An Open Label Phase 3 Trial to Evaluate the Safety of ALD403 Administered Intravenously in Patients With Chronic Migraines
Phase: PHASE3
Conditions: Migraine Disorder
Sponsor: Alder Biopharmaceuticals, Inc.

Protocol ALD403-CLIN-013
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16 January 2018
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ALDER BIOPHARMACEUTICALS, INC.
Clinical Trial Protocol
Confidential Information
The confidential information in this document is provided to you as an Investigator, potential Investigator, or 
Consultant, for review by you, your staff, and applicable institutional review committees. This information will not 
be disclosed to others without written authorization from Alder BioPharmaceuticals, Inc., except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered.
Clinical Trial Title
An Open Label Phase 3 Trial to Evaluate the Safety of 
ALD403 Administered Intravenously in Patients with 
Chronic Migraine 
Protocol Number
ALD403-CLIN-013
Investigational Product
ALD403 
Indication
Treatment for the Prevention of Chronic Migraine 
Sponsor
Alder BioPharmaceuticals, Inc.
11804 North Creek Pkwy S
Bothell, WA 98011 USA
Phone: +1 425-205-2900
Fax: +1 425-205-2901
Sponsor’s Medical Monitor
Alder BioPharmaceuticals, Inc.
Phone: 
Clinical Trial Compliance
This clinical trial will be conducted in accordance with 
standards of Good Clinical Practice, as defined by the 
International Conference on Harmonisation and all 
applicable federal and local regulations.
Protocol Date (original)
Amendment 1 Date
24 October 2016 
25 January 2017
Amendment 2 Date
Amendment 3 Date
16 June 2017
20 November 2017
16 January 2018 (Administrative Changes Only)

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DECLARATION OF THE PRINCIPAL INVESTIGATOR
Title: An Open Label Phase 3 Trial to Evaluate the Safety of ALD403 Administered 
Intravenously in Patients with Chronic Migraine
This clinical trial protocol was subject to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the Investigational Product, with moral 
ethical and scientific principles governing clinical research, and in accordance with Good 
Clinical Practice and applicable federal and local regulations.
Principal Investigator 
_____________________________________
______________________
Signature
Date
_____________________________________
Name (printed)
_____________________________________
Title
_____________________________________
Institution

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1.
PROTOCOL SYNOPSIS
Title
An Open Label Phase 3 Trial to Evaluate the Safety of ALD403 
Administered Intravenously in Patients with Chronic Migraine 
Sponsor
Alder BioPharmaceuticals, Inc. (Alder)
Investigational Product
ALD403, a humanized anti-(calcitonin gene-related peptide) 
(CGRP) monoclonal antibody
Safety Objective
To evaluate the long term safety of repeat doses of ALD403 
administered intravenously (IV) in chronic migraine (CM) 
patients.
Immunogenicity and 
Patient Reported 
Outcomes
To evaluate the pharmacokinetics (PK) and immunogenicity of 
repeat doses of ALD403 administered IV to patients with chronic 
migraine.
To further evaluate the impact of ALD403 on various patient 
reported outcomes.
Methodology
This is an open label trial in which 120 eligible subjects will 
receive infusions of ALD403.  The trial will include two 
treatment phases.  The primary treatment phase will include 4
ALD403 infusions 12 weeks apart.  The secondary treatment 
phase will include 4 additional ALD403 infusions 12 weeks
apart.
In the primary treatment phase, visits will occur on Day 0, Weeks 
2, 4, 8, 12, 24, and 36 and subjects will receive 4 IV infusions of 
ALD403 on Days 0, Weeks 12, 24, and 36.
Subjects who receive all 4 infusions of ALD403 in the primary 
treatment phase may enter the secondary treatment phase. In the 
secondary treatment phase, subjects will receive up to 4 
additional IV infusions of ALD403 for a total of 8 infusions. 
Visits and ALD403 IV infusions will occur on Weeks 48, 60, 72, 
and 84. Subjects will be followed for 20 weeks until Week 104 
for a total study duration of approximately 106 weeks, including 
the screening period. 
Subjects who don’t receive all 4 infusions of ALD403 in the 
primary treatment phase or don’t consent for participation in the 
secondary treatment phase will be followed at Week 48 and
Week 56, at which point they will have their End of Trial visit.    
Number of Subjects 
Planned
Approximately 120 subjects will be enrolled and treated at 
approximately 20 centers in the US.
Subject Selection Criteria
Males and females between 18 and 65 years of age, inclusive, 
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screening.  
Investigational Product, 
Dose and Schedule
Eight intravenous infusions of 300mg ALD403 will be given 
12 weeks apart.  Infusions will occur on Day 0, Week 12 (Day 84 
+/- 3 days); Week 24 (Day 168 +/- 3 days); Week 36 (Day 252 
+/- 3 days); Week 48 (Day 336 -7/+14 days); Week 60 (Day 420 
+/- 7 days); Week 72 (Day 504 +/- 7 days); and Week 84 (Day 
588 +/- 7 days).
Duration of Treatment
Up to 8 IV infusions of ALD403 will be given approximately 12 
weeks apart over an 84 week period. 
Duration of Clinical Trial 
Participation
The trial participation period is approximately 106 weeks which 
includes:
x
2-week screening period,
x
48-week primary treatment administration period,
x
36-week secondary treatment administration period
x
20-week follow-up period.
Clinical Trial Endpoints
Safety Endpoints
x
Adverse events (AEs) and serious adverse events (SAEs)
x
Clinical laboratory assessments 
x
Vital Signs
x
Electrocardiograms (ECGs)
x
Columbia-Suicide Severity Rating Scale (C-SSRS)
Patient Reported Outcomes
x
Patient Global Impression of Change (PGIC) 
x
Short-Form Health Survey (SF-36)
x
Health-Related Quality of Life (EQ-5D-5L)
x
Headache Impact Test (HIT-6)
x
Most Bothersome Symptom (MBS)
x
Migraine Disability Assessment (MIDAS)
PK and Immunogenicity Endpoints
x
Free ALD403 plasma concentrations
x
Development of specific anti-ALD403 antibodies
x
Characterization of specific anti-ALD403 antibodies for 
neutralizing activity
Concomitant Medications
x
Subjects on stable medication for headache prophylaxis for 
3 months prior to screening will be permitted to continue use 
during the study, provided there are no alterations to their 
regimen, except as allowed per Investigator discretion. After 
Week 48, changes to migraine prophylactic treatment are 

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allowed per Investigator or the subject’s primary treating 
healthcare professional.
x
Barbiturates and prescription opiates are allowed for 
 4 days per month provided the subject has been on a stable 
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screening and through entire study. After enrollment, the use 
of prescription barbiturates and opiates is allowed as 
medically necessary and prescribed by a licensed healthcare 
professional for indications other than migraine. 
x
Botulinum toxin for migraine or for any other 
medical/cosmetic reasons requiring injections in the head, 
face, or neck are prohibited 4 months prior to screening and 
through entire study.
x
Devices, neuromodulation, neurostimulation, or injectable 
therapy (trigger point injections) for headache prophylaxis 
are prohibited 2 months prior to screening and through entire 
study.
x
Any use of monoamine oxidase inhibitors (MAOIs), 
ketamine, methysergide, methylergonovine, or nimesulide 
within 3 months prior to screening and throughout the entire 
trial is prohibited.
Sample Size
The planned sample size for the study is 120 treated subjects.  It 
is assumed that over 75% of these subjects will complete the 
primary treatment phase resulting in at least 90 subjects with one 
year of safety data collection. 
Statistical Analysis
Study endpoints will be summarized with descriptive statistics 
These summary measures will include change from baseline, 
where baseline is the last result prior to treatment. Testing of 
these change from baseline results for the SF-36, MIDAS and 
HIT-6 will be performed.
PK and Immunogenicity 
Analyses
The concentrations of ALD403 will be measured in plasma from 
all ALD403 treated subjects using a validated assay method. 
The PK analysis of plasma will include determination of the 
ALD403 concentrations at Day 0 (pre-dose), immediately post-
dose (within 15 minutes of end of infusion), and Weeks 2, 4, 
8, 12 (pre-dose), 24 (pre-dose), 36 (pre-dose), 48 (pre-dose), 72 
(pre-dose), and 104 End of Trial/Early Withdrawal. 
Population PK analysis will be performed on the results for 
ALD403 concentrations obtained during this study in 
combination with the results from other studies of ALD403 in 
normal subjects and migraine patients.
Blood samples will be collected for the detection of anti-ALD403 
antibody, and when appropriate the samples will be analyzed also 
for neutralizing anti-ALD403 antibody activity at Day 0 (pre-

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dose), and on Weeks 2, 4, 8, 12 (pre-dose), 24 (pre-dose), 
36 (pre-dose), 48 (pre-dose), 72 (pre-dose), and 104 End of 
Trial/Early Withdrawal. Subjects who test positive for specific 
anti-ALD403 antibodies at the time of the last study visit will be 
asked to provide up to two additional blood samples for 
immunogenicity testing at approximately 3 month intervals for up 
to 6 months. 

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2.
SCHEDULE OF EVENTS 
Assessments
Screening
Day
-14 to -11
Day 0
Treat
ment 
Day 0
Wk 2
Day 14
r3 
days
Wk 4
Day 28
r 3 days
Wk 8
Day 56
r 3 days
Wk 12
Treatmen
t
Day 84
r 3 days
Wk 24
Treatme
nt 
Day 168
r 3 
days
Wk 36
Treatme
nt 
Day 252
r 3 days
Wk 48
Treatment
Day 336  -
7/+ 14 days 
Wk 60
Treatmen
t
Day 420
r 7 days
Wk 72
Treatmen
t
Day 504 
r 7 days
Wk 84
Treatment
Day 588
r 7 days
Wk 569 or 104 
End of Trial / 
Early Withdrawal
Day 392 or 728
± 7 days
Informed Consent
X
In/Ex Criteria
X
X
Demographics
X
Medical History
X
Height 
X
Weight
X
X
X
X
X
X
Physical Exam1
X
X
X
X
X
X11
X
X
X
X
Vital Signs3
X
X
X
X
X
X
X
X
X
X
C-SSRS4,1
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Global Impression of 
Change (PGIC)2
X
X
X
X
X
X
X
X
X
X
SF-36, HIT-61
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L12
X
X
X
X
X
X
X
X10
Most Bothersome Symptom 
(MBS)
X
X
X
X
X
X
X
X
X10
MIDAS1
X
X
X
X
X
X
X
X
X
AE Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Meds Review
X
X
X
X
X
X
X
X
X
X
X
X
X
ALD403 infusion5
X
X
X
X
X11
X
X
X
12-lead ECG7
X
X
X
X
X
X
X
X
X
X
Hematology, Chemistry1
X
X
X
X
X
X
X
X
X
X
HIV/Hepatitis B and C
X
Plasma PK6,8
X
X
X
X
X
X
X
X
X
X
Serum Anti-ALD4036
X
X
X
X
X
X
X
X
X
X
Urine Drugs of Abuse Screen
X
Urine Pregnancy (hCG) Test1
X
X
X
X
X
X
X
X
X
X
X
X
1 Conduct assessment pre-dose on Day 0 and Week 12, 24, 36, 48, 60, 72, and 84.
2 Conduct assessment pre-dose on Week 12, 24, 36, 48, 60, 72, and 84.
3 Conduct assessments pre-dose and up to 2 hours (+ 30 min) post-dose on Day 0 and Week 12, 24, 36, 48, 60, 72, and 84.
4 Conduct C-SSRS Baseline/Screening Version at screening and C-SSRS Since Last Visit Version at remaining visits where C-SSRS required.
5 Monitor subjects for at least 2 hours after the end of each dosing to assess for the occurrence of adverse events.
6 Collect samples pre-dose on Day 0 and Week 12, 24, 36, 48, and 72.  Subjects who test positive for anti-ALD403 antibodies at the last study visit will be asked to provide up to 2 additional blood samples for immunogenicity 
testing at approximately 3 month intervals for up to 6 months.
7Conduct assessment pre-dose, and within 2 hours (+30 min) post dose on Day 0 and Week 12, 24, 36, 48, 60, 72, and 84.  
8 On Day 0, collect additional sample immediately post-dose (within 15 minutes of end of infusion).
9 Subjects who don’t receive all 4 infusions of ALD403 in the primary treatment phase or don’t consent to participate in the secondary treatment phase will have the End of Trial/Early Withdrawal visit at Week 56.  
10 Only for subjects who have the End of Trial/Early Withdrawal visit at Week 56.
11 Only for subjects who participate in secondary treatment phase.
12 Conduct assessment pre-dose on Day 0 and Week 12, 24, 36, and 48.

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3.
LIST OF ABBREVIATIONS
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase  
AST
Aspartate aminotransferase 
AUC
Area under the concentration-time curve
BMI
Body Mass Index
BP
Blood pressure
CGRP
Calcitonin Gene-Related Peptide 
CRF
Case Report Form
C-SSRS
Columbia-Suicide Severity Rating Scale
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
EQ-5D-5L
Health-Related Quality of Life
ET
Early Termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIT-6
Headache Impact Test
IB
Investigator’s Brochure
ICD
International Classification of Diseases
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICHD
International Classification of Headache Disorders
IHS
International Headache Society
IgG1
Immunoglobulin G1
IP
Investigational Product
IRB
Institutional Review Board
IV
Intravenous
Kg
Kilogram
LLOQ
Lower Limit of Quantification
M
Molarity
m2
Meter squared
mAb
Monoclonal antibody

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MAOI
Monoamine oxidase inhibitor
MBS
Most Bothersome Symptom
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
mm
Millimeter
MRM
Menstrually-related migraine
NOAEL
No-observed-adverse-effect-level
NSAID
Non-steroidal anti-inflammatory drug
PK
Pharmacokinetic
PGIC
Patient Global Impression of Change 
QTcF
QT corrected using Fridericia formula
RBC
Red blood cell
SAE
Serious adverse event
SF-36
Short Form Health Survey
TMD
Temporomandibular Disorder
WBC
White blood cell

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4.
TABLE OF CONTENTS
1
PROTOCOL SYNOPSIS .............................................................................................4
2
SCHEDULE OF EVENTS...........................................................................................8
3
LIST OF ABBREVIATIONS.......................................................................................8
4
TABLE OF CONTENTS ...........................................................................................11
5
INTRODUCTION......................................................................................................15
5.1 
       Investigational Product ...............................................................................................15
5.2 
       Background.................................................................................................................15
5.3 
       Investigational Product ...............................................................................................17
5.3.1
Summary of Nonclinical Studies................................................................................17
5.3.2
Summary of Clinical Trials ........................................................................................19
5.3.3
Dose Justification........................................................................................................20
5.4 
       Risks and Benefits ......................................................................................................20
5.5 
       Compliance Statement................................................................................................21
6
OBJECTIVES.............................................................................................................22
6.1 
       Safety Objective.......................................................................................................  22
6.2 
       Immunogenicity and Patient Reported Outcomes ......................................................22
7
TRIAL DESIGN.........................................................................................................23
7.1 
       Clinical Trial Endpoints..............................................................................................23
7.1.1
Safety Endpoints.........................................................................................................23
7.1.2
Patient Reported Outcomes: .......................................................................................23
7.1.3
PK and Immunogenicity Endpoints:...........................................................................23
7.2 
       Clinical Trial Design...................................................................................................23
8
SELECTION AND WITHDRAWAL OF SUBJECTS..............................................25
8.1 
       Inclusion Criteria ........................................................................................................25
8.2 
       Exclusion Criteria .......................................................................................................26
8.3 
       Registration and Treatment Assignment ....................................................................28
8.3.1
Registration Procedure, Subject Numbering ..............................................................28
8.4 
       Subject Treatment Discontinuation and Early Withdrawal ........................................28
8.4.1
Criteria for Discontinuation from Study Treatment ...................................................28
8.4.2
Criteria for Withdrawal from the Clinical Trial .........................................................29
8.4.3
Replacement Policy ....................................................................................................30

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8.4.4
Lost to Follow-Up.......................................................................................................30
9
CLINICAL TRIAL TREATMENTS .........................................................................31
9.1 
       Investigational Product ...............................................................................................31
9.2 
       Investigational Product Administration......................................................................31
9.2.1
Packaging and Labeling..............................................................................................32
9.2.2
Storage and Handling of Investigational Product.......................................................32
9.2.3
Accountability and Disposition of ALD403...............................................................32
9.3 
       Concomitant Medications...........................................................................................33
10
STUDY ASSESSMENTS AND PROCEDURES......................................................35
10.1 
       Schedule of Events .....................................................................................................35
10.2 
       Assessments and Procedures ......................................................................................35
10.2.1
Demographics.............................................................................................................35
10.2.2
Medical History ..........................................................................................................35
10.2.3
Physical Examinations................................................................................................35
10.2.4
Vital Signs ..................................................................................................................36
10.2.5
Questionnaires ............................................................................................................36
10.2.6
12-Lead ECG..............................................................................................................38
10.2.7
Laboratory Samples and Testing ................................................................................38
11
ASSESSMENT OF SAFETY.....................................................................................40
11.1 
       Adverse Events ...........................................................................................................40
11.1.1
Definitions ..................................................................................................................40
11.1.2
Assessment of Adverse Events...................................................................................40
11.1.3
Recording Adverse Events .........................................................................................43
11.1.4
Reporting Serious Adverse Events .............................................................................43
11.1.5
Unexpected and Related Serious Adverse Events......................................................44
11.1.6
Follow-up of Adverse Events .....................................................................................45
11.1.7
Clinical Laboratory Tests ...........................................................................................45
11.1.8
Pregnancy ...................................................................................................................45
11.1.9
Suicidal Ideation and Behavior...................................................................................46
11.2 
       Management of Reactions to ALD403 .......................................................................46
12
ASSESSMENT OF QUESTIONNAIRES, PK, AND IMMUNOGENICITY ..........48
12.1 
        Questionnaires ............................................................................................................48

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12.2 
       Pharmacokinetics........................................................................................................49
12.3 
       Immunogenicity..........................................................................................................50
13
STATISTICAL CONSIDERATIONS .......................................................................51
13.1 
       Sample Size ................................................................................................................51
13.2 
       General Considerations...............................................................................................51
13.2.1
Definition of Baseline.................................................................................................51
13.2.2
Handling of Missing Data...........................................................................................51
13.2.3
Populations to be Analyzed ........................................................................................51
13.3 
       Interim Analyses.........................................................................................................51
13.4 
       Statistical Methods......................................................................................................51
13.4.1
Subject Disposition, Demographics, and Baseline Characteristics ............................52
13.4.2
Efficacy Analyses .......................................................................................................52
13.4.3
Pharmacokinetic Analyses..........................................................................................52
13.4.4
Safety Analyses ..........................................................................................................53
14
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS.....................................55
14.1 
       Data Quality Assurance ..............................................................................................55
14.2 
       Case Report Forms and Source Documents ...............................................................55
14.2.1
Study Documentation .................................................................................................55
14.2.2
Case Report Form.......................................................................................................55
14.3 
       Archiving Clinical Trial Records................................................................................56
14.4 
       Good Clinical Practice................................................................................................57
14.5 
       Informed Consent .......................................................................................................57
14.6 
       Protocol Approval and Amendment ...........................................................................57
14.6.1
Premature Termination of the Clinical Trial ..............................................................58
14.7 
             Confidentiality ............................................................................................................58
14.8 
       Publication Policy.......................................................................................................59
15
APPENDICES ............................................................................................................60
15.1 
       Migraine preventive therapies with established or probable efficacy 13, 14, 15.............60
15.2 
       Columbia-Suicide Severity Rating Scale (C-SSRS) Risk Assessment ......................61
15.2.1
Baseline/Screening Version........................................................................................61
15.2.2
Since Last Visit Version.............................................................................................63
15.3 
       Headache Impact Test (HIT-6 v1.0)...........................................................................67

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15.4 
       Short-Form Health Survey (SF-36 v2.0) ....................................................................68
15.5 
       Health Related Quality of Life (EQ-5D-5L) ..............................................................72
15.6 
       Patient Global Impression of Change (PGIC) ............................................................75
15.7 
       Most Bothersome Symptom (MBS) ...........................................................................76
15.8 
       The Migraine Disability Assessment (MIDAS) .........................................................77
15.9 
       References...................................................................................................................78

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5.
INTRODUCTION 
5.1.
Investigational Product
ALD403 is a humanized anti-(calcitonin gene-related peptide) (CGRP) monoclonal antibody 
(anti-CGRP) that is being developed by Alder for the prophylaxis of migraine. 
5.2.
Background
Migraine is a highly prevalent paroxysmal neurological disease characterized by recurrent 
episodes of moderate to severe headache associated with physiological disruptions of 
neurological, gastrointestinal, and sensory function.  Episodes typically last between 4 and 
72 hours and recur often without warning over decades of time.  It is most prevalent through the 
3rd and 4th decades of life with a significant gender bias of 3:1 for women.1 Migraine is the most 
prevalent neurological disease for which medical treatment is sought, and considered the 6th 
leading cause of disability in the world.2 Annually, lost work time and diminished productivity 
attributable to migraine costs American employers an estimated $19.6 billion.3
Migraine appears to have a significant genetic/epigenetic component to its etiology and it is 
observed in all age groups, races, and ethnicities.  Generally, migraine begins as an episodic 
disease.  Between episodes of migraine the nervous system returns to a normal (premorbid) state 
of function.  However, approximately 2.5% of people with episodic migraine will annually 
transform from episodic to chronic migraine, meaning they are experiencing migraine on greater 
than 15 days per month for at least 3 consecutive months.4 For those with chronic migraine, the 
headaches are more intense; migraine-associated symptoms, more severe; and the disease-related 
impact and disability are much greater than observed for episodic migraine.5 In addition, chronic 
migraine is associated with more co-morbid diseases such as anxiety, depression, and non-
headache pain.6
The pathophysiology of migraine is complex and incompletely understood.  Current models of 
migraine are based on a genetically determined hyper-excitable nervous system characterized by 
a lowered threshold to sensory activation and uniqueness in its sensory processing.7 Interactions 
between this migraine nervous system and specific internal and external stimuli (migraine 
triggers) can result in activation of the trigeminovascular system (TVS).  Once activated the TVS 
releases various vasoactive peptides generating peripheral sensitization of trigeminal and upper 

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cervical nociceptors. The ensuing peripheral nociceptive stimuli synapse in the Trigeminal 
Nucleus Caudalis to ultimately create a state of central sensitization.8 Clinically, this process is 
observed as a fully developed attack of migraine.  
Central to this model of migraine is calcitonin gene-related peptide (CGRP). CGRP is one of the 
most abundant peptides in the human body and is produced in both peripheral and central 
neurons.  It is abundant in trigeminal neurons and when released is involved in the vasodilation, 
inflammatory cascade, and pain transmission associated with migraine. In both peripheral and 
central pain pathways CGRP is associated with pain transmission and neuronal sensitization.9
Intravenous (IV) infusions of CGRP can cause a migraine-like headache in susceptible 
individuals with migraine.10 In addition, many pharmacological agents used as acute or 
prophylactic treatment of migraine are known to inhibit CGRP. Thus, CGRP is an attractive 
target for development of novel migraine pharmacology.
Currently the pharmacological treatment of migraine can be divided into acute treatment, that is, 
medications designed to reverse a migraine after it is initiated and preventive treatment that is 
designed to protect the nervous system from generating migraine. Acute treatments are used 
intermittently only as needed to stop an attack while preventative treatments are used on a 
sustained basis for periods of months to years. Acute treatment while generally quite effective 
can worsen the severity and frequency of migraine when used too frequently, a condition called 
medication overuse headache (MOH).4 MOH is common in populations with frequent episodic 
and chronic migraine.11
Numerous medications are used to prevent migraine but to date none have been designed 
specifically for migraine. These commonly include tricyclic antidepressants, beta-blockers, and 
certain anticonvulsants. It is estimated that 45% of adults with frequent episodic migraine and 
virtually all with chronic migraine would benefit from effective preventive medications yet only 
an estimated 12% of this population are currently using a migraine preventive.1 In large 
measure, this is due to poor tolerability, lack of efficacy, and failure to adhere to treatment.  
Clearly there is a medical need to develop effective, well-tolerated and safe preventive 
treatments for migraine. 

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5.3.
Investigational Product
ALD403 is a genetically engineered humanized immunoglobulin G1 (IgG1) antibody that binds 
to human-Į-CGRP with an affinity of 1.5E-11 M and human-ȕ-CGRP with an affinity of 
5.7E-11 M.
5.3.1.
Summary of Nonclinical Studies
A nonclinical testing program has been conducted supporting the use of ALD403 in clinical 
trials. More detailed discussion is provided in the current version of the ALD403 Investigator’s 
Brochure (IB).
$/'LVDJHQHWLFDOO\HQJLQHHUHGKXPDQL]HG,J*DQWLERG\WKDWELQGVWRĮ- DQGȕ- forms of 
KXPDQF\QRPROJXVPRQNH\DQGUDW&*537KHDPLQRDFLGVHTXHQFHIRUĮ- DQGȕ-CGRP is 
identical in cynomolgus monkeys and humans (data on file); therefore, the in vitro binding 
characteristics of cynomolgus monkey and human CGRP to ALD403 would be 
LQGLVWLQJXLVKDEOH5DWĮ-&*53LVRQHDPLQRDFLGGLIIHUHQWIURPKXPDQĮ-&*53DQGUDWȕ-CGRP 
LVDPLQRDFLGVGLIIHUHQWIURPKXPDQȕ-CGRP. Based on comparable binding affinity and in 
vitro SRWHQF\IRUUDWF\QRPROJXVPRQNH\DQGKXPDQĮ- DQGȕ-CGRP, the rat and cynomolgus 
monkey were selected for nonclinical safety assessments.
Pharmacodynamic activity by ALD403 in the species selected for toxicological investigations 
(rats, rabbits, and monkeys) was confirmed in vivo by conducting studies to determine the ability 
of ALD403 to inhibit CGRP-mediated neurogenic dermal vasodilation.
In the single-dose nonclinical toxicology studies, the no-observed-adverse-effect-level (NOAEL) 
for IV administration of ALD403 to rats and cynomolgus monkeys was 100 mg/kg.
Toxicological investigations in rats and monkeys indicated that repeated-dose IV administration 
of ALD403 at 10, 30, or 100 mg/kg once weekly for four weeks was well tolerated, with no signs 
of adverse effects related to treatment. Under the conditions of these studies, the no-observed-
adverse-effect-level (NOAEL) for once weekly IV administration of ALD403 to rats or monkeys 
for four weeks was 100 mg/kg.
A chronic multiple-dose toxicology study in cynomolgus monkeys was conducted to evaluate the 
potential effects by ALD403 following 6-months administration via slow bolus injection once 

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every two weeks (a total of fourteen dosing occasions) at 0, 20, 50, or 150 mg/kg/dose followed 
by a three month recovery period in select animals. 
Following the sixth dosing occasion on study day 71, one low-dose (20 mg/kg/dose) female 
animal exhibited an anaphylactoid-like reaction and died within approximately 30 minutes. 
Collectively, the clinical, gross, and microscopic findings were consistent with an ADA-
mediated anaphylactoid event as the cause of death.  Humanized monoclonal antibodies are 
known for their potential to illicit severe immunologic reactions in monkeys and therefore, the 
death of one animal was considered as a class effect.
Administration of ALD403 via intravenous (slow bolus) injection once every 2 weeks for 
approximately 6-months (for a total of 14 doses) did not result in any treatment-related effects 
upon the parameters evaluated in this study.  The NOAEL for ALD403 following chronic 
administration in monkeys was considered to be 150 mg/kg/dose (Day 183 mean Cmax of 
19,600/6,160 ȝg/mL; mean AUC (0-2wk) of 1,610,000/904,000 ȝg·h/mL for males/females, 
respectively).
ALD403 is not expected to interact directly with DNA or other chromosomal materials, and 
genotoxicity assessments have not been conducted. The carcinogenic potential for ALD403 has 
not been thoroughly investigated. The results of toxicological and clinical investigations to date 
with ALD403 have provided no indications of effects with the potential to support or induce the 
proliferation of malignant cells.
Definitive embryo-fetal development studies with ALD403 in rats and rabbits have been 
conducted.  The administration of ALD403 by intravenous (slow bolus) injection to pregnant 
female rats on Days 6, 12 and 18 post coitum or pregnant female New Zealand White rabbits on 
Days 7, 13 and 20 post coitum, at 75 or 150 mg/kg/dose was well tolerated, and there was no 
evidence of embryo-fetal mortality (embryolethality), alterations in growth (fetotoxicity), or 
structural abnormalities (teratogenicity) in either species.  
The local tolerance of ALD403 was assessed following repeated-(once weekly) dose studies in 
rats and cynomolgus monkeys utilizing ALD403 administered IV. Following the end-of-
treatment, no gross or microscopic lesions were observed in the ALD403 injection sites excised 
from rats. In the injection sites obtained from cynomolgus monkeys, only procedure-related 

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findings were observed and included (in order of decreasing incidence) minimal and/or mild 
superficial perivascular infiltrates, fibroplasia/fibrosis, myointimal hyperplasia of the injected 
vein, hemorrhage, and sporadic observations in the epidermis and skeletal muscle. 
5.3.2.
Summary of Clinical Trials
Detailed descriptions of the relevant clinical findings for ALD403 are provided in the 
Investigator’s Brochure (IB).
A summary of completed and ongoing ALD403 clinical trials is shown in Table 5.3.
Table 5.3
ALD403 Clinical Trials
Trial ID
Phase/Objective
Trial Subject 
Population
Total 
Number of 
Subjects in 
the Trial
Number of 
Subjects 
Randomized to 
ALD403
Number of 
Subjects 
Randomized 
to Placebo
ALD403-CLIN-001
(completed)
Phase 1
Safety
Healthy 
Volunteer1
104
67
37
ALD403-CLIN-002
(completed)
Phase 1b
Safety & Efficacy
Frequent 
Episodic 
Migraine
163
81
82
ALD403-CLIN-003
(completed)
Phase 1
Safety
Healthy 
Volunteer
60
36
24
ALD403-CLIN-007
(completed)
Phase 1
(Safety)
Healthy 
Volunteer
60
49
11
ALD403-CLIN-009
(completed)
Phase 1
(Safety)
Healthy 
Volunteer
36
24
12
ALD403-CLIN-005
(completed)
Phase 2 
Safety & Efficacy
Chronic 
Migraine
665
531
134
ALD403-CLIN-0062
(ongoing)
Phase 3 
Safety & Efficacy
Frequent 
Episodic 
Migraine
900
ALD403-CLIN-0101
(completed)
Phase 1
(Safety)
Healthy 
Volunteer
24
16
8
ALD403-CLIN-0112
(ongoing)
Phase 3 
Safety & Efficacy
Chronic 
Migraine
1121
ALD403-CLIN-0121
(ongoing)
Phase 1
(Safety)
Type 1 Diabetic 
(T1DM)
21
14
7
1ALD403-CLIN-001 included a subset of seven migraine subjects.
2 Enrollment in this blinded clinical trial has been completed and subjects are in the follow-up phase of the trial.

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5.3.3.
Dose Justification
A dose of 300mg ALD403 administered by IV infusion every 12 weeks has shown efficacy in 
the treatment of CM and is the maximum anticipated dose and schedule. No dose limiting, 
treatment related adverse effects have been observed following ALD403 administration up to 
1000mg. ALD403 single dose levels up to 1000mg have generally been well tolerated.
5.4.
Risks and Benefits
ALD403 may prevent migraine from occurring in patients treated in this trial.  No specific 
toxicities or adverse effects related to the blockade of CGRP by ALD403 have been identified in 
either the nonclinical toxicology program or the clinical trials with ALD403 that have been 
completed to date. 
There may be unknown adverse effects and unforeseeable risks associated with study drug 
administration or unexpected interactions with another drug that have not yet been identified. 
As with all protein therapeutics, there is a risk of a serious allergic reaction.  In completed 
ALD403 trials conducted to date, no serious allergic reactions have been observed with the 
administration of ALD403 in humans. 
In the completed ALD403 clinical trials with headache patients, the most common observed 
adverse events (>5%) with receiving ALD403 or placebo included upper respiratory tract 
infection, back pain, dizziness, arthralgia, urinary tract infection, and headache.  The majority of 
these adverse events were categorized as mild to moderate.
Long term data with ALD403 is limited. 
x
Healthy volunteer trials have included limited dosing, short duration of follow up and 
have not included long term follow-up.
x
Trials in migraine patients have also included limiting dosing.  These trials are currently 
ongoing and no new significant findings have been noted during the follow-up period to 
date.

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The safety findings to date indicate that ALD403 Injection is well tolerated, with ALD403 
demonstrating a favorable benefit-risk profile based on review of nonclinical, clinical, and 
scientific literature data.
The sponsor will continue to monitor for significant new information and suspected adverse 
reactions associated with the use of ALD403.
5.5.
Compliance Statement
This clinical trial will be conducted in accordance with standards of Good Clinical Practice 
(GCP) as defined by the International Conference on Harmonisation (ICH) and all applicable 
federal and local regulations.

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6.
OBJECTIVES
6.1.
Safety Objective
The primary objective is:
x
To evaluate the long term safety of repeat doses of ALD403 administered intravenously (IV) 
in chronic migraine patients 
6.2.
Immunogenicity and Patient Reported Outcomes
The secondary objective is:
x
To evaluate the pharmacokinetics (PK) and immunogenicity of repeat doses of ALD403 
administered IV to patients with chronic migraine.
x
To further evaluate the impact of ALD403 on various patient reported outcomes.

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7.
TRIAL DESIGN
7.1.
Clinical Trial Endpoints
7.1.1.
Safety Endpoints
x
Adverse events (AEs) and serious adverse events (SAEs)
x
Clinical laboratory assessments 
x
Vital Signs
x
ECGs  
x
Columbia-Suicide Severity Rating Scale (C-SSRS)
7.1.2.
Patient Reported Outcomes:
x
Patient Global Impression of Change (PGIC) 
x
Short-Form Health Survey (SF-36)
x
Health-Related Quality of Life (EQ-5D-5L)
x
Headache Impact Test (HIT-6)
x
Most Bothersome Symptom (MBS)
x
The Migraine Disability Assessment (MIDAS)
7.1.3.
PK and Immunogenicity Endpoints: 
x
Free ALD403 plasma concentrations 
x
Development of specific anti-ALD403 antibodies
x
Characterization of specific anti-ALD403 antibodies for neutralizing activity
7.2.
Clinical Trial Design
This is an open label trial of intravenous (IV) infusions of ALD403 in patients with chronic 
migraine.  The trial will include two treatment phases.  The primary treatment phase will include
4 infusions of ALD403 12 weeks apart. The secondary treatment phase will include up to 4 
additional infusions of ALD403 12 weeks apart following the primary treatment phase.
Subjects who provide informed consent will be evaluated for eligibility based upon the inclusion 
and exclusion criteria. In the primary treatment phase, visits will occur on Day 0, Weeks 2, 4, 8, 
12, 24, and 36 and subjects will receive 4 IV infusions of ALD403 on Days 0, Weeks 12, 24, and 
36.

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Subjects who receive all 4 infusions of ALD403 in the primary treatment phase may enter the 
secondary treatment phase. In the secondary treatment phase, subjects will receive up to 4
additional infusions for a total of 8 infusions. Visits and ALD403 IV infusions will occur on 
Weeks 48, 60, 72, and 84. Subjects will be followed for 20 weeks until Week 104 for a total 
study duration of approximately 106 weeks, including the screening period. 
Subjects who don’t receive all 4 infusions of ALD403 in the primary treatment phase or don’t 
consent for participation in the secondary treatment phase will be followed at Week 48 and 
Week 56, at which point they will have their End of Trial visit.    
Approximately 120 subjects will be enrolled and treated. Study specific assessments will be 
conducted according to the Schedule of Events presented in Section 2.

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8.
SELECTION AND WITHDRAWAL OF SUBJECTS
8.1.
Inclusion Criteria
A subject must meet all of the following criteria during the screening period and on Day 0 to be 
eligible for inclusion in the trial:
1. Willing and able to read and understand the consent process and sign an Informed 
Consent Form (ICF) for the clinical trial approved by an Institutional Review Board 
(IRB) or Ethics Committee (EC).
2. Male or female 18 – 65 years of age inclusive at time of informed consent.
3. 'LDJQRVLVRIPLJUDLQHDW\HDUVRIDJHZLWKKLVWRU\RIFKURQLFPLJUDLQH\HDU
(ICHD-3 beta, 2013 Section 1.3).
4. Prescription or over-the-counter medication for acute and/or prophylactic treatment of 
migraine has been prescribed or recommended by a healthcare professional.
5. Women of child-bearing potential, and males with partners of child-bearing potential, 
must agree to use adequate contraception for six months after last dose of study drug.   
Adequate contraception includes oral, transdermal or injectable [depot] estrogen, and/or 
progestogen, selective estrogen receptor modulator therapy, intrauterine contraceptive 
device, double barrier method (e.g., condom and diaphragm or spermicidal gel) or 
vasectomy.  Non-childbearing potential is defined as post-menopausal for at least 1 year 
or surgical sterilization or hysterectomy at least 3 months before screening. 
6. Has adequate venous access for administration of the investigational product and 
collection of blood samples.
7. Any hormonal therapy (e.g., contraceptives, hormone replacement therapy) use is stable 
and ongoing for at least 3 months prior to screening and throughout the trial.
8. Willing, committed, and able to comply with scheduled clinic visits and complete all 
trial-related procedures.
9. Any prophylactic use of medications for headaches must be stable for at least 3 months 
prior to screening.  

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10. Limited use of barbiturates (including Fiorinal®, Fioricet®, or any other combination 
containing butalbital) or prescription opiates is allowed if a stable dose is maintained for 
2 months prior to screening and is not expected to exceed 4 days per month.  
11. Subject agrees not to post any personal medical data related to the trial or information 
related to the trial on any website or social media site (e.g., Facebook, Twitter) during the 
trial.
8.2.
Exclusion Criteria
A subject who meets any of the following criteria will be excluded from the trial:
1. Receipt of any monoclonal antibody treatment, including ALD403 or any monoclonal 
antibody targeting the CGRP pathway (within or outside a clinical trial) within 6 months 
before screening.
2. Confounding and clinically significant pain syndromes (e.g. fibromyalgia, chronic low 
back pain, complex regional back syndrome, temporomandibular disorders).
3. Psychiatric conditions that are uncontrolled and/or untreated, including conditions that 
are not controlled for a minimum of 6 months prior to screening.  Patients with a 
lifetime history of psychosis, mania, or dementia are excluded.
4. History or diagnosis of complicated migraine (ICHD-III beta version, 2013), chronic 
tension-type headache, hypnic headache, cluster headache, hemicrania continua, new 
daily persistent headache, or sporadic and familial hemiplegic migraine 
5. Any use of approved devices, neuromodulation, neurostimulation or injectable therapy 
(trigger point injections, extracranial nerve blocks, facet joint for headache prophylaxis 
are prohibited 2 months prior to screening and during screening. 
6. Any use of botulinum toxin for migraine or for any other medical/cosmetic reasons 
requiring injections in the head, face, or neck within 4 months prior to screening and 
during screening. 
7. Any use of monoamine oxidase inhibitors (MAOIs), ketamine, methysergide, 
methylergonovine, or nimesulide within 3 months prior to screening.
8. Have present or previous malignancies, except:

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x
Squamous or basal skin cell carcinoma with excision, without evidence of recurrence, 
or
x
0DOLJQDQF\\HDUVVLQFHGLDJQRVLVWUHDWPHQWZLWKRXWHYLGHQFHRIUHFXUUHQFH
9. Subject has known history or evidence of cardiovascular disease, arteriosclerosis, 
cardiomyopathy, coronary artery disease, serious heart rhythm abnormalities, 
neurological disease, cerebrovascular disease, diabetes, Raynaud’s disease, or life-
threatening allergy (e.g, anaphylaxis).  If questions arise, the Investigator should contact 
the Medical Monitor for guidance.  
10. Primary hypertension that is uncontrolled or newly diagnosed (systolic BP of >139 mm 
Hg or diastolic BP of >89 mm Hg) at screening or secondary hypertension. Mild 
primary hypertension that is well-FRQWUROOHGIRUPRQWKVSULRUWRVFUHHQLQJLVDOORZHG
11. Clinically significant abnormal ECG at screening or on Day 0. 
12. Any clinically significant concurrent medical condition or clinically significant 
laboratory abnormality at screening or on Day 0.
13. %RG\0DVV,QGH[%0,NJPDWVFUHHQLQJ
14. The subject is at risk of self-harm or harm to others in the investigator’s opinion, based 
on clinical interview and responses provided on the Columbia-Suicide Severity Rating 
Scale (C-SSRS).  Subjects must be excluded if they have a lifetime history of a serious 
suicide attempt or multiple suicide attempts (i.e., actual, interrupted, or aborted 
attempts), had any suicidal behavior in the past 5 years (i.e., preparatory acts or 
behavior), or had suicidal ideation of Type 3, 4 or 5 (i.e., suicidal ideation with any 
method without intent to act or suicidal ideation with intent to act, with or without a 
plan), in the past 6 months, as measured by the C-SSRS at screening or on Day 0.
15. Any history or evidence of substance abuse or dependence (e.g., alcohol, opiates, 
amphetamines, and barbiturates) within the past 2 years according to the International 
Classification of Diseases (ICD) 10: F10-19.
16. Pregnant, breastfeeding, or planning to become pregnant during the trial.
17. Receipt of any experimental, unregistered therapy (within or outside a clinical trial) 

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within 30 days or 5 plasma half-lives (whichever is longer) before screening.
18. Planned or current participation in any other clinical trial for the duration of this clinical 
trial, or within 6 months prior to screening. NOTE: Subjects who participated in prior 
clinical trials of CGRP antagonists, including ALD403-CLIN-005, may be eligible to 
participate if they 
x
had their last dose of study drug more than 6 months prior to screening, AND
x
had no clinically significant adverse events related to study drug during their 
participation in the prior trial as assessed by the Investigator prior to enrollment. 
19. Recent or planned surgery, requiring general anesthesia, within 8 weeks prior to 
screening and during the duration of this clinical trial.
20. Positive for HIV, hepatitis B surface antigen, or hepatitis C antibody at screening.
21. Any condition that, in the opinion of the investigator, would make the subject unsuitable 
for the clinical trial.
22. Employees of Alder, the CRO(s), or any clinical trial site involved in this trial and their 
immediate family members (i.e., parents, spouse, siblings, children). 
8.3.
Registration and Treatment Assignment
8.3.1.
Registration Procedure, Subject Numbering
Each participating investigative site will be assigned a 3-digit site number (e.g., 101, 102). At the 
screening visit, once the subject signs the ICF they are registered in the Interactive Web 
Response System (IWRS), which will assign a unique subject number. The first three digits of 
the subject number identify the site, and the remaining digits identify the subject.
Subjects who fail screening may be rescreened if approved in advance by the Medical Monitor.  
8.4.
Subject Treatment Discontinuation and Early Withdrawal
Subjects may discontinue treatment or withdraw from the clinical trial at any time and for any 
reason without penalty or prejudice to his or her future medical care. 
8.4.1.
Criteria for Discontinuation from Study Treatment
Study treatment must be discontinued for the following reasons:

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x
Pregnancy
x
Suicidal ideation with intent, with or without a plan (i.e., ‘Yes’ to suicidal ideation 
questions 4 or 5) or any suicidal behavior as determined by the C-SSRS.       
Subjects discontinued due to suicidal ideation and/or suicidal behavior must be referred to a 
mental health specialist as specified in Section 11.1.9.
Study treatment may also be discontinued for the following reasons:
x
Adverse Event
x
Subject decision
x
Investigator decision 
x
Termination of the study by Alder
If a subject discontinues study treatment due to a medical condition, Investigators must provide 
adequate medical treatment during study visits.  Prior to removing a subject from study 
treatment, the decision should be discussed with the Medical Monitor or designee. The reason for 
discontinuation from study treatment must be recorded on the CRF. Subjects who discontinue 
study treatment will be encouraged to continue with study assessments until the end of the study.
8.4.2.
Criteria for Withdrawal from the Clinical Trial
Subjects will be withdrawn from the clinical trial for any of the following reasons:
x
Withdrawal of consent for the collection of clinical trial data including further access 
to medical records. The reason for withdrawal of consent will be recorded.
x
Termination of the trial by Alder
x
Investigator decision
x
Lost to follow-up
The reason for withdrawal and the date of withdrawal must be recorded on the CRF.
8.4.2.1.
Timing of Withdrawal
Subjects are considered withdrawn from the clinical trial at the time that any of the criteria listed 
in Section 8.4.2 are met and the last study assessment is performed.

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8.4.2.2.
Follow-up for Early Withdrawal
Subjects who withdraw early from study participation due to any reasons will be asked to have 
an early termination visit with associated visit assessments (see Schedule of Events in Section 2).  
Subjects who withdraw consent after screening but do not receive study treatment may 
discontinue the study without any further procedures.
8.4.3.
Replacement Policy
Subjects who are withdrawn from the clinical trial after dosing will not be replaced. 
8.4.4.
Lost to Follow-Up
If the subject fails to attend scheduled study visits or to respond to requests for follow-up, the 
clinical trial site will send a registered letter, at a minimum, to the subject requesting contact with 
the clinic.  All attempts to resume contact (including copies of written correspondence and 
documentation of telephone and email contact attempts) will be included in the source 
documentation.  Subjects who do not respond to requests for follow-up after all reasonable 
attempts to establish contact will be considered lost to follow-up.

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9.
CLINICAL TRIAL TREATMENTS
9.1.
Investigational Product 
ALD403 is an anti-(calcitonin gene-related peptide) humanized monoclonal antibody (anti-
CGRP mAb) that is being developed by Alder for the prevention of migraine.  
ALD403 Injection, 100 mg/vial, is presented in 2-mL Type I glass vials as a single-use 
preservative-free solution for IV administration.  ALD403 is formulated at a concentration of 
100 mg/mL with a pH of 5.8.  Subjects will receive an IV infusion of ALD403 300 mg Injection 
in 100 mL of 0.9% saline.  
9.2.
Investigational Product Administration
ALD403 (approximate volume of 100 mL) is administered IV over a period of 30 (+15) minutes 
at the visits specified in Schedule of Events in Section 2, by the Investigator or designee. 
Infusions may be administered for a total duration of up to 1 hour, if needed in the judgement of 
the Investigator.  
If the subject experiences a headache or migraine on dosing day, dosing may occur if, in the 
investigator’s opinion, it will not compromise the safety of the subject.  The Medical Monitor 
may be consulted as needed.  Subjects must remain in the care facility and be monitored by site 
staff for at least 2 hours after the infusion ends.  The Investigator or sub-investigator must be 
immediately available during the infusion and for at least 2 hours after the end of infusion to 
assess each subject for the occurrence of adverse events. Subjects will be requested to stay longer 
than 2 hours after the end of infusion should the investigator determine it is clinically warranted 
(i.e., subjects should be observed until all AEs are resolved or clinically stable).  The timeframe 
for the post-dose observation period must be documented in the source record.
Further instructions on ALD403 preparation and administration can be found in the Pharmacy 
Manual.

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9.2.1.
Packaging and Labeling
Before the shipment to the investigative sites, ALD403 will be labeled with information required 
by regulatory agencies, such as a statement that it is limited to investigational use. At the 
investigative site, each ALD403 preparation will be labeled by the site.
9.2.2.
Storage and Handling of Investigational Product
ALD403 will be stored at a central depot or at the clinical site at -20°C (-10°C to -25°C) in 
accordance with any accompanying instructions.  Please refer to the Pharmacy Manual for 
additional storage and handling procedures.  Diluent (0.9% saline) will be stored according to 
manufacturer instructions.
Investigators shall take adequate precautions, including storage of ALD403 in a securely locked, 
substantially constructed cabinet or other securely locked, substantially constructed enclosure, 
access to which is limited to prevent theft or diversion of the substance into illegal channels of 
distribution.
9.2.3.
Accountability and Disposition of ALD403
The Investigator is responsible for maintaining accurate ALD403 accountability records 
throughout the clinical trial. The site must maintain an Investigational Product Accountability 
Logas per the study Pharmacy Manual. Where more than one secure area is being used for 
storage at a site, all movement of ALD403 through the chain of custody must be recorded in 
accountability records such that full reconciliation may be completed at the end of the trial. 
Included with each ALD403 shipment is a form listing lot numbers and quantity shipped. The 
Investigator, responsible pharmacist, or designee, will sign and return to Alder, or designee, a 
statement that certifies the receipt and integrity of these supplies. A copy will be retained for the 
site clinical trial file.
After completion of the clinical trial, the Investigator is responsible for either returning or 
destroying all unused ALD403. The Investigator must verify that no remaining supplies are in 
his/her possession. All used/partially used vials/IV bags will be destroyed onsite according to the 
site SOPs or returned according to Alder directive. Destruction must be in accordance with local 
regulations for the product type and destruction documentation must be provided to Alder.  

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If the clinical trial is terminated, suspended, discontinued, or completed, the Investigator or 
designee shall return the unused supplies to Alder or designee, or otherwise provide for 
disposition of the unused supplies (as authorized by Alder). 
9.3.
Concomitant Medications
Any concomitant therapy used from the time the subject signs the informed consent through 
Week 104 must be recorded on the CRF, including medications required for treatment of any 
AEs or SAEs. The medication name, dosage, date, and indication for use must be recorded. The 
Medical Monitor or designee should be notified in advance of (or as soon as possible after) any 
instances in which restricted therapies are administered. 
Subjects on stable medication for headache prophylaxis for 3 months prior to screening will be 
permitted to continue use during the study, provided there are no alterations to their regimen, 
except as allowed per Investigator discretion. After Week 48, changes to migraine prophylactic 
treatment are allowed per Investigator or the subject’s primary treating healthcare professional. 
A list of the migraine preventive therapies with established or probable efficacy is in 
Section 15.1 for reference. Sites are required to indicate if a medication is used for prophylaxis 
purposes or if it is used for the acute treatment of migraines.
The following medications are restricted:
x
Prescription EDUELWXUDWHVDQGRSLDWHVDUHDOORZHGIRUGD\VSHUPRQWKSURYLGHGWKH
VXEMHFWKDVEHHQRQDVWDEOHUHJLPHQGD\VSHUPRQWKIRUDWOHDVWPRQWKVSULRUWR
screening and throughout the entire trial. After enrollment, the use of prescription 
barbiturates and opiates is allowed as medically necessary and prescribed by a licensed 
healthcare professional for indications other than migraine.
x
Botulinum toxin for migraine or for any other medical/cosmetic reasons requiring 
injections in the head, face, or neck are prohibited 4 months prior to screening and 
throughout the entire trial.
x
Devices, neuromodulation, neurostimulation, or injectable therapy (trigger point 
injections) for headache prophylaxis are prohibited 2 months prior to screening and 
throughout the entire trial.

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x
Any use of monoamine oxidase inhibitors (MAOIs), ketamine, methysergide, 
methylergonovine, or nimesulide within 3 months prior to screening and throughout the 
entire trial.

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10.
STUDY ASSESSMENTS AND PROCEDURES
10.1.
Schedule of Events
Assessments and procedures at each visit are summarized in Section 2 - Schedule of Events. 
10.2.
Assessments and Procedures
10.2.1.
Demographics
The year of birth, age, sex, ethnicity, race, and how the subject was recruited to the trial will be 
collected in source records and in the CRF.  
10.2.2.
Medical History
Significant historic and current medical conditions or illnesses, allergies to medications, and 
prior surgical interventions will be recorded in the source records and in the CRF.  Symptoms 
that are ongoing at the time of informed consent will be considered medical history.
Migraine history will also be collected in the source records and the CRF, including age at 
diagnosis of chronic migraine as well as other details of the subjects’ history with migraine.  If 
the subject is not a current or past user of a prescribed medication for migraine, the Medical 
Monitor should be consulted.  
Investigators should demonstrate due diligence in trying to obtain medical records.  All attempts 
to obtain medical records should be documented.  If medical records cannot be obtained, history 
may be confirmed via patient interview in order to obtain sufficient information to confirm all 
eligibility criteria are met.
10.2.3.
Physical Examinations
Physical examinations will be performed at the times noted in the Schedule of Events in 
Section 2 and must be performed by an Investigator who has been trained and delegated the task 
on the Delegation of Authority Log.
The screening physical examination will include a review of all body systems. For all other visits 
that call for a physical examination, the body systems reviewed will be at the discretion of the 
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Physical examination may include weight measurement as specified in Schedule of Events in 
Section 2.  Height will be measured at screening only.
Abnormal physical examination findings at the screening visit will be recorded as medical 
history.  Any new or worsening physical examination finding identified after informed consent 
will be considered an AE.
10.2.4.
Vital Signs
Vital signs, including blood pressure (BP) and pulse will be measured at the time points specified 
in the Schedule of Events in Section 2.
When measuring vital signs, the subject should be seated comfortably, with back supported and 
rested for 5 minutes before the measurements begin.  
For BP measurements, the subject should have their upper arm positioned so that it is level with 
their heart and feet flat on the floor.  Excess clothing that might interfere with the BP cuff or 
constrict blood flow in the arm should be removed. A blood pressure cuff of appropriate size 
should be wrapped around the bare upper arm such that the bladder portion of the cuff extends at 
least 80% around the arm.  The center of the bladder should be in line with the brachial artery so 
as to allow the stethoscope diaphragm clear access to the brachial artery.  Site staff and subject 
should refrain from talking during the reading.  Blood pressure may be repeated to confirm 
measurement.
10.2.5.
Questionnaires
Questionnaires should be administered to subjects in the order listed below at the time points 
specified in the Schedule of Events in Section 2:
1. Columbia-Suicide Severity Rating Scale (C-SSRS)
2. Most Bothersome Symptom (MBS)
3. Patient Global Impression of Change (PGIC)
4. Short-Form Health Survey (SF-36)
5. Health-Related Quality of Life (EQ-5D-5L)
6. Headache Impact Test (HIT-6)
7. The Migraine Disability Assessment (MIDAS)

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All questionnaires should be administered prior to dosing at dosing visits. Protocol number, 
subject number and date and time of administration must be captured on all questionnaires.  All 
questionnaires completed by subjects must be reviewed for completeness and clarity by site staff 
prior to the subject leaving the clinic.  The subject should be asked to complete any unanswered 
questions.
10.2.5.1.
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be administered by trained (i.e., C-SSRS certified) site staff at the time points 
specified in the Schedule of Events in Section 2.  The C-SSRS must be administered prior to 
dosing at dosing visits. The C-SSRS “Baseline/Screening” version will be used for the screening 
visit, and the C-SSRS “Since Last Visit” version will be used for all subsequent visits.
10.2.5.2.
Most Bothersome Symptom (MBS)
The Investigator will verbally obtain the most bothersome symptom associated with the subject’s 
migraines during the screening visit.  The most bothersome symptom will be captured in the 
eCRF and may include nausea, vomiting, sensitivity to light, sensitivity to sound, mental 
cloudiness, fatigue, pain with activity, mood changes, or other migraine related symptom.  
At each subsequent visit, the site staff will provide the questionnaire along with the other 
subject-completed questionnaires listed in Section 10.2.5.
10.2.5.3.
Other Questionnaires
The following questionnaires will be administered at days and times provided in the Schedule of 
Events in Section 2.  Subjects will be given the questionnaires in the order specified below and 
asked to review the brief instructions on each questionnaire and complete.    
x
Patient Global Impression of Change (PGIC)
x
Short-Form Health Survey (SF-36)
x
Health-Related Quality of Life (EQ-5D-5L)
x
Headache Impact Test (HIT-6)
x
The Migraine Disability Assessment (MIDAS)

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10.2.6.
12-Lead ECG
ECGs will be performed using a 12-lead ECG device provided for the study at the time points 
specified in the Schedule of Events in Section 2.  On dosing visits ECGs must be performed prior 
to dosing and up to 2 hours (+ 30 min) after dosing.
ECG data will be transmitted and read centrally by a cardiologist, however, the Investigator must 
review the ECG to ensure there are no clinically significant abnormalities prior to dosing.  In 
addition, all centrally read ECG reports must be reviewed by the Investigator and evaluated for 
clinical significance. 
All ECGs are expected to be performed on the ECG device provided to the site by Alder.  A 
local ECG device may be used only in the event that there are technical issues with the central 
ECG device that cannot be resolved while the subject is onsite.   All technical issues must be 
reported immediately to the ECG vendor help desk.
10.2.7.
Laboratory Samples and Testing
10.2.7.1.
Urine Drug Screening
Drugs of abuse testing will be performed on urine samples during the screening visit.  Urine drug 
screen kits will be provided by the central lab and the test performed on site.
10.2.7.2.
Pregnancy Testing
Urine pregnancy tests will be performed for all female subjects, regardless of childbearing 
potential, at the specified time points in the Schedule of Events, Section 2.  On dosing visits 
urine pregnancy tests must be performed prior to dosing.
Urine pregnancy test kits will be provided by the central lab, and the test performed on site.
The contraceptive method used by females of child-bearing potential and males with partners of 
child-bearing potential must be confirmed with the subject and recorded in the source record at 
screening, and reconfirmed with the subject and recorded in the source record at each subsequent 
study visit.

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10.2.7.3.
Clinical Laboratory Testing
Blood samples for clinical laboratory tests, including hematology, serum chemistry and serology 
(including HIV, Hepatitis B, and Hepatitis C), will be collected at the time points specified in the 
Schedule of Events in Section 2.  Clinical laboratory tests performed are listed in Section 11.1.7.
All clinical laboratory samples will be initially processed by site staff and shipped to a central 
laboratory for analysis as specified in the Laboratory Manual.  An Investigator listed on the Form 
FDA 1572 will review all lab reports and document clinical significance for any out-of-range lab 
value(s) listed in the report.  
10.2.7.4.
Pharmacokinetic and Immunogenicity Sampling
Blood samples will be collected for ALD403 plasma PK and for determination of anti-ALD403 
antibodies in serum (immunogenicity) at specified time points in the Schedule of Events in 
Section 2.  All samples will be initially processed, stored, and shipped as specified in the 
Laboratory Manual.

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11.
ASSESSMENT OF SAFETY
11.1.
Adverse Events
11.1.1.
Definitions
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product that does not necessarily have a causal 
relationship with the treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH E6)
11.1.2.
Assessment of Adverse Events
The Investigator is required to monitor the occurrence of adverse events for each subject from 
the time of informed consent through the course of the clinical trial.  Adverse events may be 
reported by the subject, reported by a caregiver, or reported by the investigative site through 
Investigator site personnel open-ended questioning, through physical examination, laboratory 
test, documentation in medical records, or by other means.  Adverse events include:
x
Any new undesirable medical experience or an unfavorable and unintended change of an 
existing condition that occurs during or after treatment, whether or not considered related 
to the Investigational Product.
x
Any abnormal assessment or laboratory findings considered by the Investigator to be 
clinically significant.  Clinically significant findings include but are not limited to those 
that lead to discontinuation or interruption of study treatment, require therapeutic 
intervention, or require a change in subject management.
A new or worsening of a pre-existing or chronic condition is considered an adverse event and 
must be reported as such.  Medical conditions, which existed prior to the time of informed 
consent into the clinical trial, will not be considered an adverse event unless the condition 
worsens.  Unchanged, chronic, non-worsening or pre-existing conditions from the time of 
informed consent are not adverse events and should not be recorded on the AE eCRF.  

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Pre-existing medical conditions of clinical significance must be included in the subject’s medical 
history and recorded on the medical history eCRF page. 
Each event recorded on the AE eCRF is required to be assessed by the Investigator with regard 
to the following; seriousness, severity, and relationship to ALD403, as outlined below.
Seriousness
An adverse event or suspected adverse event is considered serious if in the view of either the 
Investigator or Alder, it results in;
x
Death
x
Is life-threatening (this means that the subject is at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more 
severe)
x
Inpatient hospitalization or prolonged existing hospitalization. 
x
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
x
Congenital anomaly/ birth defect
x
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgement, they may jeopardize the patient or subject and/or may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition (21 CFR 
312.32(a) and ICH E2A).
Of note: 
o
A social hospitalization (i.e., hospitalizations for pre-admissions not due to an 
acute medical issue) is not considered an SAE.
o
Hospitalization is considered a greater than 24 hour hospital admission.

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Severity
The severity of an AE will be graded as follows:
x
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
x
Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL).
x
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.
x
Grade 4 Life-threatening consequences; urgent intervention indicated.
x
Grade 5 Death related to AE.
Relationship to ALD403
The Investigator is required to assess the causality/relationship between each AE and the 
ALD403 as not related or related and record the assessment on the source documents and in the 
eCRF AE page. Medical judgment should be used to determine the likely relationship of the AE 
to the ALD403 considering all relevant factors including (but not limited to) relevant history, 
concomitant medical condition, and concomitant medications.  Determination should be based 
on assessment of temporal relationships, biologic plausibility, association (or lack of association) 
with underlying disease, and presence (or absence) of a more likely cause.  
Not Related: It is plausible that the AE has an etiology other than the ALD403 (e.g., pre-
existing condition, underlying disease, concomitant medical condition, or concomitant 
medication).
Related: The AE cannot reasonably be explained by the subject’s clinical state,
concomitant\medical condition or concomitant therapies, and a temporal relationship 
exists between the event onset and administration of the ALD403. 

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11.1.3.
Recording Adverse Events
Event reporting will extend from time of informed consent until completion of the final visit. 
Serious adverse events occurring after the end of the clinical trial must be reported if the 
Investigator considers there to be a causal relationship with ALD403. 
An SAE Notification Form should be used to report any related SAEs which occur after the end 
of the clinical trial. 
Adverse events (AEs) should be recorded on the AE eCRF, whether believed by the Investigator 
to be related or not related to the ALD403. 
AE reporting should contain:
x
A brief description of the event
x
Date of onset 
x
Date of resolution
x
Severity
x
Actions taken or treatment required 
x
Relationship to Investigational Product 
x
Outcome 
x
Whether the event is considered serious
Whenever possible, the Investigator should group signs or symptoms that constitute a single 
diagnosis into a single event term.  For example, “cough, rhinitis, and sneezing” might be 
grouped together as “upper respiratory tract infection.”
Asymptomatic abnormal findings considered by the Investigator to be clinically significant 
should be recorded as an AE, unless it is associated with a clinical syndrome that has already 
been reported as an AE.
11.1.4.
Reporting Serious Adverse Events
All SAEs that occur during the period of observation, whether considered to be related to 
ALD403 or not, must be reported within 24 hours of awareness or knowledge of the event.  The

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date the site personnel became aware of the serious adverse event must be recorded in the source 
document.  To report the SAE, complete the eCRF AE page and indicate the reason for 
seriousness.  The minimum information required for an initial report is:
x
Sender of report (name, address of Investigator)
x
Subject identification (screening/enrollment number, NOT subject name)
x
Protocol number
x
Description of SAE (e.g., event term)
x
Seriousness criteria
x
Relationship assessment
After receipt of the initial report, the Medical Monitor or designee will review the information 
and, if necessary, contact the Investigator to obtain further information for assessment of the 
event.  Alder, or Alder’s designee will be responsible for information processing and reporting in 
accordance with applicable local and regulatory requirements. 
Alder will determine if an SAE requires expedited reporting to regulatory agencies.  The clinical 
trial site personnel are responsible for reporting these events to their EC/IRB according to the 
institution’s EC/IRB reporting requirements and in accordance with applicable local and 
regulatory requirements.
Should the EDC System not be available, serious adverse events must be reported on the paper 
SAE Notification Form. Additional details can be found in the Site Manual. This does not 
replace the EDC reporting system; information must be entered in the EDC system once the 
system returns to normal function.
11.1.5.
Unexpected and Related Serious Adverse Events
Unexpected SAEs are those which:
x
Are not previously reported as associated with ALD403, as referenced in the 
Investigator’s Brochure.

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x
May be symptomatically and pathophysiologically related to an AE listed in the 
Investigator’s Brochure, but differ from the event due to greater severity, frequency, or 
specificity.
Alder, or Alder’s designee will report, to the appropriate regulatory authorities according to local 
and regulatory requirements, unexpected SAEs which are considered related to ALD403 
(suspected unexpected serious adverse reactions [SUSARs]).  The clinical trial site personnel are 
responsible for reporting these events to their EC/IRB in accordance with applicable local and 
regulatory requirements.
11.1.6.
Follow-up of Adverse Events
Irrespective of the suspected causality, AEs will be monitored until resolution, stabilization in 
the judgment of the Investigator, or the subject is lost to follow up or withdraws from the trial.
11.1.7.
Clinical Laboratory Tests
Serum chemistry tests include albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), urea nitrogen, calcium, bicarbonate, creatinine, 
globulin, glucose, phosphorus, potassium, sodium, total bilirubin, total cholesterol, total protein, 
triglycerides, magnesium, and uric acid.
Hematology tests include hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, and 
white blood cell (WBC) count with differentials (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils).
11.1.8.
Pregnancy
In the event that a female subject becomes pregnant following administration of ALD403 or may 
have been pregnant at the time of ALD403 exposure, or the partner of a male subject becomes 
pregnant following ALD403 administration to the male subject, the pregnancy must be reported 
to Alder within five business days of the Investigator becoming aware of the pregnancy.  
Pregnancy information will be reported to Alder using the Exposure In-Utero Forms in EDC.  An 
Exposure In-Utero Notification Form should be used to report a pregnancy that occurs within 30 
days after completion of the trial.

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Although pregnancy per se is not considered an AE, the outcome of a pregnancy that results in a 
birth defect or congenital anomaly or hospitalization for any reason is considered to be an SAE.  
Every attempt should be made to follow a pregnancy to conclusion.  
Follow-up information is to be collected by the Investigator and provided to Alder regarding:
x
The course of the pregnancy including perinatal and neonatal outcome, premature
termination of the pregnancy, or miscarriage 
x
Offspring information including birth weight and birth defects (if any) 
11.1.9.
Suicidal Ideation and Behavior 
Recent meta-analyses, spontaneous reports, and published case reports regarding suicidal 
ideation and behavior arising from drugs tested in clinical trials have been noted as an area of 
general concern. Based on this information, the United States Food and Drug Administration 
(FDA) has provided guidance to prospectively assess suicidal ideation and behavior in clinical 
trials to ensure that subjects in clinical trials who are experiencing suicidal ideation and behavior 
are properly recognized and adequately treated and to ensure the collection of more timely and 
more complete data on suicidal ideation and behavior than have been collected in the past.12 The 
C-SSRS (Columbia-Suicide Severity Rating Scale) will be used for this purpose.  Any subject 
who answers “yes” to questions 4 or 5 of the C-SSRS during the screening visit will be referred 
to a mental health specialist by the Investigator.  During the course of the trial after dosing, any 
subject who answers “yes” to questions 4 or 5 in the Suicidal Ideation section or answers “yes” 
to any question in the Suicidal Behavior section of the C-SSRS will be discontinued from the 
study treatment as specified in Section 8.4.1, and referred by Investigators to a mental health 
specialist.  Affirmative answers to questions 4 or 5 for suicidal ideation or to any question for 
suicidal behavior will be reported in EDC as an AE.
11.2.
Management of Reactions to ALD403 
There are no specific antidotes to ALD403. 
Each medical emergency should be treated appropriately by the Investigator using proper 
standard of care, according to their typical clinical practice and local guidelines for that 
emergency condition. Emergency equipment and medication for the treatment of these potential 
adverse events must be available for immediate use.  

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Should a medical condition arise that the Investigator believes is related to ALD403, clinical 
judgment should be used to provide the appropriate response including the consideration of 
discontinuation of ALD403. Subjects who have experienced a potential significant allergic 
reaction after administration of ALD403 should not receive subsequent doses until discussed 
with the Medical Monitor and an appropriate disposition has been agreed upon.
If a subject experiences a potential systemic allergic reaction, as assessed by the Investigator, the 
site will collect additional blood specimens using the immune response lab kit at the time of the 
event as per laboratory manual. The Medical Monitor may request a 2nd immune response lab kit 
be collected in approximately 4-6 weeks after the 1st collection. This immune response 
assessment includes serum histamine, serum tryptase, immunoglobulin E, and complement 
components.
Whether maintained in a “formal crash cart” or separately, the following is a requirement at the 
site:
x
CPR certification by site staff performing study assessments
x
Automated external defibrillator (AED)
x
Emergency medications including antihistamines, bronchodilators, IV saline, 
corticosteroids, acetaminophen, and epinephrine
The AED and emergency medication should be immediately available on an Investigational 
product infusion day.

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12.
ASSESSMENT OF QUESTIONNAIRES, PK, AND 
IMMUNOGENICITY 
12.1.
Questionnaires
Patient Global Impression of Change (PGIC)
The PGIC includes a single question concerning the subject’s impression of the change in their 
disease status since the start of the study. Seven responses are possible: Very Much Improved, 
Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse, Very Much 
Worse.
SF-36 Health Survey (SF-36 v2.0)
The SF-36 v2.0 is a health survey containing 36 questions consisting of eight scaled scores to 
measure quality of life over the past 4 weeks. See Appendix 15.4.  The eight sections measured 
are vitality, physical functioning, bodily pain, general health perceptions, physical role 
functioning, emotional role functioning, social role functioning, and mental health.  
EQ-5D-5L
The EQ-5D-5L is a descriptive system of health-related quality of life states consisting of five 
dimensions/questions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) 
each of which can take one of five responses. The responses record five levels of severity (no 
problems/slight problems/moderate problems/severe problems/extreme problems) within a 
particular EQ-5D dimension. The EQ-5D-5L additionally includes a VAS scale.  Each item will 
be summarized separately.
Headache Impact Test (HIT-6 v1.0)
The Headache Impact Test (HIT) is a tool used to measure the impact and effect on the ability to 
function normally in daily life when a headache occurs. The HIT is a 6 question, Likert-type, 
self-reporting questionnaire with responses ranging from “Never” to “Always” with the 
following response scores: Never=6, Rarely=8, Sometimes=10, Very Often=11, Always=13. See 
Appendix 15.3. The total score for the HIT is the sum of each response score and will be treated 

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as missing if the response is missing for one or more questions. The HIT total score ranges from 
36 to 78, with score ranges having the following life impact:
Score Range
Life Impact
>= 60
56-59
50-55
<= 49
Severe
Substantial
Some
Little to None
Most Bothersome Symptom (MBS)
At screening, subjects will identify migraine related symptom that is most bothersome for them.  
Subjects will be asked to rate the improvement in this symptom from screening on a seven-point 
scale identical to the scale used for the PGIC.
The Migraine Disability Assessment (MIDAS)
The MIDAS questionnaire measures the effect headaches have on the subject’s daily 
functioning.  Midas is composed of five questions that ask about the subject’s performance over 
the past 3 months.  The response to each question is provided in number of days which are 
totaled to determine the level of disability: 0-5, MIDAS Grade I, Little or no disability; 6-10,
MIDAS Grade II, Mild disability; 11-20, MIDAS Grade III, Moderate disability; 21+, MIDAS 
Grade IV, Severe disability.
12.2.
Pharmacokinetics
The concentrations of ALD403 will be measured in plasma from all treated subjects using a 
validated assay. The PK analysis will include evaluations of concentration-time profiles for free 
ALD403 on Day 0 (pre-dose and immediately post-dose (within 15 minutes of end of infusion), 
and Weeks 2, 4, 8, 12 (pre-dose), 24 (pre-dose), 36 (pre-dose), 48 (pre-dose), 72 (pre-dose), and 
104 or ET. 
All plasma PK samples will be stored at -20°C or below prior to shipping to the central 
laboratory.
Additional sample handling, processing, storage, labeling, and shipping instructions will be 
provided to the site in a laboratory manual.

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If a subject terminates early from the clinical trial, all efforts will be made to collect blood 
samples to analyse for free ALD403 unless consent has been withdrawn.
12.3.
Immunogenicity
Serum blood samples will be taken on Day 0 (pre-dose), and Weeks 2, 4, 8, 12 (pre-dose), 
24 (pre-dose), 36 (pre-dose), 48 (pre-dose), 72 (pre-dose) and 104 or ET to test for the 
development of antibodies to ALD403. The immunogenicity will be assessed in serum from all 
ALD403-treated subjects using a validated assay.  
If a subject terminates early from the clinical trial, all efforts will be made to collect blood 
samples to analyze for antibodies against ALD403 unless consent has been withdrawn. For any 
samples that are positive for anti-ALD403 antibody, there may be additional testing to 
characterize the anti-ALD403 antibody for the potential to neutralize (NAb) ALD403 activity.  
Subjects who test positive for specific anti-ALD403 antibodies at the time of the last study visit 
will be asked to provide up to 2 additional blood samples for immunogenicity testing at 
approximately 3 month intervals for up to 6 months.
Additional sample handling, processing, storage, labeling, and shipping instructions will be 
provided to the site in a laboratory manual. 

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13.
STATISTICAL CONSIDERATIONS
13.1.
Sample Size
The planned sample size for the study is 120 treated subjects.  It is assumed that over 75% of 
these subjects will complete the primary treatment phase resulting in at least 90 subjects with one 
year of safety data collection.
13.2.
General Considerations
13.2.1.
Definition of Baseline
The baseline assessment will be the latest available valid measurement taken prior to the 
administration of Investigational Product. This will generally be Day 0.
13.2.2.
Handling of Missing Data
Summary statistics will be reported based upon observed data. If the start date of an AE or 
concomitant medication is incomplete or missing, it will be assumed to have occurred on or after 
the intake of ALD403, except if an incomplete date (e.g., month and year) clearly indicates that 
the event started prior to treatment. 
13.2.3.
Populations to be Analyzed
The Safety Population, the analysis population for this study, includes all subjects who received 
at least one dose of treatment. 
13.3.
Interim Analyses
This study will include a formal interim analysis after all subjects have completed the primary 
treatment phase. 
13.4.
Statistical Methods
Continuous variables will be summarized with mean, median, standard deviation, minimum, and 
maximum. Categorical variables will be summarized with frequency and percentage. Change 
from baseline will be summarized as well as the results at the time point. 

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13.4.1.
Subject Disposition, Demographics, and Baseline Characteristics
An accounting of subjects by disposition will be presented. This summarization will include a 
summary of all subjects who have received trial drug ALD403. Demographic, baseline 
characteristics, migraine history and concomitant medications (coded by the World Health 
Organization Drug Dictionary) will be summarized descriptively.
13.4.2.
Efficacy Analyses
The Secondary endpoints will be summarized with descriptive statistics by time point.  These 
summary measures will be based upon the observed results and where appropriate the change 
from baseline results. Testing of these change from baseline results for the SF-36, MIDAS and 
HIT-6 will be performed at Weeks 12, 24, 36, 48, 60, 72, 84 and 104. For SF-36 tests will be 
performed for the change in the Mental Component and Physical Component scores and for the 
HIT-6 and MIDAS tests will be performed based upon the change in total score. The tests will be 
a t-test. 
13.4.3.
Pharmacokinetic Analyses
Analysis of Drug Concentrations
The concentrations of ALD403 will be listed and summarized by time point and dose group, and 
descriptive statistics will be provided. In this analysis, concentrations below the lower limit of 
quantification (LLOQ) will be set to zero.  
Plots of the individual concentrations of ALD403 will be presented over time (linear and log 
scales). Plots of the mean or median concentration will be presented over time (linear and log 
scales). When the scale is linear, concentrations below the lower limit of quantification will be 
set to zero. In the log-scaled figures, concentrations below the LLOQ will be imputed as 
LLOQ/2.  Population pharmacokinetic analysis will be performed on the results for ALD403 
concentrations obtained during this study in combination with the results from other studies of 
ALD403 in normal subjects and migraine patients. 

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13.4.4.
Safety Analyses
13.4.4.1.
Adverse Events
The incidence of all AEs will be tabulated. These AEs will be classified by system organ class 
and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). For 
incidence reporting, if a subject reported more than 1 AE that was coded to the same preferred 
term/system organ class, the subject will be counted only once for that specific preferred 
term/system organ class. Events recorded between the time the informed consent is signed and 
the first treatment administration will be listed.
An overview of AEs, which includes subject incidence of AEs, SAEs, deaths, and AEs leading to 
discontinuation, will be presented. For AEs presented by severity, the worst severity during the 
clinical trial will be presented for each subject.
The subject incidence of AEs will be summarized by system organ class and preferred term.
13.4.4.2.
Serious Adverse Events
All SAEs will be listed and summarized in a similar manner to AEs. 
13.4.4.3.
Clinical Laboratory Results
Summary statistics for actual values and for changes from baseline will be tabulated for clinical 
laboratory results by scheduled visit. Subjects with clinical laboratory values outside of the 
normal reference range at any post-baseline assessment will be summarized. Shifts from baseline 
clinical laboratory values based upon the normal range will be tabulated. Subjects developing an 
antibody response will be listed.
13.4.4.4.
Electrocardiogram (ECG) Results
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics.  
13.4.4.5.
Vital Signs
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics. 

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13.4.4.6.
C-SSRS
The C-SSRS assesses lifetime suicidality during an initial baseline evaluation, and then monitors 
suicidal ideation and suicidal behavior at subsequent follow-up assessments.  Four constructs are 
measured.  The first and second are the severity and intensity of ideation, rated on a 5-point 
ordinal scale.  The third is the behavior subscale, which is rated on a nominal scale and the fourth 
is the lethality subscale, which assesses actual attempts.  These results will be reported at 
baseline and post baseline.  Results for individual time points will be provided in a listing.

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14.
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS
14.1.
Data Quality Assurance
Alder, or Alder’s designee will assess each site to verify the qualifications of the Investigator, 
according to Alder’s, or designee’s SOPs. Site facilities will be inspected, and the Investigator 
will be informed of responsibilities and the procedures for ensuring adequate and correct 
documentation.
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the clinical trial for each clinical 
trial subject. All information recorded on the CRFs for this clinical trial must be consistent with 
the subjects’ source documentation (i.e., medical records).
14.2.
Case Report Forms and Source Documents 
As part of the responsibilities assumed by participating in the study, the principal investigator or 
sub-investigator agrees to maintain adequate case histories for the patients treated as part of the 
research under this protocol. The principal investigator or sub-investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories. These source documents 
include, but are not limited to, laboratory reports and original ECGs. 
14.2.1.
Study Documentation
Source document is defined as any hand written or computer generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, e.g., clinical laboratory reports, clinic notes, drug disbursement log, subject sign 
in sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary and pre-final iterations of a final report are also considered to be source documents, 
e.g., faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard 
copy, final report.
14.2.2.
Case Report Form 
The data collected during the study (except clinical laboratory test results, ECG results, PK 
analyses, Immunogenicity) will be recorded in the subject’s eCRF. The Short-Form Health 

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Survey (SF-36), Health related Quality of Life (EQ-5D-5L), Headache Impact Test (HIT-6), 
Patient Global Impression of Change (PGIC), Most Bothersome Symptom (MBS) and C-SSRS 
will be completed on paper forms and then entered into the EDC system. The study site(s) will 
use an electronic data capture (EDC) system that is compliant with relevant Food and Drug 
Administration (FDA) regulatory requirements per 21 CFR Part 11. Data queries and data 
corrections will be handled through the same system. All transactions within the EDC system are 
fully documented within an electronic audit trail. Each set of completed eCRFs must be reviewed 
after being source verified by the Monitor and electronically signed and dated by the 
Investigator.  
14.3.
Archiving Clinical Trial Records
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the Investigational Product. However, 
these documents should be retained for a longer period if required by applicable legal 
requirements. 
It is the responsibility of the Investigator and clinical trial staff to maintain a comprehensive and 
centralized filing system of all clinical trial-related documentation. This centralized file should 
be available for inspection at any time by the Monitor or Quality Assurance staff for monitoring 
or auditing by Alder and regulatory authorities. Elements of clinical trial documentation should 
include:
x
Subject files containing the completed CRF-supporting source documentation and the 
signed ICF
x
Clinical trial files, containing the protocol with all amendments, the Investigator 
Brochure, copies of all clinical trial documentation, and all correspondence to and 
from the ethics committee and Alder Inc.
x
Pharmacy files, containing the Investigational Product Accountability Records or 
dispensation logs and all clinical trial agent-related correspondence

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14.4.
Good Clinical Practice
The procedures set out in this clinical trial protocol are designed to ensure that Alder and the 
Investigator abide by the principles of the GCP guidelines of the ICH and applicable federal and 
local regulations. The clinical trial also will be conducted in keeping with local legal 
requirements.
14.5.
Informed Consent
Before each subject is admitted to the clinical trial, informed consent will be obtained from the 
subject (or his/her legally authorized representative) according to the regulatory and legal 
requirements of the participating country. The consent forms must be dated and retained by the 
Investigator as part of the clinical trial records. The Investigator will not undertake any 
investigation specifically required for the clinical trial until valid consent has been obtained. The 
terms of the consent and when it was obtained must also be documented in the CRF. Each 
subject will receive a fully-signed copy of each consent form that he/she signs for the clinical 
trial.
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the consent form is revised, it must be reviewed and approved by the appropriate 
ethics committee, and signed by all subjects subsequently screened for the clinical trial as well as 
those currently enrolled in the clinical trial. If a male subject’s partner becomes pregnant during 
the subject’s participation in the trial, the partner will be asked to sign a separate pregnancy 
informed consent form to follow the pregnancy outcome, any complications, and the health of 
the baby.  The pregnancy consent should be obtained at the time the Investigator becomes aware 
of the pregnancy.
14.6.
Protocol Approval and Amendment
Before the start of the clinical trial, the clinical trial protocol and/or other relevant documents 
will be approved by the ethics committee, in accordance with local legal requirements. Alder 
must ensure that all ethical and legal requirements have been met before the first subject is 
screened in the clinical trial.
The procedures outlined in the protocol and eCRFs will be carefully reviewed by the Investigator 
and staff prior to clinical trial initiation to ensure appropriate interpretation and implementation. 

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No deviations from the protocol should be made except in emergency situations where 
alternative treatment is necessary for the protection, proper care, and well-being of subjects.
This protocol is to be followed exactly. To alter the protocol, amendments must be written, and 
approvals must be received from the appropriate personnel and from the ethics committee before 
implementation (if appropriate). Amendments will originate from Alder and will be provided to 
the Investigator for submission to his/her ethics committee for their review and approval prior to 
implementation (if appropriate). It should be noted that when an amendment to a protocol 
substantially alters the clinical trial design or increases potential risk to the clinical trial subject, 
the ICF should be revised and, if applicable, subject’s consent to continue participation should be 
obtained.
Administrative changes may be made without the need for a formal amendment. All amendments 
will be distributed to all protocol recipients, with appropriate instructions.
14.6.1.
Premature Termination of the Clinical Trial
Alder reserves the right to terminate this clinical trial at any time. The FDA or other governing 
national authority may also terminate the clinical trial.
The Investigator may discontinue participation in the trial. If the clinical trial is terminated prior 
to scheduled completion, the Investigator will be notified and given any necessary instructions 
concerning final examinations that are required. If the Investigator, Alder, or the Medical 
Monitor becomes aware of conditions or events that suggest a possible hazard to subjects if the 
clinical trial continues, the clinical trial may be terminated after appropriate consultation between 
the relevant parties. 
14.7.
Confidentiality
All clinical trial findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from Alder.
The anonymity of participating subjects must be maintained. Subjects will be identified on CRFs 
and other documents by their subject number and year of birth date, not by name and in 

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accordance with local requirements. Documents that identify the subject (e.g., the signed 
informed consent) must be maintained in confidence by the Investigator. 
14.8.
Publication Policy
By signing the clinical trial protocol, the Investigator agrees with the use of results of the clinical 
trial for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. If necessary, the authorities will be notified of the 
Investigator's name, address, qualifications, and extent of involvement.
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
with Alder in advance. The information provided in support of or generated as a result of this 
clinical trial is confidential. Any use or reproduction thereof, including but not limited to 
publications or presentations by the Investigator or his/her associates, must be submitted to Alder 
for review and approval in accordance with the provisions contained in the clinical trial 
agreement. All publications must acknowledge the sponsorship of Alder.
All information not previously published concerning ALD403 and Alder operations, including 
but not limited to patent applications, formulas, manufacturing processes, basic scientific data, 
and formulation information, supplied by Alder to the Investigator is considered confidential and 
shall remain the sole property of Alder. The Investigator agrees to use and maintain the 
confidentiality of this information in accordance with the provisions contained in the clinical trial 
agreement.

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15.
APPENDICES
15.1.
Migraine preventive therapies with established or probable efficacy 13, 
14, 15
x
Divalproex sodium
x
Valproic Acid
x
Topiramate
x
Amitriptyline
x
Venlafaxine
x
Flunarizine
x
Cinnarizine
x
Fluoxetine
x
Gabapentin
x
Verapamil
x
Lamotrigine
x
Metoprolol
x
Propranolol
x
Timolol
x
Atenolol
x
Nadolol
x
Bisoprolol
x
Butterbur
x
Feverfew
x
Pizotifen
x
Frovatriptan*
x
Naratriptan*
x
Zolmitriptan*
*only considered as prophylaxis when specifically, used for menstrually-related 
migraine (MRM)
Other drugs for prophylaxis will be considered on a case by case basis.

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15.2.
Columbia-Suicide Severity Rating Scale (C-SSRS) Risk Assessment
15.2.1.
Baseline/Screening Version

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15.2.2.
Since Last Visit Version

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15.3.
Headache Impact Test (HIT-6 v1.0)

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15.4.
Short-Form Health Survey (SF-36 v2.0)

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15.5.
Health Related Quality of Life (EQ-5D-5L)

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15.6.
Patient Global Impression of Change (PGIC)
g

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15.7.
Most Bothersome Symptom (MBS)

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15.8.
The Migraine Disability Assessment (MIDAS)

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15.9.
References
1. Lipton R, Bigal M, Diamond M, Freitag F, Reed M, Stewart W. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology. 2007; 68:343-349.
2. Leonardi M, Steiner TJ, Scher AT, Lipton RB. The global burden of migraine: measuring 
disability in headache disorders with WHO’s classification of functioning, disability and 
health (ICF). J Headache Pain. 2005; 6(6):429-440.
3. Stewart WF, Ricci JA, Chee E, et al. Lost productive work time costs from health 
conditions in the United States: results from the American Productivity Audit J Occup 
Environ Med 2003; 45(12): 1234-1246.
4. Headache Classification Committee of the International Headache Society. The 
International Classification of Headache Disorders, 3rd edition (beta version). 
Cephalalgia. 2013:33(9):629-808.
5. Katsarava, Buse D. Defining differences between episodic and chronic migraine. Curr 
Pain and Headache. 2012; 1:86-92.
6. Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and 
comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol 
Neurosurg Psychiatry. 2010; 81 (4):428-432.
7. Durham PL. CGRP-receptor antagonists—a fresh approach to migraine therapy? N Engl 
J Med. 2004; 350:1073-1075.
8. Cady RJ, Shade CL, Cady RK. Advances in drug development for acute migraine. Drugs. 
2012:72(17):1-19.
9. Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006; 
46(Suppl 1):S3-S8.
10. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers 
migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010; 
30(10):1179-1186.
11. Schmid CW, Konrad M, Schmid DM, et al. Prevalence of medication overuse headache 
in an interdisciplinary pain clinic. Journal of Headache and Pain 2013; 14:4.
12. United States Food and Drug Administration, United States Department of Health and 
Human Services. Guidance for Industry: Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials, Draft Guidance. August 2012. Revision 1. 
13. Esternalik E, Tepper S.  Preventive treatment in migraine and the new US guidelines.  
Neuropsychiatr Dis Treat. 2013; 9; 709-720.
14. Antonaci F, Dumitrache C, De Cillis I, Allena M.  A review of current European 
treatment guidelines for migraine.  J Headache Pain.  2010; 11: 13-19.
15. Pringsheim T, Davenport W, Mackie G, et al. Canadian Headache Society Guideline for 
Migraine Prophylaxis - Section II.  Can J Neurol Sci 2012; 39: Suppl. 2 – S8-28.