Clinical trial NCT02559895
Conditions: Migraine Disorders
Sponsor: Alder Biopharmaceuticals, Inc.
Start date: 2015-09-01; Completion date: 2017-12-01
Enrollment: 898 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess ALD403 in the prevention of migraine headache in frequent episodic migraineurs.

Detailed description:

Arms: arm 1: ALD403 Dose Level 1 (IV) arm 2: ALD403 Dose Level 2 (IV) arm 3: ALD403 Dose Level 3 (IV) arm 4: Placebo (IV)
Interventions: intervention 1: ALD403 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Protocol ALD403-CLIN-006   
Alder BioPharmaceuticals, Inc. 
24-Apr-2017 
 
CONFIDENTIAL 
Page 1 of 104 
 
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 Trial to Evaluate the Efficacy and Safety of 
ALD403 Administered Intravenously in Patients with 
Frequent Episodic Migraines 
Protocol Number 
ALD403-CLIN-006 
Investigational Product 
ALD403  
Indication 
Treatment for Prevention of Frequent Episodic Migraine 
Headaches 
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. 
Date of Protocol (original release) 30-June-2015  
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
Date of Amendment 4 
05-February-2016 
14-June-2016 
22-Nov-2016 
24-Apr-2017 




Protocol ALD403-CLIN-006  
Alder BioPharmaceuticals, Inc. 
24-Apr-2017
CONFIDENTIAL 
Page 3 of 104 
Declaration of the Principal Investigator 
Title: A Parallel Group Double-Blind Randomized Placebo Controlled Trial to Evaluate the 
Efficacy and Safety of ALD403 Administered Intravenously in Patients with Frequent Episodic 
Migraines 
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 
_____________________________________ 
______________________ 
<Name> 
Date 
<Title> 
<Institution> 


Protocol ALD403-CLIN-006  
Alder BioPharmaceuticals, Inc. 
24-Apr-2017
CONFIDENTIAL 
Page 4 of 104 
1 Protocol Synopsis 
Title 
A Parallel Group Double-Blind Randomized Placebo 
Controlled Trial to Evaluate the Efficacy and Safety of 
ALD403 Administered Intravenously in Patients with Frequent 
Episodic Migraines 
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 Frequent Episodic Migraine (FEM). 
Secondary Objectives 
To evaluate the safety of repeat doses of ALD403 administered 
IV compared to placebo in patients with FEM.  
To evaluate the pharmacokinetics (PK) and immunogenicity of 
repeat doses of ALD403 administered IV to patients with 
FEM. 
Methodology 
This is a phase 3, a parallel group, double-blind, randomized, 
placebo-controlled trial. Subjects will be randomized into one 
of three ALD403 dose levels (30 mg, 100 mg, and 300 mg) or 
placebo. Randomization will be stratified by migraine days 
during screening (≤9 days vs. >9 days).  Subjects will be 
allocated equally to each treatment group.  
The total study duration is 60 weeks with 12 scheduled visits.  
The visits will occur on Screening, Day 0, and Weeks 4, 8, 12, 
16, 20, 24, 28, 36, 48 and 56. Following the screening visit, 
subjects will be followed for four weeks to confirm eligibility. 
Once subjects are eligible, they will be randomized and treated 
on Day 0, which is 29-35 days after the screening visit.  
Patients must complete eDiary from Screening through Week 
48.   
Study drug treatment includes four infusions of ALD403 or 
placebo on Days 0, 84 (Week 12), 168 (Week 24) and 252 
(Week 36) with 20 weeks follow up after the final dose.   
A DMC, guided by a charter, will review safety data during the 
enrollment and treatment phases of this study.  The DMC will 


Protocol ALD403-CLIN-006  
Alder BioPharmaceuticals, Inc. 
24-Apr-2017
CONFIDENTIAL 
Page 5 of 104 
advise the Sponsor regarding the continuing safety of trial 
subjects and those yet to be recruited to the trial, as well as the 
continuing validity and scientific merit of the trial.  The DMC 
is not charged with stopping the trial early for efficacy. 
Number of Subjects 
Planned 
Approximately 800 subjects will be randomized and treated at 
approximately 85 centers in the US and Republic of Georgia.  
Subject Selection Criteria 
Males and females between 18 and 75 years of age inclusive, 
who were diagnosed with migraines at ≤ 50 years of age, and 
have a history of migraine for ≥ 12 months at a frequency of 
≤ 14 headache days of which at least 4 have to be migraine 
days (migraine days count as headache days) per 28 day 
period, and have met eDiary compliance criteria during the 
screening period.   
Investigational Product, 
Dose and Schedule 
There will be 4 treatment groups. 
1.
30 mg ALD403 administered IV on Day 0 and Week 12,
24, and 36.
2.
100 mg ALD403 administered IV on Day 0 and Week 12,
24, and 36.
3.
300 mg ALD403 administered IV on Day 0 and Week 12,
24, and 36.
4.
Placebo administered IV on Day 0 and Week 12, 24, and
36.
Duration of Treatment 
Four doses of ALD403/placebo will be given 12 weeks apart.  
Duration of Clinical Trial 
Participation 
The trial participation period will be 60 weeks, which will 
include a 4 week screening period, randomization and the start 
of treatment on Day 0, dosing at Week 12, 24 and 36 with 
20 weeks of post-dose follow-up at Week 56.   
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.


Protocol ALD403-CLIN-006  
Alder BioPharmaceuticals, Inc. 
24-Apr-2017
CONFIDENTIAL 
Page 6 of 104 
Other Secondary Endpoints 
•
Change in acute migraine medication days (Weeks
1-12)
•
Headache/migraines with acute medication usage
•
100% migraine responder rates (Weeks 1-12)
•
Short-Form Health Survey (SF-36)
•
Health-Related Quality of Life (EQ-5D-5L)
•
Allodynia Symptom Checklist-12 (ASC-12)
•
Brush (dynamic mechanical) Allodynia
•
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/migraine days
•
Time to first migraine after dosing
•
Headache/migraine hours
•
Headache/migraines with severe intensity
Tertiary Endpoints 
•
Headache episodes/migraine attacks
Safety Endpoints 
•
Adverse events (AEs) and serious adverse events
(SAEs)
•
Changes in Clinical laboratory assessments
•
Vital Signs
•
Electrocardiogram (ECGs)
•
Suicidal ideation and behavior as measured by the
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


Protocol ALD403-CLIN-006  
Alder BioPharmaceuticals, Inc. 
24-Apr-2017
CONFIDENTIAL 
Page 7 of 104 
Concomitant Medications 
•
Concomitant medications must be recorded in the Case
Report Form (CRF) through Week 56. The following
medications are restricted through Week 24: Any
prophylactic headache medication is prohibited and its
regular use (greater than 7 days) is not allowed within
2 months prior to screening through randomization
(medication details in Section 15.1).
•
Short-term (no more than 7 days in a month) menstrual
migraine prophylactics are allowed.
•
Additional restriction applies to the following
medications: barbiturates and opiates are allowed for
≤ 4 days per month through Week 24, provided the
subject does not meet the criteria for Medication
Overuse Headache overall and 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 requiring injections in
the head, face, or neck are prohibited within 4 months
prior to screening and through Week 24.
•
Devices, neuromodulation, neurostimulation, or
injectable therapy (trigger point injections, extracranial
nerve blocks, facet joint injections) for headache
prophylaxis are prohibited within 2 months prior to
screening and through Week 24.
Sample 
Size 
The planned sample size for this study is 800 randomized and 
treated subjects.  These subjects will be allocated into 
4 treatment groups in a 1:1:1:1 ratio.  Pair-wise testing of each 
ALD403 group vs. placebo will be performed. Testing will be 
at the 5% alpha level. Two hundred subjects per group 
provides at least 95% power for the change from baseline tests 
individually assuming a treatment effect of at least 1 day and a 
common standard deviation of 2.7 days or less.  For the key 
secondary 75% responder rate endpoints 95% power is 
achieved for the pair-wise comparisons, the 75% responder 
rates are 24% for placebo and 42% for ALD403. 
Statistical Analysis 
The primary periods for efficacy and safety for this study are 
through Week 12 and 24, respectively.  The primary efficacy 


Protocol ALD403-CLIN-006  
Alder BioPharmaceuticals, Inc. 
24-Apr-2017
CONFIDENTIAL 
Page 8 of 104 
evaluations will encompass results from Weeks 1-12.  
Following Week 24, the study will continue so that long term 
safety data can be captured.  The efficacy analyses are based 
upon migraine days.  A migraine day is defined as any day 
with a migraine or probable migraine as outlined in the IHS 
classification ICHD-II. (migraine without aura, Section 1.111). 
Specifically, a migraine is defined as a self-reported headache 
which meets each of the following conditions:  
1) lasted 4 to 72 hours
2) had at least 2 of the following: unilateral location,
pulsating quality, moderate or severe pain intensity
and/or aggravation by or causing avoidance of
routine physical activity, and
3)
had at least 1 of the following: nausea and/or
vomiting and/or photophobia and phonophobia.
A probable migraine is defined as a headache that meets only 
2 of the 3 criteria listed above.  The migraine days reported 
during the initial 28-days following screening will be used as 
baseline. Following treatment, migraine data will be 
summarized and analyzed in 4 week intervals, 12 week 
intervals and a 24 week interval.  A 75% responder for a given 
four week interval will be a subject with at least a 75% 
reduction in migraine days during that interval.  A 75% 
responder over a 12 week interval will be a subject who 
achieves an average reduction of 75% over the twelve weeks.  
The 50% and 100% responder rates are similarly defined. The 
12 weeks average change from baseline in frequency of 
migraine days is the average change from baseline in each of 
the 4 weeks intervals that make up weeks 1-12. Subjects who 
do not complete their migraine eDiary will have their missing 
data imputed.   
Efficacy and safety endpoints will be summarized with 
descriptive statistics.  Testing of the key secondary responder 
rate endpoints and the primary Weeks 1-12, change from 
baseline in migraine day endpoint will be performed.  The 
testing of the primary endpoint will be with an ANCOVA.  
The key secondary responder rate and percentage of subjects 
with a migraine on the day after dosing endpoints will be tested 


Protocol ALD403-CLIN-006  
Alder BioPharmaceuticals, Inc. 
24-Apr-2017
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with a Cochran Mantel Haenszel (CMH) test controlling for 
the randomization stratification factor.     
Pharmacokinetic and 
Immunogenicity Analyses 
The concentrations of Free ALD403 will be measured in 
plasma from all ALD403 treated subjects using validated assay 
methods. 
The PK analysis of plasma will include determination of the 
Free ALD403 concentrations at the following times:  Day 0 
Weeks 4, 8, 12, 16, 20, 24, 36, 48 and 56.  The PK plasma 
samples will be collected pre-dose within 1 hr before dosing on 
Day 0, and Weeks 12, 24 and 36. For subjects receiving 
placebo, selected samples will be analysed.   
Blood will be taken for the detection of anti-ALD403 antibody, 
and when appropriate neutralizing anti-ALD403 antibody, at 
the following times: Day 0, Weeks 4, 8, 12 16, 20, 24, 36, 48 
and 56. 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. The anti-ALD403 antibody blood samples will be 
collected pre-dose within 1 hour before dosing on Day 0, and 
Weeks 12, 24 and 36.  


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24-Apr-2017
CONFIDENTIAL 
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2  Schedule of Events and Assessments 
Primary Efficacy and Safety Period 
Long Term Safety Period 
Assessment 
Screen 
D-35 to -29
Rand/ 
D0 
Tx 
Wk 4 
D28 ± 3 
Wk 8 
D56 ± 3 
Wk 12  
D84 ± 3 
Tx 
Wk 16 
D112 ± 3 
Wk 20 
D140 ± 3 
Wk 2411  
D168 + 3 
Tx 
Wk 28 
D196 ± 7 
Wk 36 
D252 ± 3 
Tx 
Wk 4812 
D336 +7 
Wk 56 
EOS/ET 
D392 + 
713  
Informed Consent  
X 
In/Ex Criteria 
X 
X 
Demographics 
X 
Medical History 
X 
Headache eDiary 
Review and Compliance 
Check1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hgt/Wgt2 
X 
X 
X 
X 
X 
Physical Exam3 
X 
X 
X 
X 
X 
Brush Allodynia Test 
X 
X 
X 
X 
X 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BDI-II 
X 
C-SSRS5
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG4
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hem/Chem6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV/Hepatitis B and C 
X 
Urine Drugs Abuse 
Screen7 
X 
Urine Preg (hCG) Test 
X 
X 
X 
X 
X 
X 
X 
Plasma ALD403 (PK) 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Anti-ALD403 
Ab9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L, ASC-12 
X 
X 
X 
X 
X 
X 
X 
AE Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
ALD403/placebo 
administration10 
X 
X 
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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24-Apr-2017
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1Headache eDiary distributed at screening. eDiary review and compliance check through Week 48. 
2Height and Weight on Screening visit. Weight only on Day 0, Weeks 24, 36 and 56. 
3Physical exam must be done pre-dose on Day 0, Week 24, and 36. 
4Vital signs and 12-lead ECG pre-dose and 4 hours post-dose (± 30 minutes) on Day 0, Weeks 12, 24 and 36. 
5C-SSRS “Baseline/Screening Version” at screening, C-SSRS “Since Last Visit Version” Day 0 (pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48 and 56. 
6All blood draws obtained pre-dose on dosing days. 
7"International Classification of Diseases (ICD)". World Health Organization. Retrieved 23 November 2010. 
8Sample for Plasma Free ALD403 drawn pre-dose on dosing days (within 1 hour prior to dosing). 
9Sample for anti-ALD403 antibody drawn pre-dose on dosing days (within 1 hour prior to dosing).  
10 Subjects must be monitored for at least 4 hours after the dosing completion. 
11Week 24 must be done on the target day or 3 days after. Three days earlier than target date is not allowed. 
12Week 48 must be done on the target day or seven days after. Seven days earlier than target date is not allowed. 
13Subjects who test positive for anti-ALD403 antibodies at the last study visit will be asked to provide up to 2 additional blood samples for immunogenicity 
testing at approximately 3 month intervals for up to 6 months.  


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24-Apr-2017
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3 List of Abbreviations 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase   
ANC 
Absolute neutrophil count 
ANCOVA 
Analysis of Covariance 
ASC-12 
Allodynia Symptom Checklist 
AST 
Aspartate aminotransferase  
AUC 
Area under the concentration-time curve 
AUC0-inf 
Area under the concentration-time curve from time=0 to infinity 
AUC0-tlast 
Area under the plasma concentration-time curve from time zero to time of 
last quantifiable concentration 
BDI-II 
Beck Depression Inventory 
BMI 
Body Mass Index 
CGRP 
Calcitonin Gene-Related Peptide  
CMH 
Cavg 
Cochran–Mantel–Haenszel 
Average steady-state concentration; computed as AUC(0-Tau)/Tau
Cmax 
Cmin 
CL 
Peak plasma concentration 
Minimum concentration between 0 and Tau at steady-state  
Total body clearance 
CRF 
Case Report Form 
C-SSRS
DNA
Columbia-Suicide Severity Rating Scale 
Deoxyribonucleic acid 
EC
EQ-5D-5L
Ethics Committee 
Health-Related Quality of Life 
FDA
Food and Drug Administration 
FEM
hCG
Frequent Episodic Migraine 
Human chorionic gonadotropin 
IB
Investigator Brochure 
ICD
ICHD
ICF
International Classification of Diseases 
International Classification of Headache Disorders 
Informed Consent Form 
ICH
IHS
International Conference on Harmonization 
International Headache Society 
IgG1
Immunoglobulin G1 
IRB
Institutional Review Board 
IV
Intravenous 
kg
Kilogram 
L
Liter 


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24-Apr-2017
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LLOQ 
Lower Limit of Quantification 
M 
Molarity 
m2 
Meter squared 
mAb 
Monoclonal antibody 
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 
mM 
Millimolar 
msec 
Milliseconds 
NAb 
Neutralizing antibody 
NOAEL 
No-observed-adverse-effect-level 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over-The-Counter 
PK 
Pharmacokinetic 
QTcF 
QT corrected using Fridericia formula 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
SF-36 
SOP 
Tau 
Subcutaneous 
Short Form Health Survey 
Standard Operating Procedure 
The dosing interval for steady-state data 
t½ 
Elimination half-life during the terminal elimination phase 
Tmax 
Time to peak plasma concentration 
TEAE 
TMD 
Treatment-emergent adverse event 
Temporo-mandibular Disorders 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
Vz 
Apparent volume of distribution during the terminal elimination phase 
WBC 
White blood cell 
WHO 
World Health Organization 
µg 
Micrograms 


Protocol ALD403-CLIN-006  
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24-Apr-2017
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Page 14 of 104 
4 Table of Contents 
1 
Protocol Synopsis ................................................................................................................... 4 
2 
Schedule of Events and Assessments.................................................................................. 10 
3 
List of Abbreviations ........................................................................................................... 12 
4 
Table of Contents ................................................................................................................. 14 
5 
Introduction.......................................................................................................................... 18 
5.1 
Investigational Product ................................................................................................. 18 
5.2 
Background .................................................................................................................. 18 
5.3 
Investigational Product ................................................................................................. 19 
5.3.1 Summary of Nonclinical Studies .......................................................................... 19 
5.3.2 Summary of Clinical Trials ................................................................................... 23 
5.4 
Risks and Benefits ........................................................................................................ 24 
5.5 
Compliance Statement .................................................................................................. 25 
6 
Objectives ............................................................................................................................. 25 
6.1.1 Primary Objective ................................................................................................. 25 
6.1.2 Secondary Objectives............................................................................................ 26 
7 
Trial Design .......................................................................................................................... 26 
7.1 
Clinical Trial Endpoints ............................................................................................... 26 
7.1.1 Primary Efficacy Endpoint ................................................................................... 26 
7.1.2 Key Secondary Endpoint ...................................................................................... 26 
7.1.3 Other Secondary Endpoints .................................................................................. 26 
7.1.4 Tertiary Endpoints ................................................................................................ 27 
7.1.5 Safety Endpoints ................................................................................................... 27 
7.1.6 Pharmacokinetic Endpoints .................................................................................. 27 
7.1.7 Immunogenicity Endpoints ................................................................................... 27 
7.2 
Clinical Trial Design .................................................................................................... 27 
7.3 
Data Monitoring Committee ........................................................................................ 28 
7.4 
Methods to Minimize/Avoid Bias ................................................................................ 28 
8 
Selection and Withdrawal of Subjects ............................................................................... 29 
8.1 
Inclusion Criteria .......................................................................................................... 29 
8.2 
Exclusion Criteria ......................................................................................................... 31 
8.3 
Registration and Treatment Assignment ...................................................................... 33 


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8.3.1 Registration Procedure, Subject Numbering ......................................................... 33 
8.3.2 Randomization and Treatment Assignment .......................................................... 33 
8.4 
Subject Treatment Discontinuation and Withdrawal ................................................... 34 
8.4.1 Criteria for Discontinuation from Study Treatment.............................................. 34 
8.4.2 Criteria for Withdrawal from Clinical Trial .......................................................... 34 
8.4.3 Timing of Withdrawal........................................................................................... 35 
8.4.4 Follow-up for Early Withdrawal ........................................................................... 35 
8.4.5 Replacement Policy .............................................................................................. 35 
9 
Clinical Trial Treatments .................................................................................................... 35 
9.1 
Investigational Product ................................................................................................. 35 
9.2 
Control Drug................................................................................................................. 35 
9.3 
Investigational Product Dosing and Administration .................................................... 36 
9.3.1 Packaging and Labeling ........................................................................................ 36 
9.3.2 Blinding................................................................................................................. 36 
9.3.3 Storage and Handling of Investigational Product ................................................. 37 
9.3.4 Accountability and Disposition of Investigational Product .................................. 37 
9.4 
Concomitant Medications............................................................................................. 38 
10 Schedule of Assessment and Procedures ........................................................................... 39 
10.1 
Screening Day (Day -35 to -29) ................................................................................... 39 
10.2 
Day 0 (Randomization and Treatment) ........................................................................ 39 
10.3 
Week 4 Visit (Day 28 ± 3 days) ................................................................................... 41 
10.4 
Week 8 Visit (Day 56 ± 3 days) ................................................................................... 41 
10.5 
Week 12 Visit (Day 84 ± 3 days) ................................................................................. 42 
10.6 
Week 16 Visit (Day 112 ± 3 days) ............................................................................... 43 
10.7 
Week 20 Visit (Day 140 ± 3 days) ............................................................................... 43 
10.8 
Week 24 Visit (Day 168 +3 days) ................................................................................ 44 
10.9 
Week 28 Visit (Day 196 ± 7 days) ............................................................................... 45 
10.10 
Week 36 Visit (Day 252 ± 3 days) ............................................................................... 45 
10.11 
Week 48 Visit (Day 336 + 7 days) ............................................................................... 46 
10.12 
Week 56 Visit (Day 392 ± 7 days) End of Study or Early Termination ...................... 46 
10.13 
Early Termination......................................................................................................... 47 
11 Assessment of Safety ............................................................................................................ 47 


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11.1 
Adverse Events ............................................................................................................. 47 
11.1.1 Definitions............................................................................................................. 47 
11.1.2 Assessment of Adverse Events ............................................................................. 48 
11.1.3 Recording Adverse Events .................................................................................... 50 
11.1.4 Reporting Serious Adverse Events ....................................................................... 51 
11.1.5 Unexpected and Related Serious Adverse Events ................................................ 52 
11.1.6 Follow-up of Adverse Events ............................................................................... 52 
11.1.7 Clinical Laboratory Tests ...................................................................................... 52 
11.1.8 Pregnancy .............................................................................................................. 52 
11.1.9 Suicidal Ideation and Behavior ............................................................................. 53 
11.2 
Management of Reactions to ALD403 ......................................................................... 53 
12 Assessment of Efficacy, Pharmacokinetics and Immunogenicity ................................... 54 
12.1 
Efficacy….. .................................................................................................................. 54 
12.1.1 eDiary.. .................................................................................................................. 54 
12.1.2 Endpoints .............................................................................................................. 55 
12.2 
Pharmacokinetics.......................................................................................................... 58 
12.3 
Immunogenicity............................................................................................................ 59 
13 Statistical Considerations .................................................................................................... 59 
13.1 
Decision Rule ............................................................................................................... 59 
13.2 
Sample Size .................................................................................................................. 60 
13.3 
General Considerations ................................................................................................ 61 
13.3.1 Definition of Baseline ........................................................................................... 61 
13.3.2 Handling of Missing Data ..................................................................................... 61 
13.3.3 Populations to be Analyzed .................................................................................. 62 
13.4 
Statistical Methods ....................................................................................................... 62 
13.4.1 Subject Disposition, Demographics and Baseline Characteristics ....................... 62 
13.4.2 Efficacy Analyses ................................................................................................. 63 
13.4.3 Pharmacokinetic Analyses .................................................................................... 64 
13.4.4 Safety Analyses ..................................................................................................... 64 
14 Ethical, Legal and Administrative Aspects ....................................................................... 66 
14.1 
Data Quality Assurance ................................................................................................ 66 
14.2 
Case Report Forms and Source Documents ................................................................. 66 


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14.3 
Study Documentation ................................................................................................... 66 
14.4 
Data Collection and Electronic Data Capture (EDC) ................................................... 67 
14.5 
Archiving Clinical Trial Records ................................................................................. 67 
14.6 
Good Clinical Practice.................................................................................................. 68 
14.7 
Informed Consent ......................................................................................................... 68 
14.8 
Protocol Approval and Amendment ............................................................................. 68 
14.8.1 Premature Termination of the Clinical Trial ......................................................... 69 
14.9 
Confidentiality .............................................................................................................. 69 
14.10 
Publication Policy......................................................................................................... 70 
15 Appendices............................................................................................................................ 71 
15.1 
Preventative Medications or Supplements with Evidence of Efficacy ........................ 71 
15.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) Risk Assessment ........................ 72 
15.2.1 Baseline/Screening Version .................................................................................. 72 
15.2.2 Since Last Visit Version ....................................................................................... 75 
15.3 
Short-Form Health Survey (SF-36 v2.0) ...................................................................... 80 
15.4 
Health Related Quality of Life (EQ-5D-5L) ................................................................ 84 
15.5 
Allodynia Symptom Checklist (ASC-12)..................................................................... 87 
15.6 
Change Table for Amendment 4 ................................................................................. .88 
16 References ........................................................................................................................... 103 


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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 
According to the International Classification of Headache Disorder, migraine is a common 
disabling primary headache disorder manifesting in attacks lasting 4 to 72 hours. Migraine 
headaches range from moderate to very severe and are debilitating. Episodic migraine affects 17 
percent of women and 6 percent of men.  Migraine frequency is divided into episodic and 
chronic episodic migraine is characterized by <15 migraine days and chronic migraine by ≥15 
headache days per month of which 8 or more must be migraine days. All migraine types 
significantly affect the physical, psychological, and social well-being of patients, and can impose 
serious lifestyle restrictions. Each year lost work time and diminished productivity from 
migraine costs American employers $225.8 billion. Forty percent of adults with episodic 
migraine and all patients with chronic migraine might benefit from preventive medication; yet, 
only about 12 percent of adults with migraines take preventive medication. This is largely due to 
poor tolerability and/or lack of efficacy of currently marketed drugs for the prevention of 
migraine. There is therefore a need for new therapeutic alternatives1. 
CGRP is a member of the calcitonin family of peptides, which in humans exists in two forms, α-
CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative 
splicing of the calcitonin/CGRP gene located on chromosome 11. The less-studied β-CGRP 
differs in three amino acids (in humans) and is encoded in a separate gene in the same vicinity of 
the genome. 
CGRP is one of the most abundant peptides produced in both peripheral and central neurons. It is 
the most potent peptide vasodilator and can function in the transmission of pain. In the spinal 
cord, the function and expression of CGRP may differ depending on the location of synthesis. 
CGRP is derived mainly from the cell bodies of motor neurons when synthesized in the ventral 
horn of the spinal cord and may contribute to the regeneration of nervous tissue after injury. 


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Conversely, CGRP is derived from dorsal root ganglion when synthesized in the dorsal horn of 
the spinal cord and may be linked to the transmission of pain. In the trigeminal vascular system, 
the cell bodies on the trigeminal ganglion are the main source of CGRP where it is thought to 
have a role in cardiovascular homeostasis and nociception.2 
CGRP is thought to have a multiplicity of actions within the brain, including the facilitation of 
pain transmission and the induction of the nociceptive state, both of which may contribute to the 
mechanism of migraine. 3, 4 
During migraine attacks, there is an increase in the plasma levels of CGRP in the external jugular 
vein. 5 In addition, intravenous (IV) infusion of CGRP causes migraine and headache in patients 
with migraine, suggesting that the increase in CGRP observed during spontaneous migraine 
attacks plays a causative role.6 
CGRP is thought to play an important role in migraine by facilitating the transmission of 
migraine pain, thereby contributing to the induction of the pronociceptive stage through 
modulation of the central nervous system (CNS).4, 5  Studies in animals and humans indicate that 
the trigeminal ganglion and the trigeminal nucleus caudalis are likely to be sites of action of 
CGRP in migraine. In addition, CGRP is expressed in many locations within the CNS, including 
regions that may be relevant to migraine pain. 7, 8 
CGRP dilates intracranial and extracranial blood vessels, and can additionally activate adjacent 
mast cells, which leads to the secretion of vasoactive, proinflammatory, and sensitizing 
mediators, thereby contributing to migraine pathogenesis. 9, 10 
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). 


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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 rats, changes in 
dermal blood perfusion were measured using Laser Doppler, while in rabbits and monkeys a 
Laser Speckle Contrast Analysis (LASCA) imaging system was utilized.  The parenteral 
administration of ALD403 inhibited increases in dermal blood perfusion induced by topical 
capsaicin in rats and cynomolgus monkeys, and intravenous ALD403 administration in rabbits 
inhibited increased dermal blood perfusion secondary to intradermal β-CGRP challenge. 
The toxicokinetic profile for ALD403 has been evaluated following single and once weekly 
repeated-dose IV administrations for four weeks in rats and cynomolgus monkeys, and following 
administration once every two weeks for 6-months in cynomolgus monkeys.  
The plasma concentration profiles for ALD403 following single or repeated-dose IV 
administrations in rats or cynomolgus monkeys were characterized by an apparent mono-
exponential decline. The plasma half-life for ALD403 ranged between 102-155 hours following 
single administration in rats, and 142 to 323 hours following single or multiple weekly 
administrations in cynomolgus monkeys. The distribution for ALD403 appeared limited to the 
vascular compartment, and the systemic exposure was dose proportional from 10 to 
150 mg/kg/dose. No gender differences were observed among any of the toxicokinetic 
parameters evaluated.  
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. 


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Toxicological investigations in rats and monkeys indicated that repeated-dose IV administration 
of ALD403 at 10, 30, or 100 mg/kg once weekly for four weeks was well tolerated, with no signs 
of adverse effects related to treatment. Under the conditions of these studies, the no-observed-
adverse-effect-level (NOAEL) for once weekly IV administration of ALD403 to rats or monkeys 
for four weeks was 100 mg/kg. 
A chronic multiple-dose toxicology study in cynomolgus monkeys was conducted to evaluate the 
potential effects by ALD403 following 6-months administration via slow bolus injection once 
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.  
The following parameters were evaluated in this study: clinical signs, body weights, food 
consumption, blood pressure, heart rate, and body temperature, ophthalmology, 
electrocardiology, clinical pathology parameters (hematology, coagulation, clinical chemistry, 
and urinalysis), insulin analysis, flow cytometry parameters, toxicokinetic parameters and anti-
drug antibody (ADA) formation, gross necropsy findings, organ weights, and histopathologic 
examinations. 
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 a class effect and was not included in the determination of 
the no-adverse-effect-level (NOAEL). 
There were no ALD403-related clinical signs or changes in body weight, food consumption, 
ophthalmology, electrocardiology, blood pressure, heart rate, body temperature, clinical 
pathology, insulin, or flow cytometry parameters. There were no ALD403-related effects on 
organ weights or organ weight ratios. Additionally, there were no ALD403-related macroscopic 
or microscopic changes. 
The presence of ADA was confirmed in 5/10 (50%) animals from the 20 mg/kg group, 5/10 
(50%) animals from the 50 mg/kg group, and 11/14 (79%) animals from the 150 mg/kg group. 


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Considering that the ALD403 exposure did not decrease after repeated administration and that 
the exposure of ADA positive animals was not notably or consistently different from ADA 
negative animals, the presence of ADA did not appear to impact exposure. 
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. 
Range-finding embryo-fetal development studies with ALD403 have been completed to support 
the selection of dosages for use in definitive studies.   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 definitive embryo-fetal development studies with ALD403 in pregnant rats 
and rabbits are currently in progress.   
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 
superficial perivascular infiltrates, fibroplasia/fibrosis, myointimal hyperplasia of the injected 
vein, hemorrhage, and sporadic observations in the epidermis and skeletal muscle.  


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5.3.2 
Summary of Clinical Trials 
Detailed descriptions of the relevant clinical findings for ALD403 are provided in the 
Investigator’s Brochure (IB). 
A summary of completed and ongoing ALD403 clinical trials is shown in Table 5.3 
Table 5.3 
ALD403 Clinical Trials 
Trial ID 
Phase/Objective 
Trial Subject 
Population 
Total 
Number of 
Subjects in 
the Trial 
Number of 
Subjects 
Randomized to 
ALD403 
Number of 
Subjects 
Randomized 
to Placebo 
ALD403-CLIN-001 
(completed) 
Phase 1 
Safety 
Healthy 
Volunteer1 
104 
67 
37 
ALD403-CLIN-002 
(completed) 
Phase 1b 
Safety & Efficacy 
Frequent 
Episodic 
Migraine 
163 
81 
82 
ALD403-CLIN-003 
(completed) 
Phase 1 
Safety 
Healthy 
Volunteer 
60 
36 
24 
ALD403-CLIN-007 
(ongoing) 
Phase 1 
(Safety) 
Healthy 
Volunteer 
60 
49 
11 
ALD403-CLIN-009 
(ongoing) 
Phase 1 
(Safety) 
Healthy 
Volunteer 
36 
24 
12 
ALD403-CLIN-0052 
(ongoing) 
Phase 2  
Safety & Efficacy 
Chronic Migraine 
616 
ALD403-CLIN-0062
(ongoing) 
Phase 3  
Safety & Efficacy 
Frequent 
Episodic 
Migraine 
800 
(planned) 
ALD403-CLIN-011 
(ongoing) 
Phase 3  
Safety & Efficacy 
Chronic Migraine 
1050 
(planned) 
ALD403-CLIN-013 
(ongoing) 
Phase 2 
Safety 
Chronic Migraine 
128 
128 
NA 
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. 
5.3.3 Dose Justification 
In study ALD403-CLIN-002, a single intravenous infusion of 1000 mg ALD403 produced 
sustained efficacy in terms of mean change from baseline in migraine days and the responder 
analysis.  The mean Free ALD403 (ALD403 available for binding to the CGRP ligand) plasma 
concentrations observed at weeks 12 and 24 in subjects receiving 1000 mg ALD403 were 


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25.6 and 3.4 µg/mL, respectively.  Results from a prior study, ALD403-CLIN-001, demonstrated 
marked suppression of capsaicin-induced skin blood flow at doses ranging from 30-1000 mg 
ALD403 given as a single intravenous infusion.   Prolonged suppression of capsaicin-induced 
skin blood flow for 12 weeks was observed following IV infusion of ≥ 100 mg ALD403.     
The ALD403-CLIN-006 study design will explore ALD403 given by repeat IV administration at 
doses of 30, 100, and 300 mg every 12-weeks.  
For subjects participating in ALD403-CLIN-006 at the highest dose level, 300 mg ALD403 
administered by IV infusion every 12-weeks, the estimated systemic exposure to Free ALD403 
following the last (fourth) administration is Cmax = 110.2 µg/mL and AUC (0-12wk) = 
46,648 µg*hr/mL.  These ALD403 exposure levels are at least 56- and 19-fold less than the 
mean Cmax and AUC(0-2Wk) systemic exposures, 19,600 µg/mL in males and 6,160 µg/mL in 
females, and 1,610,000 µg*hr/mL in males and 904,000 µg*hr/mL in females, respectively, 
observed in cynomolgus monkeys following a chronic 6-month evaluation of ALD403 
administered IV at the no-observed-adverse-effect-level (NOAEL) of 150 mg/kg once every 
2-weeks.
The high dose of 300 mg administered during ALD403-CLIN-006 is expected to provide 
efficacious treatment in FEM.  The low and mid doses, 30 and 100 mg ALD403, respectively, 
were selected to explore the potential for dose-related efficacy following ALD403 treatment.   
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.  


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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, with ALD403 
demonstrating a favorable benefit-risk profile based on review of nonclinical, clinical, and 
scientific literature data. 
The sponsor will continue to monitor for significant new information and suspected adverse 
reactions associated with the use of ALD403. 
5.5 Compliance Statement 
This clinical trial will be conducted in accordance with standards of Good Clinical Practice 
(GCP), as defined by the International Conference on Harmonisation (ICH) and all applicable 
federal and local regulations. 
6 Objectives 
6.1.1 
Primary Objective 
The primary objective is: 
•
To evaluate the efficacy of repeat doses of ALD403 administered IV compared to
placebo in patients with FEM.


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6.1.2 
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 FEM.
•
To evaluate the pharmacokinetics (PK) and immunogenicity of repeat doses of ALD403
administered IV to patients with FEM.
7 Trial Design 
7.1 Clinical Trial Endpoints 
More detail regarding the clinical trial endpoints and their derivation can be found in 
Section 12.1. Migraine headaches for the efficacy endpoints are defined as migraines or probable 
migraines as outlined in the International Headache Society (IHS), International Classification of 
Headache Disorders (ICHD II 2004-II), Section 1.1 and 1.6.11 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
7.1.3 
Other Secondary Endpoints 
•
Change in acute migraine medication days (Weeks 1-12)
•
Headache/migraines with acute medication usage
•
100% migraine responder rates (Weeks 1-12)
•
Short-Form Health Survey (SF-36)
•
Health-Related Quality of Life (EQ-5D-5L)
•
Allodynia Symptom Checklist-12 (ASC-12)


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•
Brush (dynamic mechanical) Allodynia
•
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/migraine days
•
Time to first migraine after dosing
•
Headache/migraine hours
•
Headache/migraines with severe intensity
7.1.4 
Tertiary Endpoints 
•
Headache episodes/migraine attacks
7.1.5 
Safety Endpoints 
•
Adverse events (AEs) and serious adverse events (SAEs)
•
Changes in clinical laboratory assessments
•
Vital signs
•
Electrocardiogram (ECGs)
•
Suicidal ideation and behavior as measured by the C-SSRS
7.1.6 
Pharmacokinetic Endpoints 
•
Free ALD403 plasma concentrations
7.1.7 
Immunogenicity Endpoints 
•
Development of specific anti-ALD403 antibodies
•
Characterization of specific anti-ALD403 antibodies for neutralizing activity
7.2 Clinical Trial Design 
This is a phase 3, parallel group, double-blind, randomized, placebo-controlled trial of multiple 
infusions of ALD403 or placebo in subjects with FEM.  Subjects who provide informed consent 
will be qualified based upon the inclusion and exclusion criteria and compliance with the eDiary. 


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The subject will be instructed to complete the eDiary daily from the screening visit through 
Week 48. During the screening period, an eDiary Eligibility Report will calculate headache and 
migraine results, and provide an eDiary compliance report. The headache and compliance data 
from the eDiary will be made available to and reviewed by the clinical site on a regular basis via 
the eDiary system portal.  Subjects will return to the site on Day 0 for randomization and first 
treatment which should occur at least 29 days but no more than 35 days after the screening visit. 
Subject eligibility will be re-confirmed on Day 0, prior to randomization.  Any subject found to 
be no longer eligible for the study on Day 0, will not be randomized nor dosed.  
The subjects randomized and dosed will continue the study for 56 weeks.  These 56 weeks are 
divided into two periods, i.e., a primary efficacy and safety period (Weeks 1-24) and a long term 
safety period (Weeks 25-56). Subjects will complete the eDiary daily through Week 48.   
Approximately 800 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), which includes appropriately qualified members who are 
independent of the Sponsor, will be formed to consider safety data generated during the clinical 
trial. These members will be appointed externally by the Sponsor, and will not be connected with 
management of the clinical trial.  
The primary focus of the DMC will be the safety experience 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.  DMC analyses will be conducted periodically through-out the study. 
7.4 Methods to Minimize/Avoid Bias 
To minimize bias, this clinical trial is randomized, double-blind and placebo controlled.  At the 
point of infusion, there are no obvious differences between ALD403 and placebo, and there are 


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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.  
8 Selection and Withdrawal of Subjects 
8.1 Inclusion Criteria 
A subject must meet all of the following criteria within the 28 days prior to randomization to be 
eligible for inclusion in the trial: 
1.
Willing and able to read and understand the consent process and sign an Informed
Consent Form (ICF) for the clinical trial approved by the Investigator’s local Review
Board or a central Institutional Review Board (IRB) or Ethics Committee (EC)
2.
Male or female between 18 and 75 years of age inclusive (age determined at time of
informed consent)
3.
Diagnosis of migraine at ≤ 50 years of age (ICHD-II, 2004 Section 1 11)
4.
History of migraine ≥ 12 months with
a.
≤ 14 headache days of which at least 4 have to be migraine days (migraine days
count as headache days) in each 28 day period in the 3 months prior to screening
b. During the 28 days following the screening visit, the subject experiences
< 14 headache days of which at least 4 have to be migraine days (migraine days
count as headache days) as recorded in the eDiary;
5. Use of acute migraine medications ≤ 14 days per 28 day period in the 3 months prior to
screening and the 28 day period prior to randomization
6. Use of triptans must be ≤ 10 days per 28 day period in the 3 months prior to screening
and the 28 day period prior to randomization
7.
No regular use (greater than 7 days) of prophylactic headache medication (any
preventive medication or supplement with evidence of efficacy from at least 1 placebo-
controlled trial, see Section 15.1) within 2 months prior to screening and during the


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28 day period prior to randomization; short-term (no more than 7 days in a month) 
menstrual migraine prophylactics are allowed 
8. No use of any botulinum toxin for migraine or for any other medical/cosmetic reasons
requiring injections in the head, face, or neck 4 months prior to screening and during the
28 day period prior to randomization
9. Limited use of barbiturates (including Fiorinal®, Fioricet®, or any other combination
containing butalbital) and prescription opiates by maintaining stable dose for 2 months
prior to screening and dosing does not exceed 4 days per month through Week 24.  (as
outlined in Section 9.4), Drugs containing non-prescription codeine (16 mg or less) are
permitted.
10. Not to use any approved devices, neuromodulation, neurostimulation or injectable
therapy (trigger point injections, extracranial nerve blocks, facet joint injections) for
headache prophylaxis are prohibited 2 months prior to screening and during the 28 day
period prior to randomization
11. Women of child-bearing potential, and males with partners of child-bearing potential,
must agree to use adequate contraception throughout study participation and for up to six
months after last dose.   Adequate contraception includes oral, transdermal or injectable
[depot] estrogen, and/or progestogen, selective estrogen receptor modulator contraceptive
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.
12. Any hormonal therapy (e.g., contraceptives, hormone replacement therapy) use is stable
and ongoing for at least 3 months prior to screening and through Week 56
13. Willing, committed, and able to comply with scheduled clinic visits and complete all
trial-related procedures
14. Headache eDiary was completed on at least 25 of the 28 days prior to randomization


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15. Subject agrees not to post any personal medical data related to the trial or information
related to the trial on any website or social media site (e.g., Facebook, Twitter) during the
trial
16. Subject is willing to complete the daily eDiary for the duration of the study and agrees to
use the eDiary device for the sole purpose of the ALD403-CLIN-006 study without
alteration
8.2 Exclusion Criteria 
  A subject who meets any of the following criteria will be excluded from the trial: 
1.
Confounding pain syndromes, e.g. fibromyalgia, complex regional pain syndrome or
any pain syndrome that requires regular analgesia
2.
Psychiatric conditions that are uncontrolled and untreated, including conditions that are
not controlled for a minimum of 6 months prior to screening
3.
Known or suspected Temporo-Mandibular Disorders (TMD)
4.
History or diagnosis of complicated migraine (ICHD- II, 2004 Section 1 11), chronic
tension-type headache, hypnic headache, cluster headache, hemicrania continua, new
daily persistent headache, migraine with brainstem aura, sporadic and familial
hemiplegic migraine
5.
Unable to differentiate migraine from other headaches
6.
Have present or previous malignancies, except:
•
Subjects with a history of squamous or basal skin cell carcinoma with excision for
cure
•
Subjects with a history of breast or cervical cancer ≥ 10 years since
diagnosis/treatment without evidence of recurrence
7.
Cardiovascular disease (hypertension, ischemic heart disease), neurological disease,
cerebrovascular disease, diabetes, or Raynaud’s disease, life-threatening allergy (e.g,
anaphylaxis); if questions arise, the Investigator should contact the Medical Monitor for
guidance


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8.
Have a clinically significant abnormal ECG at screening or pre-dose on Day 0.  An alert
for a clinically significant abnormality will be set at the following interval values:
•
RR < 460 msec (or HR > 130 bpm)
•
RR > 1700 msec (or HR < 35 bpm)
•
QRS > 180 msec
•
QTcF > 500 msec (or any other QTc method if QTcF is not utilized)
9.
Have any clinically significant concurrent medical condition as shown by, but not
limited to:
Hepatic 
•
ALT ≥ 2 x ULN; AST ≥ 2 x ULN
Hematology 
•
Hemoglobin < 10 g/dL
•
Absolute neutrophil count < 1000cells/µL
•
Platelet count < 100,000 cells/µL (patients with 75,000-100,000 cells/ µL
can be considered for enrollment if there are no comorbid conditions;
contact Medical Monitor prior to enrollment)
Renal 
•
Creatinine > 2.0 mg/dL
10. Systolic blood pressure (BP) 140 mm Hg and/or diastolic BP 90 mm Hg or greater at
Treatment/Day 0 (can repeat 15 minutes later to confirm)
11. Beck Depression Inventory (BDI-II) score >24 at screening
12. The subject is at imminent risk of self-harm or harm to others in the investigator’s
opinion, based on clinical interview and responses provided on the Columbia-Suicide
Severity Rating Scale (C-SSRS).  Subjects must be excluded if they report suicidal
ideation of Type 4 or 5 (i.e., suicidal ideation with intent, with or without a plan) in the
past 6 months or suicidal behavior in the past 2 years, as measured by the C-SSRS at
Screening or Baseline.
13. Any history or evidence of substance abuse (e.g., alcohol, opiates, and barbiturates)
within the past 2 years according to the International Classification of Diseases (ICD)
10: F10-19.12


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14. Pregnant, breastfeeding, or planning to become pregnant during the trial
15. 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
16. Receipt of any monoclonal antibody treatment within 6 months of screening (within or
outside a clinical trial)
17. Previously dosed with ALD403 or any monoclonal antibody targeting the CGRP
pathway
18. Planned or current participation in any other clinical trial during the duration of this
clinical trial, or within 6 months of screening
19. Recent or planned surgery, requiring general anesthesia, within 8 weeks prior to
screening and during the duration of this clinical trial
20. Positive for HIV, hepatitis B surface antigen, or hepatitis C antibody at screening
21. 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)
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 ICF is signed, a subject will be assigned a unique subject number. The 
first part of the subject number identifies the site and the second part identifies the subject. 
8.3.2 
Randomization and Treatment Assignment 
Randomization will occur 29 to 35 days after the screening visit after eligibility assessments are 
completed and eligibility verified. Sites will complete the randomization in an Interactive Web or 
Voice Response System (IWRS or IVRS) and the randomization assignment will be obtained by 
the clinical trial site’s unblinded pharmacist or Investigational Product consignee.  Subjects will 
be randomized in equal ratios to one of the dose groups.  Stratified permuted block 
randomization will be used. Stratification will be by migraine days during the screening period 
(≤9 days vs. >9 days).   


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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 
subject number.  
8.4 Subject Treatment Discontinuation and Withdrawal 
Subjects may discontinue treatment or withdraw from the clinical trial at any time without 
penalty and for any reason without prejudice to his or her future medical care.    
8.4.1 
Criteria for Discontinuation from Study Treatment 
Study treatment may be discontinued for the following reasons: 
•
Adverse Event
•
Subject decision
•
Investigator decision
•
Subject lost to follow-up
•
Termination of the study by the sponsor
If subjects discontinue from study treatment due to a medical condition, investigators must 
provide adequate medical treatment during the follow up 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 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
The reason for withdrawal and the time of withdrawal must be recorded on the CRF. 


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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. 
8.4.4 
Follow-up for Early Withdrawal 
Subjects, who wish to withdraw their consent to have their medical information collected, 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. 
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 prophylaxis 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 active will receive an IV infusion of 
ALD403 Injection in 100 mL of 0.9% saline.   
9.2 Control Drug 
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. 


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9.3 Investigational Product Dosing and Administration 
The pharmacist or Investigational Product consignee responsible for dispensing and preparing 
the ALD403 and Placebo IV infusions will be unblinded and will not be responsible for other 
aspects of the clinical trial where blinding is necessary. The infusions will be prepared using 
aseptic techniques. 
The doses of ALD403 or Placebo (total volume of 100 mL) will be administered IV over a 
period of 1 hour (± 15 minutes) on Day 0 and Week 12, 24 and 36, by the blinded Investigator or 
designee. Subjects must be monitored for 4 hours after the dosing completion.  If the subject 
experiences a headache or migraine on dosing day, dosing may occur if it doesn’t compromise 
the safety of the subject in the judgment of the Investigator.   
Further instructions on the preparation and procedure 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 and Placebo will be 
labeled with the protocol number, contents (“ALD403” or “Placebo”), directions for storage, the 
Sponsor, and any other information required by regulatory agencies, such as a statement that it is 
limited to investigational use. Investigational Product and Placebo to be administered to the 
subject will be labeled by the investigators in a manner (after dose preparation) that protects 
blinding. 
9.3.2 
Blinding 
This clinical trial is double-blind, meaning the subjects and site personnel are blinded to 
treatment assignment, except for clinical trial site’s unblinded pharmacist or Investigational 
Product consignee. 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 Investigational 
Product is critical to the subject safety and /or trial management. The Principal Investigator will 
report any cases of unblinding to the sponsor within 24 hours of the incident.  
Immediately prior to PK/immunogenicity sample analysis, the bioanalytical laboratory will be 
unblinded in order to obtain the treatment assignments. The study will remain blinded until the 


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last subject has completed the Week 24 visit at which time aggregate efficacy and safety data 
will be unblinded.  
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 institutional standards. 
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. 
9.3.4 
Accountability and Disposition of Investigational Product 
The Investigator is responsible for maintaining accurate Investigational Product and Placebo 
accountability records throughout the clinical trial. The site must maintain a record of 
Investigational Product Accountability Log on which the unblinded responsible pharmacist, or 
designee, will record the receipt, lot number/retest date, quantity, dispensation and return of 
Investigational Product to the Pharmacy, as well as any destruction of Investigational 
Product/Placebo including empty Investigational Product/Placebo containers (e.g., vials) or 
returns to the Sponsor.  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 or Placebo 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 (if authorized by Sponsor) all unused Investigational Product/Placebo. 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. Where the Sponsor has 


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indicated in writing that Investigational Product/Placebo is to be destroyed on site, destruction 
must be in accordance with local regulations for the product type and destruction documentation 
must be provided to the Sponsor.   
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 through 
Week 56, must be recorded on the CRF, including medications required for treatment of any AEs 
or SAEs. 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. Use of regular 
prescription medications for condition other than migraine must be preapproved by Medical 
Monitor. 
The following medications are restricted through Week 24: 
•
Any prophylactic headache medication (any preventive medication or supplement with
evidence of efficacy from at least 1 placebo-controlled trial, see Section 15.1) is
prohibited.
•
Barbiturates and prescription opiates are allowed for ≤ 4 days per month through Week
24, provided the subject does not meet the criteria for Medication Overuse Headache and
has been on a stable regimen (≤ 4 days per month) for at least 2 months prior to
screening. Drugs containing non-prescription codeine (16 mg or less) are permitted.
•
Botulinum toxin for migraine or for any other medical/cosmetic reasons requiring
injections in the head, face, or neck are prohibited 4 months prior to screening through
Week 24.
•
Devices, neuromodulation, neurostimulation, or injectable therapy (trigger point
injections, extracranial nerve blocks, facet joint injections) for headache prophylaxis are
prohibited 2 months prior to screening through Week 24.


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10 Schedule of Assessment and Procedures 
Assessment and procedures at each visit are summarized in Section 2 (Schedule of Events and 
Assessments). An electronic headache eDiary will be distributed to each subject at the time of 
screening visit. The subject will record information daily regarding headache characteristics, 
severity and length. Compliance data from the eDiary will be made available and reviewed by 
the trial site. 
10.1 Screening Day (Day -35 to -29) 
The following assessments will be performed and measurements recorded: 
•
Written informed consent
•
Inclusion/exclusion criteria reviewed
•
Demographics (gender, age, race, ethnicity)
•
Medical history including Migraine History
•
Height and body weight
•
Physical examination
•
Vital signs including blood pressure (BP) and pulse
•
Beck Depression Inventory (BDI-II)
•
Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening Version
•
12-lead ECG
•
Clinical laboratory tests, including hematology, serum chemistry, and serology (including
HIV, Hepatitis B and Hepatitis C)
•
Urine drugs of abuse screening
•
Pregnancy test (urinary hCG) on all female subjects
•
Adverse events
•
Concomitant medications
•
Distribute headache eDiary and instruct subject on completion and compliance of diary
10.2 Day 0 (Randomization and Treatment) 
Day 0 must be 29 to 35 days after the screening visit. 


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The following assessments will be performed pre-dose (unless otherwise specified) and 
measurements recorded with review of data from eDiary: 
•
Review inclusion/exclusion criteria including:
o
Verification of completion of eDiary for at least 25 of 28 days following screening
o
Verification that during the 28 day period following screening, the subject
experienced ≤ 14 headache days of which at least 4 have to be migraine days
(migraine days count as headache days) as recorded in the eDiary.
•
Body weight
•
Physical examination
•
Brush allodynia test
•
Vital signs including BP and pulse
o
Vital signs will be obtained and recorded prior to the start of Investigational Product
infusion and 4 hours post-end of infusion (± 30 minutes).
•
C-SSRS Since Last Visit Version
•
12-lead ECG
o
12-lead ECGs will be performed prior to the start of Investigational Product infusion
and 4 hours post-end of infusion (± 30 minutes)
•
Clinical laboratory tests, including hematology and serum chemistry
•
Pregnancy test (urinary hCG) on all female subjects
o
Subjects with a positive pregnancy test will not be dosed and will be withdrawn from
the trial
•
Plasma Free ALD403 PK sample
o
Blood will be drawn pre-dose (within one hour prior to Investigational Product
administration)
•
A blood sample will be taken pre-dose for baseline determination of anti-ALD403
antibodies in serum (immunogenicity)
•
SF-36 v2.0, EQ-5D-5L and ASC-12 completion by subject
•
Adverse events (throughout visit)
•
Concomitant medications (throughout visit)
•
Randomize subject via the IWRS or IVRS system


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•
Dosing of ALD403 or Placebo; subject must be monitored for at least 4 hours after the
dosing completion
10.3 Week 4 Visit (Day 28 ± 3 days)  
The following assessments will be performed and measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Brush allodynia test
•
Vital signs including BP and pulse
•
C-SSRS Since Last Visit Version
•
12-lead ECG
•
Clinical laboratory tests, including hematology and serum chemistry
•
Plasma Free ALD403 PK sample
•
A blood sample will be taken for anti-ALD403 antibodies in serum (immunogenicity)
•
SF-36 v2.0, EQ-5D-5L and ASC-12 completion by subject
•
Adverse events
•
Concomitant medications
10.4 Week 8 Visit (Day 56 ± 3 days) 
The following assessments will be performed and measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Vital signs including BP and pulse
•
C-SSRS Since Last Visit Version
•
12-lead ECG
•
Plasma Free ALD403 PK sample
•
A blood sample will be taken for determination of anti-ALD403 antibodies in serum
(immunogenicity)


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•
SF-36 v2.0, EQ-5D-5L and ASC-12 completion by subject
•
Adverse events
•
Concomitant medications
10.5  Week 12 Visit (Day 84 ± 3 days)
The following assessments will be performed pre-dose (unless otherwise specified) and 
measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Brush Allodynia test
•
Vital signs including BP and pulse
o
Vital signs will be obtained and recorded prior to the start of Investigational Product
infusion and 4 hours post-end of infusion (± 30 minutes).
•
C-SSRS Since Last Visit Version
•
12-lead ECG
o
12-lead ECGs will be performed prior to the start of Investigational Product infusion
and 4 hours post-end of infusion (± 30 minutes)
•
Clinical laboratory tests, including hematology and serum chemistry
•
Pregnancy test (urinary hCG) on all female subjects
•
Plasma Free ALD403 PK sample
o
Blood will be drawn pre-dose (within one hour prior to Investigational Product
administration)
•
A blood sample will be taken pre-dose for baseline determination of anti-ALD403 antibodies
in serum (immunogenicity)
•
SF-36 v2.0, EQ-5D-5L and ASC-12 completion by subject
•
Adverse events
•
Concomitant medications
•
Dosing of ALD403 or Placebo; subject must be monitored for at least 4 hours after the
dosing completion


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10.6  Week 16 Visit (Day 112 ± 3 days) 
The following assessments will be performed and measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Brush allodynia test
•
Vital signs including BP and pulse
•
C-SSRS Since Last Visit Version
•
Plasma Free ALD403 PK sample
•
A blood sample will be taken for determination of anti-ALD403 antibodies in serum
(immunogenicity)
•
SF-36 v2.0, EQ-5D-5L and ASC-12 completion by subject
•
Adverse events
•
Concomitant medication
10.7  Week 20 Visit (Day 140 ± 3 days)
The following assessments will be performed and measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Brush allodynia test
•
Vital signs including BP and pulse
•
C-SSRS Since Last Visit Version
•
Plasma Free ALD403 PK sample
•
A blood sample will be taken for determination of anti-ALD403 antibodies in serum
(immunogenicity)
•
SF-36 v2.0, EQ-5D-5L and ASC-12 completion by subject
•
Adverse events
•
Concomitant medications


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10.8  Week 24 Visit (Day 168 +3 days)  
Week 24 must be done on the target day or 3 days after. Three days earlier than target date is not 
allowed. The following assessments will be performed and measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Body weight
•
Physical examination
•
Brush allodynia test
•
Vital signs including BP and pulse
o
Vital signs will be obtained and recorded prior to the start of Investigational Product
infusion and 4 hours post-end of infusion (± 30 minutes).
•
C-SSRS Since Last Visit Version
•
12-lead ECG
o
12-lead ECGs will be performed prior to the start of Investigational Product infusion
and 4 hours post-end of infusion (± 30 minutes)
•
Clinical laboratory tests, including hematology and serum chemistry
•
Pregnancy test (urinary hCG) on all female subjects
•
Plasma Free ALD403 PK sample
o
Blood will be drawn pre-dose (within one hour prior to Investigational Product
administration)
•
A blood sample will be taken pre-dose for baseline determination of anti-ALD403 antibodies
in serum (immunogenicity)
•
SF-36 v2.0, EQ-5D-5L and ASC-12 completion by subject
•
Adverse events
•
Concomitant medications
•
Dosing of ALD403 or Placebo; subject must be monitored for at least 4 hours after the
dosing completion


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10.9  Week 28 Visit (Day 196 ± 7 days)  
The following assessments will be performed and measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Vital signs including BP, pulse
•
12-lead ECG
•
Clinical laboratory tests, including hematology and serum chemistry
•
C-SSRS Since Last Visit Version
•
Adverse events
•
Concomitant medications
10.10 Week 36 Visit (Day 252 ± 3 days)
The following assessments will be performed pre-dose (unless otherwise specified) and 
measurements recorded: 
•
Headache eDiary data reviewed by trial site
o
Review compliance with completion of eDiary; if subject is not compliant with the
daily eDiary, instruct regarding importance of daily completion
•
Physical examination
•
Body weight
•
Vital signs including BP, pulse will be obtained prior to the start of Investigational Product
infusion and 4 hours post-end of infusion (± 30 minutes)
•
12-lead ECG
o
12-lead ECGs will be performed prior to the start of Investigational Product infusion
and 4 hours post-end of infusion (± 30 minutes)
•
Clinical laboratory tests, including hematology and serum chemistry
•
Pregnancy test (urinary hCG) on all female subjects
•
C-SSRS Since Last Visit Version
•
SF-36


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24-Apr-2017
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•
Plasma Free ALD403 PK sample
o
Blood will be drawn pre-dose (within one hour prior to Investigational Product
administration)
•
A blood sample will be taken pre-dose for determination of anti-ALD403 antibodies in serum
(immunogenicity)
•
Adverse events
•
Concomitant medications
•
Dosing of ALD403 or Placebo; subject must be monitored for at least 4 hours after the
dosing completion
10.11  Week 48 Visit (Day 336 + 7 days) 
The following assessments will be performed and measurements recorded: 
•
Return of Headache eDiary
•
Vital signs including BP, pulse
•
12-lead ECG
•
Clinical laboratory tests, including hematology and serum chemistry
•
Pregnancy test (urinary hCG) on all female subjects
•
Plasma Free ALD403 PK sample
•
A blood sample will be taken for determination of anti-ALD403 antibodies in serum
(immunogenicity)
•
C-SSRS Since Last Visit Version
•
Adverse events
•
Concomitant medications
10.12  Week 56 Visit (Day 392 ± 7 days) End of Study or Early Termination
The following assessments will be performed and measurements recorded: 
•
Body weight
•
Physical examination
•
Vital signs including BP, pulse
•
12-lead ECG


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•
Clinical laboratory tests, including hematology and serum chemistry
•
Pregnancy test (urinary hCG) on all female subjects
•
Plasma Free ALD403 PK sample
•
A blood sample will be taken for determination of anti-ALD403 antibodies in serum
(immunogenicity)
o
Subjects who test positive for anti-ALD403 antibodies at the last study visit will be
asked to provide up to 2 additional blood samples for immunogenicity testing at
approximately 3 month intervals for up to 6 months.
•
C-SSRS Since Last Visit Version
•
SF-36
•
Adverse events
•
Concomitant medications
10.13 Early Termination
All subjects will be encouraged to complete all evaluations through Week 56.  However, subjects 
who prematurely discontinue the study will have Early Termination assessments completed at 
the time of discontinuation.   Subjects who are randomized but do not receive study treatment 
may discontinue the study without any further procedures. 
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) 


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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.
•
Asymptomatic abnormal findings considered by the Investigator to be clinically
significant.  For example, abnormal ECG or abnormal lab findings.
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.  
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)


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•
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)
Severity 
The severity of an AE will be graded as follows: 
o
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic
observations only; intervention not indicated.
o
Grade 2 Moderate; minimal, local or noninvasive intervention indicated;
limiting age-appropriate instrumental Activities of Daily Living (ADL).
o
Grade 3 Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting
self-care ADL.
o
Grade 4 Life-threatening consequences; urgent intervention indicated.
o
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 


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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.   
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, and
•
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”. 


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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
•
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 or designee 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. 


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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. 
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, mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), platelet count, 
red blood cell (RBC) count, RBC morphology, 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(s) or may have been pregnant at the time of Investigational Product(s) exposure, or the 
partner of a male subject becomes pregnant following administration of Investigational 


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Product(s), 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. 
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, or premature
termination of the pregnancy, or miscarriage
•
offspring information including; birth weight, and birth defects (if any)
11.1.9 Suicidal Ideation and Behavior  
Recent meta-analyses, spontaneous reports, and published case reports regarding suicidal 
ideation and behavior arising from drugs tested in clinical trials have been noted as an area of 
general concern. Based on this information, the United States Food and Drug Administration 
(FDA) has provided guidance to prospectively assess suicidal ideation and behavior in clinical 
trials to ensure that subjects in clinical trials who are experiencing suicidal ideation and behavior 
are properly recognized and adequately treated and to ensure the collection of more timely and 
more complete data on suicidal ideation and behavior than have been collected in the past 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 C-SSRS will be discontinued 
from the study treatment and referred by investigators to a mental health specialist. 
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 


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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. 
If a subject experiences a potential systemic allergic reaction as assessed by the PI, the site will 
collect additional blood specimen(s) using the anaphylactic kit (unscheduled kit Type E) at the 
time of the event as per the PPD laboratory manual.  This assessment includes serum histamine, 
serum tryptase, immunoglobulin E, and complement components. 
As a guideline, if a site does not have a formal “crash cart”, the following should be considered 
as a requirement at the site: 
• Clinical personnel should be CPR certified 
• Clinic should have an automated external defibrillator 
The site should have the following emergency medications available: antihistamines, 
bronchodilators, IV saline, corticosteroids, acetaminophen, and epinephrine. 
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 48.  The 
diary 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 compliance data 
from the eDiary will be made available to the trial site for review. Sites are to review the diary 
results with the subject and if the subject has not completed the diary daily, counsel the subject 
on the importance of daily completion of the diary.  
The eDiary data from the 28 days following screening visit will be used to determine eligibility 
criteria, and the baseline migraine and headache results.   


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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 four week, twelve week and the twenty-four week 
interval.  Specifically, migraine and headache endpoints will be summarized for the four week 
intervals: Weeks 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, … 44-48, the twelve week intervals 1-12, 
13-24, 25-36, 37-48 and Weeks 1-24, 25-48.
Migraine Day 
A migraine day is defined as any day with a headache that meets the migraine or probably 
migraine characteristics as outlined in Section 7.  Specifically, a migraine is defined as a self-
reported headache which: 
1. Lasted 4 – 72 hours
2. had at least 2 of the following
a.
Unilateral location
b. Pulsating quality
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
A probable migraine is a headache that meets only 2 of the above criteria. 
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 


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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.  
Results from these four week intervals will be combined to produce 12 and 24 week responder 
endpoints.  A responder will be a subject who achieves the specified percent reduction in 
migraine headache days within these intervals based upon the average change from baseline 
measures.    
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. 
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 / 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 included with a rate of zero. 
Acute Medication Usage 
The percent of migraines and headaches with acute medication usage will be summarized. 
Subjects with no migraines/headaches will be included with a rate of zero. 


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Acute Migraine Medication Usage 
The number of days within 4 week intervals 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 first dose will be summarized. 
Time to First Migraine 
Time to the first migraine after dosing will be analyzed based upon the migraine data entered 
into the eDiary.   
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.   
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. 


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Allodynia Symptom Checklist (ASC-12) 
The ASC-12 includes 12 questions about the frequency of various allodynia symptoms in 
association with headache attacks. For individuals with more than one type of headache, 
questions are directed to the “most severe type of headache.”  Each item is measured on a Likert 
type scale option with response categories: “Does not apply to me”, “never,” “rarely,” “less than 
half the time,” and “half the time or more,” see Appendix 15.5.     ASC items were scored as 0 
(i.e., never, rarely, or does not apply to me), 1 (less than half the time), and 2 (half the time or 
more), yielding scores that ranged from 0 to 24.  In this study, if a single item is missing it will 
be scored as a zero.  If more than one item is missing the total score will be missing.  The 
interpretation of the total score is provided below. 
Score Range 
Allodynia 
0-2
3-5
6-8
≥9
None 
Mild 
Moderate 
Severe 
Brush Allodynia 
Dynamic mechanical brush allodynia will be tested by lightly brushing a 10 by 10 cm gauze pad 
bilaterally, 1-2 cm over each eyebrow at a rate of 2/second, for a total of 10 times. 14 For each 
side of their forehead, subjects will be asked to assess the degree of pain elicited by the gauze on 
a scale of 0 to 10 with 0 being no pain and 10 being the worst imaginable pain.15 
12.2 Pharmacokinetics 
The concentrations of Free ALD403 will be measured in plasma from all ALD403-treated 
subjects using validated assay methods. The PK analysis will include evaluations of 
concentration-time profiles for Free ALD403 at the following times: pre-dose on Day 0, and 
Weeks 4, 8, 12, 16, 20, 24, 36, 48 and 56. Plasma collected at Week 4 from all placebo-treated 
subjects will be analysed for the potential presence of Free ALD403 using validated assay 
methods.  
Additional sample handling, processing, storage, labelling and shipping instructions will be 
provided to the site in a laboratory manual. 


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If a subject terminates early from the clinical trial, all efforts will be made to collect blood 
samples to analyse for Free ALD403 unless consent has been withdrawn. 
12.3 Immunogenicity 
Serum blood samples will be taken pre-dose on Day 0, and Weeks 4, 8, 12, 16, 20, 24, 36, 48 and 
56 to test for antibodies to ALD403. The immunogenicity will be assessed in serum from all 
ALD403-treated subjects using validated assay methods.  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 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 potential for neutralizing (NAb) ALD403 activity.  Subjects who test positive for 
specific anti-ALD403 antibodies at the time of the last study visit will be asked to provide up to 
2 additional blood samples for immunogenicity testing at approximately 3 month intervals for up 
to 6 months. 
Additional sample handling, processing, storage, labelling and shipping instructions will be 
provided to the site in a laboratory manual.  
13 Statistical Considerations 
13.1 Decision Rule 
A serial procedure will be used to account for multiplicity of dose level for the primary endpoint 
and the 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 a subset of the key 
secondary endpoints for 300 mg (first the Weeks 1-4 75% responder endpoint, then the 
Weeks 1-12 75% responder endpoint, and then the Weeks 1-12 50% responder endpoint).  The 
procedure will then move on to the primary endpoint for the 100 mg group and subsequently to 
the same subset of key secondary endpoints as tested for the 300 mg dose.  The procedure will 
then move on to the remaining key secondary endpoint for 300 mg and 100 mg (i.e., percentage 
of subjects with a migraine on the day after dosing).  Only if all of these secondary endpoints 


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reach statistical significance will the 30 mg group be tested.  This testing algorithm is presented 
below. 
Statistical testing will be conducted at the 5% alpha level. 
13.2 Sample Size 
The planned sample size for this study is 800 randomized and treated subjects.  These subjects 
will be allocated into 4 treatment groups in a 1:1:1:1 ratio.  Pair-wise testing of each ALD403 
group vs. placebo will be performed. Two hundred subjects per group provides at least 95% 
power for each change in frequency of migraine days (Weeks 1-12) test individually assuming a 
treatment effect of at least 1 day and a common standard deviation of 2.7 days or less.  Ninety 
percent power is retained for standard deviations up to 3 days.  For the key secondary 75% 
responder rates endpoints 95% power is achieved for the pair-wise comparisons assuming rates 
of 24% for placebo and 42% for ALD403.  For the 50% responder rate endpoints 95% power is 
achieved for the pair-wise comparisons assuming rates of 50% for placebo and 68% for 
300 mg Wks 1-12 change in migraine days 
  
300 mg Wks 1-4 75% responder rate 
  
300 mg Wks 1-12 75% responder rate 
  
300 mg Wks 1-12 50% responder rate 
100 mg Wks 1-12 change in migraine days 
  
100 mg Wks 1-4 75% responder rate 
 
100 mg Wks 1-12 75% responder rate 
  
100 mg Wks 1-12 50% responder rate 
300 mg Percentage of subjects with a 
migraine on the day after dosing 
 
100 mg Percentage of subjects with a 
migraine on the day after dosing 
30 mg Wks 1-12 change in migraine days 
 
30 mg Wks 1-4 75% responder rate 
 
30 mg Wks 1-12 75% responder rate  
 
30 mg Wks 1-12 50% responder rate 
 
30 mg Percentage of subjects with a 
migraine on the day after dosing  


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ALD403.  For the percentage of subjects with a migraine on the day after dosing endpoint, 95% 
power is achieved for pair-wise comparisons assuming rates of 15% for placebo and 4% for 
ALD403. 
These sample size calculations have been performed using Pass 2008 and are based upon t-tests 
and Chi-squared tests that should approximate the ANCOVA and CMH tests, respectively. 16 
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 diary 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 
trial medication, except if an incomplete date (e.g., month and year) clearly indicates that the 
event started prior to treatment.  
Summary statistics will be reported based upon observed data except for the diary 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 
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 diary data will be sporadic.  If the diary 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 diary on 5 days they will have completed the diary on 82% of the days and the 
normalized results will be the observed results times 1.22).  If the diary 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 


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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 diary was completed and will 
provide greater weight to the results from the current interval as the diary completion rate 
increases.  Specifically, the results will be derived as 
28൫𝑊𝑊𝑋𝑋𝑐𝑐+ (1 −𝑊𝑊)𝑋𝑋𝑝𝑝൯, 
where W is the days the diary 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 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.   
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. 


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13.4.2 Efficacy Analyses 
Efficacy endpoints will be summarized with descriptive statistics.  The migraine and headache 
endpoints will be summarized by four, twelve and twenty-four week intervals with the remaining 
endpoints being summarized by study week.  
Primary Efficacy Analyses 
Hypothesis testing will be performed for the primary endpoint: change from baseline in migraine 
days from 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.  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 variable: baseline migraine days (continuous predictor) will be the independent 
variables.   
Secondary Efficacy Analyses 
Summary statistics including confidence interval for the treatment differences will be used to 
summarize the results for the secondary endpoints. Testing will be performed for the key 
secondary endpoints and for the change in acute migraine medication days endpoint.  For the key 
secondary endpoints (responder rates and percentage of subjects with a migraine on the day after 
dosing) this testing will utilize a CMH/extended CMH test.  The tests will be stratified by the 
randomization stratification factor.  The change in acute migraine medication day endpoints will 
be tested using an ANCOVA model similar to the one used for the primary endpoints:  change 
from baseline measure as the response, treatment and baseline acute migraine medication days as 


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independent variables. 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 of subjects with a migraine (prevalence) on the day after dosing 
endpoint.  Subjects who did not complete the diary on the day following dosing will be included 
in the prevalence rate calculation based upon their month 1 daily migraine rate. Hence, subjects 
with a migraine will be included in the rate calculation as a value of 1, subjects who completed 
the diary and did not have a migraine will be included as a zero and subjects who did not 
complete the diary will be included with a value between 0 and 1 equal to the number of month 1 
migraine days / 28. 
13.4.3 Pharmacokinetic Analyses 
Analysis of Drug Concentrations 
The concentrations of Free 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 Free 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 Free 
ALD403 concentrations obtained during this study in combination with the results from previous 
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 and treatment-related 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 


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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, treatment-related 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 and treatment-related 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 
Clinical laboratory values will be measured by a central laboratory. 
Summary statistics for actual values and for changes from baseline will be tabulated for clinical 
laboratory results by scheduled visit. Subjects with clinical laboratory values outside of the 
normal reference range at any post-baseline assessment will be summarized. Shifts from baseline 
clinical laboratory values based upon the normal range 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 


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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. 
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 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, eg, 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, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy, 
final report. 


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14.4 Data Collection and Electronic Data Capture (EDC) 
The data collected during the study (except clinical laboratory test results, ECG results, PK 
analyses, Immunogenicity) will be recorded in the subject’s electronic CRF. The Short-Form 
Health Survey (SF-36), Health related Quality of Life (EQ-5D-5L), Allodynia Symptom 
Checklist-12 (ASC-12) 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 CRFs 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 CRF 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.


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•
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 
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. 


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The procedures outlined in the protocol and CRFs 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 
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. 


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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 subject 
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 
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 Preventative Medications or Supplements with Evidence of Efficacy 
The list below includes, but is not limited to following medications or supplements which have 
evidence of efficacy with at least 1 randomized, placebo-controlled trial: 18, 19 
•
Antiepileptic drugs
o
divalproex sodium
o
sodium valproate
o
topiramate
•
Β-Blockers
o
metoprolol
o
propranolol
o
timolol
o
atenolol
o
nadolol
•
Triptans
o
frovatriptan
o
naratriptan
o
zolmitriptan
•
Antidepressants
o
amitriptyline
o
venlafaxine
•
Herbal preparations, vitamins, minerals
o
petasites
o
magnesium
o
MIG-99 (feverfew)
o
riboflavin
•
NSAIDS
o
fenoprofen
o
ibuprofen
o
ketoprofen
o
naproxen
o
naproxen sodium
•
Histamines
o
histamine SC


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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 
 COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The 
questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the 
determination of the presence of suicidal ideation or behavior depends on the judgment of the individual 
administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia 
Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the 
Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 Riverside 
Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal 
behavior: utility and limitations of research instruments. In M.B. First [Ed.] Standardized Evaluation in 
Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 
Riverside Drive, New York, New York, 10032; inquiries and training requirements contact 
posnerk@nyspi.columbia.edu 


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© 2008 The Research Foundation for Mental Hygiene, Inc. 
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 
is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
Since 
Last 
Visit 
1. Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
If yes, describe: 
Yes       No 
 □    □ 
2. Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of 
ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
If yes, describe: 
 Yes      No 
 □    □ 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would 
say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…and I would 
never go through with it.” 
Have you been thinking about how you might do this? 
If yes, describe: 
 Yes      No 
 □    □ 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
If yes, describe: 
Yes       No 
 □    □ 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
 Yes      No 
 □    □ 


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If yes, describe: 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
   Most Severe Ideation:  
  _____  
  _________________________________________________ 
  Type # (1-5)  
Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes 
 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time 
 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty 
(5) Unable to control thoughts 
(3) Can control thoughts with some difficulty 
 (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on thoughts 
of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide 
 (4) Deterrents most likely did not stop you
(2) Deterrents probably stopped you
(5) Deterrents definitely did not stop you
(3) Uncertain that deterrents stopped you
 (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way you were 
feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, revenge or a reaction 
from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others 
  living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others 
(5) Completely to end or stop the pain (you couldn’t go on 
____ 


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SUICIDAL BEHAVIOR 
Since 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to 
kill oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual 
suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For 
example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping 
from window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be 
inferred.  
Have you made a suicide attempt? 
Have you done anything to harm 
yourself?
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel 
better, get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes      No 
□   □ 
Total # of 
Attempts 
______ 
Yes     No 
□   □ 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from 
pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Yes      No 
□   □ 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Yes      No 
□  □ 
  and to end/stop the pain   
  living with the pain or  how you were feeling) 
(0)  Does not apply 


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Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, 
writing a suicide note).  
Yes      No 
□   □ 
Suicidal Behavior: 
Yes      No 
Suicide: 
  Yes    No 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Actual Lethality/Medical Damage: 
0. No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2. Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding 
of major vessel). 
3. Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact;
third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 
20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
Enter Code 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for 
very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with 
oncoming train but pulled away before run over). 
Enter Code 


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


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


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15.5 Allodynia Symptom Checklist (ASC-12) 


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15.6  Change Table for Amendment 4 
Section 
Pg 
Change From 
Change To 
Justification 
Cover page 
1 
 
 
  
 
 
 
Change in 
Sponsor’s 
Medical 
Monitor 
Signature Page 
2 
 
 
 
 
Change in 
Sponsor’s 
Medical 
Monitor 
1 Protocol 
Synopsis - 
Clinical Trial 
Endpoints 
5 
Key Secondary Endpoints 
 
• 
75% migraine 
responder rate (Weeks 
1-4) 
• 
75% migraine 
responder rate 
(Weeks1-12) 
 
 
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 
 
Inclusion of 
additional 
endpoints that 
are believed to 
be clinically 
meaningful and 
would provide 
additional 
support and 
understanding 
of ALD403’s 
effectiveness in 
migraine 
prophylaxis. 
6 
Other Secondary Endpoints 
• 
Headache/migraines 
with acute medication 
usage 
• 
50% and 100% 
migraine responder 
rates (Weeks 1-12)  
• 
Short-Form Health 
Survey (SF-36) 
• 
Health-Related Quality 
of Life (EQ-5D-5L) 
• 
Allodynia Symptom 
Checklist-12 (ASC-12) 
• 
Brush (dynamic 
mechanical) Allodynia 
• 
Migraine responder 
rates for time periods 
other than Weeks 1-12. 
Other Secondary Endpoints 
• 
Change in acute 
migraine medication 
days (Weeks 1-12) 
• 
Headache/migraines 
with acute medication 
usage 
• 
100% migraine 
responder rates 
(Weeks 1-12)  
• 
Short-Form Health 
Survey (SF-36) 
• 
Health-Related 
Quality of Life (EQ-
5D-5L) 
• 
Allodynia Symptom 
Checklist-12 (ASC-
12) 
The change in 
acute migraine 
medication days 
endpoint has 
been added as 
requested by the 
FDA. 


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Section 
Pg 
Change From 
Change To 
Justification 
•
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/migraine
days
•
Time to first migraine
after dosing
•
Headache/migraine
hours
•
Headache/migraines
with severe intensity
•
Brush (dynamic
mechanical) Allodynia
•
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/migraine
days
•
Time to first migraine
after dosing
•
Headache/migraine
hours
•
Headache/migraines
with severe intensity
1 Protocol 
Synopsis - 
Statistical 
Analysis 
9 
The key secondary endpoints 
will be tested with a Cochran 
Mantel Haenszel (CMH) test 
controlling for the 
randomization stratification 
factor.     
The key secondary responder 
rate and percentage of subjects 
with a migraine on the day after 
dosing endpoints will be tested 
with a Cochran Mantel 
Haenszel (CMH) test 
controlling for the 
randomization stratification 
factor.     
Based upon 
changes to the 
key secondary 
endpoints. 
2 Schedule of 
Events 
11 
13Subjects 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.  
13Subjects who test positive for 
anti-ALD403 antibodies at the 
last study visit will be asked to 
provide up to 2 additional 
blood samples for 
immunogenicity testing at 
approximately 3 month 
intervals for up to 6 months.  
Clarification in 
immunogenicity 
testing visit 
window. 


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Section 
Pg 
Change From 
Change To 
Justification 
5.3.2 Summary 
of Clinical 
Trials 
23-26
A double-blind, randomized, 
placebo-controlled, ascending 
dose phase 1 study (Protocol 
ALD403-CLIN-001) to 
determine the safety and 
tolerability of ALD403 was 
conducted in two parts. In Part 
A (dose escalation), 1 of 7 
ALD403 dose levels (range 1 
mg to 1000 mg) or placebo was 
administered intravenously to 
healthy male subjects, and 
ALD403 300 mg or placebo 
was administered intravenously 
to healthy female subjects. 
Additionally, ALD403 100 mg 
or placebo was subcutaneously 
(SC) administered to a cohort of 
healthy male subjects.  
In Part B, sumatriptan 6 mg was 
administered SC 4 hours after 
either ALD403 300 mg IV or 
placebo IV to healthy subjects.   
In this trial, a total of 55 
subjects received a single 
intravenous dose of ALD403 
(range 1 mg to 1000 mg) and 31 
subjects received a single dose 
of placebo, 12 subjects received 
a single subcutaneous dose of 
ALD403 (100 mg) and 6 
subjects received a single 
subcutaneous dose of placebo. 
A total of 179 treatment 
emergent adverse events 
(TEAEs) were reported during 
the trial period in 73 subjects 
(70.2%).   Only one serious 
adverse event (SAE) was 
reported.  This event was 
considered unrelated to 
ALD403.  There were no 
TEAEs that resulted in study 
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 
Added Table 5.3 ALD403 
Clinical Trials 
Summary of 
Clinical Trials 
section updated 
with most 
current 
information. 


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drug administration 
interruption, death, or study 
discontinuation; no TEAEs 
were considered to be severe, 
life-threatening/disabling, or 
fatal. 
ALD403 inhibited capsaicin 
induced increases in skin blood 
flow (mediated by CGRP) in a 
dose dependent manner. The 
terminal elimination half-life of 
ALD403 was approximately 28 
days. 
In a second study of frequent 
episodic migraine (Protocol 
ALD403-CLIN-002), subjects 
with 5 to 14 migraine days per 
month were randomized to 
receive a single intravenous 
dose of ALD403 1000 mg or 
placebo in a double-blind 
fashion. The primary endpoint 
was the mean change in 
frequency of migraine headache 
days from baseline to Weeks 5-
8. Subjects were followed for
24 weeks for additional safety
and efficacy analyses.
Of 174 subjects randomized, 
163 subjects received either 
ALD403 (81) or placebo (82). 
There were no significant 
differences in baseline 
demographics or characteristics 
between the two treatment 
groups. The mean change in 
migraine days between Weeks 
5-8 and baseline was -5.6 (66%
decrease) vs. -4.6 (52%
decrease) for ALD403 and
placebo, respectively (one-sided
p = 0.034). The proportion of
subjects with a 100% reduction
in migraine days for 12 weeks


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for ALD403 and placebo was 
16% vs 0%, respectively (p < 
0.001). There were no 
differences in the type or 
frequency of adverse events, 
vital signs, or laboratory safety 
data between the two treatment 
groups.  A single intravenous 
dose of ALD403 1000 mg 
demonstrated efficacy for the 
preventive treatment of 
migraine in subjects with 
frequent episodic migraine.  
Overall, 89 subjects 
experienced a total of 199 AEs.  
Most AEs were transient and 
mild to moderate in severity. In 
the ALD403 treatment group, 
46 (56.8%) subjects had at least 
1 TEAE, and in the placebo 
group, 43 (52.4%) subjects had 
at least 1 TEAE. Three subjects 
(2 in the ALD403 group; 1 in 
the placebo group) had a total 
of 6 SAEs, all of which were 
considered unrelated. There 
were no TEAEs that resulted in 
study drug infusion 
interruption, death, or study 
discontinuation; no TEAEs 
were considered to be life-
threatening/disabling, or fatal. 
A second clinical trial 
(ALD403-CLIN-003) in healthy 
volunteers has been completed.  
The trial was a multiple dose, 
placebo-controlled trial to 
determine the safety, 
tolerability, pharmacodynamics, 
and pharmacokinetics of 
ALD403 administered 
subcutaneously in healthy 
volunteers.  


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In ALD403-CLIN-003 study 60 
subjects were dosed; 36 
subjects with ALD403 and 24 
subjects with placebo.  A total 
of 58 out of 60 subjects 
received three doses of assigned 
study treatment with an interval 
of one month between each 
dose. Two out of 60 subjects 
only received one dose of 
assigned study treatment. One 
subject who received one dose 
withdrew from the trial due to a 
job change and one subject 
experienced an unrelated 
serious adverse event and 
withdrew from treatment.  
There were no changes in 
laboratory parameters, vital 
signs, or ECGs in subjects 
dosed with ALD403 or placebo. 
Treatment-emergent adverse 
events were reported in 52 
(86.7%) of 60 subjects.  No 
significant differences were 
observed between subjects who 
received ALD403 and subjects 
who received placebo in terms 
of incidence, type, severity, 
relationship or frequency of 
TEAEs with the exception of 
injection site reactions.  Only 
subjects who received ALD403 
experienced injection site 
reactions.  These reactions were 
mild to moderate and included 
erythema, pruritus and 
induration.  
One serious adverse event was 
reported: musculoskeletal soft 
tissue injury secondary to a car 
accident. The event was 
considered not related to study 
treatment by the Investigator. 


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There were no deaths during the 
trial. 
A clinical trial (ALD403-CLIN-
007) in healthy volunteers was
conducted in Australia.  This
was a multi- dose, placebo-
controlled trial to determine the
safety, tolerability,
pharmacodynamics, and
pharmacokinetics of ALD403, a
humanized anti-(calcitonin
gene-related peptide)
monoclonal antibody
administered by intramuscular
injection. All study visits have
been completed as of Dec 10th,
2015 and final data analysis is
ongoing.
Another clinical trial (ALD403-
CLIN-005) in patients with 
chronic migraine is ongoing in 
the United States, Australia, 
New Zealand and Georgia.  
This trial is a randomized, 
placebo- controlled, dose-
ranging phase 2 trial to evaluate 
the efficacy, safety, and 
pharmacokinetics of 10, 30, 
100, and 300 mg of ALD403 
administered as a single dose 
intravenously in patients with 
chronic migraine.  Recruitment 
for this study is complete and 
follow-up visits are ongoing.  
 Eighteen serious adverse 
events in twelve subjects have 
been reported in the ongoing 
ALD403-CLIN-005 clinical 
trials as of Feb 5th, 2016.  There 
have been no TEAEs that 
resulted in death; no TEAEs 
have been considered to be, 


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life-threatening/disabling, or 
fatal.  
5.4 Risks and 
Benefits 
27-28
Migraine patients may gain 
benefit from the prevention of 
their migraine with ALD403. 
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 three clinical trials with 
ALD403 that have been 
completed to date. Given the 
limited number (N=184) of 
subjects who have received 
ALD403 as of this protocol, 
there may be uncommon 
treatment related adverse 
effects that have not yet been 
identified. As with all protein 
therapeutics, there is a risk of a 
serious allergic reaction.  
However, no serious allergic 
reactions have been observed 
with the administration of 
ALD403 in humans, to date.  
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. 
Risk section 
updated with 
most current 
information. 


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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, with ALD403 
demonstrating a favorable 
benefit-risk profile based on 
review of nonclinical, clinical, 
and scientific literature data. 
The sponsor will continue to 
monitor for significant new 
information and suspected 
adverse reactions associated 
with the use of ALD403. 
7.1.2 Key 
Secondary 
Endpoints 
29 
•
75% migraine
responder rate (Weeks
1-4)
•
75% migraine
responder rate (Weeks
1-12)
•
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
Inclusion of 
additional 
endpoints that 
are believed to 
be clinically 
meaningful and 
would provide 
additional 
support and 
understanding 
of ALD403’s 
effectiveness in 


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migraine 
prophylaxis. 
7.1.3 Other 
Secondary 
Endpoints 
29-30
•
Headache/migraines
with acute medication
usage
•
50% and 100%
migraine responder
rates (Weeks 1-12)
•
Short-Form Health
Survey (SF-36)
•
Health-Related Quality
of Life (EQ-5D-5L)
•
Allodynia Symptom
Checklist-12 (ASC-12)
•
Brush (dynamic
mechanical) Allodynia
•
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/migraine
days
•
Time to first migraine
after dosing
•
Headache/migraine
hours
•
Headache/migraines
with severe intensity
•
Change in acute
migraine medication
days (Weeks 1-12)
•
Headache/migraines
with acute medication
usage
•
100% migraine
responder rates
(Weeks 1-12)
•
Short-Form Health
Survey (SF-36)
•
Health-Related
Quality of Life (EQ-
5D-5L)
•
Allodynia Symptom
Checklist-12 (ASC-
12)
•
Brush (dynamic
mechanical) Allodynia
•
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/migraine
days
•
Time to first migraine
after dosing
•
Headache/migraine
hours
The change in 
acute migraine 
medication days 
endpoint has 
been added as 
requested by the 
FDA. 


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•
Headache/migraines
with severe intensity
10.12 Week 56 
Visit (Day 392± 
7 days) End of 
Study or Early 
Termination 
50 
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.   
Subjects who test positive for 
anti-ALD403 antibodies at the 
last study visit will be asked to 
provide up to 2 additional 
blood samples for 
immunogenicity testing at 
approximately 3 month 
intervals for up to 6 months.   
Clarification in 
immunogenicity 
testing visit 
window. 
12.1.1 eDiary 
57 
Subjects will complete a daily 
headache eDiary from the time 
of screening to Week 48.  The 
diary should be completed each 
trial day whether or not the 
subject had a headache. The 
compliance data from the 
eDiary will be made available 
to the trial site for review. Sites 
are to review the diary results 
with the subject and if the 
subject has not completed the 
diary daily, counsel the subject 
on the importance of daily 
completion of the diary.  
Subjects will complete a daily 
headache eDiary from the time 
of screening to Week 48.  The 
diary should be completed each 
trial day whether or not the 
subject had a headache. These 
daily entries should also record 
if the subject took acute 
migraine medication on that 
day.  The compliance data from 
the eDiary will be made 
available to the trial site for 
review. Sites are to review the 
diary results with the subject 
and if the subject has not 
completed the diary daily, 
counsel the subject on the 
importance of daily completion 
of the diary.  
Provide 
additional 
information 
related to the 
new acute 
migraine 
medication 
endpoint. 
12.1.2 
Endpoints 
60 
Acute Migraine Medication 
Usage 
The number of days within 4 
week intervals 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 
Provide 
additional 
information 
related to new 
endpoints. 


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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 first 
dose will be summarized. 
12.3 
Immunogenicity 
62 
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. 
Subjects who test positive for 
specific anti-ALD403 
antibodies at the time of the last 
study visit will be asked to 
provide up to 2 additional 
blood samples for 
immunogenicity testing at 
approximately 3 month 
intervals for up to 6 months. 
Clarification in 
immunogenicity 
testing visit 
window. 
13.1 Decision 
Rule 
62-63
A serial procedure will be used 
to account for multiplicity of 
dose level for the primary 
endpoint and the 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 the key secondary endpoints 
for 300 mg (first the Weeks 1-4, 
75% responder endpoint and 
then the Weeks 1-12 75% 
responder endpoint).  The 
procedure will then move on to 
the 100 mg group the primary 
endpoint and subsequently the 
secondary endpoints and then 
A serial procedure will be used 
to account for multiplicity of 
dose level for the primary 
endpoint and the 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 a subset of the key 
secondary endpoints for 300 
mg (first the Weeks 1-4 75% 
responder endpoint, then the 
Weeks 1-12 75% responder 
endpoint, and then the Weeks 
1-12 50% responder endpoint).
The procedure will then move
on to the primary endpoint for
Change in the 
multiplicity 
rules to reflect 
the new key 
secondary 
endpoints. 


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similarly to the 30 mg group. 
Statistical testing will be 
conducted at the 5% alpha 
level.   
the 100 mg group and 
subsequently to the same subset 
of key secondary endpoints as 
tested for the 300 mg dose.  
The procedure will then move 
on to the remaining key 
secondary endpoint for 300 mg 
and 100 mg (i.e., percentage of 
subjects with a migraine on the 
day after dosing).  Only if all of 
these secondary endpoints 
reach statistical significance 
will the 30 mg group be tested.  
This testing algorithm is 
presented below. 
Statistical testing will be 
conducted at the 5% alpha 
level. 
Added statistical chart 
13.2 Sample 
Size 
63-64
The planned sample size for 
this study is 800 randomized 
and treated subjects.  These 
subjects will be allocated into 4 
treatment groups in a 1:1:1:1 
ratio.  Pair-wise testing of each 
ALD403 group vs. placebo will 
be performed. Two hundred 
subjects per group provides at 
least 95% power for each 
change in frequency of 
migraine days (Weeks 1-12) 
test individually assuming a 
treatment effect of at least 1 day 
and a common standard 
deviation of 2.7 days or less.  
Ninety percent power is 
retained for standard deviations 
up to 3 days.  For the key 
secondary 75% responder rates 
endpoints 95% power is 
achieved for the pair-wise 
comparisons assuming rates of 
24% for placebo and 42% for 
ALD403.  These sample size 
The planned sample size for 
this study is 800 randomized 
and treated subjects.  These 
subjects will be allocated into 4 
treatment groups in a 1:1:1:1 
ratio.  Pair-wise testing of each 
ALD403 group vs. placebo will 
be performed. Two hundred 
subjects per group provides at 
least 95% power for each 
change in frequency of 
migraine days (Weeks 1-12) 
test individually assuming a 
treatment effect of at least 1 
day and a common standard 
deviation of 2.7 days or less.  
Ninety percent power is 
retained for standard deviations 
up to 3 days.  For the key 
secondary 75% responder rates 
endpoints 95% power is 
achieved for the pair-wise 
comparisons assuming rates of 
24% for placebo and 42% for 
ALD403.  For the 50% 
Provide 
additional 
information 
related to the 
new key 
secondary 
endpoints. 


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calculations have been 
performed using Pass 2008 and 
are based upon a t-test and Chi-
squared tests that should 
approximate the ANCOVA and 
CMH tests. 16 
responder rate endpoints 95% 
power is achieved for the pair-
wise comparisons assuming 
rates of 50% for placebo and 
68% for ALD403.  For the 
percentage of subjects with a 
migraine on the day after 
dosing endpoint, 95% power is 
achieved for pair-wise 
comparisons assuming rates of 
15% for placebo and 4% for 
ALD403. 
These sample size calculations 
have been performed using 
Pass 2008 and are based upon 
t-tests and Chi-squared tests
that should approximate the
ANCOVA and CMH tests,
respectively. 16
13.4.2 Efficacy 
Analyses 
66-67
Secondary Efficacy Analyses 
Summary statistics including 
confidence interval for the 
treatment differences will be 
used to summary the results for 
the secondary endpoints. 
Testing will be performed for 
the key secondary responder 
rate endpoints.  This testing will 
utilize a CMH test.  The tests 
will be stratified by the 
randomization stratification 
factor.  The time to first 
migraine analysis will be based 
upon Kaplan-Meier methods.   
Secondary Efficacy Analyses 
Summary statistics including 
confidence interval for the 
treatment differences will be 
used to summarize the results 
for the secondary endpoints. 
Testing will be performed for 
the key secondary endpoints 
and for the change in acute 
migraine medication days 
endpoint.  For the key 
secondary endpoints (responder 
rates and percentage of subjects 
with a migraine on the day after 
dosing) this testing will utilize 
a CMH/extended CMH test.  
The tests will be stratified by 
the randomization stratification 
factor.  The change in acute 
migraine medication day 
endpoints will be tested using 
an ANCOVA model similar to 
the one used for the primary 
Provide 
additional 
information 
related to the 
new endpoints. 


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endpoints:  change from 
baseline measure as the 
response, treatment and 
baseline acute migraine 
medication days as independent 
variables. 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 of subjects with a 
migraine (prevalence) on the 
day after dosing endpoint.  
Subjects who did not complete 
the diary on the day following 
dosing will be included in the 
prevalence rate calculation 
based upon their month 1 daily 
migraine rate. Hence, subjects 
with a migraine will be 
included in the rate calculation 
as a value of 1, subjects who 
completed the diary and did not 
have a migraine will be 
included as a zero and subjects 
who did not complete the diary 
will be included with a value 
between 0 and 1 equal to the 
number of month 1 migraine 
days / 28. 


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16 References 
1. “Effective Health Care Program, Migraine in Adults: Preventive Pharmacological
Treatments, Executive Sumamry”. Agency of Healthcare Research and Quality,
Comparative Effective Review, AHRQ Pub. No. 13-EHC08-1-EF 2013; April
2. Preibisz. Calcitonin gene-related peptide and regulation of human cardiovascular
homeostasis. Am J Hypertens. 1993; 6(5 Pt 1): 434-50.
3. Storer RJ, Akerman S, GoadsbyPJ. Calcitonin gene-related peptide (CGRP) modulates
nociceptive trigeminovascular transmission in the cat. Br J Pharmcol. 2004; 142(7):
1171-1181.
4. Jenkins DW, Langmead CJ, Parsons AA, StrijbosPJ. Regulation of calcitonin-gene
related peptide release from rat trigeminal nucleus caudalis slices in vitro. NeurosciLett.
2004; 366(3): 241-244.
5. GoadsbyPJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral
circulation of humans and the cat during activation of the trigeminalovacular system. Ann
Neurol. 1988; 23(2): 193-196.
6. Lassen L, Haderslev P, Jacobsen V, Iversen H, Sperling B, Olesen J. CGRP may play a
causative role in migraine. Cephalgia. (2002) 22: 54-61.
7. Sexton PM, McKenzie JS, Mason RT, Moseley JM, Martin TJ, Mendelsohn FAO.
Localization of binding sites for calcitonin gene-related peptide in rat brain by in vitro
autoradiography. Neuroscience. 1986; 19(4): 1235-1245.
8. Ma W, Chabot J-G, Powell KJ, Jhamandas K, Dickerson IM, Quirion R. Localization and
modulation of calcitonin gene-related-peptide receptor component protein-
immunoreactive cells in the rat central and peripheral nervous systems. Neuroscience.
2003; 120(3): 677-694.
9. Moskowitz MA. Basic mechanisms in vascularheadache. NeurolClin. 1990; 8(4): 801-
815.
10. Theoharides TC, Donelan J, Kandere-Gryzbowska K, Konstantinidou A. The role of mast
cells in migrainepathophysiology. Brain Res Rev. 2005; 49(1): 65-76.
11. http://ihs-classification.org/en/02_klassifikation/02_teil1/01.01.00_migraine.html/IHS
Classification ICHD-II
12. "International Classification of Diseases (ICD)". World Health Organization. Retrieved
23 November 2010.
13. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM225130.pdf


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14. Ashkenazi A, Young WB.  The effects of greater occipital nerve block and trigger point
injection on brush allodynia and pain in migraine. Headache 2005:45:350-354.
15. Madden T, Rosen N, Young W.  Exploring Home Allodynia Testing for Future Clinical
and Scientific Uses.
16. Hintze, J. (2008) PASS 2008. NCSS, LLC. Kaysville, Utah. www.ncss.com
17. 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.
18. Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDS and
other complementary treatments for episodic migraine prevention in adults: Report of the
Quality Standards Subcommittee of the American Academy of Neurology and the
American Headache Society. 2012; 78:1346-1353.
19. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update:
Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality
Standards Subcommittee of the American Academy of Neurology and the American
Headache Society. 2012; 78:1337-1345.

SAP_001.pdf: 
 
Confidential 
Alder BioPharmaceuticals, Inc. 
 
ALD403-CLIN-006 
 
A Parallel Group, Double-Blind, Randomized, Placebo Controlled, 
Trial to Evaluate the Efficacy and Safety of ALD403 
Administered Intravenously in Patients with Frequent Episodic 
Migraines. 
 
18MAY2017 
 
 
Statistical Analysis Plan 
 
Version 1.4 
 
 
Indication 
Treatment for Prevention of Frequent Episodic 
Migraine Headaches  
 
 
Development Stage 
Pivotal 
 
 
Sponsor 
Alder BioPharmaceuticals, Inc. 
11804 North Creek Pkwy S 
Bothell, WA 98011 USA 
Phone:   +1 425-205-2900 
Fax:       +1 425-205-2901 
 
 
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PPD 
7551 Metro Center Drive 
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whole or in part, without written authorization of Alder BioPharmaceuticals, Inc. 
 


Alder BioPharmaceuticals, Inc. 
ALD403-CLfN-006 
ALD403-CLIN-006 
Statistical Analysis Plan, Version 1.4 
Date Issued: l SMA Y201 7 
A Parallel Group, Double-Blind, Randomized, Placebo Controlled, Trial to Evaluate the 
Efficacy and Safety of ALD403 Administered Intravenously in Patients with Frequent 
Episodic Migraines. 
Issued by: 
Reviewed by
18MAY2017 
Statistical Analysis Plan Version 1.4 
Prepared by: 
PPD, Inc 
755 I Metro Center Dr. 
Austin, TX 78744 USA 
 
PPD Senior Biostatistician TI 
I approve this document 
17 May201715:50:19-05:00 
Lead Biostatistician, Biostatistics  
Principal Biostatistician 
I approve this document 
17 May 2017 16:03:07-05:00 
 
Senior Reviewer, Biostatistics 
PPD, Inc 
Date: 
I 
I 
Date: 
I 
I 
-- -
Upon review of this document, including table, listing, and figure shells, the undersigned approves the 
statistical analysis plan. The analysis methods and data presentation are acceptable, and the table, listing, 
and figure production can begin. 
Reviewed by
Reviewed by: 
Alder BioPharmaceuticals, Jnc. 
Sr Clinical Project Manager 
Alder BioPharmaceuticals, 1nc. 
Reviewed by: 
VP, Clinical Development 
Alder Bio Pharmaceuticals, Tnc. 
Date: 
Date: 
 
 
II 


Alder BioPharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 1.4 
ALD403-CLIN-006 
 
Date Issued: 18MAY2017 
 
  
Confidential 
 
 
3
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 5 
1   CLINICAL TRIAL DESCRIPTION...................................................................................... 6 
1.1 OBJECTIVES ........................................................................................................................... 6 
1.1.1   Primary Objective ........................................................................................................ 6 
1.1.2   Secondary Objectives ................................................................................................... 6 
1.2   CLINICAL TRIAL DESIGN ..................................................................................................... 7 
1.3   METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ............................................... 9 
1.4   BLINDING ............................................................................................................................ 9 
1.5   SAMPLE SIZE ....................................................................................................................... 9 
2 STATISTICAL METHODS .................................................................................................... 10 
2.1   POPULATIONS ANALYZED .................................................................................................. 10 
2.2   CLINICAL TRIAL ENDPOINTS ............................................................................................. 10 
2.2.1 eDiary .......................................................................................................................... 12 
2.2.2 Migraine and Headache Endpoints ............................................................................. 13 
2.2.3 SF-36 Health Survey (SF-36 v2.0) ............................................................................... 16 
2.2.4 EQ-5D-5L .................................................................................................................... 16 
2.2.5 Allodynia Symptom Checklist (ASC-12) ...................................................................... 16 
2.2.6 Brush Allodynia ........................................................................................................... 17 
2.2.7 Pharmacokinetics ........................................................................................................ 17 
2.2.8 Immunogenicity ............................................................................................................ 17 
2.3   TRIAL DAY ........................................................................................................................ 18 
2.4   POOLING STRATEGY FOR STRATA ...................................................................................... 19 
2.5   STATISTICAL ASSESSMENT OF THE TRIAL OBJECTIVES ...................................................... 19 
2.6   SAFETY ANALYSES ............................................................................................................ 21 
2.7   STATISTICAL/ANALYTICAL ISSUES .................................................................................... 21 
2.7.1   Adjustments for Covariates and Examination of Subgroup Analyses ....................... 21 
2.7.2   Handling of Dropouts or Missing Data ..................................................................... 21 
2.7.3   Interim Analyses and Data Monitoring ..................................................................... 23 
2.7.4   Multicenter Studies .................................................................................................... 23 
2.7.5   Multiple Comparisons/Multiplicity ............................................................................ 24 
3   STATISTICAL SUMMARIES ............................................................................................. 25 
3.1   GENERAL CONVENTIONS ................................................................................................... 25 
3.2   DEFINITION OF BASELINE .................................................................................................. 26 
3.3   CLINICAL TRIAL SUBJECTS ................................................................................................ 26 
3.3.1    Subject Disposition ................................................................................................... 26 
3.3.2   Analysis Population ................................................................................................... 26 
3.3.3   Demographics and Baseline Characteristics ............................................................ 26 
3.3.4   Prior and Concomitant Medications ......................................................................... 26 
3.3.5   Medical History ......................................................................................................... 27 
3.3.6   Clinical Trial Treatment ............................................................................................ 28 
3.3.7   eDiary Compliance .................................................................................................... 28 
3.4   ANALYSIS OF EFFICACY ENDPOINTS .................................................................................. 28 


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3.4.1 Headache/Migraine Days and Acute Migraine Medication Days .............................. 28 
3.4.2   Responder Rates ........................................................................................................ 29 
3.4.3.1   Percentage of Subjects with a Migraine on the Day after Dosing ......................... 30 
3.4.3.2   Time to First Migraine after Dosing ...................................................................... 30 
3.4.4   Remaining Headache and Migraine Secondary Endpoints ....................................... 31 
3.4.5   Tertiary and Exploratory Headache and Migraine Endpoints .................................. 31 
3.4.6   Other Secondary Efficacy Analyses ........................................................................... 31 
3.4.6.1   Short-Form Health Survey (SF-36 v 2.0) ............................................................... 31 
3.4.6.2   EQ-5D-5L ............................................................................................................... 32 
3.4.6.3   Allodynia Symptom Checklist-12 (ASC-12) ............................................................ 32 
3.4.6.4   Brush (dynamic mechanical) Allodynia .................................................................. 32 
3.5   PHARMACOKINETIC ANALYSES ......................................................................................... 32 
3.6   ANALYSIS OF SAFETY ENDPOINTS ..................................................................................... 33 
3.6.1   Adverse Events ........................................................................................................... 33 
3.6.2   Deaths, Serious Adverse Events and Other Significant Adverse Events ................... 34 
3.6.2.1   Serious Adverse Events ........................................................................................... 34 
3.6.2.2   Deaths ..................................................................................................................... 34 
3.6.3   Clinical Laboratory Evaluations ............................................................................... 35 
3.6.4   Vital Signs, Physical Findings and Other Observations Related to Safety ............... 35 
3.6.4.1   Vital Signs ............................................................................................................... 35 
3.6.4.2   Physical Exam ........................................................................................................ 35 
3.6.4.3   Electrocardiogram Results ..................................................................................... 35 
3.6.5   Immunogenicity Data Analysis .................................................................................. 36 
3.6.5.1 Anti-ALD403 Antibody Analysis ............................................................................... 37 
3.6.6   Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................... 37 
3.6.7 Pregnancies ................................................................................................................. 37 
REFERENCES ............................................................................................................................ 38 
 
LIST OF TABLES 
Table 1: Schedule of Events and Assessment ............................................................................... 8 
Table 2: Analysis Windows ........................................................................................................ 18 
Table 3: eDiary Headache/Migraine Endpoint Analysis Intervals .............................................. 19 


Alder BioPharmaceuticals, Inc. 
 
Statistical Analysis Plan, Version 1.4 
ALD403-CLIN-006 
 
Date Issued: 18MAY2017 
 
  
Confidential 
 
 
5
LIST OF ABBREVIATIONS 
AE  
Adverse event  
ASC-12  
Allodynia Symptom Checklist  
AUC  
Area under the concentration-time curve  
AUC0-inf  
Area under the concentration-time curve from time=0 to infinity  
AUC0-t  
Area under the plasma concentration-time curve  
BDI-II  
Beck Depression Inventory  
CGRP  
Calcitonin Gene-Related Peptide  
CMH  
Cavg  
Cochran–Mantel–Haenszel  
Average steady-state concentration; computed as AUC(0-Tau)/Tau  
Cmax  
Cmin  
Peak plasma concentration  
Minimum concentration between 0 and Tau at steady-state  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EQ-5D-5L  
Health-Related Quality of Life  
hCG  
Human chorionic gonadotropin  
ICD  
ICHD 
International Classification of Diseases  
International Classification of Headache Disorders  
IHS  
International Headache Society  
IV  
Intravenous  
IWRS 
Interactive Web Response System 
LLOQ  
Lower Limit of Quantification  
MedDRA  
Medical Dictionary for Regulatory Activities  
PK  
Pharmacokinetic  
SAE  
Serious adverse event  
SAP  
Statistical Analysis Plan  
SF-36  
Tau  
Short Form Health Survey  
The dosing interval for steady-state data  
Tmax  
Time to peak plasma concentration  
TEAE  
Treatment-emergent adverse event  
VAS 
Visual Analog Scale 
Vz  
Apparent volume of distribution during the terminal elimination phase  
WHO  
World Health Organization  
 


Alder BioPharmaceuticals, Inc. 
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Date Issued: 18MAY2017 
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1   CLINICAL TRIAL DESCRIPTION 
According to the International Classification of Headache Disorder (ICHD)1, migraine is a 
common disabling primary headache disorder manifesting in attacks lasting 4 to 72 hours. 
Migraine frequency is divided into episodic migraine and chronic migraine.  Frequent Episodic 
migraine (FEM, 4 to 14 migraines days per month) affects approximately 17 percent of women 
and 6 percent of men.      
Calcitonin gene-related peptide is a member of the calcitonin family of peptides and is thought to 
have a multiplicity of actions within the brain, including the facilitation of pain transmission and 
the induction of the nociceptive state, both of which may contribute to the mechanism of 
migraine2, 3. ALD403 is a humanized anti- CGRP monoclonal antibody (anti-CGRP) that binds 
to CGRP and is being developed by Alder BioPharmaceuticals, Inc. for the prophylaxis of 
migraine. 
1.1 Objectives 
1.1.1   Primary Objective 
The primary objective is: 
•
To evaluate the efficacy of repeat doses of ALD403 administered intravenous (IV)
compared to placebo in subjects with FEM.
1.1.2   Secondary Objectives 
The secondary objectives include the following: 
•
To evaluate the safety of repeat doses of ALD403 administered IV compared to placebo
in subjects with FEM.
•
To evaluate the pharmacokinetics (PK) and immunogenicity of repeat doses of ALD403
administered IV to subjects with FEM.


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1.2   Clinical Trial Design 
This phase 3, is a parallel group, double-blind, randomized, placebo-controlled trial of multiple 
infusions of ALD403 or placebo in subjects with FEM. Subjects who provide informed consent 
will be qualified based upon the inclusion and exclusion criteria and compliance with the eDiary.  
The key entry criteria are that the subject has FEM, which will be determined from the first 
28 days of eDiary data following the screening visit.  During this time the subject must 
experience ≥4 and ≤14 headache days of which at least 4 have to be migraine days and must 
have completed the eDiary at least 25 of the 28 days to be eligible. 
The subject will be instructed to complete the eDiary daily from the screening visit through 
Week 48. Subjects will return to the site on Day 0 for randomization and first treatment, which 
should occur at least 29 days but no more than 35 days after the screening visit. Subject 
eligibility will be re-confirmed on Day 0, prior to randomization. Subjects will be randomized 
into one of three ALD403 dose levels (30 mg, 100 mg, and 300 mg) or placebo.  Any subject 
found to be no longer eligible for the trial on Day 0, will not be randomized nor dosed.  The 
subjects randomized and dosed will continue the study for 56 weeks. These 56 weeks are divided 
into two periods, i.e., a primary efficacy and safety period (Weeks 1-24) and a long term safety 
period (Weeks 25-56). Subjects will complete the eDiary daily through Week 48. 
Approximately 800 subjects will be randomized and treated. Efficacy, safety, pharmacokinetic, 
and immunogenicity assessments will be conducted according to the Schedule of Events in 
Table 1.


Alder BioPharmaceuticals, Inc. 
 
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Table 1: Schedule of Events and Assessment 
 
 
Primary Efficacy and Safety Period 
Long Term Safety Period 
 
 
Assessment 
Screen 
D-35  
to -29 
Rand/  
D0  
Tx 
Wk 4 
D28 ±3  
Wk 8  
D56 ±3  
Wk 12  
D84 ±3  
Tx 
Wk 16 
D112 ±3  
Wk 20 
D140 ±3  
Wk 248 
D168 +3 
Tx      
Wk 28 
D196 ±7  
Wk 36 
D252 ±3 
Tx  
Wk 489 
D336 +7  
Wk 56 
EOT/ET 
D392 +7 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
In/Ex Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical History, BDI-II 
X 
 
 
 
 
 
 
 
 
 
 
 
Headache eDiary Review1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam Height and Weight2 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
Brush Allodynia Test 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG3 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Hematology, Chemistry5 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
HIV/Hepatitis B and C Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine Preg (hCG) Test 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Plasma ALD403 Serum Anti-ALD4036 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
SF-36  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
EQ-5D-5L, ASC-12 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
AE and Con Meds Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
ALD403/placebo administration7 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Abbreviations: TX: Treatment, Rand: Randomization, EOT/ET: End of Trial/Early Termination 
 
1Headache eDiary distributed at screening. eDiary review and compliance check through Week 48. 
2Physical exam must be done pre-dose on Day 0, Week 24, 36. Height and Weight on Screening visit. Weight only on Day 0, Weeks 24, 36, 56 
3Vital signs, 12-lead ECG pre-dose and 4 hours post-dose (± 30 minutes) on Day 0 and Weeks 12, 24 and 36 
4C-SSRS Baseline/Screening Version at screening, C-SSRS Since Last Visit Version Day 0 (pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 36, 48 and 56  
5All blood draws obtained pre-dose on dosing days 
6Sample for Plasma Free ALD403 and anti-ALD403 antibody drawn pre-dose on dosing days (within 1 hour prior to dosing) 
7 Subjects must be monitored for at least 4 hours after the dosing completion.  
8Week 24 must be done on the target day or 3 days after. Three days earlier than target date is not allowed. 
9Week 48 must be done on the target day or seven days after. Seven days earlier than target date is not allowed. 
 


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Date Issued: 18MAY2017 
 
  
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1.3   Method of Assigning Subjects to Treatment Groups 
Randomization will occur 29 to 35 days after the screening visit when the eligibility assessments 
are completed and eligibility verified. Sites will complete the randomization using an Interactive 
Web Response System (IWRS) and the randomization assignment will be obtained by the 
clinical trial site’s unblinded pharmacist or Investigational Product consignee. Subjects will be 
randomized in equal ratios to one of the four 4 treatment groups (30 mg, 100 mg, or 300 mg of 
ALD403 or Placebo). Stratified permuted block randomization will be used. Stratification will be 
by migraine days during the screening period (≤9 days vs. >9 days).  
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 
subject number. 
1.4   Blinding 
This clinical trial is double-blind, meaning the subjects and site personnel are blinded to 
treatment assignment, except for the clinical trial site’s unblinded pharmacist or Investigational 
Product consignee. Immediately prior to PK/immunogenicity sample analysis, the bioanalytical 
laboratory will be unblinded in order to obtain the treatment assignments.  Selected sponsor 
personnel in the Safety and Regulatory groups may be unblinded to individual subject’s 
treatment assignments as required for safety reporting.  More details can be found in the blinding 
plan. The study will remain blinded until the last subject has completed the Week 24 visit at 
which time the sponsor will be unblinded.  
1.5   Sample Size 
The planned sample size for this trial is 800 randomized and treated subjects. These subjects will 
be allocated into 4 treatment groups in a 1:1:1:1 ratio. Pair-wise testing of each ALD403 group 
vs. placebo will be performed. Two hundred subjects per group provides at least 95% power for 
each change in frequency of migraine days (Weeks 1-12) test individually assuming a treatment 
effect of at least 1 day and a common standard deviation of 2.7 days or less. Ninety percent 
power is retained for standard deviations up to 3 days. For the key secondary 75% responder 


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Date Issued: 18MAY2017 
 
  
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rates endpoints 95% power is achieved for the pair-wise comparisons assuming rates of 24% for 
placebo and 42% for ALD403. For the 50% responder rate endpoints 95% power is achieved for 
the pair-wise comparisons assuming rates of 50% for placebo and 68% for ALD403. For the 
percentage of subjects with a migraine on the day after dosing endpoint, 95% power is achieved 
for pair-wise comparisons assuming rates of 15% for placebo and 4% for ALD403. 
These sample size calculations have been performed using Pass 2008 and are based upon t-tests 
and Chi-squared tests that should approximate the ANCOVA and CMH tests, respectively.4 
2 STATISTICAL METHODS 
2.1   Populations Analyzed 
The analysis populations are defined as the following:  
• 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 Investigational Product/placebo. 
Subjects will be summarized within the treatment group for which they actually received 
treatment.  If a subject is treated with two different doses they will be summarized in 
treatment arm of the highest dose received. This population will be used for the safety 
analyses. 
• PK Population - All subjects who have at least one reportable plasma concentration. The 
PK population will be used for PK analyses.   
2.2   Clinical Trial Endpoints 
The efficacy, safety, pharmacokinetic and immunogenicity of ALD403 will be assessed using the 
following endpoints.  Greater detail concerning these endpoints can be found in Section 2.2.2. 


Alder BioPharmaceuticals, Inc. 
 
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Date Issued: 18MAY2017 
 
  
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Primary Efficacy Endpoint 
• Change in frequency of migraine days (Weeks 1-12)   
Key Secondary Efficacy 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 
Other Secondary Efficacy Endpoints 
• Change in acute migraine medication days (Weeks 1-12) 
• Headaches/Migraines with acute medication usage  
• 100% migraine responder rates (Weeks 1-12) 
• Short-Form Health Survey (SF-36 v 2.0)  
• Health-Related Quality of Life (EQ-5D-5L) 
• Allodynia Symptom Checklist-12 (ASC-12) 
• Brush (dynamic mechanical) Allodynia 
• 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/migraine days 
• Time to first migraine after dosing  
• Headache/Migraine hours  
• Headache/migraines with severe intensity 
Tertiary Endpoints 
• Headache episodes/migraine attacks 
 


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Exploratory Endpoints 
• Headache/Migraine characteristics 
• Headaches/Migraines with type of acute medication usage 
• Headache episode/Migraine attack average length  
Safety Endpoints 
• Adverse events (AEs) and serious adverse events (SAEs) 
• Changes in clinical laboratory assessments 
• Vital Signs 
• ECGs 
• Suicidal ideation and behavior as measured by the Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
Pharmacokinetic Endpoints 
• Free ALD403 plasma concentrations 
Immunogenicity Endpoints 
• Development of specific anti-ALD403 antibodies 
• Characterization of specific anti-ALD403 antibodies for neutralizing activity 
2.2.1 eDiary 
 
Subjects will complete a daily headache eDiary from the time of screening to Week 48. The 
diary is to 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.   


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2.2.2 Migraine and Headache Endpoints 
In the statistical analysis plan the term headache will encompass both headaches and migraine 
headaches.  Migraine headaches (migraines) are a subgroup of the headaches with the 
characteristics outlined below.  In this way all migraines are headaches but not all headaches are 
migraines.  Migraine and headache data will be collected through week 48.  Headache episodes 
will be self-reported by the subject.  An episode is a single headache event which lasts at least 
30 minutes, as defined by the subject reported start and end time.  The migraine and headache 
endpoints will be summarized in four week, twelve week and the twenty-four week intervals. 
Specifically, migraine and headache endpoints will be summarized for the four week intervals: 
Weeks 1-4, 5-8, 9-12, 13-16, 17-20, 21-24, … 44-48, the twelve week intervals 1-12, 13-24, 
25-36, 37-48, and  Weeks 1-24, 25-48 as outlined in Section 2.3.  The results from Weeks 1 to 12 
will be used for the primary analysis. 
For this trial, migraines are defined using the definition of migraine without aura and probable 
migraine without aura as outlined by the International Headache Society.  These definitions do 
not take the presence of aura into account. Subjects will report if they experienced aura with their 
headache.  Hence, in the rare case of aura that does not develop into a migraine, this will not be 
classified as a migraine but a headache that meets the definition of a migraine without aura will 
be considered a migraine regardless of if aura was present or not. 
Migraine Day 
A migraine day is defined as any day with a headache that meets the migraine or probable 
migraine characteristics as outlined in the International Headache Society (IHS), ICHD II 
2004-II, Section 1.1 and 1.6. Specifically, a migraine is defined as a self-reported headache that:  
1. Lasted 4-72 hours 
2. Had at least 2 of the following  
a. Unilateral location 
b. Pulsating quality 
c. Moderate or severe pain intensity 
d. Aggravation by or causing avoidance of routine physical activity 


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3. Had at least 1 of the following 
a. Nausea and/or vomiting 
b. Photophobia and phonophobia 
A probable migraine is a headache that meets only 2 of the above criteria. These characteristics 
will be summarized for each 4-week interval. 
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. 
Results from the four week intervals will be averaged to produce 12 and 24 week responder 
endpoints. A responder will be a subject who achieves the specified percent reduction in 
migraine headache days when response rates for each of the four week intervals are averaged.  
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. 
 


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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 / Headache Severity 
Headache severity will be collected on a 3 point scale: mild pain, moderate pain, severe pain.  
The percent of migraines and headaches with severe pain will be summarized. Subjects with no 
migraines/headaches will be included with a rate of zero. 
Acute Medication Usage 
The percent of migraines and headaches with acute medication usage as recorded in the eDiary 
will be summarized. Subjects with no migraines/headaches will be included with a rate of zero. 
Acute Migraine Medication Usage 
The number of days within 4 week intervals 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 
baseline and post baseline interval. 
Percentage of subjects with a migraine on the day after dosing 
The percent of subjects with a migraine on the day after first dose will be summarized. 
eDiary Reported Medication Usage 
The percent of days per 28 days with medication usage will be summarized overall and by the 
type of medication used.  


Alder BioPharmaceuticals, Inc. 
 
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Average Migraine / Headache Length 
The length of each migraine attack is the average of the duration of each migraine attack within a 
four week intervals. Headache hours are similarly defined but include all headaches. Subjects 
with no migraines/headaches will have a duration of zero.  
Time to First Migraine 
Time to the first migraine after dosing will be analyzed based upon the migraine data entered 
into the eDiary. 
2.2.3 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.  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.   
2.2.4 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. 
2.2.5 Allodynia Symptom Checklist (ASC-12) 
The ASC-12 includes 12 questions about the frequency of various allodynia symptoms in 
association with headache attacks. For individuals with more than one type of headache, 
questions are directed to the “most severe type of headache.”  Each item is measured on a Likert 
type scale option with response categories: “Does not apply to me”, “never,” “rarely,” “less than 
half the time,” and “half the time or more”.  ASC items were scored as 0 (i.e., never, rarely, or 
does not apply to me), 1 (less than half the time), and 2 (half the time or more), yielding scores 
that ranged from 0 to 24.  In this trial if a single item is missing it will be scored as a zero.  If 


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more than one item is missing the total score will be missing.  The interpretation of the total 
score is provided below. 
Score Range 
Allodynia 
0-2 
3-5 
6-8 
≥9 
None 
Mild 
Moderate 
Severe 
 
2.2.6 Brush Allodynia 
Dynamic mechanical brush allodynia will be tested by lightly brushing a 10 by 10 cm gauze pad 
bilaterally, 1-2 cm over each eyebrow at a rate of 2/second, for a total of 10 times. For each side 
of their forehead, subjects will be asked to assess the degree of pain elicited by the gauze on a 
scale of 0 to 10 with 0 being no pain and 10 being the worst imaginable pain. 
2.2.7 Pharmacokinetics 
The concentrations of Free ALD403 will be measured in plasma from all ALD403-treated 
subjects using validated assay methods. The PK analysis will include evaluations of 
concentration-time profiles for Free ALD403 at the following times: pre-dose on Day 0, and 
Weeks 4, 8, 12, 16, 20, 24, 36, 48, and 56.  
Plasma collected at Week 4 from all placebo-treated subjects will be analyzed for the potential 
presence of Free ALD403 using validated assay methods. 
2.2.8 Immunogenicity  
Serum blood samples to test for antibodies to ALD403 will be taken pre-dose on Day 0, and 
Weeks 4, 8, 12,16, 20, 24, 36, 48, and 56. The immunogenicity will be assessed in serum from 
all ALD403-treated subjects using validated assay methods. Immunogenicity will not be assessed 
in placebo subjects.  
For any samples that are positive for anti-ALD403 antibody, there may be additional testing to 
characterize the potential for neutralizing (NAb) ALD403 activity. Subjects who test positive for 


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specific anti-ALD403 antibodies at the time of the last study visit will be asked to provide up to 
2 additional blood samples for immunogenicity testing at approximately 3 month intervals for up 
to 6 months. See the blinding plan for details concerning blinding and the capture of these 
samples. 
2.3   Trial Day 
Trial endpoints will be reported within analysis windows or analysis intervals based upon the 
actual date of the assessment. Assignment of results to these time points is based upon the trial 
day.  Trial day is defined as: 
Trial day = date of assessment - date of treatment 
Analysis Windows used to report non-diary endpoints are outlined in Table 2. 
Table 2: Analysis Windows 
Visit 
Range 
Target Day 
If  more than one which one is used 
for analyses 
Screening 
< Day 0 
 
First value 
Day 0 
Day 0 to Day 7 
Day 0 
Day 0 
Week 4 
Day 8 to Day 42 
Day 28 
Closest to Target Day 
Week 8 
Day 43 to Day 70 
Day 56 
Closest to Target Day 
Week 12 
Day 71 to Day 98 
Day 84 
Closest to Target Day 
Week 16 
Day 99 to Day 126 
Day 112 
Closest to Target Day 
Week 20 
Day 127 to Day 154 
Day 140 
Closest to Target Day 
Week 24 
Day 155 to Day 182 
Day 168 
Closest to Target Day 
Week 28 
Day 183 to Day 210 
Day 196 
Closest to Target Day 
Week 36 
Day 211 to Day 273 
Day 252 
Closest to Target Day 
Week 48 
Day 274 to Day 357 
Day 336 
Closest to Target Day 
Week 56 
> Day 357 
Day 392 
Closest to Target Day 
Note: If two observations exist with same distance to target day, use first observation.  
For the eDiary data used to produce the migraine and headache endpoints the intervals specified 
in Table 3 will be used to collapse the daily data into 4, 12, and 24 week intervals.  For these data 
baseline is defined as the 28 days starting on the day of the first diary entry.  
 
 


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Table 3: eDiary Headache/Migraine Endpoint Analysis Intervals 
Diary 
Weeks 
Trial Time 
Comments 
Endpoints 
Baseline 
The 28 days starting from the 
first eDiary entry  
 
All eDiary related endpoints 
1-4 
Days: 0-27 
Day 0 = First day of treatment 
All eDiary related endpoints 
5-8 
Days: 28-55 
 
All eDiary related endpoints 
9-12 
Days: 56-83 
 
All eDiary related endpoints 
1-12 
Weeks 1-4, 5-8 and 9-12 
Average of the 4 week intervals after 
imputation methods are applied 
All Primary and Secondary 
eDiary related endpoints 
13-16 
Days: 84-111 
 
All eDiary related endpoints 
17-20 
Days: 112-139 
 
All eDiary related endpoints 
21-24 
Days: 140-167 
 
All eDiary related endpoints 
13-24 
Weeks 13-16, 17-20 and 21-24 Average of the 4 week intervals after 
imputation methods are applied 
All Primary and Secondary 
eDiary related endpoints 
1-24 
Weeks 1-4, 5-8, 9-12, 13-16, 
17-20 and 21-24 
Average of the 4 week intervals after 
imputation methods are applied 
All Primary and Secondary 
eDiary related endpoints 
25-28 
Days: 168-195 
 
All eDiary related endpoints 
29-32 
Days: 196-223 
 
All eDiary related endpoints 
33-36 
Days: 224-251 
 
All eDiary related endpoints 
25-36 
Weeks 25-28, 29-32 and 33-36 Average of the 4 week intervals after 
imputation methods are applied 
All Primary and Secondary 
eDiary related endpoints 
37-40 
Days:252-279 
 
All eDiary related endpoints 
41-44 
Days: 280-307 
 
All eDiary related endpoints 
45-48 
Days: 308-335 
 
All eDiary related endpoints 
37-48 
Weeks 37-40, 41-44 and 45-48 Average of the 4 week intervals after 
imputation methods are applied 
All Primary and Secondary 
eDiary related endpoints 
25-48 
Weeks 25-28, 29-32, 33-36, 
37-40, 41-44 and 45-48 
Average of the 4 week intervals after 
imputation methods are applied 
All Primary and Secondary 
eDiary related endpoints 
 
2.4   Pooling Strategy for Strata  
No pooling will be done. 
2.5   Statistical Assessment of the Trial Objectives 
Hypothesis testing will be performed for the primary endpoint: change from baseline in migraine 
days from Weeks 1-12. This endpoint will be calculated as outlined in Section 2.2.2 and will 
utilize the missing data rules provided in Section 2.7.2.  The hypotheses tested are 
Ho: Δplb = Δ403 Ha: Δplb ≠ Δ403 


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where Δ403 is the change in migraine days for subjects in the ALD403 treatment arm and Δplb 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 variable: baseline migraine days (continuous covariate) will be the independent 
variables. 
In addition, model based estimates including confidence intervals for the treatment differences 
will be used to summarize the results for the primary endpoint. 
A sensitivity analysis of the change from baseline in migraine days will be performed using the 
sensitivity missing data rule provided in Section 2.7.2. 
Secondary Efficacy Analyses 
Summary statistics including confidence interval for the treatment differences will be used to 
summarize the results for the secondary endpoints. Testing will be performed for the key 
secondary endpoints and for the change in acute migraine medication days endpoint. For the key 
secondary endpoints (responder rates and percentage of subjects with a migraine on the day after 
dosing) this testing will utilize a CMH/extended CMH test. The tests will be stratified by the 
randomization stratification factor. The change in acute migraine medication day endpoints will 
be tested using an ANCOVA model similar to the one used for the primary endpoints: change 
from baseline measure as the response, treatment and baseline acute migraine medication days as 
independent variables. The time to first migraine analysis will be descriptively summarized 
based upon Kaplan-Meier methods. 
Exploratory Analyses 
Exploratory endpoints will be summarized with descriptive statistics by treatment group.  


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2.6   Safety Analyses 
Safety endpoints will be summarized with descriptive statistics. All safety summaries and 
analyses will be performed using the safety population.  
Prior and Concomitant medications will be coded by the World Health Organization (WHO) 
Drug Dictionary version September 2012. 
Adverse Events and Medical History will be coded using MedDRA version 15.1.  
2.7   Statistical/Analytical Issues 
2.7.1   Adjustments for Covariates and Examination of Subgroup Analyses 
Summaries with descriptive statistics and frequency counts for change in migraine days will be 
provided for the subgroups indicated below. A forest plot will also be created for subgroup 
analyses and will display treatment differences. The subgroups will be  
• Calculated baseline migraine days (<9 days vs. ≥9 days) 
• Sex  
• Race (White, Black or African American, Other) 
• Age Group (≤35 yrs, >35 yrs) 
• Age Group at Diagnosis of Migraine (≤21 yrs, >21 yrs) 
• Duration of Migraine at Baseline (≤15 yrs, >15 yrs) 
2.7.2   Handling of Dropouts or Missing Data 
Summary statistics will be reported based upon observed data except for the diary 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 
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 diary data will be sporadic. 


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Missing Headache End Date and Time  
If the end date and time for a headache recorded in the eDiary is missing the headache end date 
will be set to the earlier of 23:59 on the day before the next reported headache or 23:59 on the 
last entry reported into the diary (i.e. the last evening report or if no evening report was 
completed after the start of the headache 23:59 on the day the headache started).  Headaches that 
are not reported as stopped by the subject are missing the answers to the questions that allow for 
the determination of whether the headache was a migraine or not.  In this population most 
headaches are migraines. Hence, these headaches with missing ‘end’ information will be 
classified as migraines.  
Missing Data Rule 1  
If the eDiary has been completed at least 21 days in a 28 day interval, then a normalization 
procedure will be used. The results will be normalized to 28 days by multiplying the observed 
results by the inverse of the completion rate (e.g. if a subject does not complete the eDiary on 
5 days they will have completed the diary on 82% of the days and the normalized results will be 
the observed results times 1.22). 
Missing Data Rule 2 
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 diary was completed and will provide greater weight for higher completion rates. 
Specifically, the results will be derived as  
28 (W Xc + (1 – W) Xp), 
where W is the number of days the diary was completed/20, Xc is the available average daily 
results for the current interval and Xp are the average imputed daily results for the previous 
interval.  


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Unless it is stated otherwise all primary and secondary analyses will use both Missing Data 
Rules 1 and 2, as appropriate. For the exploratory analyses, only Missing Data Rule 1 will be 
used and the denominators for will reflect the number of subjects who completed the eDiary 
21 or more days in the 28 day interval. 
Sensitivity Rule 
The primary endpoint and key secondary endpoints will also be analyzed using a modification to 
Missing Date Rule 2 to better understand the robustness of the selected algorithm.  The analysis 
replaces Xp with Xb, where Xb are the baseline average daily results, if the subject withdrew from 
the study due to an adverse event, study burden, lack of efficacy or worsening of study indication 
or if the subject died.   
2.7.3   Interim Analyses and Data Monitoring 
A DMC, guided by a charter, will review safety data during the enrollment and treatment phases 
of this study.  The DMC will advise the Sponsor regarding the continuing safety of trial subjects 
and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of 
the trial.  The DMC is not charged with stopping the trial early for efficacy. 
The primary analysis is planned when the last subject randomized and treated has completed the 
week 24 visit. The trial will remain blinded until the last subject has completed the Week 24 
visit. 
The final analysis will be repeated when the final subject has completed the Week 56 visit. A 
comparison of the Week 24 and Week 56 analyses will be performed to identify any changes in 
the database that occurred between unblinding and the final analysis.    
2.7.4   Multicenter Studies 
Data from all sites will be pooled for presentation. 


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2.7.5   Multiple Comparisons/Multiplicity 
A serial procedure will be used to account for multiplicity of dose level for the primary endpoint 
and the 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 a subset of the key 
secondary endpoints for 300 mg (first the Weeks 1-4 75% responder endpoint, then the 
Weeks 1-12 75% responder endpoint, and then the Weeks 1-12 50% responder endpoint). The 
procedure will then move on to the primary endpoint for the 100 mg group and subsequently to 
the same subset of key secondary endpoints as tested for the 300 mg dose. The procedure will 
then move on to the remaining key secondary endpoint for 300 mg and 100 mg (i.e., percentage 
of subjects with a migraine on the day after dosing). Only if all of these secondary endpoints 
reach statistical significance will the 30 mg group be tested.  
Statistical testing will be conducted at the 5% alpha level. 
 
 
300 mg Wks 1-12 change in migraine days  
  
300 mg Wks 1-4 75% responder rate 
  
300 mg Wks 1-12 75% responder rate  
  
300 mg Wks 1-12 50% responder rate 
100 mg Wks 1-12 change in migraine days  
  
100 mg Wks 1-4 75% responder rate 
 
100 mg Wks 1-12 75% responder rate  
  
100 mg Wks 1-12 50% responder rate 
 
300 mg Percentage of subjects with a 
migraine on the day after dosing 
 
100 mg Percentage of subjects with a 
migraine on the day after dosing 
30 mg Wks 1-12 change in migraine days  
 
30 mg Wks 1-4 75% responder rate 
 
30 mg Wks 1-12 75% responder rate  
 
30 mg Wks 1-12 50% responder rate 
 
30 mg Percentage of subjects with a 
migraine on the day after dosing  


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3   STATISTICAL SUMMARIES 
3.1   General Conventions 
Unless otherwise stated, summary statistics including the number of subjects (n), mean, standard 
deviation, median, minimum and maximum will be presented for continuous variables. Generally 
the minimum and maximum values will be presented to the same decimal precision as the raw 
values, the mean and median values to one more, and the standard deviation, to two more 
decimal places than the raw values. This decimal place convention may be followed for all data 
elements.  For categorical variables, per category, the absolute counts (n) and percentages (%) of 
subjects with data, and if appropriate, the number of subjects with missing data, will be 
presented. Percentages will be presented to one decimal place. 
For PK data the following applies: 
Concentration values for free ALD403 will be presented as received from the Bioanalytical 
Laboratory. 
Values for all PK parameters and for mean concentrations will be presented in three or four 
significant digits, as appropriate, i.e., 3 significant digits for minimum and maximum, 
4 significant digits for mean, SD and median; % CV is given to 1 decimal point. 
For AEs, medical history and concomitant medications reported on a per-subject basis, the 
denominator for the percentage calculation will be the number of subjects at risk in each 
treatment group. A subject will be considered at risk if the subject is in the analysis set and in the 
subgroup of interest. 
All p-values will be rounded to 4 decimal places. If a p-value is less than 0.0001 it will be 
displayed as “< 0.0001”. 
Unless otherwise specified all summaries will be performed by treatment group, all efficacy 
analyses will be based upon the full analysis population, all safety as well as demographic and 
baseline characteristic analyses will be based upon the safety population and all PK analyses will 
be based upon the PK population.  


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3.2   Definition of Baseline 
Baseline assessment 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. 
3.3   Clinical Trial Subjects 
3.3.1    Subject Disposition 
The number of subjects signed informed consent, randomized, treated, discontinued 
Investigational Product early, and terminated from the clinical trial early will be summarized. 
The reason for early termination of Investigational Product or from the clinical trial will be 
summarized. Additionally, the summary of subjects present at each visit will be summarized. 
Subjects randomized but not included in the full analysis population and the reasons for 
exclusion will be summarized. The number of subjects screened and summary of screen failure 
reasons will also be summarized. 
A listing of entry criteria that were not met will be produced. 
3.3.2   Analysis Population 
The number of subjects in each analysis population will be summarized. 
3.3.3   Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group.   
3.3.4   Prior and Concomitant Medications 
Medications with a stop date before the treatment dosing date will be considered prior 
medications. Medications with a start or stop date on or after the treatment dosing date will be 
considered concomitant medications. All medications marked as ongoing are concomitant 
medications.  


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A medication with an incomplete stop date will be considered concomitant if: 
• Month is missing and year is equal to or after the year of treatment dosing date 
• Day is missing and year is equal to the year of the treatment dosing date and month is equal 
to or after the month of the treatment dosing date. 
Concomitant medications will be summarized by treatment group.  All medications will be 
provided in a listing. 
Prophylactic and acute headache medications, identified by a clinical review of the coded 
concomitant medications data, will be summarized by treatment group. 
The headache medications recorded in the eDiary will not be integrated with the concomitant 
medications as these two data capture tools have distinctly different format, purpose and 
functionality.  These diary-based results will be summarized in a separate series of outputs.  For 
these the percent of days that subjects used headache medication within each 4 week interval and 
in the trial as a whole will be summarized by treatment group.  These summary measures will 
only include subjects who have completed the eDiary at least 21 days of the 28 days for the 
selected interval.  In addition to the overall summary, descriptive statistics will be provided for 
each type of medication: Ergotamine, Triptan, Simple Analgesic, Opioid, Combination 
Analgesic and Other.   
3.3.5   Medical History 
Medical History will be tabulated by system organ class, preferred terms and treatment groups.  
For females, menstrual medical history will be summarized by treatment groups.  
Migraine History including age at diagnosis, the average number of headache days, migraine 
days, and migraine attacks per 28 day period in the 3 months prior to screening, as well as the 
timing of the start of migraines in relation to puberty/ menarche and hormone migraine history 
for females will be summarized in a table by treatment groups. 


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3.3.6   Clinical Trial Treatment 
Total volume infused and reason for dose interruption will be listed as well as summarized in a 
table.  
3.3.7   eDiary Compliance 
The rate of missing eDiary data within each four week interval, which is defined as (number of 
days with missing eDiary data / 28) * 100, will be summarized descriptively.  A day will be 
considered as missing if the subject did not interact with their eDiary and the subject did not 
experience a headache on that day.   
3.4   Analysis of Efficacy Endpoints 
3.4.1 Headache/Migraine Days and Acute Migraine Medication Days 
Summary tables for the number of migraine/headache days, change from baseline and the 
percent change by 4, 12 and 24 week intervals and treatment group will be produced. Similar 
tables will be produced for acute migraine medication days and the change from baseline acute 
migraine medication days.  The treatment difference and associated confidence interval will also 
be provided.  These confidence intervals will be based on normal approximation. Stratification 
will not be used for these intervals. 
Additionally, the SAS procedure, Proc Mixed using the ANCOVA model controlling for the 
effects of baseline migraine days outlined in Section 2.5, will be used to calculate the estimated 
treatment difference from placebo, the change from baseline and the associated confidence 
intervals for Weeks 1-12.  The ANCOVA model will also be used to test for a treatment 
difference in the primary endpoint change from baseline in migraine days for Weeks 1-12 and 
for the change from baseline days of acute migraine medication use for Weeks 1-12. Significant 
p-values based on the formal decision rule criteria outlined in Section 2.7.5 will be clearly noted.  
Plots of the migraine days and change from baseline and for days of acute migraine medication 
use and change from baseline will be produced.  These plots will use the four week intervals as 


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the X-axis.  A separate set of graphs that provide histograms of the Week 1 to 12 results for these 
three parameters will also be produced. 
The change from baseline in migraine days for the six, 4 week intervals from Weeks 1 to 24 will 
also be analyzed using repeated measures.  The model will include treatment group, timepoint 
(Weeks 1-4, 5-8 9-12, 13-16, 17-20, 21-24), and baseline migraine days as fixed factors. 
Estimated treatment difference, for each timepoint, and associated confidence interval will be 
estimated using SAS procedure, Proc Mixed. The unstructured (UN) covariance structure will be 
specified. If the model fails to converge, an alternative covariance structure will be specified.  
The timepoint variable will be categorical and baseline migraine days will be continuous. The 
repeated measures analysis will be repeated for weeks 1-12 using the same subjects and a subset 
where only subjects/four week intervals where the eDiary was completed a minimum of 21 days 
and applying Missing Data Rule 1 described in Section 2.2.2. Only the overall week 1-12 
estimated treatment difference, associated confidence interval and p-value will be reported for 
this analysis.   
The change from baseline in migraine days for Weeks 1-12 will be summarized within the 
subgroups outlined in Section 2.7.1 forest plot of the treatment difference and associated 
confidence interval will also be presented.   
3.4.2   Responder Rates 
The responder rates will be determined as outlined in the missing data Section 2.7.2 and the 
endpoint definition in Section 2.2.2.  The number of subjects who are responders and the rate 
(full analysis population as the denominator) will be summarized for each treatment group and at 
each 4, 12 and 24-week interval.  The difference in rates and associated confidence interval will 
also be produced.  These confidence intervals will be calculated based upon the normal 
approximation for two independent proportions. Stratification will not be used for these intervals. 
The SAS procedure, Proc Freq, will be used to calculate these confidence intervals.  Any interval 
for which the normality assumption is questionable (i.e. np <5 or nq <5) will be flagged. 
Plots of the percent of responders across time, for each response level, will be produced.  These 
plots will use the four-week responder rates. 


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A p-value for the difference in rates for the key secondary endpoints will be based upon the 
CMH test outlined in Section 2.5. Significant p-values based on the formal decision rule criteria 
outlined in Section 2.7.5 will be clearly noted in the footnotes.  
Should the as randomized and ‘true’ values for the stratification factors differ the as randomized 
values will be used within these CMH tests.  The SAS procedure, Proc Freq, will be used to 
calculate this p-value.   
3.4.3.1   Percentage of Subjects with a Migraine on the Day after Dosing 
The missing data rules provided in Section 2.7.2 will be used for the key secondary endpoints 
except for the percentage of subjects with a migraine (prevalence) on the day after dosing 
endpoint. Subjects who did not complete the eDiary on the day following dosing will be included 
in to the prevalence rate calculation based upon their month 1 daily migraine rate. Hence, 
subjects with a migraine will be included in the rate calculation as a value of 1, subjects who 
completed the diary and did not have a migraine will be included as a zero and subjects who did 
not complete the diary will be included with a value between 0 and 1 equal to the number of 
month 1 migraine days / 28. 
The percentage of subjects with a migraine (full analysis population as the denominator) will be 
summarized for each treatment group at baseline and each day from Day 0 to Day 7.  A p-value 
for the difference from Placebo in the percentage of subjects with a migraine on the day after 
dosing (Day 1) key secondary endpoint will be based upon the extended CMH test stratified by 
the randomization stratification factor. Significant p-values based on the formal decision rule 
criteria outlined in Section 2.7.5 will be clearly noted in the footnotes.  
3.4.3.2   Time to First Migraine after Dosing 
The analysis of the time to the first migraine after dosing endpoint will be based upon 
Kaplan-Meier method.  The 25th percentile, 50th percentile (median), and 75th percentile, and 
their corresponding 95% confidence intervals will be reported for each treatment group. The 
percent of subjects who are migraine free at Days 1, 2, 3, 4, 5 and 6 and Weeks 1, 4, 8, 12 and 
the associated confidence intervals will be summarized for each treatment group.  A subject will 


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be censored for the eDiary analysis at the time of their last data entry. A Kaplan-Meier plot for 
time to first migraine will be presented for weeks 1-12.  
3.4.4   Remaining Headache and Migraine Secondary Endpoints 
The following summarizations will be produced for headache episodes, migraine attacks, 
headache and migraine hours, headaches and migraines with severe intensity and headaches and 
migraines with acute medication usage.  A summary table including confidence intervals for the 
treatment difference for the 4, 12, and 24-week time intervals will be produced.   
Missing data rule for both Missing Data Rules provided in Section 2.7.2 will be utilized. For 
severe intensity and acute medication usage endpoints, the missing data rule will be applied to 
the nominator and denominator separately before calculating the percent.   
3.4.5   Tertiary and Exploratory Headache and Migraine Endpoints  
The following summarizations will be produced for headache and migraine characteristics, the 
average length of a headache episode and migraine attack, and headaches and migraines 
summarized by type of acute medication usage.  A summary table including confidence intervals 
for the treatment difference for the 4-week time intervals will be produced.   
Missing data rule for Missing Data Rule 1 provided in Section 2.7.2 will be utilized for the 
exploratory analyses.  
3.4.6   Other Secondary Efficacy Analyses 
The secondary endpoints will be summarized with descriptive statistics by time point.  These 
summary measures will be based upon the observed results and where appropriate the change 
from baseline results. The denominator for percentages will be the total number of assessments 
collected at each visit.  
3.4.6.1   Short-Form Health Survey (SF-36 v 2.0) 
The actual scores and change from baseline in each of the eight sections will be summarized 
using the Full Analysis Population at each scheduled visit by treatment group using descriptive 


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statistics. Scoring software utilizing the 2009 norm-based scoring algorithm will be used to 
calculate the actual score for each of the eight sections.  
3.4.6.2   EQ-5D-5L 
The change from baseline will be summarized separately for each EQ-5D-5L item using the Full 
Analysis Population at each scheduled visit by treatment group. A shift from baseline to each 
scheduled visit by treatment group will be tabulated for each item. 
3.4.6.3   Allodynia Symptom Checklist-12 (ASC-12)  
The ASC-12 total score and change from baseline will be summarized using the Full Analysis 
Population at each scheduled visit by treatment group using descriptive statistics. In addition, 
allodynia severity will be summarized using frequency counts for each scheduled visit.  
3.4.6.4   Brush (dynamic mechanical) Allodynia 
Brush allodynia will be summarized as a continuous measure and binary (does or does not have 
brush allodynia).  The result for each side of forehead will be reported separately. The actual 
brush allodynia score will be summarized using the Full Analysis Population at each scheduled 
visit using descriptive statistics.  The percent of subjects with brush allodynia (i.e. a score >0) 
will be summarized at each scheduled visit along with the percent of subjects with a score >2. 
3.5   Pharmacokinetic Analyses 
The concentrations of Free ALD403 will be measured in plasma from all ALD403-treated 
subjects using validated assay methods. The PK analysis will include evaluations of 
concentration-time profiles for Free ALD403 at the following times: pre-dose on Day 0, and 
Weeks 4, 8, 12, 16, 20, 24, 36, 48, and 56.  
The concentrations of Free 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.  


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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.  
3.6   Analysis of Safety Endpoints 
3.6.1   Adverse Events 
Adverse events are collected from the time of Informed Consent through the final subject visit. 
The incidence of all AEs and treatment-related AEs will be tabulated by treatment received. 
These AEs will be classified by system organ class and preferred term using the 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.  
A treatment-emergent AE (TEAE) is an AE with a start date on or after the date of the treatment.  
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be imputed 
as follows: 
Missing onset dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• 
UK-MMM-YYYY: If the month and year are different from the month and year of the 
first dose of trial drug, assume 01-MMM-YYYY. If the month and year are the same as 
the first dose of trial drug month and year, and the end date (after any imputation) is on or 
after the first dose of trial drug, then assume the date of the first dose of trial drug. If the 
month and year are the same as the first dose of trial drug month, and year and the end 
date (after any imputation) is prior to the first dose of trial drug, then assume the end date 
for the onset date.  
• 
DD-UKN-YYYY/UK-UKN-YYYY: If the year is different from the year of first dose of 
trial drug, assume 01-JAN-YYYY of the collected year. If the year is the same as the first 


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dose of trial drug year, and the end date (after any imputation) is on or after the first dose 
of trial drug, then assume the date of the first dose of trial drug. If the year is the same as 
the first dose of trial drug, and the end date (after any imputation) is prior to the first dose 
of trial drug, then assume the end date for the onset date.  
Missing end dates (where UK and UKN indicate unknown or missing day and month 
respectively):  
• UK-MMM-YYYY: Assume the last day of the month; 
• DD-UKN-YYYY/UK-UKN-YYYY: Assume 31-DEC-YYYY. 
An overview of AEs, which includes subject incidence of TEAEs, treatment-related TEAEs, 
Serious TEAEs, TEAEs leading to treatment withdrawal, TEAEs leading to treatment 
interruption, TEAEs leading to discontinuation and deaths will be presented.  
The subject incidence of TEAEs and treatment-related TEAEs will be summarized by system 
organ class and preferred term. 
Treatment-emergent AEs will also be summarized in a table by severity.  For TEAEs presented 
by severity, the worst severity for each event during the clinical trial will be presented for each 
subject. 
All AEs will be presented as a listing by subject.  This listing will include the duration of the AE. 
3.6.2   Deaths, Serious Adverse Events and Other Significant Adverse Events 
3.6.2.1   Serious Adverse Events 
All SAEs will be listed and summarized in a similar manner to TEAEs. 
3.6.2.2   Deaths 
A listing of deaths will be presented.  


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3.6.3   Clinical Laboratory Evaluations 
Summary statistics for actual values and for changes from baseline will be tabulated for clinical 
laboratory results by scheduled visit. Subjects with clinical laboratory values outside of the 
normal reference range at any post-baseline assessment will be summarized. Shifts from baseline 
clinical laboratory values based upon the normal range and will be tabulated. Subjects 
developing an antibody response will be listed.  
Additional blood specimens using the immune response lab kit will be collected for subjects who 
experience a potential systemic allergic reaction that the Investigator believes is related to 
ALD403.  
Plots of average clinical laboratory parameters will be presented over time.  
3.6.4   Vital Signs, Physical Findings and Other Observations Related to Safety 
3.6.4.1   Vital Signs 
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics. A plot of average vital sign parameters will be presented 
over time.  
3.6.4.2   Physical Exam 
Clinically significant physical exam findings at screening will be documented in medical history. 
Post baseline physical examination findings, including unscheduled visits, will be reported as 
adverse events. 
3.6.4.3   Electrocardiogram Results 
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics by treatment group.  
The overall ECG assessment based upon PI assessment will be summarized including post 
treatment ECGs determined to be abnormal clinically significant. 


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The absolute QTcF values provided by the core lab will be analyzed as a categorical variable.  
Each QTcF value in a given patient will be grouped into 4 categories: 
• QTcF interval < 450 msec 
• QTcF interval 450 - 480 msec 
• QTcF interval > 480 - 500 msec 
• QTcF interval > 500 msec 
The changes in QTcF measures will also be analyzed as categorical variables.  The change in 
QTcF in a given patient will be grouped into 2 categories: 
• QTcF interval increases from baseline > 30 msec 
• QTcF interval increases from baseline > 60 msec 
The overall ECG assessment will be summarized along with a summary of how many subject 
developed a post treatment abnormal clinically significant result. Denominators for percentages 
will use the number of assessments available at each visit. 
3.6.5   Immunogenicity Data Analysis 
Analyses will be conducted using treatment group that the subjects actually received for safety 
population. Analysis of specific anti-ALD403 antibodies is restricted to subjects who are treated 
with ALD403. 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. 
For subjects with pre-existing antibodies at baseline, the number and percent of subjects with 
positive anti-ALD403 antibody samples will be summarized.  In addition, the number and 
percent of subjects who develop anti-drug antibodies to ALD403 during the trial will be 
summarized at each scheduled visit in the same table. Additional efficacy and safety analyses 
based upon the immunogenicity results will be performed. 
All the Immunogenicity Data will be listed.  


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3.6.5.1 Anti-ALD403 Antibody Analysis 
Subjects with a positive anti-ALD403 antibody result will be listed. 
3.6.6   Columbia-Suicide Severity Rating Scale (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.  
The denominator for percentages will be the number of subjects with a C-SSRS assessment at 
baseline or at any time post baseline.  The post baseline summary will list a subject as yes if they 
ever selected yes after baseline.  
3.6.7 Pregnancies 
Positive pregnancy test results will be listed. 
 


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REFERENCES 
 
                                                 
1     http://www.ihs-classification.org/_downloads/mixed/ ihc_II_main_no_print.pdf.  
2     Storer RJ, Akerman S, GoadsbyPJ. Calcitonin gene-related peptide (CGRP) modulates nociceptive   
      trigeminovascular transmission in the cat. Br J Pharmcol. 2004; 142(7): 1171-1181. 
3     Jenkins DW, Langmead CJ, Parsons AA, StrijbosPJ. Regulation of calcitonin-gene related peptide release from  
      rat trigeminal nucleus caudalis slices in vitro. NeurosciLett. 2004; 366(3): 241-244. 
4     Hintze, J. (2008) PASS 2008. NCSS, LLC. Kaysville, Utah. www.ncss.com.