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
Phase: PHASE1
Conditions: Migraine
Sponsor: Amgen

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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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