be the rank of G
(9) among the N 
observed values of (9). Then characterize the relationship between Y and X by 
performing an ordinary multiple linear regression of R on R(&), R(>), … , R(Q); calculate 
fitted values NSG, and assign as scores the residuals from this regression of ranks: ie let
TG = NG −NSG.
Finally, to test the hypothesis of identical conditional distributions of Y on X among 
treatment groups, use the following the variance ratio:
)N =
(L −K) ∑(∑TG

)>/G
G
(K −1)[∑∑TG
> −∑(∑TG

)>)/G
G

G
]


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as comparing it with the critical value of an F with (m-1,N-m) degrees of freedom. (Note 
that no explicit correction for the mean is required in VR since ∑∑TG = T̿ = 0

G
)
The methodology, which has also been described by Koch et al. (1982, 1990), can easily 
be implemented using the SAS system. First, ranks of response variable and covariate 
in the combined group of treatments are computed using PROC RANK. Then perform 
linear regression of response variable ranks on covariate ranks using PROC REG. The 
residuals are then used to compare treatment difference by the Mantel-Haenszel mean 
score statistic, which can be done in PROC FREQ using TABLE scores. See Appendix 
B for codes.


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Appendix B.  Code Fragments 
CCI


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CCI


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CCI


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CCI


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CCI


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CCI


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CCI


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Appendix C.  Reference Values/Toxicity Grades
Adverse event severity and laboratory toxicity are graded based on NCI Common 
Toxicity Criteria version 4 or higher, which is available at the following: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf


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Appendix D.  Patient-reported Outcome Forms/Instruments
D1.
Headache Impact Test (HIT-6)
Scoring:  
Scoring of HIT-6 total score is process by QualityMetrics Software with total score 
ranging from 36 to 78.  HIT-6 scores are categorized into 4 grades, representing little or 
no impact (49 or less), some impact (50-55), substantial impact (56-59), and severe 
impact (60-78) due to headache.