A Parallel Group, Double-Blind, Randomized, Placebo Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of ALD403 Administered Intravenously in Patients With Chronic Migraine
Phase: PHASE3
Conditions: Migraine Disorders
Sponsor: Alder Biopharmaceuticals, Inc.

Protocol ALD403-CLIN-011   
Alder BioPharmaceuticals, Inc. 
31-Aug-2017 
 
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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 
A Parallel Group, Double-Blind, Randomized, Placebo 
Controlled Phase 3 Trial to Evaluate the Efficacy and 
Safety of ALD403 Administered Intravenously in 
Patients with Chronic Migraine 
Protocol Number 
ALD403-CLIN-011 
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. 
 
EudraCT No. 
 
 
2016-001306-41 
 
Date of Protocol (original release) 
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
17-Aug-2016 
24-Oct-2016 
20-Mar-2017 
31-Aug-2017 
 
 

Protocol ALD403-CLIN-Ol l 
Alder BioPharmaceuticals, Inc. 
31-Aug-2017 
SIGNATURE PAGE 
Declaration of Sponsor 
Title: A Parallel Group, Double-Blind, Randomized, Placebo Controlled Phase 3 Trial to 
Evaluate the Efficacy and 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. 
VP, Clinical Development 
Alder BioPharmaceuticals, Inc. 
Version No. PR-0001.04 
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Protocol ALD403-CLIN-011  
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31-Aug-2017 
 
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DECLARATION OF THE PRINCIPAL INVESTIGATOR 
 
Title: A Parallel Group, Double-Blind, Randomized, Placebo Controlled Phase 3 Trial to 
Evaluate the Efficacy and 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 
 
 
 
 
 

Protocol ALD403-CLIN-011  
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31-Aug-2017 
 
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1. 
PROTOCOL SYNOPSIS 
Title 
A Parallel Group, Double-Blind, Randomized, Placebo 
Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of 
ALD403 Administered Intravenously in Patients with Chronic 
Migraine 
Sponsor 
Alder BioPharmaceuticals, Inc. 
Investigational Product 
ALD403, a humanized anti-(calcitonin gene-related peptide) 
(CGRP) monoclonal antibody 
Primary Objective 
To evaluate the efficacy of repeat doses of ALD403 administered 
intravenously (IV) compared to placebo in patients with chronic 
migraine. 
Secondary Objectives 
To evaluate the safety of repeat doses of ALD403 administered 
IV compared to placebo in patients with chronic migraine. 
To evaluate the pharmacokinetics (PK) and immunogenicity of 
repeat doses of ALD403 administered IV to patients with chronic 
migraine. 
Methodology 
This will be a parallel group, double-blind, randomized, placebo-
controlled trial. Subjects will be randomized into one of two 
ALD403 dose levels (100 mg or 300 mg) or placebo in a 1:1:1 
ratio. Randomization will be stratified by baseline migraine days 
(<17 and ≥17 days during screening) and prophylactic medication 
use during 3 months prior to screening (prophylactic medication 
use vs. no prophylactic medication use). 
Visits will occur at screening, randomization (on-site or phone), 
Day 0, and Weeks 2, 4, 8, 12, 16, 20, 24, and 32.  Subjects will 
complete the eDiary daily through Week 24.   
Eligible subjects will be randomized 28 to 30 days after the 
screening visit, and treated (first dose) on Day 0, 0-8 days after 
the randomization visit. Treatment includes two infusions of 
ALD403 or placebo administered on Days 0 and 84 (Week 12).  
Subjects will be followed for 20 weeks after the final dose for 
total study duration of approximately 36 weeks, including the 
screening period.   
 
Number of Subjects 
Planned 
Approximately 1050 subjects will be randomized and treated at 
approximately 150 centers in the US and worldwide.  
Subject Selection Criteria 
Males and females between 18 and 65 years of age, inclusive, 
who were diagnosed with migraines at ≤ 50 years of age, and 
have a history of chronic migraine for ≥ 12 months before 
screening.  During the 28 day screening period, subjects must 
complete the headache eDiary 24 out of 28 days and must have 

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headaches occurring on ≥ 15 to ≤ 26 days of which at least 8 
must be migraine days.   
Investigational Product, 
Dose and Schedule 
There will be 3 treatment groups of approximately 350 subjects 
each.  Subjects will receive IV infusions of the assigned 
treatment on Day 0 and on Day 84. 
1. 100 mg ALD403  
2. 300 mg ALD403  
3. Placebo  
Duration of Treatment 
Two doses of ALD403/placebo will be given 12 weeks apart  
Duration of Clinical Trial 
Participation 
The trial participation period will be approximately 36 weeks. 
This will include a 4 week screening period, a 12 week treatment 
period and a 20 week follow-up period.   
Clinical Trial Endpoints 
Primary Efficacy Endpoint: 
• Change in frequency of migraine days (Weeks 1-12) 
 
Key Secondary Endpoints: 
• 75% migraine responder rate (Weeks 1-4) 
• 75% migraine responder rate (Weeks 1-12) 
• 50% migraine responder rate (Weeks 1-12) 
• Percentage of subjects with a migraine on the day after 
dosing 
• Reduction in migraine prevalence from baseline to Week 4 
 
Other Secondary Endpoints:  
 
• Headaches/migraines with acute medication usage 
• Acute migraine medication usage 
• Change in frequency of migraine days (Weeks 1-24) 
• 100% migraine responder rate (Weeks 1-12) 
• Migraine responder rates for time periods other than Weeks 
1-12 
• Change in frequency of migraine days between baseline and 
time periods other than Weeks 1-12 
• Headache responder rates 
• Change in the frequency of headache days 
• Percent change in headache or migraine days   
• Time to first migraine after dosing 
• Headache/migraine hours 
• Headache/migraines with severe intensity 
• Patient Global Impression of Change (PGIC) 
• Short-Form Health Survey (SF-36) 
• Health-Related Quality of Life (EQ-5D-5L) 
• Headache Impact Test (HIT-6) 

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Tertiary Endpoints 
• Headache episodes/migraine attacks 
• Migraine symptom-free days 
• Most Bothersome Symptom (MBS) 
 
Safety Endpoints 
• Adverse events (AEs) and serious adverse events (SAEs) 
• Clinical laboratory assessments 
• Vital signs 
• Electrocardiograms (ECGs)   
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Pharmacokinetic and Immunogenicity Endpoints  
• Free ALD403 plasma concentrations 
• Development of specific anti-ALD403 antibodies 
• Characterization of specific anti-ALD403 antibodies for 
neutralizing activity 
 
Concomitant Medications 
Concomitant medications must be recorded in the Case Report 
Form (CRF).  
Barbiturates and prescription opiates are allowed for ≤ 4 days per 
month through Week 24, provided the subject has been on a 
stable regimen (≤ 4 days per month) for at least 2 months prior to 
screening.   
Any botulinum toxin injections for migraine or for any other 
medical/cosmetic reasons are prohibited within 4 months prior to 
screening and during the study through Week 24. 
Devices, neuromodulation, neurostimulation, or injectable 
therapy (trigger point injections) for headache prophylaxis are 
prohibited 2 months prior to screening and during the study 
through Week 24. 
Monoamine oxidase inhibitors (MAOIs), ketamine, 
methysergide, methylergonovine, and nimesulide are prohibited 
within 3 months prior to screening and during the study through 
Week 24.  
Other medications taken for headache prophylaxis will be 
permitted provided that the dose has been stable for at least 3 
months prior to screening and there are no alterations to their 
regimen through Week 24.   
Sample Size 
1050 subjects will be randomized into 3 treatment groups in a 
balanced ratio (approximately 350/group).  Pair-wise testing of 

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each ALD403 group vs. placebo will be performed using a 5% 
two-sided alpha level.  Three hundred and fifty subjects per 
group provides at least 90% power for the primary endpoint 
assuming a treatment effect of at least 1 day and a common 
standard deviation of 4 days or less.  For the key secondary 75% 
responder rate endpoints 90% power is achieved for the pair-wise 
comparisons, assuming a placebo responder rate of 20%, and an 
ALD403 rate of 31%. 
Statistical Analysis 
Efficacy and safety endpoints will be summarized with 
descriptive statistics. 
Statistical inferential testing of the primary efficacy endpoint and 
key secondary endpoints will be performed while maintaining a 
study wide type-I error rate of two sided 5%.  The primary 
analyses will test for a difference between the active treatment 
groups and placebo in Weeks 1-12, change in frequency of 
migraine days.  The primary analyses will be based on ANCOVA 
model.    The migraine responder rates and percentage of subjects 
with a migraine on the day after dosing will be tested with 
stratified Cochran Mantel Haenszel (CMH) tests. The same 
stratification factors as used in randomization will be used to 
perform these tests. Repeated measures will be used to test for the 
reduction in migraine prevalence from baseline to Week 4.  
The migraine days reported during the initial 28-days of 
screening will be used as baseline.  Following treatment, 
migraine data will be summarized and analyzed in 28 day 
intervals (e.g. Weeks 1-4, 5-8, 9-12).  The change from baseline 
in migraine days for a given 4-week interval will be the 
difference between migraine days in that interval and the 
migraine days during baseline.  The Week 1-12 change from 
baseline measure, for a subject, will be the average of the change 
from baseline results from each of the three intervals. 
A 75% responder, for a given 4-week interval, will be a subject 
with a ≥ 75% reduction in migraine days during that interval.  A 
75% responder over Weeks 1-12 will be a subject who achieves 
average reduction of ≥ 75% over this time period based upon the 
Week 1-12 change from baseline measure.  Subjects who do not 
complete their eDiary will have their missing data imputed.   
Pharmacokinetic Analysis 
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 free 
ALD403 concentrations at the following times:  Day 0 (within 1 
hour before dosing), immediately post-dose (within 15 minutes of 
end of infusion), Weeks 2, 4, 8, 12 (within 1 hour before dosing), 
24, and 32.   

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For subjects receiving placebo, selected samples will be 
analysed.   
Blood specimens will be collected for the detection of anti-
ALD403 antibody, and when appropriate the samples will be 
analysed also for neutralizing anti-ALD403 antibody activity on 
Day 0 (pre-dose within 1 hour before dosing), Weeks 2, 4, 8, 12 
(within 1 hour before dosing), 24, and 32. Subjects who test 
positive for specific anti-ALD403 antibodies at the time of the 
last study visit will be asked to provide additional blood samples 
for immunogenicity testing.  

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2. 
 SCHEDULE OF EVENTS AND ASSESSMENTS  
 
 
Assessment 
Screen 
 
Rand1 
 
28-30 
days 
after 
Screen 
Day 02 
Tx 
 
within  
8 days 
after 
Rand 
Week 2 
Day 14  
-3 days  
Week 4 
Day 28  
± 3 days  
Week 8 
Day 56 
± 3 days 
Week 12 
Day 84  
± 3 days  
Tx 
Week 16 
Day 112 
± 3 days 
Week 20 
Day 140  
± 3 days 
Week 24 
Day 168  
+7 days3 
Week 32 
EOS/ET 
Day 224  
± 7 days 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Headache eDiary Data Review and 
Compliance Check4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Headache eDiary closeout5 
 
 
 
 
 
 
 
 
 
X 
X 
Height and Weight6 
X 
 
X 
 
 
 
X 
 
 
X 
X 
Physical Exam7 
X 
 
X 
 
 
 
X 
 
 
X 
X 
Patient Global Impression of Change 
(PGIC) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Most Bothersome Symptom (MBS) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs8 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
C-SSRS9,10 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG11 
X 
 
X 
 
 
 
X 
 
 
 
X 
Hematology, Chemistry12 
X 
 
X 
 
 
 
X 
 
 
 
X 
Serology (HIV, Hepatitis B and C) 
X 
 
 
 
 
 
 
 
 
 
 
Urine Drugs Abuse Screen 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy (hCG) Test10 
X 
 
X 
 
 
 
X 
 
 
 
X 
Plasma ALD403 (PK)12 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
Serum Anti-ALD403 Ab12 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
SF-36, EQ-5D-5L, and HIT-6 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
AE Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
ALD403/placebo administration13 
 
 
X 
 
 
 
X 
 
 
 
 
Abbreviations: TX: Treatment, Rand: Randomization, EOS/ET: End of Study/Early Termination 
Please refer to next page for footnotes. 

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1 Randomization will occur 28-30 days after the screening visit after eligibility assessments are approved by the Medical Monitor and eligibility, including 
eDiary eligibility criteria, are confirmed by the investigator.  Every effort should be made to conduct an on-site randomization visit; however, a phone visit is 
acceptable in cases where the subject’s schedule will not permit an on-site visit. 
2 Dosing must occur within 8 days after randomization. 
3 Week 24 visit must be done on the target day or seven days after. The visit may not be conducted earlier than the target date. 
4 Headache eDiary distributed at the screening visit. eDiary review and compliance check through Week 24. 
5 eDiary closeout must be performed at Week 24, or at the ET visit while the subject is on site. 
6 Height and weight collected at screening visit. Weight only collected on Day 0 (pre-dose) and at Weeks 12 (pre-dose), 24, and 32 or ET. 
7 Physical exam must be done pre-dose on Day 0 and Week 12. 
8 Vital signs measured pre-dose and within 2 hours post-dose on Days 0 and Week 12. 
9 C-SSRS “Baseline/Screening Version” should be used at screening, and C-SSRS “Since Last Visit Version” should be used on Day 0 (pre-randomization), 
Weeks 2,4, 8, 12 (pre-dose), 16, 20, 24, and 32 or ET. 
10 Inclusion/exclusion criteria review, C-SSRS, and urine pregnancy test must be done prior to dosing on Day 0. C-SSRS and urine pregnancy test must be done 
prior to dosing at Week 12. 
11 Conduct ECG pre-dose, and within 2 hours post dose on Day 0 and Week 12. 
12 Blood draws obtained pre-dose on dosing days (within 1 hour before dosing). On Day 0, draw additional PK immediately post dose (within 15 minutes of end 
of infusion). 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 3 month intervals for up to 6 months. 
13 Subjects must be monitored for at least 2 hours after the dosing completion to assess for the occurrence of adverse events.  Subjects will be requested to stay 
longer than 2 hours after dosing should the investigator determine this is clinically warranted (e.g., subjects should be observed until all AEs are resolved or 
clinically stable). 
 
 
 
 
 

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3. 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ADL 
Activities of Daily Living 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase   
ANCOVA 
AST 
Analysis of Covariance 
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 
IWRS 
Interactive Web Response System 
Kg 
Kilogram 
LLOQ 
Lower Limit of Quantification 
M 
Molarity 
m2 
Meter squared 

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mAb 
MAOI 
Monoclonal antibody 
Monoamine oxidase inhibitor 
MBS 
Most Bothersome Symptom 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
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 
ALDER BIOPHARMACEUTICALS, INC. ...................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
DECLARATION OF THE PRINCIPAL INVESTIGATOR ..........................................................3 
1. 
PROTOCOL SYNOPSIS .............................................................................................4 
2. 
SCHEDULE OF EVENTS AND ASSESSMENTS.....................................................9 
3. 
LIST OF ABBREVIATIONS.....................................................................................11 
4. 
TABLE OF CONTENTS ...........................................................................................13 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Investigational Product ...............................................................................................17 
5.2. 
Background .................................................................................................................17 
5.3. 
Investigational Product ...............................................................................................19 
5.3.1. 
Summary of Nonclinical Studies ................................................................................19 
5.3.2. 
Summary of Clinical Trials ........................................................................................21 
5.3.3. 
Dose Justification ........................................................................................................22 
5.4. 
Risks and Benefits ......................................................................................................22 
5.5. 
Compliance Statement ................................................................................................23 
6. 
OBJECTIVES .............................................................................................................24 
6.1. 
Primary Objective .......................................................................................................24 
6.2. 
Secondary Objectives .................................................................................................24 
7. 
TRIAL DESIGN .........................................................................................................25 
7.1. 
Clinical Trial Endpoints ..............................................................................................25 
7.1.1. 
Primary Efficacy Endpoint .........................................................................................25 
7.1.2. 
Key Secondary Endpoints: .........................................................................................25 
7.1.3. 
Other Secondary Endpoints: .......................................................................................25 
7.1.4. 
Tertiary Endpoints ......................................................................................................26 
7.1.5. 
Safety Endpoints .........................................................................................................26 
7.1.6. 
Pharmacokinetic and Immunogenicity Endpoints ......................................................26 
7.2. 
Clinical Trial Design ...................................................................................................26 
7.3. 
Data Monitoring Committee .......................................................................................27 
7.4. 
Methods to Minimize/Avoid Bias ..............................................................................27 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................28 

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8.1. 
Inclusion Criteria ........................................................................................................28 
8.2. 
Exclusion Criteria .......................................................................................................29 
8.3. 
Registration and Treatment Assignment ....................................................................32 
8.3.1. 
Registration Procedure, Subject Numbering ..............................................................32 
8.3.2. 
Randomization and Treatment Assignment ................................................................32 
8.4. 
Subject Treatment Discontinuation and Early Withdrawal ........................................33 
8.4.1. 
Criteria for Discontinuation from Study Treatment ...................................................33 
8.4.2. 
Criteria for Withdrawal from the Clinical Trial .........................................................33 
8.4.3. 
Timing of Withdrawal ................................................................................................34 
8.4.4. 
Follow-up for Early Withdrawal ................................................................................34 
8.4.5. 
Replacement Policy ....................................................................................................34 
8.4.6. 
Lost to Follow-Up.......................................................................................................34 
9. 
CLINICAL TRIAL TREATMENTS .........................................................................35 
9.1. 
Investigational Product ...............................................................................................35 
9.2. 
Placebo ........................................................................................................................35 
9.3. 
Investigational Product Dosing and Administration ...................................................35 
9.3.1. 
Packaging and Labeling ..............................................................................................36 
9.3.2. 
Blinding ......................................................................................................................36 
9.3.3. 
Storage and Handling of Investigational Product .......................................................36 
9.3.4. 
Accountability and Disposition of Investigational Product ........................................37 
9.4. 
Concomitant Medications ...........................................................................................37 
10. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................39 
10.1. 
Schedule of Assessments ............................................................................................39 
10.2. 
Assessments and Procedures ......................................................................................39 
10.2.1. 
Randomization ............................................................................................................39 
10.2.2. 
Demographics .............................................................................................................39 
10.2.3. 
Medical History ..........................................................................................................39 
10.2.4. 
Physical Examinations ................................................................................................40 
10.2.5. 
Vital Signs ..................................................................................................................40 
10.2.6. 
Questionnaires ............................................................................................................41 
10.2.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................41 
10.2.8. 
Most Bothersome Symptom (MBS) ...........................................................................41 
10.2.9. 
Other Questionnaires ..................................................................................................42 

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10.2.10. 
12-Lead ECG ..............................................................................................................42 
10.2.11. 
Laboratory Samples and Testing ................................................................................42 
10.3. 
eDiary Completion and Compliance Review .............................................................43 
11. 
ASSESSMENT OF SAFETY .....................................................................................45 
11.1. 
Adverse Events ...........................................................................................................45 
11.1.1. 
Definitions ..................................................................................................................45 
11.1.2. 
Assessment of Adverse Events ...................................................................................45 
11.1.3. 
Recording Adverse Events .........................................................................................47 
11.1.4. 
Reporting Serious Adverse Events .............................................................................48 
11.1.5. 
Unexpected and Related Serious Adverse Events ......................................................49 
11.1.6. 
Follow-up of Adverse Events .....................................................................................50 
11.1.7. 
Clinical Laboratory Tests ...........................................................................................50 
11.1.8. 
Pregnancy ...................................................................................................................50 
11.1.9. 
Suicidal Ideation and Behavior ...................................................................................51 
11.2. 
Management of Reactions to ALD403 .......................................................................51 
12. 
ASSESSMENT OF EFFICACY, PHARMACOKINETICS, AND 
IMMUNOGENICITY ................................................................................................53 
12.1. 
Efficacy .......................................................................................................................53 
12.1.1. 
eDiary .........................................................................................................................53 
12.1.2. 
Endpoints ....................................................................................................................53 
12.2. 
Pharmacokinetics ........................................................................................................57 
12.3. 
Immunogenicity ..........................................................................................................57 
13. 
STATISTICAL CONSIDERATIONS .......................................................................59 
13.1. 
Decision Rule ..............................................................................................................59 
13.2. 
Sample Size ................................................................................................................59 
13.3. 
General Considerations ...............................................................................................59 
13.3.1. 
Definition of Baseline .................................................................................................59 
13.3.2. 
Handling of Missing Data ...........................................................................................59 
13.3.3. 
Populations to be Analyzed ........................................................................................60 
13.4. 
Statistical Methods ......................................................................................................60 
13.4.1. 
Subject Disposition, Demographics and Baseline Characteristics .............................61 
13.4.2. 
Efficacy Analyses .......................................................................................................61 
13.4.3. 
Analysis of Drug Concentrations ................................................................................63 

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13.4.4. 
Safety Analyses ..........................................................................................................63 
14. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS .....................................65 
14.1. 
Data Quality Assurance ..............................................................................................65 
14.2. 
Case Report Forms and Source Documents ...............................................................65 
14.3. 
Study Documentation .................................................................................................65 
14.4. 
Data Collection and Electronic Data Capture (EDC) .................................................65 
14.5. 
Archiving Clinical Trial Records ................................................................................66 
14.6. 
Good Clinical Practice ................................................................................................66 
14.7. 
Informed Consent .......................................................................................................67 
14.8. 
Protocol Approval and Amendment ...........................................................................67 
14.8.1. 
Premature Termination of the Clinical Trial ..............................................................68 
14.9. 
Confidentiality ............................................................................................................68 
14.10. 
Publication Policy .......................................................................................................68 
15. 
APPENDICES ............................................................................................................70 
15.1. 
Migraine preventive therapies with established or probable efficacy17,18,19 ...............70 
15.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Risk Assessment ......................71 
15.2.1. 
Baseline/Screening Version ........................................................................................71 
15.2.2. 
Since Last Visit Version .............................................................................................74 
15.3. 
Headache Impact Test (HIT-6 v1.0) ...........................................................................77 
15.4. 
Short-Form Health Survey (SF-36 v2.0) ....................................................................78 
15.5. 
Health Related Quality of Life (EQ-5D-5L) ..............................................................82 
15.6. 
Patient Global Impression of Change (PGIC) ............................................................85 
15.7. 
Most Bothersome Symptom (MBS) ...........................................................................86 
15.8. 
References ...................................................................................................................87 
 
 
 

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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 BioPharmaceuticals, Inc., 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 

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releases various vasoactive peptides generating peripheral sensitization of trigeminal and upper 
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 month to years. Acute treatment while generally quite effective can 
actually 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-α-CGRP with an affinity of 1.5E-11 M and human-β-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). 
ALD403 is a genetically engineered humanized IgG1 antibody that binds to α- and β- forms of 
human, cynomolgus monkey, and rat CGRP. The amino acid sequence for α- and β-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 
indistinguishable. Rat α-CGRP is one amino acid different from human α-CGRP and rat β-CGRP 
is 3 amino acids different from human β-CGRP. Based on comparable binding affinity and in 
vitro potency for rat, cynomolgus monkey, and human α- and β-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 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 μg/mL; mean AUC (0-2wk) of 1,610,000/904,000 μg·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 
findings were observed and included (in order of decreasing incidence) minimal and/or mild 

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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 
and Dosed with 
ALD403 
Number of 
Subjects 
Randomized 
and Dosed 
with 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-0052 
(completed) 
Phase 2 
Safety & Efficacy Chronic Migraine 
616 
495 
121 
ALD403-CLIN-0062 
(ongoing) 
Phase 3 
Safety & Efficacy 
Frequent 
Episodic 
Migraine 
888 
666 
222 
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-010 
(completed) 
Phase 1 
Safety 
Healthy 
Volunteer 
24 
16 
8 
ALD403-CLIN-0123 
(ongoing) 
Phase 1 
Safety 
Type 1 Diabetic 
(T1DM) 
21  
14 
7 
ALD403-CLIN-0133 
(ongoing) 
Phase 3 
Safety, Open 
Label 
Chronic Migraine 
128 
128 
 
1 ALD403-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. 
3 Enrollment in this open label 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 
ALD403 doses of 100 and 300 mg met the primary efficacy endpoint through Week 12 post-
treatment across a number of measures and had an acceptable safety profile in a prior phase 2 
trial, ALD403-CLIN-005. Therefore, these doses were selected for this study to be administered 
every 12 weeks.   
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.  
• 
Healthy volunteer trials have included limited dosing, short duration of follow up and 
have not include long term follow-up.  
• 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. 
The safety findings to date indicate that ALD403 Injection is well tolerated, and demonstrates a 
favorable benefit-risk profile based on review of nonclinical, clinical, and scientific literature 
data. 

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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. 
Primary Objective 
The primary objective is: 
To evaluate the efficacy of repeat doses of ALD403 administered IV compared to placebo in 
patients with chronic migraine. 
6.2. 
Secondary Objectives 
The secondary objectives include the following: 
• To evaluate the safety of repeat doses of ALD403 administered IV compared to placebo in 
patients with chronic migraine. 
• To evaluate the pharmacokinetics (PK) and immunogenicity of repeat doses of ALD403 
administered IV to patients with chronic migraine. 
 
 
 
 
 
 
 
 
 
 
 
 

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7. 
TRIAL DESIGN 
7.1. 
Clinical Trial Endpoints 
Detail regarding the clinical trial endpoints and their derivation can be found in Section 12.1. 
Migraine headaches are defined as migraines as outlined in the International Headache Society 
(IHS) International Classification of Headache Disorders (ICHD, 3rd edition, beta version 2013), 
Section 1.3.4 The presence or absence of aura will not impact the classification of a headache as 
a migraine.  
7.1.1. 
Primary Efficacy Endpoint 
• Change in frequency of migraine days (Weeks 1-12) 
7.1.2. 
Key Secondary Endpoints: 
• 75% migraine responder rate (Weeks 1-4) 
• 75% migraine responder rate (Weeks 1-12) 
• 50% migraine responder rate (Weeks 1-12) 
• Percentage of subjects with a migraine on the day after dosing 
• Reduction in migraine prevalence from baseline to Week 4 
7.1.3. 
Other Secondary Endpoints:  
• Headaches/migraines with acute medication usage 
• Acute migraine medication usage 
• Change in frequency of migraine days (Weeks 1-24) 
• 100% migraine responder rate (Weeks 1-12) 
• Migraine responder rates for time periods other than Weeks 1-12 
• Change in frequency of migraine days between baseline and time periods other 
than Weeks 1-12 
• Headache responder rates 
• Change in the frequency of headache days 
• Percent change in headache or migraine days   
• Time to first migraine after dosing 
• Headache/migraine hours 

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• Headache/migraines with severe intensity 
• Patient Global Impression of Change (PGIC) 
• Short-Form Health Survey (SF-36) 
• Health-Related Quality of Life (EQ-5D-5L) 
• Headache Impact Test (HIT-6) 
7.1.4. 
Tertiary Endpoints 
• Headache episodes/migraine attacks 
• Migraine symptom-free days 
• Most Bothersome Symptom (MBS) 
7.1.5. 
Safety Endpoints 
• Adverse events (AEs) and serious adverse events (SAEs) 
• Clinical laboratory assessments 
• Vital signs 
• Electrocardiograms (ECGs)   
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
7.1.6. 
Pharmacokinetic and Immunogenicity Endpoints  
• Free ALD403 plasma concentrations 
• Development of specific anti-ALD403 antibodies 
• Characterization of specific anti-ALD403 antibodies for neutralizing activity 
7.2. 
Clinical Trial Design 
This is a parallel group, double-blind, randomized, placebo-controlled trial of two infusions of 
ALD403 or placebo in patients with chronic migraine.  Subjects who provide informed consent 
will be evaluated for eligibility based upon the inclusion and exclusion criteria.  
Eligible subjects will be randomized 28-30 days after the screening visit and treated (first dose) 
on Day 0, within 8 days after the randomization visit. Treatment includes two infusions of 
ALD403 or placebo administered on Days 0 and 84 (Week 12).  Subjects will be followed for 20 
weeks after the final dose for total study duration of approximately 36 weeks, including the 
screening period.   

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Approximately 1050 subjects will be randomized and treated. Efficacy, safety, pharmacokinetic, 
and immunogenicity assessments will be conducted according to the Schedule of Events 
presented in Section 2.   
7.3. 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) of qualified members will be formed to review trial data 
generated during the clinical trial. These members will not be otherwise affiliated with the 
Sponsor, and will not be connected with management of the clinical trial.  
The primary focus of the DMC will be the safety of the clinical trial subjects. Based on the 
reviews and assessments of the data, the DMC will inform the Sponsor of any safety concerns 
and provide recommendations about stopping, modifying, or continuing the clinical trial. The 
DMC may also advise the Sponsor on the validity of continuing the trial and the scientific merit 
of the clinical trial.  The DMC is not tasked with stopping the study early for efficacy or futility.  
DMC reviews will be conducted periodically throughout the study as outlined in the DMC 
Charter. 
7.4. 
Methods to Minimize/Avoid Bias 
To minimize bias, this clinical trial is randomized, double-blinded, and placebo controlled.  At 
the point of infusion, there are no obvious differences between ALD403 and placebo, and there 
are no known ALD403-specific safety or tolerability signals that could potentially unblind 
subjects and clinical trial staff.  ALD403 is expected to have a fairly substantial impact on 
migraine frequency; however, the placebo effect in migraine studies is also reasonably large. 
Therefore, reduction in migraines is insufficient to deduce treatment assignment.  
 
 
 
 

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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, understand, and sign the Informed Consent Form (ICF) and 
Assent Form for the clinical trial approved by the Investigator’s local Review Board or 
a central Institutional Review Board (IRB) or Ethics Committee (EC). 
2. Has adequate venous access for administration of investigational product and collection 
of blood samples. 
3. Male or female 18-65 years of age, inclusive, at time of informed consent. 
4. Diagnosis of migraine at ≤ 50 years of age with history of chronic migraine ≥ 1 year 
prior to screening. 
5. Prescription or over-the-counter medication for acute and/or prophylactic treatment of 
migraine has been prescribed or recommended by a healthcare professional. 
6. During the 28 day screening period, must have ≥ 15 to ≤ 26 headache days, of which ≥ 
8 days were assessed as migraine days as documented in the eDiary (ICHD-III beta 
version, 2013 Section 1.34). 
7. Women of child-bearing potential, and males with partners of child-bearing potential, 
must agree to use adequate contraception for the duration of the study (from screening 
through Week 32) and for 6 months after the last dose of study drug.    The following 
types of contraception are considered adequate provided they are locally authorized for 
use: 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.  
8. Any hormonal therapy (e.g., contraceptives, hormone replacement therapy) use is stable 
and ongoing for at least 3 months prior to screening. 

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9. Willing, committed, and able to comply with scheduled clinic visits and complete all 
trial-related procedures. 
10. Headache eDiary was completed on at least 24 of the 28 days prior to randomization. 
11. Any prophylactic use of medications for headaches must be stable for at least 3 months 
prior to screening. 
12. Limited use of barbiturates (including Fiorinal®, Fioricet®, or any other combination 
containing butalbital) or prescription opiates (including single ingredient or 
combinations containing opiates, opioids, tramadol or tapentadol) by maintaining a 
stable dose for 2 months prior to screening and dosing is not expected to exceed 4 days 
per month through Week 24.   
13. Subject agrees not to post any personal medical data or information related to the trial 
on any website or social media site (e.g., Facebook, Twitter) during the trial. 
14. Subject is willing to complete the daily eDiary for the duration of the study and agrees 
to use the eDiary devices for the sole purpose of the ALD403-CLIN-011 study without 
alteration. 
8.2. 
Exclusion Criteria 
  A subject who meets any of the following criteria will be excluded from the trial: 
1. Confounding and clinically significant pain syndromes (e.g. fibromyalgia, chronic low 
back pain, complex regional pain syndrome).  
2. 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.  
3. Diagnosis of acute or active temporomandibular disorders (TMD).  
4. History or diagnosis of chronic tension-type headache, hypnic headache, cluster 
headache, hemicrania continua, new daily persistent headache, or unusual migraine 
subtypes such as hemiplegic migraine (sporadic and familial), ophthalmoplegic 
migraine and migraine with neurological accompaniments that are not typical of 
migraine aura (e.g., diplopia, altered consciousness, or long duration).  

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5. Any use of approved devices, neuromodulation, neurostimulation or injectable therapy 
(trigger point injections, extracranial nerve blocks, facet joint injections) are prohibited 
2 months prior to screening and during the screening period. 
6. Any use of botulinum toxin for migraine or for any other medical/cosmetic reasons 
requiring injections within 4 months prior to screening and during the screening period. 
7. Any use of monoamine oxidase inhibitors (MAOIs), ketamine, methysergide, 
methylergonovine, or nimesulide within 3 months prior to screening or during the 
screening period. 
8. Have present or previous malignancies, except: 
• Squamous or basal skin cell carcinoma with excision without evidence of 
recurrence 
• Malignancy ≥ 10 years since diagnosis/treatment without evidence of recurrence 
9. Subject with known history or evidence of arteriosclerosis, cardiomyopathy, coronary 
artery disease, serious heart rhythm abnormalities, cerebrovascular disease, diabetes, 
Raynaud’s disease, hereditary fructose intolerance, life-threatening allergy (e.g., 
anaphylaxis), or any active, progressive, or unstable cardiovascular, neurological, or 
autoimmune disorder.  If questions arise, the Investigator should contact the Medical 
Monitor for guidance.   
10. Clinically significant abnormal ECG during the screening period or on Day 0. 
11. Any clinically significant concurrent medical condition or clinically significant 
laboratory abnormality during the screening period or on Day 0.  
12. Body Mass Index (BMI) ≥ 39 kg/m2 at screening. 
13. 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-controlled for ≥ 6 months prior to screening is 
allowed.   
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 

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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), have had any suicidal behavior in the past 5 years (i.e., preparatory acts or 
behavior), or have 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: F10-1912 
16. Pregnant, breastfeeding, or planning to become pregnant during the trial. 
17. Receipt of any experimental, unregistered therapy (within or outside a clinical trial) 
within 30 days or 5 plasma half-lives (whichever is longer) before screening. 
18. Receipt of any monoclonal antibody treatment (within or outside a clinical trial) within 
6 months before screening. 
19. Previously dosed with ALD403 or any monoclonal antibody targeting the CGRP 
pathway. 
20. Planned or current participation in any other clinical trial during the duration of this 
clinical trial, or within 6 months before screening. 
21. Recent or planned surgery, requiring general anesthesia, within 8 weeks prior to 
screening and during the duration of this clinical trial. 
22. Positive for HIV, hepatitis B surface antigen, or hepatitis C antibody at screening. 
23. Any condition that, in the opinion of the Investigator, would make the subject 
unsuitable for the clinical trial. 
24. Employees of the Sponsor, CRO, or any clinical trial site involved in this trial and their 
immediate family members (i.e., parents, spouse, siblings, children).  
 
 

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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.   
8.3.2. 
Randomization and Treatment Assignment 
Randomization will occur 28-30 days after the screening visit after eligibility assessments are 
approved by the Medical Monitor and eligibility, including eDiary criteria, are reconfirmed by 
the investigator.  
Every effort should be made to conduct an on-site randomization visit, however a phone visit is 
acceptable in cases where the subject’s schedule will not permit an on-site visit. Sites will 
complete randomization in IWRS, and the randomization assignment will be obtained by the 
clinical trial site’s unblinded pharmacist or designee.  Subjects will be randomized in equal ratios 
to one of the treatment groups.  Stratified permuted block randomization will be used. 
Stratification will be by migraine days during the screening period (<17 days vs. ≥17 days) and 
prophylactic medication use during the 3 months prior to screening (prophylactic medication use 
vs. no prophylactic medication use).  
Prophylactic medication use for migraine will be determined at screening based upon the 
subjects’ medical history.  Stratification for prophylactic medication use will be defined as any 
migraine preventive therapies listed in Appendix 15.1 that have been taken as a stable regimen 
for 3 months prior to screening.  Use of other medications taken for migraine prophylaxis that 
are not listed in Appendix 15.1 will not be considered when determining stratification by 
prophylactic medication use.   
Randomized subjects who terminate their clinical trial participation for any reason, regardless of 
whether Investigational Product was taken or not, will retain their randomization assignment and 
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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: 
• Pregnancy 
• 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: 
• Adverse Event 
• Subject decision 
• Investigator decision  
• Termination of the study by the Sponsor 
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 Sponsor 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: 
• 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. 
• Termination of the trial by the Sponsor 
• Investigator decision 
• Lost to follow-up 

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The reason for withdrawal and the date of withdrawal must be recorded on the CRF. 
8.4.3. 
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. 
8.4.4. 
Follow-up for Early Withdrawal 
Subjects who wish to withdraw their consent from study participation 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 randomization but do not receive study treatment may 
discontinue the study without any further procedures. 
8.4.5. 
Replacement Policy 
Subjects who are withdrawn from the clinical trial after randomization will not be replaced, 
including subjects who withdraw between randomization and treatment.  However, the target 
sample size is based upon the number of subjects randomized and treated. 
8.4.6. 
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 BioPharmaceuticals, Inc., 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.  Those subjects randomized to the ALD403 treatment group will 
receive an IV infusion of ALD403 Injection in 100 mL of 0.9% saline.   
9.2. 
Placebo 
Placebo will be supplied as a single-use preservative-free solution in a 2-mL Type I glass vial 
formulated with the same excipients as ALD403, without the active ingredient. Those subjects 
randomized to placebo will receive an IV infusion Placebo in 100 mL of 0.9% saline. 
9.3. 
Investigational Product Dosing and Administration 
The pharmacist or designee responsible for receiving, storing, preparing and dispensing ALD403 
and placebo IV infusions will be unblinded and will not be responsible for other aspects of the 
clinical trial where blinding is necessary. Dosing must occur within 8 days after randomization. 
Doses of ALD403 or placebo (total volume of 100 mL) will be administered IV over a period of 
30 (+15) minutes on Day 0 and Week 12 (Day 84 ±3 days) by the blinded 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 and has no other clinically 
significant findings on Day 0, dosing may occur if it does not compromise the safety of the 
subject in the judgment of the Investigator.  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 post-
dose.  The Investigator or sub-investigator must be immediately available during the infusion and 
for at least 2 hours post-dose to assess each subject for the occurrence of adverse events.  
Subjects will be requested to stay longer than 2 hours after dosing should the investigator 
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or clinically stable).  The timeframe for the post-dose observation period must be documented in 
the source record. 
Further instructions on preparation and procedures associated with administering the IV can be 
found in the Pharmacy Manual. 
9.3.1. 
Packaging and Labeling 
Before the shipment to the investigative sites, Investigational Product (IP) will be labeled with 
information required by regulatory agencies, such as a statement that it is limited to 
investigational use. Investigational Product to be administered to the subject will be labeled by 
the site after dose preparation by the unblinded pharmacist or designee in a manner that protects 
blinding. 
9.3.2. 
Blinding 
This clinical trial is double-blinded, meaning the subjects and site personnel are blinded to 
treatment assignment, except for the clinical trial site’s unblinded pharmacist or designee. The 
study site must have a written plan in place to ensure blinding is adequately maintained for the 
study.  If the blind is broken, the date, time, and reason must be recorded. The blind should only 
be broken for reasons in which knowledge of the treatment assignment is critical to the 
management of subject safety. The Principal Investigator will report any cases of unblinding to 
the Sponsor within 24 hours of the incident.  
9.3.3. 
Storage and Handling of Investigational Product 
Investigational Product/Placebo 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 the Investigational Product 
and Placebo in a securely locked, substantially constructed cabinet or other securely locked, 
substantially constructed enclosure, access to which is limited to maintain blind, prevent theft or 
diversion of the substance into illegal channels of distribution. 

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9.3.4. 
Accountability and Disposition of Investigational Product 
The Investigator is responsible for maintaining accurate Investigational Product accountability 
records throughout the clinical trial. The site must maintain an Investigational Product 
Accountability Log as instructed in the Pharmacy Manual.  Where more than one secure area is 
being used for storage at a site, all movement of Investigational Product 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 Investigational Product shipment is a form listing lot numbers and quantity 
shipped. The Investigator, responsible pharmacist, or designee, will sign and return to Alder 
BioPharmaceuticals, Inc., 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 Investigational Product. 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 BioPharmaceuticals, Inc. directive. 
Destruction must be in accordance with local regulations for the product type.   
If the clinical trial is terminated, suspended, discontinued, or completed, the Investigator or 
designee shall return the unused supplies to the Sponsor or designee, or otherwise provide for 
disposition of the unused supplies (as authorized by the Sponsor).  
9.4. 
Concomitant Medications 
Any concomitant therapy used from the time the subject signs the informed consent form 
through Week 32 must be recorded on the eCRF, 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.  
The following medications are restricted through Week 24: 
• Barbiturates and prescription opiates are allowed for ≤ 4 days per month through Week 
24, provided the subject has been on a stable regimen (≤ 4 days per month) for at least 2 
months prior to screening.   

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• Any botulinum toxin injections for migraine or for any other medical/cosmetic reasons 
are prohibited within 4 months prior to screening and during the trial through Week 24. 
• Devices, neuromodulation, neurostimulation, or injectable therapy (trigger point 
injections) for headache prophylaxis are prohibited 2 months prior to screening and 
during the trial through Week 24. 
• Monoamine oxidase inhibitors (MAOIs), ketamine, methysergide, methylergonovine, and 
nimesulide are prohibited within 3 months prior to screening and during the trial through 
Week 24. 
Any hormonal therapy (e.g., contraceptives, hormone replacement therapy) use must be stable 
for 3 months prior to screening and remain stable during the trial through Week 32.  
Medications taken for headache prophylaxis will be permitted provided that the dose has been 
stable for at least 3 months prior to screening and there are no alterations to their regimen 
through Week 24.  In general, changes to prophylactic headache medications during the trial are 
not allowed through Week 24.  At the discretion of the Investigator, on a case by case basis, 
changes to the regimen that might be clinically warranted may be made prior to Week 24 after 
consulting with the Medical Monitor and obtaining approval. 
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 Investigator should reevaluate the patient’s risk factors 
relative to the prescribing information for both prophylactic and acute treatments that the patient 
is using, and judge that the use of these medications continues to be considered safe. 

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10. 
STUDY ASSESSMENTS AND PROCEDURES 
10.1. 
Schedule of Assessments 
Assessment and procedures at each visit are summarized in Section 2 - Schedule of Events and 
Assessments.  
10.2. 
Assessments and Procedures 
10.2.1. 
Randomization 
Randomization must occur after the subject completes the 28-day eDiary screening period. Every 
effort should be made to conduct an onsite randomization visit; however, a phone visit is 
acceptable in cases where the subject’s schedule will not permit an onsite visit.   
All subjects will be randomized via the IWRS (Interactive Web Response System) after the 
following:   
• Eligibility has been approved by the Medical Monitor 
• Review of all inclusion/exclusion criteria to confirm subject continues to meet 
inclusion/exclusion criteria. 
• Verification that subject meets eDiary-related eligibility criteria as calculated within the 
eDiary portal. 
• Subject confirms continued interest in participating in the study. 
10.2.2. 
Demographics 
The year of birth, age, sex, ethnicity, race, and how the subject was recruited to the study will be 
collected in source records and in the CRF.   
10.2.3. 
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 

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the subject is not a current or past user of a prescribed or over-the-counter medication for 
migraine, the Medical Monitor will 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. 
10.2.4. 
Physical Examinations 
Physical examinations will be performed at the times noted in the Schedule of Events and 
Assessments 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 physical examination at the screening visit will be comprehensive and appropriate to 
determine the overall physical health of each subject. Examination of the genitourinary system 
and rectum may be deferred by the Investigator if the subject’s related medical history and 
review of systems are negative.  For all other visits that call for a physical examination, the body 
systems examined will be at the discretion of the Investigator.   
Each physical examination will include weight measurement.  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. 
10.2.5. 
Vital Signs 
Vital signs, including blood pressure (BP) and pulse, will be measured at the time points 
specified in the Schedule of Events and Assessments in Section 2. 
When measuring vital signs, the subject should be seated comfortably, with back supported and 
rested for 5 minutes before obtaining vital signs.  Blood pressure may be repeated to confirm 
measurement.  
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 

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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.   
10.2.6. 
Questionnaires 
Questionnaires should be administered to subjects in the order listed below.  On Day 0 and Week 
12, all questionnaires should be administered prior to dosing.   
Protocol number, subject number and date 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. 
10.2.7. 
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 and Assessments in Section 2.  The C-SSRS must be 
administered prior to dosing at dosing visits (Day 0 and Week 12). 
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. 
10.2.8. 
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 as specified in the Schedule of Events and Assessments in 
Section 2. 
 
 

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10.2.9. 
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.     
• Patient Global Impression of Change (PGIC) 
• Short-Form Health Survey (SF-36) 
• Health-Related Quality of Life (EQ-5D-5L) 
• Headache Impact Test (HIT-6) 
10.2.10. 
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 and Assessments in Section 2.  On Day 0 and at Week 12, 
ECG must be performed pre-dose, and within 2 hours post-dose. ECG data will be transmitted 
and read centrally by a cardiologist; however, the Investigator must review the ECG prior to 
dosing and ensure there are no clinically significant abnormalities prior to dosing.   In addition, 
all confirmed (i.e., centrally-read) ECGs will be reviewed by the Investigator and evaluated for 
clinical significance in a timely manner.   
All ECGs are expected to be performed on the ECG device provided to the site by the trial 
Sponsor.  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.  If a local ECG device 
is used, a paper ECG must be submitted to the ECG vendor for central reading.  All technical 
issues must be reported immediately to the ECG vendor help desk. 
10.2.11. 
Laboratory Samples and Testing 
10.2.11.1. Urine Drug Screening 
Drugs of abuse screening test 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.  If a urine drug 
screen is positive and there is no medical record documentation of prescribed medications to 
explain the result, the subject should be considered for exclusion from the study.   Questions 
regarding the eligibility can be addressed with the Medical Monitor. 

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10.2.11.2. 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 Assessments, Section 2.  On Day 0 and 
at Week 12, urine pregnancy test 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. 
10.2.11.3. 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 and Assessments in Section 2.  Clinical laboratory tests performed are listed 
in Section 11.1.7. 
All clinical laboratory blood 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.   
10.2.11.4. Pharmacokinetic and Immunogenicity Sampling 
Blood samples will be collected for the analysis of plasma PK of ALD403 and for determination 
of anti-ALD403 antibodies in serum (immunogenicity) at specified time points in the Schedule 
of Events and Assessment in Section 2.  All samples will be initially processed, stored, and 
shipped as specified in the Laboratory Manual. 
10.3. 
eDiary Completion and Compliance Review 
The subject will be instructed to complete an electronic diary (eDiary) daily from screening 
through Week 24. 
The eDiary will be distributed to each subject at the screening visit after subject training on 
eDiary use by site staff.  The day of eDiary distribution will start the 28 day eDiary screening 

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period.  The subject will record information daily regarding headache characteristics, severity, 
and length.  During the screening period, an eDiary Eligibility Report will summarize baseline 
headache and migraine days and eDiary compliance. The headache and compliance data from the 
eDiary will also be made available to the clinical site for review on a regular basis via the eDiary 
system portal.   
Subject eligibility will be confirmed prior to randomization.  Any subject found to be ineligible 
for the study during the screening period or prior to randomization or dosing will not be 
randomized or dosed.  
Site staff will monitor each subjects eDiary compliance on an ongoing basis through Week 24, 
and will counsel subjects as needed on the on the importance of completing the eDiary daily.  All 
follow-up with subjects regarding eDiary compliance should be documented in the source 
records. 
During the Week 24 visit, or Early Termination visit if subject discontinues prior to Week 24, 
eDiary closeout must be performed while the subject is on site. 
 
 
 
 
 
 
 
 
 
 
 

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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: 
• 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. 
• 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.   
Pre-existing medical conditions of clinical significance must be included in the subject’s medical 
history and recorded on the medical history eCRF page.  

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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 Investigational Product, as outlined 
below. 
Seriousness 
An adverse event or suspected adverse event is considered serious if in the view of either the 
Investigator or Sponsor, it results in; 
• Death 
• 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) 
• Inpatient hospitalization or prolonged existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.  
• Congenital anomaly/ birth defect 
• 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: 
• A social hospitalization (i.e., hospitalizations for pre-admissions not due to an acute 
medical issue) is not considered an SAE 
• Hospitalization is considered a greater than 24 hour hospital admission. 
Severity 
The severity of an AE will be graded as follows: 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 

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• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). 
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
Relationship to Investigational Product 
The Investigator is required to assess the causality/relationship between each AE and the 
Investigational Product 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 Investigational Product 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 Investigational 
Product (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 Investigational Product.  
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 the Investigational Product.  
SAE Notification Form should be used to report any related SAEs which occur after the end of 
the clinical trial.   

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Adverse events (AEs) should be recorded on the AE eCRF, whether believed by the Investigator 
to be related or not related to the Investigational Product.  
AE reporting should contain: 
• A brief description of the event 
• Date of onset  
• Date of resolution 
• Severity 
• Actions taken or treatment required  
• Relationship to Investigational Product  
• Outcome  
• 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 the 
Investigational Product or not, must be reported within 24 hours of awareness or knowledge of 
the event.  The 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: 
• Sender of report (name, address of Investigator) 
• Subject identification (screening/randomization number, initials, NOT subject name) 
• Protocol number 

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• Description of SAE (e.g., event term) 
• Seriousness criteria 
• 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.  The Sponsor or designee will be responsible for information processing and reporting in 
accordance with applicable local and regulatory requirements.  
The Sponsor 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: 
• Are not previously reported as associated with ALD403, as referenced in the 
Investigator’s Brochure. 
• 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. 
The Sponsor or 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. 

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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 Investigational 
Product or may have been pregnant at the time of Investigational Product exposure, or the 
partner of a male subject becomes pregnant following administration of Investigational Product, 
the pregnancy must be reported to the Sponsor within five business days of the Investigator 
becoming aware of the pregnancy.  Pregnancy information will be reported to the Sponsor 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 study completion of the trial. 
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 the Sponsor 
regarding: 
• The course of the pregnancy including perinatal and neonatal outcome, premature 
termination of the pregnancy, or miscarriage  
• Offspring information including birth weight and birth defects (if any)  
 

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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.13  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 of 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.   
Should a medical condition arise that the Investigator believes is related to the Investigational 
Product, clinical judgment should be used to provide the appropriate response including the 
consideration of discontinuation of Investigational Product. Any events believed to be potential 
allergic reactions should be discussed with the Medical Monitor. 
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, per the laboratory 
manual, at the time of the event and again at the next scheduled visit.  This assessment includes 
serum histamine, serum tryptase, immunoglobulin E, and complement components.  Subjects 

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who have experienced a potential significant allergic reaction after administration of 
Investigational Product should not receive subsequent doses.  
Whether maintained in a “formal crash cart” or separately, the following is a requirement at the 
site: 
• CPR certification by site staff performing study assessments 
• Automated external defibrillator (AED) 
• 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 EFFICACY, PHARMACOKINETICS, AND 
IMMUNOGENICITY  
12.1. 
Efficacy 
12.1.1. 
eDiary 
Subjects will complete a daily headache eDiary from the time of screening to Week 24.  The 
eDiary should be completed each trial day whether or not the subject had a headache. These 
daily entries record if the subject took acute migraine medication on that day.  The eDiary data 
from the 28 days following screening visit will be used to determine eligibility criteria, and the 
baseline migraine and headache results.   
12.1.2. 
Endpoints   
Headache episodes will be self-reported by the subject.  An episode is a single headache event 
that the subject reported as having a start and an end and which lasts at least 30 minutes.  The 
term headache will encompass both headaches and migraine headaches.  The migraine and 
headache endpoints will be summarized in 4-week intervals.  Specifically, migraine and 
headache endpoints will be summarized for the 4-week intervals: Weeks 1-4, 5-8, 9-12,…21-24, 
the 12-week intervals: Weeks 1-12, 13-24, and the 24-week interval: Weeks 1-24. 
Migraine Day  
A migraine day is defined as any day with a headache that meets the chronic migraine definition 
as outlined in the International Headache Society (IHS) International Classification of Headache 
Disorders (ICHD, 3rd edition, beta version 2013), Section 1.3 with diagnostic criteria C limited to 
items 1 and 3.4  Criteria C defines what characteristics must be present for a headache to be 
considered a migraine.  These characteristics define a migraine as a self-reported headache that: 
1. Lasted  
a. 4 hours or more or  
b. 30 minutes to 4 hours, and believed by the subject to be a migraine that was 
relieved by medication 
2. Had at least 2 of the following:  
a. Unilateral location 
b. Pulsating quality 

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c. Moderate or severe pain intensity 
d. Aggravation by or causing avoidance of routine physical activity 
3. Had at least 1 of the following: 
a. Nausea and/or vomiting 
b. Photophobia and phonophobia 
Frequency, Change and Percent Change of Migraine Days/Headache Days 
The frequency of migraine days is the number of migraine days within four week intervals and 
the average four week frequency in twelve and twenty-four week intervals.  Change from 
baseline is the difference in frequency between baseline and the counts within these four week 
intervals.  The 12 and 24 week change is the difference in the frequency between baseline and 
the average of the, 4 week intervals.  The percent change is 100 times the ratio of the change and 
the baseline frequency.  Similar measures will be produced based upon headache frequency. 
Migraine/Headache Responder Rate 
Three responder rates will be utilized: 50%, 75% and 100%.  A responder is a subject who 
achieves a ≥50% reduction, ≥75% reduction, or 100% reduction in migraine days, respectively. 
These reductions will be evaluated by comparing the baseline frequency of migraine days to the 
migraine frequency in four week intervals. The same analyses will be conducted for headache 
days.  
Results from these four week intervals will be combined to produce 12 and 24 week responder 
endpoints.  The Weeks 1-4, 5-8, and 9-12 change from baseline measures are averaged, and the 
average value is compared to baseline. A percent change from baseline is determined, which is 
used to determine the responder status.  A 75% migraine responder will be a subject who 
achieves the specified percent reduction in migraine days within these intervals based upon the 
average change from baseline measures. A 50% migraine responder will be similarly defined.   
A 100% migraine responder rate over Weeks 1-12, 13-24 and 1-24 is the average of the 100% 
responder rate for four week intervals that make up these intervals.  Hence, the 100% migraine 
responder rate over weeks 1-12 is the average of the 100% migraine responder rates in Weeks 1-
4, 5-8 and 9-12 for the treatment arm.   

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Time to First Migraine 
Time to the first migraine after dosing will be analyzed based upon the migraine data entered 
into the eDiary.   
Migraine Hours/Headache Hours 
Migraine hours are the sum of the duration of migraines within four week intervals, and the 
average four week duration within 12 and 24 week intervals.  Headache hours are similarly 
defined but include all headaches. Subjects with no migraines/headaches will have a duration of 
zero. 
Acute Medication Usage 
The percent of migraines and headaches with acute medication use will be summarized.  
Subjects with no migraines/headaches will be included with a rate of zero. 
Acute Migraine Medication Usage 
The number of days that subjects used acute migraine medication (i.e. triptan or ergotamine) will 
be summarized in 4, 12, and 24 week intervals.  The 12 and 24 week results will be the average 
of the individual 4 week results that make up those wider intervals (e.g. the secondary endpoint 
of Weeks 1-12 will be the average of the Weeks 1-4, 5-8, and 9-12 results).  The change from 
baseline for these measures will be the difference between the post baseline interval and 
baseline.   
Percentage of subjects with a migraine on the day after dosing 
The percent of subjects with a migraine on the day after dosing will be summarized  
Reduction in migraine prevalence from baseline to Week 4 
The average percent of subjects with a migraine on any given day during baseline and the 
equivalent average rate over Weeks 1, 2, 3 and 4 will be evaluated for the active and the control 
arms.   
Migraine/Headache Severity 
Headache severity will be collected on a 3 point scale: mild pain, moderate pain, severe pain.  
Subjects with no migraines/headaches will be concerned as having zero percent of severe pain 
migraines/headaches. 
Patient Global Impression of Change (PGIC) 

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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 15.3.  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.  These 
sections are combined into the mental component score and physical component score. 
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 normal 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 
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 

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Migraine Attack/Headache Episode 
A migraine attack is defined as 1 continuously recorded migraine.  One attack may result in 
multiple migraine days.  Headache episodes are similarly defined.   
Migraine symptom-free days 
The number of days the subject is free of migraine symptoms (e.g. pulsating, moderate or severe 
pain, nausea) will be summarized for each 4-week period. 
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. 
12.2. 
Pharmacokinetics 
The concentrations of ALD403 will be measured in plasma from all ALD403-treated subjects 
using a validated assay. The PK analysis will include evaluations of concentration-time profiles 
for free ALD403 at the following times: pre-dose on Day 0, immediately post-dose (within 15 
minutes of end of infusion) and Weeks 2, 4, 8, 12 (pre-dose), 24, and 32 or ET.  
For subjects receiving placebo, selected plasma samples may be analysed for the potential 
presence of ALD403 using a validated assay.  
All plasma PK samples will be stored at -20°C or below prior to shipping to the central 
laboratory.  
Additional sample handling, processing, storage, labelling and shipping instructions will be 
provided to the site in a laboratory manual. 
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 pre-dose on Day 0, and Weeks 2, 4, 8, 12 (pre-dose), 24, and 
32 or ET to test for the development of antibodies to ALD403. The immunogenicity will be 

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assessed in serum from all ALD403-treated subjects using a validated assay.  Immunogenicity 
will not be assessed in placebo subjects. 
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 3 month 
intervals for up to 6 months.  
Additional sample handling, processing, storage, labelling and shipping instructions will be 
provided to the site in a laboratory manual.  
 
 
 
 
 
 
 
 
 

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13. 
STATISTICAL CONSIDERATIONS 
13.1. 
Decision Rule 
A multiplicity procedure will be used to account for multiplicity of dose levels for the primary 
endpoint and the key secondary endpoints.  This procedure will start with the 300 mg vs placebo 
comparison for the primary endpoint.  If this is significant, testing will continue to key secondary 
endpoints for 300 mg.  The procedure will then move on to the 100 mg group for the primary 
endpoint and subsequently the secondary endpoints.  Statistical testing will be conducted to 
maintain study wide two-sided 5% alpha level.   
13.2. 
Sample Size 
The planned sample size for this study is 1050 randomized and treated subjects.  These subjects 
will be allocated into 3 treatment groups in a 1:1:1 ratio.  Pair-wise testing of each ALD403 
group vs. placebo will be performed. Three hundred and fifty subjects per group provides at least 
90% power for the primary endpoint for each comparison assuming a treatment effect of at least 
1 day and a common standard deviation of 4 days or less.  For the key secondary 75% responder 
rate endpoints 90% power is achieved for the pair-wise comparisons, assuming a placebo 
responder rate of 20%, and an ALD403 rate of 31%.  These sample size calculations have been 
performed using Pass 2008 and are based upon a t-test and chi-squared test that should 
approximate the ANCOVA and CMH tests.14 
13.3. 
General Considerations 
13.3.1. 
Definition of Baseline 
Baseline for migraine and headache endpoints will be based upon the data recorded in the 
headache eDiary during the 28-days following screening. For other variables, the baseline 
assessment will be the latest available valid measurement taken prior to the administration of 
Investigational Product. This will generally be Day 0. 
13.3.2. 
Handling of Missing Data 
Summary statistics will be reported based upon observed data except for the eDiary data which 
will utilize the imputation outlined below. Additionally, 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 

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trial medication, except if an incomplete date (e.g., month and year) clearly indicates that the 
event started prior to treatment.  
Subjects who do not complete the eDiary daily will have missing data. It is expected that most 
missing eDiary data will be sporadic.  If the eDiary has been completed at least 21 days in a 28 
day interval, then normalization will be used. The results will be normalized to 28 days by 
multiplying the observed results by the inverse of the completion rate (i.e. if a subject does not 
complete the eDiary on 5 days they will have completed the eDiary on 82% of the days and the 
normalized results will be the observed results times 1.22).  If the eDiary has been completed on 
less than 21 days in the 28 day interval then the results for the 28 day interval will be a weighted 
function of the observed data for the current four week interval and the results from the previous 
interval.  The weights will be proportional to how many days the eDiary was completed and will 
provide greater weight to the results from the current interval as the eDiary completion rate 
increases.  Specifically, the results will be derived as 
28൫𝑊𝑊𝑋𝑋𝑐𝑐+ (1 −𝑊𝑊)𝑋𝑋𝑝𝑝൯, 
where W is the days the eDiary was completed/20, Xc is the available average daily results for the 
current interval and Xp are the average daily results for the previous interval.  
13.3.3. 
Populations to be Analyzed 
The populations to be analyzed are as follows: 
Full Analysis Population: Randomized subjects who received Investigational Product/placebo. 
Subjects will be summarized within the treatment group to which they were randomized. This 
population will be used for efficacy analyses. 
Safety Population: Includes all subjects who received at least one dose of Investigational 
Product/placebo. Subjects will be summarized within the treatment group for which they actually 
received treatment. This population will be used for the safety analyses. 
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.   

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13.4.1. 
Subject Disposition, Demographics and Baseline Characteristics 
An accounting of all randomized trial subjects by disposition will be presented. This 
summarization will include a summary of all subjects who have received trial drug. 
Demographic, baseline characteristics, migraine history and concomitant medications (coded by 
the World Health Organization Drug Dictionary) will be summarized descriptively by treatment 
group. 
13.4.2. 
Efficacy Analyses 
Efficacy endpoints will be summarized with descriptive statistics.  The migraine and headache 
endpoints will be summarized by 4, 12, and 24 week intervals with the remaining endpoints 
being summarized by study week.  
Primary Efficacy Analyses 
Hypothesis testing will be performed for the primary endpoint: change in frequency of migraine 
days (Weeks 1-12).  This endpoint will be calculated as outlined in Section 12.1.2 and will 
utilize the missing data rules provided in Section 13.3.2.  Summary statistics including 
confidence intervals for the treatment differences will be used to summarize the results for the 
primary endpoint.  Testing will also be employed. The hypotheses tested are 
Ho: ∆ plb = ∆ 403 
 
Ha: ∆ plb ≠ ∆ 403 
where ∆403 is the change in migraine days for subjects in the ALD403 treatment arm and ∆plb is 
similarly defined for the placebo subjects.  The change from baseline is expected to be negative 
as migraines are being reduced.  While the test outlined above is two sided, as is the alpha level 
used for this study (i.e. 5%), clinically relevant results require a larger reduction of migraines on 
the ALD403 arms.   
An ANCOVA model will be used to test for a difference between treatment arms.  This model 
will include the change from baseline measure as the response variable.  Treatment and the 
stratification variables: baseline migraine days (continuous predictor) and prophylactic 
medication use (use vs. no use) will be the independent variables.   
Secondary Efficacy Analyses 

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Summary statistics including confidence interval for the treatment differences will be used to 
summarize the results for the secondary endpoints. Testing will be used for the key secondary 
endpoints.  A CMH test controlling for the randomization stratification factors will be used for 
the responder rate key secondary endpoints, and the percent of subjects with a migraine on the 
day after dosing endpoint will be tested with an extended CMH test.15  
The acute migraine medication day endpoint will be tested using an ANCOVA model similar to 
the one used for the primary endpoint. The time to first migraine analysis will be descriptively 
summarized based upon Kaplan-Meier methods.   
The missing data rules provided in Section 13.3.2 will be used for the key secondary endpoints, 
except for the percentage (prevalence) of subjects with a migraine on the day after dosing 
endpoint.  Subjects who did not complete the eDiary on the day following dosing will be 
included in the prevalence rate calculation based upon their Week 1-4 daily migraine rate. 
Hence, subjects with a migraine will be included in the rate calculation as a value of 1, subjects 
who completed the eDiary and did not have a migraine will be included as a 0, and subjects who 
did not complete the eDiary will be included with a value between 0 and 1 equal to their 
prevalence rate in Weeks 1-4 (i.e. the number of Weeks 1-4 migraine days divided by 28).   
The reduction in migraine prevalence from baseline to Week 4 endpoint will be difference in 
daily prevalence rates between Week 1 and baseline, Week 2 and baseline, and so on.  The 
baseline daily prevalence will be calculated as the number of migraine days in baseline divided 
by 28.  The Week 1 daily prevalence will be the number of migraine days in Week 1 divided by 
7, with a similar definition for Weeks 2, 3, and 4.  The same missing data approach for the day 
after dosing endpoint will be used for these weekly measures (i.e. any day the subject does not 
complete the diary will be assigned a value equal to the Weeks 1-4 prevalence rate).  The 
treatment effect will be evaluated using a repeated-measures approach.16  The model will specify 
an unstructured variance/covariance matrix and include the treatment group, visit, baseline value 
of the outcome variable and treatment group-by-visit interaction. The Kenward-Roger 
approximation will be used to estimate the degrees of freedom.  Pharmacokinetic Analyses 

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13.4.3. 
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. 
13.4.4. 
Safety Analyses 
13.4.4.1. Adverse Events 
The incidence of all AEs will be tabulated by treatment received. 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 Investigational Product 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 

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normal reference range at any post-baseline assessment will be summarized. Shifts from baseline 
clinical laboratory values based upon the normal range and 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.  
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 
The Sponsor or designee will assess the site to verify the qualifications of each Investigator, 
according to Sponsor’s or applicable SOPs. There will be an inspection of site facilities, and 
Investigator will be further 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.  
14.3. 
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. 
14.4. 
Data Collection and Electronic Data Capture (EDC)  
The data collected during the study (except clinical laboratory test results, eDiary results, ECG 
results, PK analyses, Immunogenicity) will be recorded in the subject’s eCRF. The Short-Form 
Health Survey (SF-36), Health related Quality of Life (EQ-5D-5L), Headache Impact Test (HIT-

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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 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 monitor and electronically signed and dated by the Investigator.   
14.5. 
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 BioPharmaceuticals, Inc. and regulatory authorities. Elements of clinical 
trial documentation should include: 
• Subject files containing the completed CRFs supporting source documentation and 
the signed ICF 
• 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 BioPharmaceuticals, Inc. 
• Pharmacy files, containing the Investigational Product Accountability Records or 
dispensation logs and all clinical trial agent-related correspondence 
14.6. 
Good Clinical Practice 
The procedures set out in this clinical trial protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH and applicable federal and 

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local regulations. The clinical trial also will be conducted in keeping with local legal 
requirements. 
14.7. 
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 enrolled in the clinical trial as well as 
those currently enrolled in the clinical trial. If subject or subject’s partner, becomes pregnant 
during their participation in the trial, a separate pregnancy informed consent form will be 
obtained, to follow the pregnancy, any complications, and the health of the baby.  The pregnancy 
consent should be obtained at the time the Investigator becomes aware of the pregnancy. 
14.8. 
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. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first subject 
is enrolled 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. 
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 

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implementation (if appropriate). Amendments will originate from Alder BioPharmaceuticals, 
Inc., 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. 
14.8.1. 
Premature Termination of the Clinical Trial 
Alder BioPharmaceuticals, Inc., 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 Principal 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, the 
Sponsor, 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.  
14.9. 
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 the Sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be identified on CRFs 
and other documents by their subject number, initials and/or birth date, not by name and in 
accordance with local requirements. Documents not to be submitted that identify the subject 
(e.g., the signed informed consent) must be maintained in confidence by the Investigator.  
14.10. 
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 

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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 the Sponsor 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 
BioPharmaceuticals, Inc., for review and approval in accordance with the provisions contained in 
the clinical trial agreement. All publications must acknowledge the Sponsorship of Alder 
BioPharmaceuticals, Inc. 
All information not previously published concerning ALD403 and Alder BioPharmaceuticals, 
Inc., operations, including but not limited to patent applications, formulas, manufacturing 
processes, basic scientific data, and formulation information, supplied by Alder 
BioPharmaceuticals, Inc., to the Investigator is considered confidential and shall remain the sole 
property of Alder BioPharmaceuticals, Inc. 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 
efficacy17,18,19 
• Divalproex sodium 
• Valproic Acid 
• Topiramate 
• Amitriptyline 
• Venlafaxine 
• Flunarizine 
• Cinnarizine 
• Fluoxetine 
• Gabapentin 
• Verapamil 
• Lamotrigene 
• Metoprolol 
• Propranolol 
• Timolol 
• Atenolol 
• Nadolol 
• Bisoprolol 
• Butterbur 
• Feverfew 
• Pizotifen 
• Frovatriptan* 
• Naratriptan* 
• Zolmitriptan* 
Other drugs for prophylaxis will be considered on a case by case basis 
*only considered  prophylaxis when specifically used as such (e.g., menstrually-related 
migraine (MRM)) 

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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) 
 

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15.7. 
Most Bothersome Symptom (MBS) 
 

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15.8. 
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. the Journal of Headache and Pain 2013; 14:4 
12. World Health Organization. International Classification of Diseases (ICD). Retrieved 23 
Nov 2010. 
13. 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.  
14. Hintze, J. (2008) PASS 2008. NCSS, LLC. Kaysville, Utah. www.ncss.com 
15. LaVange L, Durham T, Koch G. Randomization-based Nonparametric Methods for the 
Analysis of Multicenter Trials. Statistical Methods in Medical Research. 2005; 14:281-
301. 
16. Mallinckrodt, C., Lipkovich, I. (2016). Analyzing Longitudinal Clinical Trial Data: A 
Practical Guide. Chapman and Hall/CRC Press, New York. 

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17. Esternalik E, Tepper S.  Preventive treatment in migraine and the new US guidelines.  
Neuropsychiatr Dis Treat. 2013; 9; 709-720.  
18. 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.  
19. 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.