Conditions: Migraine
Keywords: Migraine Headache Migraine Headache Headache, Migraine Amgen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: no

Brief summary:
Phase I, Randomized, Parallel-group, Double-Blind, Placebo-Controlled, Single Dose Study to Evaluate the Blockade of CGRP Receptor by AMG 334 in Preventing PACAP-38 Induced Migraine-like Attacks in Migraine Patients.

Detailed description:

Arms:
arm 1: In Part A, 4 cohorts of 2 to 5 participants sequentially received an intravenous infusion of 10 picomol/kilogram/minute (pmol/kg/minute) PACAP-38 for 2.5, 5, 7.5 and 10 minutes each in order to determine the dose for Part B. arm 2: Participants were randomized to receive matching erenumab placebo by intravenous administration over 30 minutes on day 1. On day 8 participants were administered the dose of PACAP-38 determined from Part A of the study (100 pmol/kg) and were followed up for 11 weeks. arm 3: Participants were randomized to receive 140 milligrams (mg) erenumab by intravenous administration over 30 minutes on day 1 in Part B. On day 8 participants were administered the dose of PACAP-38 determined from Part A of the study (100 pmol/kg) and were followed up for 11 weeks.

Interventions: intervention 1: Erenumab intervention 2: Placebo intervention 3: PACAP-38 Challenge Agent
Intervention descriptions: intervention 1: Administered once on day 1 of Part B of the study by intravenous infusion. intervention 2: Administered once on day 1 of Part B of the study by intravenous infusion. intervention 3: Administered by intravenous infusion during Part A of the study for dose selection for Part B.

Administered by intravenous infusion on day 8 in Part B as a challenge agent to induce a migraine-like attack.

Protocol document:
Prot_000.pdf: 
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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 17 of 108 
CONFIDENTIAL 
 
 
1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the inhibition of PACAP-38 induced migraine-like attacks by AMG 334  
1.2 
Secondary 
 
To evaluate the inhibition of PACAP-38 induced headaches by AMG 334 
 
To evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of a single 
intravenous (IV) dose of AMG 334 in migraine patients 
1.3 
Exploratory 
 
To evaluate the reduction in severity of PACAP-38 induced migraine-like attacks and 
headaches by AMG 334 
 
To evaluate the duration of PACAP-38 induced migraine-like attacks and headaches 
by AMG 334 
 
To evaluate the safety and tolerability of a single intravenous (IV) dose of exogenous 
PACAP-38 
 
To evaluate CGRP and PACAP-38 levels in migraine patients 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
2.1.1 
Migraines 
Migraines are episodic headaches that can involve significant pain and are sometimes 
preceded by sensory warning symptoms or signs (auras) and are often accompanied by 
nausea, vomiting, and extreme sensitivity to light (photophobia) and sound 
(phonophobia).  Migraine is a highly prevalent disease world-wide with approximately 
15% of the European population and 12% of the United States population suffering from 
migraine attacks.  A study to assess the prevalence of migraine in the United States 
reported that nearly half the migraine patient population had experienced three or 
more migraines per month.  Based on existing treatment guidelines, roughly 
40% of the migraine patient population would benefit from preventive therapy 
(Lipton et al., 2001).  Globally, migraines affect more than 10% of the world’s population 
(Robbins & Lipton 2010) and have been found to be associated with a number of 
psychiatric and medical comorbidities such as depression and vascular disorders  
(Buse et al., 2010, Bigal et al.,2009).  
Migraine was historically considered to be due to vasodilatation of cranial blood vessels 
and is currently treated primarily with a class of drugs called triptans 
(Houston & Van Houtte 1986, Humphrey et al., 1990).  More recent understanding of the 
pathophysiology of migraine indicates that the vasodilatation of the cranial blood vessels 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 20 of 108 
CONFIDENTIAL 
 
 
2.2.2 
AMG 334 Clinical Experience 
2.2.2.1 
Study 20101267 - First in Human Study in Healthy Adult Volunteers 
and Subjects With Migraine  
2.2.2.1.1 
Subject Disposition and Demographic Characteristics 
A total of 61 subjects enrolled in this study and 60 subjects (48 healthy subjects and 
12 subjects with migraine) received investigational product and completed the study.  Of 
the 60 subjects, 42 (36 healthy subjects and 6 subjects with migraine) received 
AMG 334 at single doses of 1 to 210 mg SC or 140 mg IV, and the remainder of the 
subjects received placebo.  The mean (standard deviation [SD]) age of the healthy 
subjects was 27.4 (6.8) years and all were men.  The majority of healthy subjects 
(97.9%) were white.  The mean age (SD) of the subjects with migraine was 
26.2 (9.6) years; 9 were women, and 3 were men, all 12 (100%) were white.   
2.2.2.1.2 
Pharmacokinetics 
AMG 334 exhibited nonlinear pharmacokinetics after single-dose SC administrations 
over the dose range of 1 to 210 mg.  AMG 334 exposure increased more than dose 
proportionally from 1 to 70 mg and appeared to increase approximately dose 
proportionally from 70 to 210 mg after a single SC administration of AMG 334.  The 
mean area under the serum concentration-time curve from time 0 to the last quantifiable 
time point (AUClast) increased from 171 to 650 μg•day/mL (3.8-fold) and mean Cmax 
increased from 6.25 to 15.2 μg/mL (2.5-fold) following the 3-fold increase in dose from 
70 to 210 mg.  The cohort median time of maximum concentration (tmax) ranged from 
4 to 11 days within the dose range of 1 to 210 mg.  The relative exposure (area under 
the concentration-time curve [AUC]) for SC administration compared with IV 
administration was approximately 54% for the 140-mg AMG 334 dose.  There was no 
apparent difference in pharmacokinetic parameters between the healthy and migraine 
subjects.   
2.2.2.1.3 
Safety 
Treatment-emergent adverse events were reported for 30 of the 36 healthy subjects 
(83.3%) who received AMG 334 at any dose and for 10 of the 12 healthy subjects 
(83.3%) who received placebo.  Treatment-emergent adverse events were reported for 
11 of 12 migraine subjects (91.7%; 5 subjects [83.3%] placebo, 6 subjects [100%] 
140 mg SC AMG 334).  No adverse events with a Common Terminology Criteria for 
Adverse Events (CTCAE) of grade ≥ 3 were reported in the study; all events were mild 
(grade 1) or moderate (grade 2) in severity.  The types and frequency of adverse events 
were similar for healthy and migraine subjects.  No relationship was apparent between 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 23 of 108 
CONFIDENTIAL 
 
 
Five (10.4%) of the 48 total subjects tested developed persistent binding antibodies to 
AMG 334.  Of these 5 subjects with positive binding antibodies, 1 (2.1%) subject also 
showed neutralizing capability to AMG 334. 
2.2.2.3 
Study 20120130 - Phase 1 Multiple Ascending-dose Study in Healthy 
Japanese Adults  
2.2.2.3.1 
Subject Disposition and Demographic Characteristics 
A total of 32 subjects (24 AMG 334; 8 placebo) were screened and enrolled in this study, 
and all subjects received and completed treatment with the investigational product.  
Twenty-six subjects (81.3%) completed the study; 6 subjects (18.8%; 5 AMG 334, 
1 placebo) discontinued the study and were lost to follow-up.  The mean (SD) age was 
33.1 (8.4) years (range: 18 to 45 years) and all were men; 24 subjects (75%) were Asian 
of Japanese ancestry and 8 (25%) were white. 
2.2.2.3.2 
Pharmacokinetics 
AMG 334 exposure (Cmax, AUClast, and AUCinf) increased greater than dose 
proportionally from 21 mg to 70 mg and increased proportionally with dose from 70 mg 
to 140 mg in the healthy Japanese subjects.  The tmax ranged from 4.0 to 7.0 days 
following a single SC dose in the 21 mg to 140 mg dose range.  The pharmacokinetics of 
AMG 334 at 70 mg SC was similar for healthy Japanese and white subjects (ratio of 
geometric means or Cmax, AUClast, and AUCinf = 1.02, 1.12, and 1.12 respectively). 
2.2.2.3.3 
Safety 
All 32 enrolled subjects received a single dose of investigational product (24 AMG 334; 
8 placebo) and were included in the safety analysis set.  Nine subjects (37.5%) who 
received AMG 334 and 3 subjects (37.5%) who received placebo had 
treatment-emergent adverse events.  All adverse events were mild or moderate (CTCAE 
grade 1 or 2) in severity.  There were no deaths, serious adverse events, adverse events 
leading to discontinuation of investigational product or study, or adverse events 
considered by the investigator to be related to treatment.  There was no apparent effect 
of AMG 334 on clinical laboratory values, vital signs, or ECGs recorded during the study.  
One Japanese subject who received 140 mg AMG 334 tested positive for anti-AMG 334 
neutralizing antibodies.  The AUCinf value for this subject (196 day•μg/mL) was lower 
than the mean AUCinf value in the other 5 subjects in the 140-mg dose group 
(478 day•μg/mL; range: 301 to 585 day•μg/mL).  
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 29 of 108 
CONFIDENTIAL 
 
 
PACAP-38 dosing.  Lastly, the highest dosing cohort is 115 pmol/kg, which provides an 
approximate 10X safety margins based on the NOAEL in the rodent study.  Refer to 
Table 6.   
2.5 
Rationale 
The primary purpose of this study is to further our understanding of migraine trigger 
pathology using an established experimental medicine model of migraine.  The two 
major challenge agents which have been used in experimental medicine migraine 
models are CGRP and PACAP-38 both of which reliably elicit migraines.  The main 
objective of this study is to test the hypothesis of whether these pathways are 
independent of one another or if CGRP is downstream of PACAP-38.  If PACAP-38 
causes MLA due to release of CGRP one might expect that AMG 334 would inhibit these 
attacks.  This is relevant for the treatment of migraine as there are currently several anti 
CGRP medications under development and if these are efficacious in inhibiting an 
additional pathway it may expand their therapeutic effect. 
2.6 
Clinical Hypotheses 
A single dose of 140 mg IV of AMG 334 will inhibit migraine-like attacks in subjects 
challenged with PACAP-38. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group study in subjects 
with episodic migraines.  This study will evaluate the efficacy of AMG 334 as measured 
by inhibition of PACAP-38 induced migraine-like attacks after a single dose of AMG 334.  
Migraine-like attacks (MLA) will be defined as attacks fulfilling one of the two criteria:  
(1) Headache fulfilling criteria C and D for migraine without aura (IHS 2004) 
C. Headache has at least two of the following characteristics: 
 
unilateral location 
 
pulsating quality 
 
moderate or severe pain intensity (≥ 4 on headache questionnaire) 
 
aggravation by or causing avoidance of routine physical activity 
D. During headache at least one of the following: 
 
nausea and/or vomiting 
 
photophobia and phonophobia 
(2) Headache described as mimicking usual migraine attack treated with triptan. 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 34 of 108 
CONFIDENTIAL 
 
 
which includes the initial screening phase up to 3 weeks, 1 day of challenge agent 
administration, and 7 day safety follow-up. 
For Part B: Randomized (AMG 334 or Placebo) Subjects, the planned length of 
participation in the study for an individual subject is approximately 106 days, which 
includes the initial screening phase up to 3 weeks, 1 day of treatment, 6 days to allow 
drug distribution, 1 day of challenge agent administration, and 11-week safety follow-up.   
3.5.2 
End of Study 
See Section 3.5.1 for study duration for individual subjects. 
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 migraine questionnaire 24 hours after challenge agent 
administration 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 11 weeks after the challenge agent administration, or is 
discontinued from the study).  
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).  
4.1 
Inclusion Criteria 
To be eligible for the study, subjects must provide written informed consent to participate 
and must fulfill the following criteria: 
4.1.1 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures  
4.1.2 
Adults ≥ 18 to ≤ 45 years of age upon entry into screening 
4.1.3 
History of migraine headaches without aura for ≥ 6 months prior to screening 
according to the IHS Classification ICHD-II (Headache Classification 
Committee of the International Headache Society, 2004) based on medical 
records and/or patient self-report 
4.1.4 
Migraine frequency: ≥ 1 and ≤ 5 migraine days per month in each of the 
3 months prior to screening  
 
 
 


Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 35 of 108 
CONFIDENTIAL 
 
 
4.1.5 
Body mass index between 18 and 35  kg/m2, inclusive at screening 
4.1.6 
No history or evidence of clinically relevant medical disorders as determined 
by the investigator in consultation with the Amgen physician 
4.1.7 
Physical, neurological, clinical laboratory values and ECGs are clinically 
acceptable to the investigator and Amgen 
4.2 
Exclusion Criteria 
Subjects who fulfill any of the following criteria are not eligible for the study:  
4.2.1 
History of migraine with aura, cluster headache or hemiplegic migraine 
headache according to the IHS Classification ICHD-II (Headache 
Classification Committee of the International Headache Society, 2004) based 
on medical records and/or patient self-report 
4.2.2 
Greater than or equal to 6 migraine days per month in the last 3 months prior 
to study enrollment and during screening period 
4.2.3 
Other headache disorders (except for episodic tension-type headache 
<5 days/month) 
4.2.4 
Recent nicotine or tobacco users (should have stopped approximately 
6 months prior to screening) 
4.2.5 
History or evidence of clinically significant disorder (including psychiatric), 
condition or disease that, in the opinion of the Investigator or Amgen 
physician would pose a risk to subject safety or interfere with the study 
evaluation, procedures, or completion 
4.2.6 
Pregnant or breastfeeding, or is a female expecting to conceive during the 
study, including through 12 weeks after the last dose of investigational 
product 
4.2.7 
Female subject of childbearing potential who is unwilling to use an acceptable 
method of effective contraception during treatment with investigational 
product through 12 weeks after the last dose of investigational product.  
Acceptable methods of effective birth control include not having intercourse 
(true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject), hormonal birth control methods (pills, shots/injections, implants, 
or patches), intrauterine devices, surgical contraceptive methods (vasectomy 
with medical assessment of the surgical success of this procedure or bilateral 
tubal ligation), or two barrier methods (each partner must use one barrier 
method) with spermicide - males must use a condom with spermicide; 
females must choose either a diaphragm with spermicide, OR cervical cap 
with spermicide, OR contraceptive sponge with spermicide.  Female subjects 
not of childbearing potential are defined as any female who:  
 
Is post-menopausal by history, defined as: 
 
Age ≥ 55 years with cessation of menses for 12 or more 
months, OR 
 
Age < 55 years but no spontaneous menses for at least 
2 years, OR  
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 45 of 108 
CONFIDENTIAL 
 
 
dosing decisions.  If deemed necessary, unblinding will be performed to assist dose 
decisions in accordance with Amgen standard procedures. 
6.3.1.3 
PACAP-38 - Dosage Adjustments, Delays, Rules for Withholding, or 
Restarting Stopping or Permanent Discontinuation  
Dosing of PACAP-38 will be stopped or modified by the DLRM voting members if 
suspected unexpected treatment related adverse events of Grade 2 or greater in the 
same system organ class occur in 2 or more subjects or Grade 3 occur in 1 or more 
subject.  Dosing of PACAP-38 will also be stopped or modified by the DLRM voting 
members under the following circumstances: 
a) Blood pressure: 
a. Systolic BP > 150 mm Hg OR 
b. Diastolic BP > 100 mm Hg OR 
c. Decrease in SBP from baseline > 30 mm Hg OR 
d. Decrease in DBP from baseline > 15 mm Hg and considered clinically 
relevant after consultation between the investigator and the medical 
monitor. 
Any changes in blood pressure as defined above must be confirmed with 
3 consecutive measurements taken approximately 5 minutes apart and with the 
subject remaining in a semi-recumbent position.  The mean of the 3 measurements 
will be the final recorded value.  
b) Mean heart rate increase of subjects in a given cohort is greater than 50% or 
greater than 20% decrease over baseline during a 2 hour period after dosing 
c) Changes in other vital signs or clinical laboratory results considered to pose a 
significant health risk to subjects 
In addition, any clinically or medically significant suspected adverse drug reactions and 
serious adverse events considered to be related to study procedures will be followed 
until resolved or considered stable. 
The study may be terminated at any point in time at the discretion of the sponsor. 
6.4 
Criteria for Additional Safety Assessment Due to Potential 
Hepatotoxicity 
Following the single-dose administration of study drug, the subject should be followed 
according to the recommendations in Appendix A (Additional Safety Assessment 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 51 of 108 
CONFIDENTIAL  
 
 
Table 3.  Schedule of Assessments Part A: For Non Randomized (PACAP-38 Only) Dose Selection Subjects 
Activity 
Screening 
Treatment Period 
Follow-Up 
Period 
EOS
Visit 
Study Day 
-21 to -2 
-1 
Day 1 c d 
Day 2 
Day 3 
Day 8
Time (in hours) 
 
 
Pre-Dose 
0 
0.25
0.5 
1 
2 
3 
4 
8 
24 
48 
General & Safety Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Residency 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, TEMP) d 
X 
X 
X d
 
X 
X d
X 
X d
X 
X 
X 
X d
X 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological Examination 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
12-lead Electrocardiogram  a 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Adverse Event Recording 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Serious Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
Laboratory Assessments 
Creatinine Clearance 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Clinical Chemistry 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Clinical Hematology 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Drug, Alcohol & Cotinine Screen 
X 
X e
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HepCAb, HBsAg, HbcAb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Postmenopausal status test (females only) f 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (females only) b 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Cardiac Enzymes g 
X 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
Questionnaires 
Headache Questionnaire 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Columbia-Suicide Severity Rating Scale 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Dosing 
Challenge-agent (PACAP-38) c 
 
 
 
X c 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic and Other Blood Samples 
CGRP Plasma Collection 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
PACAP-38 Plasma Collection 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Cell Pellet for Pharmacogenetics 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Footnotes are defined on the next page of table 
 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 58 of 108 
CONFIDENTIAL 
 
 
7.2.16 
Creatinine Clearance 
For determining eligibility, estimated glomerular filtration rate (eGFR) will be calculated 
by the estimated Modification of Diet in Renal Disease (MDRD) formula based on 
serum creatinine, age, sex and race values at time points indicated in the Schedule of 
Assessments (Table 2 and Table 3 ). 
7.2.17 
Clinical Chemistry 
Blood samples for clinical chemistry will be collected at time points specified in the 
Schedule of Assessments (Table 2 and Table 3).  All laboratory tests must be reviewed 
and signed by the principal investigator or qualified designee.  Additional safety 
laboratory assessments may be performed for subject safety.  
The tests listed below will be conducted and analyzed by standard laboratory 
procedures: 
Table 4.  Clinical Chemistry 
Albumin 
Blood urea nitrogen (BUN) or Urea 
Calcium 
Chloride
Glucose 
Phosphorus or Phosphate 
Potassium  
Creatinine 
Magnesium  
Sodium 
Carbon Dioxide or Bicarbonate 
Uric acid 
Aspartate aminotransferase (AST / SGOT)  
Alanine aminotransferase (ALT / SGPT) 
Cholesterol  
Total bilirubin (TBIL) 
Alkaline phosphatase (ALP) 
Direct bilirubin 
Total protein  
Triglycerides 
High-density lipoprotein (HDL) 
Cardiac enzymes (CPK-MB and Troponin I or 
Troponin T) 
Creatinine Phosphokinase (CPK) 
Hemoglobin A1C 
 
7.2.18 
Hematology 
Blood samples for hematology tests will be collected at time points specified in the 
Schedule of Assessments (Table 2 and Table 3).  All laboratory tests must be reviewed 
and signed by the principal investigator or qualified designee.  Additional safety 
laboratory assessments may be performed for subject safety. 
 
 
 


Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 59 of 108 
CONFIDENTIAL 
 
 
The tests listed below will be conducted and analyzed by standard laboratory 
procedures: 
Table 5.  Hematology 
Red blood cells 
White Blood Cell (WBC) 
White blood cells differential count: 
 
Total neutrophils (OR segmented 
neutrophils and band cells) 
 
Eosinophils 
 
Lymphocytes 
 
Basophils 
 
Monocytes 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Platelet count 
Mean corpuscular hemoglobin concentration 
7.2.19 
Urinalysis 
Urine samples will be collected at time points specified in the Schedule of Assessments 
(Table 2 and Table 3 ). 
All laboratory tests must be reviewed and signed by the principal investigator or qualified 
designee.  Additional safety laboratory assessments may be performed for subject 
safety. 
The tests listed below will be conducted and analyzed by standard laboratory 
procedures: 
Table 6.  Urinalysis 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Microscopic exam (performed at the discretion of the principal investigator or qualified 
designee): 
White blood cells 
Red blood cells 
Epithelial Cells 
Bacteria 
Casts 
Crystals 
7.2.20 
Drug, Alcohol, and Cotinine Screen 
Drug, alcohol, and cotinine assessments are to be completed at time points indicated in 
the Schedule of Assessments (Table 2 and Table 3).  The drug and alcohol tests will 
include testing for drugs with a high potential for abuse, including amphetamines, 
barbiturates benzodiazepines, cocaine, ethanol, opiates, and tetrahydrocannabinol. 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 69 of 108 
CONFIDENTIAL 
 
 
The investigator must assess whether the serious adverse event is possibly related to 
any study mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Adverse Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
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/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.4 
Serious Adverse Events That are not to be Reported In an Expedited 
Manner  
Migraine requiring hospitalization does not need to be reported in an expedited manner. 
AEs, SAEs, safety labs will be reviewed by the GSO, MM, and PI throughout the study 
and at the DRLM. 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  01 September 2016 
Page 103 of 108 
CONFIDENTIAL 
 
 
Appendix E.  Columbia Suicide Severity Rating Scale (C-SSRS) 
– Screening/Baseline 
 
 
 
 


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Product:  AMG 334 
Protocol Number:  20140207 
Date:  27 May 2016 
Page 1 of 51 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  Phase I, Randomized, Parallel-group, Double-Blind, Placebo-Controlled, 
Single Dose Study to Evaluate the Blockade of CGRP Receptor by AMG 334 in 
Preventing PACAP-38 Induced Migraine-like Attacks in Migraine Patients   
 
Amgen Protocol Number AMG 334 20140207 
 
Amendment Date: 
27 May 2016 
 
Rationale: 
The primary objective of this protocol amendment is to 1) allow dosing of an additional 
cohort up to 115 pmol/kg in the non-randomized portion of the study (Part A), 2) clarify 
the criteria required prior to advancement to the randomized portion of the study 
(Part B), 3) increase the sample size in Part A to no more than 5 subjects per cohort, 
and 4) include additional safety monitoring of all subjects throughout the duration of the 
study.  
The aforementioned dosing options support the goal of establishing an appropriate dose 
of IV PACAP-38 to be used in Part B of the study. The generation of headaches and 
migraine-like attacks (MLAs) are the pharmacodynamic (PD) effects desired to advance 
the study. The decision to proceed with Part B will be based on the objective of ensuring 
subject safety and ideally triggering headache in all subjects within a given cohort and 
moderate to severe MLAs in the majority of subjects within the same cohort. However, 
the trigger of headaches in the majority of subjects within a given cohort and moderate 
to severe MLAs in the majority of subjects within the same cohort may be considered 
acceptable to advance to Part B of the study. In order to ensure the reliability of these 
subjective PD assessments, the sample size per cohort, has been increased to up to 
5 subjects in Part A of the study. 
The maximum dose of 115 pmol/kg was chosen because it provides a safety margin of 
approximately 10X (based on body weight) from the single-dose GLP IV rat study 
NOAEL. In this study, acute myocardial necrosis was observed at the mid and high 
doses. By day 15, repair of the myocardium at these doses was almost complete, with 
only scattered minimal to mild areas of immature connective tissue (fibroplasia) 
remaining.  This is an anticipated pharmacologic effect of potent vasodilators in 


 
 
 
Product:  AMG 334 
Protocol Number:  20140207 
Date:  27 May 2016 
Page 2 of 51 
CONFIDENTIAL 
 
 
nonclinical species: potent vasodilating drugs when administered at high doses to rats 
are known to produce necrosis and inflammation of the myocardium and cardiac arteries 
(Greaves, 2012). This is a rat-specific finding not known to translate to humans. 
As the dose will be increased and the possible number of subjects exposed to 
PACAP-38 may also increase, additional risk mitigation steps have been added in order 
to ensure subject safety throughout the duration of the study. These include 
measurement of cardiac enzymes (Troponin T and CK-MB) pre-dose, and then at 
2 hours, 4 hours, 8 hours and 24 hours after PACAP-38 dosing, and the addition of an 
ECG 48 hours after PACAP-38 dosing. Stopping rules have also been modified to 
include potential of PACAP-38 to decrease BP and are now as follows: 
 
Blood pressure: 
o Systolic BP > 150 mm Hg OR 
o Diastolic BP > 100 mm Hg OR 
o Decrease in SBP from baseline > 30 mm Hg OR 
o Decrease in DBP from baseline > 15 mm Hg and considered clinically 
relevant after consultation between the investigator and the medical 
monitor 
 
Mean heart rate increase of subjects in a given cohort is greater than 50% or 
greater than 20% decrease over baseline during a 2 hour period after dosing 
 
Changes in other vital signs or clinical laboratory results considered to pose a 
significant health risk to subjects 
To date, IV PACAP-38 has been found to be safe and well tolerated with subjects 
experiencing the anticipated PD effects. 
Safety: In the 3 cohorts dosed, the safety profile has been consistent with the exerted 
pharmacological effects of PACAP-38.  Majority of reported events were CTCAE 
Grade 1.The following adverse events were assessed as being CTCAE Grade 2: feeling 
of pressure on the head (n=1), dry eyes (n=2), MLA (n=1), facial flushing (n=1), 
muscular tension in the face (n=1) and headache (n=2). Transient effects on blood 
pressure and heart rate were noted in subjects, however none met stopping criteria. 
PD effect: In Cohort 1 (25 pmol/kg), both subjects experienced a mild headache. In 
Cohort 2 (50 pmol/kg, 1 subject experience a mild headache, and 2 subjects 
experienced a moderate MLA. However, in the most recent cohort (Cohort 3; 75 pmol/kg 
of IV PACAP-38), one subject did experience a moderate MLA, however the other 
subject did not experience either a headache or MLA. 


 
 
 
Product:  AMG 334 
Protocol Number:  20140207 
Date:  27 May 2016 
Page 3 of 51 
CONFIDENTIAL 
 
 
In addition to the aforementioned updates, the amendment explicitly outlines the 
decision the Principal Investigator (PI), Global Safety Officer (GSO), and Medical 
Monitor (MM)  may jointly make regarding whether the safety, tolerability, and 
pharmacodynamics effects of IV PACAP-38 observed in Part A of the study support 
advancing to Part B. 
Lastly, clarification regarding the difference between a Safety Review Meeting and Dose 
Level Review Meeting (DLRM) has been added, along with more precise questions in 
the Headache Questionnaire. The criteria for post-menopausal status has been added. 
Administrative, typographical and formatting changes were also made throughout the 
protocol.   
References 
Greaves P.  Cardiovascular system.  In:  Greaves P, ed.  Histopathology of Preclinical 
Toxicity Studies.  Amsterdam, The Netherlands:  Academic Press; 2012;293-294.   
 


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Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 2 
Table of Contents 
Table of Abbreviations ..................................................................................................... 4 
1. 
Introduction ............................................................................................................. 6 
2. 
Objectives ............................................................................................................... 6 
2.1 
Primary ....................................................................................................... 6 
2.2 
Secondary ................................................................................................... 6 
2.3 
Exploratory .................................................................................................. 6 
3. 
Study Overview ...................................................................................................... 6 
3.1 
Study Design ............................................................................................... 6 
3.2 
Sample Size .............................................................................................. 13 
4. 
Study Endpoints and Covariates ........................................................................... 13 
4.1 
Study Endpoints ........................................................................................ 13 
4.2 
Planned Covariates and Subgroups .......................................................... 14 
5. 
Hypotheses and/or Estimations ............................................................................ 14 
6. 
Definitions ............................................................................................................. 14 
7. 
Analysis Subsets .................................................................................................. 16 
7.1 
Safety Analysis Set ................................................................................... 16 
7.2 
Pharmacokinetic (PK) Analysis Set ........................................................... 16 
8. 
Interim Analysis and Early Stopping Guidelines .................................................... 17 
8.1 
Dose Level Review Meetings and Safety Review Meetings ...................... 17 
8.2 
Interim Analysis ......................................................................................... 18 
9. 
Data Screening and Acceptance ........................................................................... 20 
9.1 
General Principles ..................................................................................... 20 
9.2 
Data Handling and Electronic Transfer of Data ......................................... 20 
9.3 
Handling of Missing and Incomplete Data ................................................. 20 
9.4 
Detection of Bias ....................................................................................... 21 
9.5 
Outliers ..................................................................................................... 21 
9.6 
Distributional Characteristics ..................................................................... 21 
9.7 
Validation of Statistical Analyses ............................................................... 21 
10. 
Statistical Methods of Analysis.............................................................................. 21 
10.1 
General Principles ..................................................................................... 21 
10.2 
Subject Accountability ............................................................................... 22 
10.3 
Important Protocol Deviations ................................................................... 22 
10.4 
Demographic and Baseline Characteristics ............................................... 23 
10.5 
Primary Endpoint Planned Analysis........................................................... 23 
10.6 
Secondary Endpoint(s) .............................................................................. 23 
10.6.1 
Number of Headaches ............................................................... 23 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 3 
10.6.2 
Safety Endpoints ....................................................................... 23 
10.6.2.1 
Adverse Events (AEs) ............................................. 23 
10.6.2.2 
Vital Signs ............................................................... 24 
10.6.2.3 
Electrocardiogram (ECG) ........................................ 24 
10.6.2.4 
Physical Examination .............................................. 24 
10.6.2.5 
Laboratory Test Results .......................................... 24 
10.6.2.6 
Neurologic Assessment ........................................... 24 
10.6.3 
Pharmacokinetic Endpoints ....................................................... 24 
10.6.4 
AMG 334 Antibody Assessment ................................................ 25 
10.7 
Exploratory Endpoint(s) ............................................................................. 25 
10.7.1 
Migraine-like Attacks (MLA) and Headaches ............................. 25 
10.7.2 
Duration of Migraine-like Attacks (MLA) and 
Headaches ................................................................................ 25 
10.7.3 
Migraine Characteristics ............................................................ 25 
10.7.4 
Plasma Concentration of PACAP-38 and CGRP ....................... 25 
10.8 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................... 26 
10.9 
Exposure to Investigational Product (IP) ................................................... 26 
10.10 Exposure to Non-Investigational Medicinal Product (NIMP) ...................... 26 
10.11 Exposure to Concomitant Medication ........................................................ 26 
11. 
Changes From Protocol-specified Analyses.......................................................... 26 
12. 
Literature Citations / References ........................................................................... 26 
13. 
Data Not Covered by This Plan............................................................................. 26 
14. 
Appendices ........................................................................................................... 27 
Appendix A. Code Fragments ............................................................................... 28 
 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 4 
Table of Abbreviations 
Abbreviation/Acronym 
Definition 
AE 
Adverse event 
AUC84d 
Area under the concentration-time curve from time 0 to 
84 Days 
BMI 
Body Mass Index 
BP 
Blood pressure 
C1hour 
Maximum observed concentration from time 0 to 1 hour 
CGRP 
Calcitonin gene-related peptide 
CPMS 
Clinical pharmacology modeling and simulation 
CRF 
Case report form 
C-SSRS 
Columbia suicide severity rating scale 
CTCAE 
Common terminology for adverse events 
DBP 
Diastolic blood pressure 
DLRM 
Dose level review meeting 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EOS 
End of study 
GBS 
Global biostatistical science 
GSO 
Global safety officer 
GSO-DM 
Global study operations-Data management 
HR 
Heart Rate 
IP 
Investigational product 
IPD 
Important protocol deviation 
IV 
Intravenous 
kg 
kilogram 
m 
meter 
MedDRA 
Medical dictionary for regulatory activities 
Mg 
Milligram 
MLA 
Migraine-like attacks 
MM 
Medical monitor 
NIMP 
Non-investigational medicinal product 
PACAP 
Pituitary adenylate cyclase-activating polypeptides 
PI 
Principle investigator 
PK 
Pharmacokinetic(s) 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 5 
Abbreviation/Acronym 
Definition 
PKDM 
Pharmacokinetics and drug metabolism 
pmol 
picomole 
SAE 
Serious adverse events 
SBP 
Systolic blood pressure 
TFL 
Tables, Figures, and Listings 
 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
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 AMG 334 Study 20140207 Protocol 
Amendment 4 (dated 21 Oct 2016), entitled “Phase I, Randomized, Parallel-group, 
Double-Blind, Placebo-Controlled, Single Dose Study to Evaluate the Blockade of CGRP 
Receptor by AMG 334 in Preventing PACAP-38 Induced Migraine-like Attacks in 
Migraine Patients”. The scope of this plan includes the interim analysis and the final 
analyses that are planned and will be executed by the Global Biostatistical Science 
(GBS) department unless otherwise specified (eg, standard pharmacokinetic (PK) tables 
will be provided by Clinical Pharmacology Modeling and Simulation [CPMS]). 
2. 
Objectives 
2.1 
Primary 
To evaluate the inhibition of PACAP-38 induced migraine-like attacks by AMG 334 
2.2 
Secondary 
• 
To evaluate the inhibition of PACAP-38 induced headaches by AMG 334 
• 
To evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of a 
single intravenous (IV) dose of AMG 334 in migraine patients 
2.3 
Exploratory 
• 
To evaluate the reduction in severity of PACAP-38 induced migraine-like attacks 
and headaches by AMG 334 
• 
To evaluate the duration of PACAP-38 induced migraine-like attacks and 
headaches by AMG 334 
• 
To evaluate the safety and tolerability of a single intravenous (IV) dose of 
exogenous PACAP-38 
• 
To evaluate CGRP and PACAP-38 levels in migraine patients 
3. 
Study Overview 
3.1 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group study in subjects 
with episodic migraines. This study will evaluate the efficacy of AMG 334 as measured 
by inhibition of PACAP-38 induced migraine-like attacks (MLA) after a single dose of 
AMG 334. MLAs will be defined as attacks fulfilling one of the two criteria:  
(1) Headache fulfilling criteria C and D for migraine without aura (IHS 2004) 
C. 
Headache has at least two of the following characteristics: 
 
unilateral location 
 
pulsating quality 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 7 
 
moderate or severe pain intensity (≥ 4 on headache 
questionnaire) 
 
aggravation by or causing avoidance of routine physical activity 
D. 
During headache at least one of the following: 
• 
nausea and/or vomiting 
• 
photophobia and phonophobia 
(2) Headache described as mimicking usual migraine attack treated with triptan. 
Part A: PACAP-38 Dose Selection Phase: In order to ensure subject safety and select 
the lowest PACAP-38 dose that will ideally trigger headache in all subjects within a given 
cohort and moderate to severe MLA in the majority of the subjects within the same 
cohort, a dose selection strategy, along with Safety Review Meetings and Dose-Level 
Review Meetings (DLRM) have been implemented. Dosing of PACAP-38 shall not 
exceed a total dose of 115 pmol/kg, providing an approximate 10X exposure margin 
over the non-clinical NOAEL dose. However, the trigger of headaches in the majority of 
the subjects within a given cohort and mild, moderate or severe MLAs in the majority of 
the subjects within the same cohort may be considered acceptable to advance to the 
randomized portion of the study (Part B). 
Up to five cohorts consisting of approximately 2 to 5 subjects are planned. Based on 
emerging safety and tolerability data, as well as the number of subjects experiencing a 
headache and/or MLA, the voting members of the Safety Review Meetings or DLRM, 
may decide cohorts should be removed or additional cohorts should be added, with a 
maximum of 5 total cohorts. Subject numbers within each cohort may also be increased 
or decreased based on the decision from the Safety Review Meeting or DLRM. Doses to 
be administered within each cohort may be repeated, higher or lower than the last dosed 
cohort. Dosing of any subject shall not exceed 115 pmol/kg. 
On Day 1, approximately 2 subjects in Cohort 1 will receive an infusion of 
10 pmol/kg/min over 2.5 minutes (total dose 25 pmol/kg). The Principal Investigator (PI) 
will be responsible to review heart rate (HR) and blood pressure (BP). The BP 
assessment is based on a single measurement of systolic blood pressure (SBP) of 
>150 mm Hg or diastolic blood pressure (DBP) >100 mm Hg. If the mean HR increase of 
the subjects in Cohort 1 is greater than 50% over baseline during a 2 hour period after 
dosing and SBP does not increase to >150 mm Hg or DBP to >100 mm Hg, then 
approximately 3 subjects in Cohort 2 will receive an infusion of 10 pmol/kg/min over 
5 minutes (total dose 50 pmol/kg). Written documentation from Amgen of the decision to 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 8 
proceed with enrollment in Cohort 2 is required. After dosing Cohort 2 and any 
subsequent cohort, the PI will again be responsible to review HR and BP using 
previously outlined criteria. These same criteria shall also be assessed for Cohort 3.  
After dosing Cohort 3, up to 5 subjects in Cohort 4 will receive 10 pmol/kg/min over 
10 minutes (total dose 100 pmol/kg). Following Cohort 4, a DLRM will occur to decide 
the dose of PACAP-38 to be used in the randomized portion of the study (Part B). This 
decision will be primarily based on safety and tolerability data, and number of subjects 
experiencing a headache and/or MLA in Cohort 4, although all of the available data for 
Cohorts 1 to 4 will be reviewed. The dose-selection for Part B will be based on the goal 
of ensuring subject safety and ideally triggering headache in all subjects within a given 
cohort and moderate to severe MLAs in the majority of subjects within the same cohort. 
However, the trigger of headaches in the majority of subjects within a given cohort and 
mild, moderate or severe MLAs in the majority of subjects within the same cohort may 
be considered acceptable to advance to the randomized portion of the study (Part B). If 
this goal is not achieved, following the DLRM review of the Cohort 4 data, then Cohort 
5 dosing of 10pmol/kg/ min over 11.5 minutes (total dose 115 pmol/kg) can commence. 
Cohorts 2, 3 and 4 enrollment will occur after a Safety Review Meeting between the 
principal investigator (PI), medical monitor (MM), and global safety officer (GSO) or 
designee. At that time, available vital signs and adverse events occurring at least 
24 hours following PACAP-38 dosing will be reviewed. 
If the PI, MM, and GSO or designee decides not to proceed with enrollment into a 
subsequent cohort, then a Safety Review Meeting or DLRM will be held after the last 
dosed cohort. The Safety Review Meeting or DLRM voting members will decide whether 
or not to proceed with enrollment in Part B Randomization (AMG 334 or Placebo) Phase 
and if the decision is made to proceed, the Safety Review Meeting or DLRM voting 
members will select the appropriate PACAP-38 dose from the Dose Selection Phase, 
Part A. The decision to proceed with Part B of the study will be based on the goal of 
ensuring subject safety and ideally triggering headache in all subjects within a given 
cohort and moderate to severe MLAs in the majority of subjects within the same cohort. 
However, the trigger of headaches in the majority of subjects within a given cohort and 
mild, moderate or severe MLAs in the majority of subjects within the same cohort may 
be considered acceptable to advance to Part B of the study. 
Part B: Randomization (AMG 334 or Placebo) Phase: PACAP-38 responders from 
part A, as well as PACAP-38 naïve subjects (those who never received PACAP-38 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 9 
before) can enter screening in part B. Subjects will be enrolled in Part B following the 
21 day screening period. There will be a minimum duration of 2 weeks between the first 
and second PACAP-38 doses for all subjects enrolling in Part B of the study. 
Eligible PACAP-38 responders from Part A will immediately be randomized to receive 
either AMG 334 or placebo, whereas eligible PACAP-38 naïve subjects will first enter a 
PACAP-38 challenge phase. Only PACAP-38 responders (those who experienced a 
MLA within 24 hours after the challenge) will be randomized to receive either AMG 334 
or placebo. 
A minimum of 16 and a maximum of 36 PACAP-38 responders will be randomized to 
receive AMG 334 or Placebo.  
PACAP-38 Responders from Part A 
On Day 1, PACAP-38 responders from Part A will receive 140 mg IV AMG 334 over 
30 minutes or placebo, in a one to one allocation ratio. On Day 8, the subjects will be 
administered the dose of PACAP-38 determined from the PACAP-38 Dose Selection 
Phase (Part A).  
PACAP-38 Naïve Subjects 
On Phase 1 Day 1 (Challenge Period), PACAP-38 naïve subjects will receive the dose of 
PACAP-38 determined from the PACAP-38 Dose Selection Phase (part A) and will be 
followed until Day 8. For subjects that do not experience a MLA within 24 hours following 
PACAP-38 administration (non-responders), Day 8 will be their End of Study (EOS) visit. 
Those subjects who experience a MLA within 24 hours following PACAP-38 
(responders) will be randomized to receive 140 mg IV AMG 334 over 30 minutes or 
placebo on Phase 2 Day 1 (Treatment Period), in a one to one allocation ratio. On 
Day 8, the PACAP-38 responders will be administered the dose of PACAP-38 
determined from the PACAP-38 Dose Selection Phase (part A). 
All subjects will remain in-house for 24 hours of observation following PACAP-38 
infusion. Subjects (respectively PACAP-38 responders from part A and PACAP-naïve 
subjects) will be followed until Day 85. 
Subjects will be monitored and asked questions from the headache questionnaire, as 
per the Schedule of Assessment in Table 2 of Protocol Amendment 4, to determine if 
they have experienced a MLA. Previous challenge studies have shown that for 
migraineurs the median onset of a MLA is within 4 hours with some patients 
experiencing a MLA as late as 12 hours following PACAP-38 infusion. Therefore, a 
 


Product: AMG 334 
Statistical Analysis Plan: 20140207 
Dated: 17 May 2017 
Page 10 
headache questionnaire covering the 24 hours after infusion will ensure capture of all the 
PACAP-38 induced MLAs. After 24 hours of data from the first 16 randomized (AMG 334 
or Placebo) subjects challenged with PACAP-38 is available, an interim analysis will be 
conducted to determine if challenge rates are comparable to historical rates (~66%) and 
if AMG 334 has greater efficacy than placebo. If AMG 334 is found to completely block 
PACAP-38 induced migraines, or have the same efficacy as placebo, the study will be 
terminated. Otherwise, approximately 20 randomized (AMG 334 or Placebo) subjects 
will be added. 
The overall study design is described in the study schema below:
 


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Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 12 
 
 
 
  
 
Day 1 
Day 2-7 
Day 8-9 
Day 10 – Day 84 
Day 85 
Administer 
Placebo 
Out-patient 
Challenge with 
PACAP-38 
Follow Up Period 
End of Study 
Day 1 
Day 2-7  
Day 8-9 
Day 10-84  
Day 85 
Administer 
AMG 334 
Out-patient 
Challenge with 
PACAP-38 
Follow Up Period  
End of Study 
Day 1 
Day 2-7 
Day 8-9 
Day 10– Day 84 
Day 
85 
Administer AMG 
334 
Out-patient 
Challenge with 
PACAP-38 
Follow Up Period 
End 
of 
Study 
Day 1 
Day 2-7 
Day 8-9 
Day 10– Day 84 
Day 
85 
Administer 
Placebo 
Out-patient 
Challenge with 
PACAP-38 
Follow Up Period  
End 
of 
Study 
Part B: AMG334 or Placebo Commences  
Screening 
Period 
For PACAP-
38 
Responders 
from Part A 
Residency 
Screening 
Period 
For PACAP-
38 Naïve 
Subjects 
PACAP-38 
challenge 
(Phase 1)  
Residency 
End of Study on 
day 8 (Phase1) 
PACAP-38 non-
responders 
   PACAP-38  
   
Responders 
(Phase 2) 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 13 
3.2 
Sample Size 
Up to 25 subjects may participate in Part A. An adequate number of migraine subjects 
are planned to be randomized and enrolled into Part B of the study, in order to obtain 16 
PACAP-38 responders to participate in the interim analysis and depending on those 
results an additional 20 PACAP-38 responders to complete the study. If ambiguous 
results in Part A occur regarding the ability of PACAP-38 to ideally safely trigger a 
headache in all subjects within a given cohort (although, safely triggering headaches in 
the majority of subjects within a given cohort may be considered acceptable to advance 
to Part B of the study) and mild, moderate or severe MLAs in the majority of subjects 
within the same cohort, then a previously dosed cohort sample size may be expanded to 
up to 5 subjects per cohort. Once the PACAP-38 dose has been selected, enrollment in 
part B can start. The data collected for the 16 subjects that received AMG 334 or 
Placebo will be included in the interim analysis. Following the interim analysis, if the 
decision is to continue enrollment for the study, an additional 10 subjects will be planned 
to receive placebo, and another 10 subjects to receive AMG 334.  
The sample size is not based on any power calculations; it is based on practical 
considerations and is consistent with this type of study. The results from 10,000 
simulated trials demonstrate that, if, PACAP-38 produces MLA in 70% of placebo 
treated PACAP-38 responders, and AMG 334 is effective in blocking MLA such that only 
20% of AMG 334 treated subjects have a headache, then there is approximately a 91% 
chance of overall trial success (see Section 8 for more details).  
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
Primary Endpoints:  
• 
Occurrence of a MLA within 24 hours of challenge-agent infusion 
Secondary Endpoint(s):  
• 
Occurrence of a headache within 24 hours of challenge-agent infusion  
• 
Treatment-emergent AE 
• 
Clinical significant changes in vital signs, ECGs, physical examinations, 
laboratory safety tests, and neurological assessments 
• 
AMG 334 PK parameters, including C1 hour and AUC84d  
• 
Anti-AMG 334 antibodies 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 14 
Exploratory Endpoint(s):  
• 
Severity of PACAP-38 induced MLA and headaches 
• 
Duration of PACAP-38 induced MLA and headaches 
• 
Migraine characteristics: localization, accompanying symptoms and pre-monitory 
symptoms. 
• 
PACAP-38 related treatment-emergent AE  
• 
Evaluate the concentration of PACAP-38 and CGRP following administration of 
AMG 334 
4.2 
Planned Covariates and Subgroups 
Planned covariates consist of baseline measures. No subgroup analysis is planned. 
5. 
Hypotheses and/or Estimations 
A single dose of 140 mg IV of AMG 334 will inhibit MLAs in subjects challenged with 
PACAP-38. 
6. 
Definitions 
Adverse Event (AE) 
Serious Adverse Event (SAE): 
SAE determined by the flag indicating if the adverse events is serious on the AE eCRF 
page will include these that occur after signing the informed consent and up to and 
including end of study (EOS).  
Treatment-Emergent AE: 
A treatment-emergent AE is that occurs on or after the initial dose of investigational 
product (IP) as determined by the flag indicating if the AE started prior to the first dose 
on the AE eCRF and up to and including end of study.  
Disease-Related AE: 
Migraine will be considered a disease related event; however, worsening of migraines 
(ie. increased frequency and/or intensity) should be reported as an AE. 
Baseline 
Unless otherwise stated, baseline will be defined as the last assessment taken prior to 
the first IP (AMG 334 or placebo) administration (ie, Day 1 pre-dose or Screening if 
Day 1 pre-dose is not available). 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
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Page 15 
Change from Baseline: 
The arithmetic difference between a post-baseline value and the baseline value: 
Change (absolute) from Baseline = (Post-baseline Value – Baseline Value) 
Change (percent) from Baseline = [(Post-baseline Value – Baseline Value) / Baseline 
Value] x 100 
Body Mass Index (BMI)  
BMI will be calculated as {weight (kg)/ [height (m)]2} in the clinical database.  
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a clinical rating of suicidal ideation and behavior. Refer to Appendix E 
and Appendix F in the protocol for complete details on the C-SSRS. The 
Baseline/Screening version of the C-SSRS will be administered at screening (Day -21 to 
-2), while the Since Last Visit version of the C-SSRS will be administered at the other 
time point(s) on the Schedule of Assessments. Reports of suicidal ideation with intent to 
act (endorse item 4 or 5) and reports of actual, aborted, or interrupted suicide attempts 
or a behavior preparatory for making an attempt indicate subjects at high risk for suicide. 
If such reports are identified, the investigator is to appropriately manage the subject in 
accordance with standard of care. 
End-of-Study (EOS) 
The EOS is the last planned clinical visit for each subject enrolled in this study.  
Primary Completion: 
Defined as 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 migraine questionnaire 24 hours after challenge agent (PACAP-38) 
administration or is discontinued from the study).  
End of Trial: 
Defined as 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 11 weeks after the challenge agent (PACAP-38) administration, 
or is discontinued from the study).  
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 16 
Subject-level EOS Date  
EOS for each subject is defined as the date the subject last participated in the study. 
The date will be recorded on the EOS case report form (CRF) page. 
Enrollment  
A subject will be considered enrolled when the investigator decides that the subject has 
met all eligibility criteria. Enrollment Date is defined as the date collected on the CRF. 
Investigational Product (IP) 
The term IP is used in reference to AMG 334 or placebo. 
PACAP-38 
Pituitary adenylate cyclase-activating polypeptides-38 is a neuropeptide belonging to the 
VIP/secretin/glucagon superfamily. PACAP-38 is a non-investigational medicinal product 
(NIMP) and used as a challenge agent. 
Randomization Date 
The day the subject was assigned a randomization number.  
Study Day 1 
Day 1 is defined as the first day that IP is administered to the subject. The day before 
Day 1 is referenced as Day-1. 
Study Day 
Post day of dose: 
 
study day= (study date - date of study Day 1) +1 
Pre day of dose: 
 
study day= (study date - date of study Day 1)  
The day prior to the first IP dosing is Day –1 while the day of the first IP dose is Day 1. 
7. 
Analysis Subsets 
7.1 
Safety Analysis Set  
The safety analysis set will consist of all subjects who receive IP (AMG 334 or placebo). 
Subjects will be analyzed according to the IP received (AMG 334 or Placebo). 
7.2 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set will contain all subjects who receive IP and have at least one PK 
concentration result. 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 17 
8. 
Interim Analysis and Early Stopping Guidelines 
8.1 
Dose Level Review Meetings and Safety Review Meetings  
The DLRM members will be composed of the PI, Amgen MM, Amgen GSO or designee, 
Early Development Leader or designee, Clinical Study Manager or designee, and 
Biostatistics representative or designee. Additional members may be added as needed 
(eg, PK Scientist). The Safety Review Meeting members include the PI, Amgen MM, and 
Amgen GSO or designee. The DLRM and Safety Review Meeting voting members will 
include the PI, Amgen MM, and Amgen GSO or designee. 
A Safety Review Meeting will be held after PACAP-38 dosing has been completed in 
each cohort in Part A. Available vital signs and AE occurring at least 24 hours following 
PACAP-38 dosing for each cohort will be reviewed by the Safety Review Meeting 
members to decide enrollment in subsequent cohort. If the Safety Review Meeting 
members decide not to proceed with enrollment in subsequent cohort, then a Safety 
Review Meeting or DLRM will be held after the last dosed cohort. Unscheduled DLRMs 
can be called at any time by any of the DLRM voting members. 
The Safety Review Meeting and DLRM voting members will decide whether or not to 
proceed with enrollment in the Randomization (AMG 334 or Placebo) Phase and if the 
decision is to proceed with enrollment in the Randomization (AMG 334 or Placebo) 
Phase, the Safety Review Meeting and DLRM voting members will select a PACAP-38 
dose. The maximum dose of PACAP-38 will not exceed 115 pmol/kg. At any time the 
Safety Review Meeting members may decide to add additional Non Randomized 
(PACAP-38 Only) Dose Selection Subjects pending review of emerging safety, and/or 
tolerability data. A future modification of the PACAP-38 dose may occur based on 
emerging safety, and/or tolerability findings.  
All available study data, including the headache questionnaires, demographics, IP 
administration, medical history, concomitant medications, AE (including MLA), ECGs, 
vital signs, and laboratory results will be reviewed. Data to be reviewed at the Safety 
Review Meeting and DLRMs during the PACAP-38 Dose Selection Phase will not be 
blinded. Data to be reviewed for any unscheduled DLRM post the PACAP-38 Dose 
Selection Phase will be reviewed blinded (ie., treatment assignment will not be revealed) 
unless unblinding is deemed necessary for the review team to make dosing decisions. If 
deemed necessary, unblinding will be performed to assist dose decisions in accordance 
with Amgen standard procedures. 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 18 
8.2 
Interim Analysis 
Once 24 hours of data is collected from 16 PACAP-38 responders dosed with AMG 334 
or Placebo (8 per group) after PACAP-38 infusion on Day 8, an interim analysis will be 
performed to determine if the challenge-agent, PACAP-38, invokes historical rates of 
MLA (~66%) and if AMG 334 has greater efficacy than placebo. If the number of MLAs 
does not meet historical rates, AMG 334 does not appear to be better at blocking 
PACAP-38 induced migraines compared with placebo, or AMG 334 appears to be 
sufficiently better at blocking PACAP-38 induced migraines compared with placebo, the 
study will be terminated (see below for more details). Otherwise, another 20 PACAP-38 
responders will be randomized. Appropriate decision rules, outlined below were 
developed to determine whether to increase the sample size (another 20 responders 
dosed with AMG 334 or Placebo, 10 per treatment group) or to stop, either due to 
demonstration of treatment effect or treatment utility.  
Decision rules to be applied during the trial are: 
1. At the interim analysis, if 3 or less of the 8 placebo subjects have a MLA, 
randomization will be stopped and it will be concluded that PACAP-38 
does not induce a sufficient proportion of MLA for the study to test the 
hypothesis.  
2. At the interim analysis, if 4 or more placebo subjects have a MLA, yet 
more subjects receiving AMG 334 have MLA than placebo subjects, then 
randomization will be stopped and it will be concluded that AMG 334 is 
ineffective in blocking PACAP-38 induced MLA.  
3. If the difference at the interim analysis in the proportion of subjects with 
MLA (placebo-AMG 334) is greater than or equal to 75% then 
randomization will be stopped and it will be concluded that AMG 334 is 
effective in blocking PACAP-38 induced MLA.  
4. If none of the first 3 decision rules apply at the interim analysis, an 
additional 20 subjects will be randomized in the trial. At the end of trial, if 
the p-value from the one-sided Fisher’s Exact test is less than 0.1, it will 
be concluded that AMG 334 is effective in blocking MLA (TRIAL 
SUCCESS –LATE), or if the p-value from the one-sided Fishers Exact 
test is greater than or equal to 0.1, it will be concluded that AMG 334 is 
ineffective at blocking MLA. 
The results from 10,000 simulated trials demonstrating the probability of failing at the 
interim analysis, as well as the probability of overall trial result, for different potential 
scenarios of the proportion of subjects with MLA in each treatment group are shown 
below: 
 


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Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 20 
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. 
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.  
Details of PK, Antibody, and external lab data transfer to the data base is provided in the 
corresponding study data transfer plans. See Data Management Plan (DMP). 
9.3 
Handling of Missing and Incomplete Data 
Imputation Rules for Partial or Missing Start Dates 
 
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 
 
Imputation Rules for Partial or Missing Stop Dates 
If the month and year are present, impute the last day of the month. If only the year is 
present, impute December 31 of that year. If the stop date is entirely missing, assume 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 21 
the event or medication is ongoing. If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial. Ensure the imputed stop date is on 
or after the complete or imputed start date.  
9.4 
Detection of Bias  
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations (IPD) in each 
treatment group. The clinical study team will identify and document the criteria for IPD. 
9.5 
Outliers 
All confirmed outlier data will be included in the analyses presented in this SAP unless 
there is sufficient scientific justification (eg, IPD leading to invalid data) to exclude them. 
PK concentration data will be evaluated for outliers by visual inspection and decisions to 
re-assay individual samples will be made in accordance with standard Pharmacokinetics 
and Drug Metabolism (PKDM) practice. All excluded observations will be detailed by 
PKDM along with reasons for exclusion, in accordance with standard PKDM practices. 
9.6 
Distributional Characteristics 
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. If required data transformations or alternative non-parametric methods 
of analyses will be utilized. 
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 (TFL) will be produced with validated standard macro 
programs where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software, for example the SAS System version 9.4 or 
later.  
Additional statistical software may be used to perform exploratory/ad-hoc analyses. 
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
Unless otherwise stated, data from PACAP-38 responders who go on to be randomized 
and receive IP will be summarized. Data from PACAP-38 non-responders, and data from 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 22 
PACAP-38 responders that do not receive IP, will not be included in the summaries, but 
will be reviewed. 
Unless otherwise specified, data will be summarized using the safety analysis set, by 
actual treatment group (AMG 334 or Placebo). 
Descriptive statistics will be provided for selected demographics, safety and PK data. 
Descriptive statistics on continuous measurements will include means, medians, 
standard deviations (and standard errors for post-baseline data), quartiles, and ranges, 
while categorical data will be summarized using frequency counts and percentages. 
Where statistical models are applied to the data, estimates of the differences/ratios, 
confidence intervals and corresponding p-values will be presented, as applicable. 
However, these are for descriptive and illustrative purposes only and to aid interpretation 
of the data; no formal statistical hypothesis testing will be performed. 
When data are summarized by time, the values recorded against the scheduled time 
points, including any time windows specified in the protocol will be used.  
When assessing minimum/maximum increases or decreases over the study, all 
assessments, including unscheduled assessments will be used. 
10.2 
Subject Accountability 
The number and percent of subjects who received IP (AMG 334 or placebo), completed 
study and discontinued the study (including reasons for discontinuing) will be 
summarized. A list of subjects who withdraw early will be reviewed. It will include the 
reason and timing of the withdrawal. Similarly, the reason any subject is excluded from 
an analysis set will also be reviewed.  
10.3 
Important Protocol Deviations 
IPD 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.  
The final IPD list will be used to produce the Summary of IPDs table and the list of 
subjects with IPDs. In addition, a separate listing of all inclusion and exclusion deviations 
will be provided.  
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
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Page 23 
10.4 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized. 
Demographics: 
• 
Age (years) at enrollment (continuous summary statistics)  
• 
Age groups (years) [18-64, 65-74, 75-84, >=85] at enrollment (number and 
percentage of subjects in each age group category)  
• 
Sex (number and percentage of males and females) 
• 
Ethnicity (number and percentage in each ethnicity category) 
• 
Race (number and percentage of subjects in each race, or mixed race 
combination)  
Baseline Characteristics: 
• 
Height, Weight and BMI (continuous summary statistics) 
10.5 
Primary Endpoint Planned Analysis 
The number and percent of subjects experiencing a MLA within 24 hours after 
PACAP-38 infusion will be summarized for each treatment group. Comparison of 
PACAP-38 ability to produce MLA between AMG 334 and placebo will be done using the 
Fisher’s Exact test. 
10.6 
Secondary Endpoint(s) 
10.6.1 
Number of Headaches 
The number and percent of subjects experiencing a headache within 24 hours after 
PACAP-38 infusion will be summarized for each treatment group. Comparison of 
PACAP-38 ability to produce headaches between AMG 334 and placebo will be done 
using the Fisher’s Exact test. 
10.6.2 
Safety Endpoints 
10.6.2.1 
Adverse Events (AEs)  
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.1 or later will be 
used to code all AE to a system organ class and a preferred term. The subject incidence 
of AEs will be summarized for all treatment-emergent, serious treatment-emergent, 
those leading to withdrawal of IP, fatal, and events of interest (EOI), where treatment 
refers to IP. The identification of EOI is a continuous process. Events may be identified 
and documented as the safety profile of the drug is characterized. The severity of each 
AE will be graded using common terminology for AE (CTCAE) version 4.0 criteria.  
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 24 
Subject incidence of all treatment-emergent, serious treatment-emergent, those leading 
to withdrawal of IP, and fatal AE will be tabulated by system organ class and preferred 
term, where treatment refers to IP. Where appropriate, the tables will also be presented 
by worst grade. The above AE tables will not be created if two or fewer subjects 
experience the AE. The above AE tables will be summarized separately for events 
occurring between Day 1 and Day 7 following administration of IP and events occurring 
from Day 8 onwards following administration of IP and the second dose of PACAP-38. 
For PACAP-38 related treatment-emergent AEs, all treatment-emergent AEs where the 
question “Is there a reasonable possibility that the event may have been caused by 
PACAP-38?” is ticked “yes” will be summarized by treatment group.  
Details of each AE will be listed. 
10.6.2.2 
Vital Signs  
Vital signs will be reviewed for each subject. Summaries of HR and BP data over time 
and change from baseline will be provided. Depending on the size and scope of change 
in other vital signs, summaries may be provided. 
10.6.2.3 
Electrocardiogram (ECG)  
All on-study ECG data will be reviewed for each subject. 
10.6.2.4 
Physical Examination  
Physical examination results will be reviewed for each subject. Depending on the size 
and scope of change in weight and BMI, summaries may be provided. 
10.6.2.5 
Laboratory Test Results 
Hematology, chemistry and urinalysis data will be reviewed for each subject. Depending 
on the size and scope of changes in laboratory data, summaries of laboratory data over 
time and/or changes from baseline over time may be provided. Liver function 
abnormalities will be summarized. 
10.6.2.6 
Neurologic Assessment 
Neurological assessment data will be reviewed for each subject. 
10.6.3 
Pharmacokinetic Endpoints  
Serum AMG 334 concentrations will be determined using a validated assay. Individual 
serum concentration-time plots for AMG 334 will be presented for each subject as well 
as mean concentration-time plots for each treatment group. PK parameters C1 hour, and 
AUC84d will be estimated using either compartmental (eg, PK modeling) or 
non-compartmental methods. Actual dosing and sampling times will be used for 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 25 
calculation of PK parameters. Summary statistics will be generated for each PK 
parameter for each treatment group and provided by CPMS. The PK analysis set will be 
used for these analyses. 
10.6.4 
AMG 334 Antibody Assessment  
Binding antibody and neutralizing antibody formation will be assessed at predose and at 
various time points throughout the study including EOS. Antibody data will be listed for 
each subject. The incidence and percentage of subjects who develop anti-AMG 334 
antibodies (binding and if positive, neutralizing) at any time will be tabulated by treatment 
group.  
10.7 
Exploratory Endpoint(s) 
10.7.1 
Migraine-like Attacks (MLA) and Headaches 
The reduction in severity of MLA and headaches by AMG 334 within 24 hours after 
infusion of PACAP-38 on day 8 will be assessed and summarised based on a severity 
score (0-10; 0=pain free; 10=extreme pain). Severity of MLA and headaches will be 
analysed separately using a repeated measure analysis of variance model. Independent 
variables will be treatment, hour, and treatment by hour interaction. Subject will serve as 
a random effect. For each treatment by hour combination, least square means, ratio to 
placebo, 95% confidence intervals and corresponding nominal p-values for the null 
hypothesis of no difference from placebo will be presented. Graphical summaries of 
severity scores will also be provided. For SAS code, see Appendix A1. 
10.7.2 
Duration of Migraine-like Attacks (MLA) and Headaches 
Descriptive statistics will be provided for the duration of MLA and headaches by 
treatment group.  
10.7.3 
Migraine Characteristics 
Descriptive summaries of measured characteristics of MLA and headaches, such as 
localization and accompanying symptoms and pre-monitory symptoms, within 24 hours 
after infusion with PACAP-38 will be presented for each treatment group. 
10.7.4 
Plasma Concentration of PACAP-38 and CGRP 
Summary statistics will be generated for plasma PACAP-38 and CGRP levels pre/post 
dosing with PACAP-38. Summaries will be produced by treatment group for the second 
dose of PACAP-38 (ie., the dose administered after administration of IP). 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 26 
10.8 
Columbia Suicide Severity Rating Scale (C-SSRS)  
Subject incidence of treatment-emergent suicidal ideation and behavior as assessed by 
C-SSRS will be reviewed and may be summarized. 
10.9 
 Exposure to Investigational Product (IP) 
Subject listings of manufacturing lot numbers and a separate listing of unique 
manufacturing lot numbers used in this study will be provided. Details for each AMG 334 
administration will be listed for every subject.  
10.10 
Exposure to Non-Investigational Medicinal Product (NIMP) 
Subject listings of PACAP-38 used in this study will be provided. Details for PACAP-38 
administration will be listed for every subject. 
10.11 
Exposure to Concomitant Medication 
All medication will be coded using the World Health Organization Drug (WHO DRUG) 
dictionary. All prior and concomitant medications will be reviewed. 
11. 
Changes From Protocol-specified Analyses 
Minor changes to the protocol-specified analyses have been made and clarified in this 
SAP. 
The safety analysis set has been modified slightly to include all subjects who receive IP 
(AMG 334 or placebo), but excludes any reference to whether the subject receives 
PACAP-38 or not. This is to take into account any subjects that receive IP, but do not 
receive PACAP-38 (eg, subject withdrew from the study before PACAP-38 could be 
administered). In these cases, the subject’s data will be reviewed, but will not be 
included in any data summaries. 
ECG data will not be summarized as specified in the protocol, as the data was collected 
as part of the standard of care and not in a thorough manner. 
12. 
Literature Citations / References 
Headache Classification Subcommittee of the International Headache Society. The 
international classification of headache disorders, 2nd edition. Cephalalgia. 2004; 
24(Suppl. 1):8-160. 
13. 
Data Not Covered by This Plan 
The following analyses will be analyzed outside of this SAP: 
• 
The changes in plasma PACAP-38 and CGRP concentrations pre- and 
post-dosing with AMG 334 
• 
Blood samples collected for biomarker development 
 


Product:  AMG 334 
Statistical Analysis Plan:  20140207 
Date:  17 May 2017 
Page 27 
14. 
Appendices 
 


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