Conditions: Acute Migraine With or Without Aura
Keywords: acute migraine aura sumatriptan nasal powder AVP-825 adolescents
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 159
Healthy volunteers: no

Brief summary:
This study will be conducted to evaluate the safety and efficacy of sumatriptan nasal powder (AVP-825) compared to placebo in the acute treatment of migraine in adolescent participants, 12 through 17 years of age.

Detailed description:
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating AVP-825 for the acute treatment of migraine with or without aura in adolescent subjects (12 to 17 years old).

Arms:
arm 1: Participants will be dosed with 22 milligrams (mg) sumatriptan nasal powder via two nosepieces (11 mg per nosepiece). arm 2: Participants will be dosed with matching placebo via nosepieces containing capsules filled with lactose instead of sumatriptan.

Interventions: intervention 1: sumatriptan nasal powder intervention 2: Placebo
Intervention descriptions: intervention 1: nasal powder administered via nosepiece intervention 2: lactose monohydrate powder administered via nosepiece

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL AND PROPRIETARY 
CURRAX PHARMACEUTICALS LLC 
Page 1 
 
 
 
 
 
Protocol: 
          17-AVP-825-301 
       
Version:  
IND:  
Date: 
          2.0 
          110090 
          19 November 2020 
Replaces: 
Protocol version 1.0 dated: 26 July 2017 
Drug: 
          AVP-825; Breath Powered®  Nasal Sumatriptan 
          Trade Name: ONZETRA® Xsail® 
       
 
Sponsor: 
            Currax Pharmaceuticals, LLC 
10 North Park Place, Suite 201 
Morristown, NJ 07690 
 
Medical Monitor:           Dr. Robert Pennington 
Phone: 
 
         1-908-239-0292 
Mobile: 
 
         1-732-589-2478 
Email: 
                     robert.pennington@ecrscorp.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This submission contains CONFIDENTIAL material and information and should be restricted in its distribution. 
Do not copy without the permission of the Sponsor.
PROTOCOL TITLE: 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the 
Safety and Efficacy of ONZETRA® Xsail® (Sumatriptan Nasal Powder) for the Acute 
Treatment of Episodic Migraine With or Without Aura in Adolescents. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 2 
LIST OF TABLES.......................................................................................................................................... 4 
LIST OF FIGURES........................................................................................................................................ 4 
LIST OF ABBREVIATIONS ........................................................................................................................ 5 
PROTOCOL AGREEMENT ........................................................................................................................ 6 
STUDY SYNOPSIS ........................................................................................................................................ 7 
1 
BACKGROUND AND CLINICAL RATIONALE ......................................................................... 15 
2 
STUDY OBJECTIVES ...................................................................................................................... 18 
3 
STUDY DESIGN ................................................................................................................................ 19 
4 
STUDY POPULATION .................................................................................................................... 21 
4.1 
Inclusion Criteria ............................................................................................................................... 21 
4.2 
Exclusion Criteria .............................................................................................................................. 21 
4.3 
Subject Withdrawal from the Study ................................................................................................ 23 
5 
STUDY TREATMENTS ................................................................................................................... 25 
5.1 
Treatments Administered ................................................................................................................. 25 
5.1.1 
Description and Composition of Study Medications.......................................................... 25 
5.1.2 
Packaging ............................................................................................................................... 26 
5.1.3 
Labeling ................................................................................................................................. 26 
5.1.4 
Storage of Clinical Supplies ................................................................................................. 26 
5.1.5 
Study Medication Administration ....................................................................................... 26 
5.2 
Accountability of Study Supplies ...................................................................................................... 26 
5.3 
Subject Compliance ........................................................................................................................... 27 
5.4 
Concomitant and Prohibited Medication ........................................................................................ 27 
5.5 
Rescue Medication ............................................................................................................................. 28 
6 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................ 30 
6.1 
Efficacy Measures .............................................................................................................................. 30 
6.1.1 
Primary Measure .................................................................................................................. 30 
6.1.2 
Secondary Measures ............................................................................................................. 30 
6.2 
Safety ................................................................................................................................................... 30 


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6.2.1 
Adverse Events ...................................................................................................................... 30 
6.2.1.3 
Reporting ............................................................................................................................... 33 
6.2.2 
Physical and Neurological Examination ............................................................................. 34 
6.2.3 
Vital Signs .............................................................................................................................. 35 
6.2.4 
Urine Drug Screen Tests ...................................................................................................... 35 
6.2.5 
Pregnancy Tests .................................................................................................................... 35 
6.2.6 
Columbia Suicide Severity Rating Scale (C-SSRS)............................................................ 35 
6.3 
Schedule of Evaluations and Procedures ......................................................................................... 35 
6.3.1 
Description of Study Procedures ......................................................................................... 36 
6.3.1.1 
Visit 1 (Screening/Enrollment) ............................................................................................ 36 
7 
DATA MANAGEMENT ................................................................................................................... 39 
7.1 
Data Collection ................................................................................................................................... 39 
8 
STATISTICAL METHODS ............................................................................................................. 40 
8.1 
Analysis Populations .......................................................................................................................... 40 
8.2 
Efficacy Analysis ................................................................................................................................ 40 
8.3 
Safety Analysis ................................................................................................................................... 41 
8.3.1 
Interim Analysis .................................................................................................................... 41 
8.4 
Sample Size Calculations ................................................................................................................... 41 
9 
ADMINISTRATIVE PROCEDURES ............................................................................................. 42 
9.1 
Institutional Review Board Approval .............................................................................................. 42 
9.2 
Informed Consent Form .................................................................................................................... 42 
9.3 
Subject’s Diary ................................................................................................................................... 42 
9.4 
Electronic Case Report Forms .......................................................................................................... 42 
9.5 
Quality Assurance .............................................................................................................................. 43 
9.5.1 
Documentation ...................................................................................................................... 43 
9.5.2 
Monitoring ............................................................................................................................. 43 
9.6 
Record Retention ............................................................................................................................... 44 
9.7 
Source Data ........................................................................................................................................ 44 
9.8 
Data Handling .................................................................................................................................... 44 
9.9 
Guidelines for Good Clinical Practice .............................................................................................. 44 
9.10 
Conditions for Amending the Protocol ............................................................................... 44 


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9.11 
Conditions for Terminating the Study ................................................................................ 45 
9.12 
Confidentiality of Study Documents and Patient Records ................................................ 45 
9.13 
Reports ................................................................................................................................... 45 
9.14 
Publications ........................................................................................................................... 45 
9.15 
Audits/Inspections ................................................................................................................. 46 
10 
REFERENCES ................................................................................................................................... 47 
11 
APPENDICES .................................................................................................................................... 51 
 
 
LIST OF TABLES 
 
Table 1 Schedule of Evaluations and Visits ................................................................................................. 13 
Table 2 Time and Event Schedule for Migraine Attacks 1 and 2 .............................................................. 14 
Table 3 Composition of One Capsule/Nosepiece ......................................................................................... 25 
 
LIST OF FIGURES 
Figure 1  Study Schematic ............................................................................................................................. 12 
  


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
5-HT 
5-hydroxytryptamine 
AAN 
American Academy of Neurology 
AE 
Adverse event 
ADE 
Adverse device effect 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CRO 
Contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DMP 
Data management plan 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
Early termination 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HPMC 
Hydroxypropyl methylcellulose 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICHD 
International Classification of Headache Disorders 
IFU 
Instructions for use 
IP 
Investigational product 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
LOCF 
Last observation carried forward 
MAO-A 
Monoamine oxidase-A 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MM 
Medical Monitor 
NF 
National Formulary 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over–the-counter 
SAE 
Serious adverse event 
SDV 
Source data verification 
UADE 
Unanticipated adverse device effect 
USP 
United States Pharmacopoeia 
WHO 
World Health Organization 


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PROTOCOL AGREEMENT 
 
Protocol Title: 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the 
Safety and Efficacy of ONZETRA® Xsail® (Sumatriptan Nasal Powder) for the Acute Treatment 
of Episodic Migraine With or Without Aura in Adolescents 
Protocol Number: 17-AVP-825-301 
This document is a confidential communication of Currax Pharmaceuticals. The recipient agrees 
that no unpublished information contained within this document or protocol will be disclosed or 
published without prior consent and written approval from Currax. An exception to this 
agreement may be made for the purposes of ethical or regulatory review, in which case this 
document may be disclosed to an Ethics Review Board or any authorized representative of a 
national authority as required by regulation. 
The signatures of the principal investigator and representative of the sponsor below constitute 
their approval of this protocol and further provide the necessary assurances that: 
1. This study will be conducted according to Good Clinical Practice (GCP) and to all 
stipulations, as specified in both clinical and administrative sections of the protocol 
including the Declaration of Helsinki. 
2. The conduct and results of this study will be kept confidential, and the electronic case report 
forms (eCRFs) and other pertinent data will become the property of Currax Pharmaceuticals. 
3. The protocol contains all necessary information required to conduct the study, as outlined in 
the protocol, and that the study will not be initiated without the approval of an appropriate 
Institutional Review Board (IRB). 
4. All participants in this study will provide written informed consent in accordance with the 
requirements specified in the Code of Federal Regulations (21 CFR Parts 50, 56, 312) 
and/or the Declaration of Helsinki. All participants will also be informed that their medical 
records will be kept confidential except for review by Currax or its representatives, the U.S. 
Food and Drug Administration (FDA), or other regulatory agencies if applicable. 
 
 
 
Principal Investigator Signature 
Date 
Principal Investigator Name:   
 
Currax Representative Signature 
Date 
Currax Representative Name: Errol M. Gould, PhD 
02 February 2021


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STUDY SYNOPSIS 
Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess 
the Safety and Efficacy of ONZETRA® Xsail® (Sumatriptan Nasal Powder) for the Acute 
Treatment of Episodic Migraine With or Without Aura in Adolescents. 
Study Objectives 
The objective of the study is to evaluate the safety and efficacy of ONZETRA Xsail (AVP-825) 
compared to placebo in the acute treatment of migraine in adolescent subjects, 12 through 17 
years of age. 
Study Population 
Number of Subjects: Approximately 236 adolescent subjects will be randomized (~420 subjects 
to be enrolled for placebo run-in), at approximately 30 centers in the United States. 
Condition/Disease: Acute migraine with or without aura. 
Key Inclusion Criteria: 
• Male and female subjects 12 to 17 years (inclusive) of age at the time of informed consent; 
• Have a diagnosis of episodic migraine with or without aura according to International 
Classification of Headache Disorders-3rd edition, beta version (ICHD-IIIB, 1.2.1 or 1.1) 
criteria, for at least 1 year prior to the screening/enrollment visit; 
• Experienced migraine attacks or moderate-to-severe intensity and typically lasting ≥ 3 hours 
untreated, occurring at a frequency of ≥ 2 to ≤ 14 attacks per month for the past  6 months 
prior to the screening/enrollment visit; 
• Subject’s parent or legal guardian must be willing to sign a copy of informed consent form 
(ICF) as well as documentation for Written Authorization for Use and Release of Health and 
Research Study Information, after the nature and risks of study participation have been fully 
explained. Subjects must be willing to provide informed assent. 
Key Exclusion Criteria: 
• Subjects with ≥ 15 headache days per month in total (migraine, probable migraine, or 
tension-type); 


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• Subjects with the following headache types: retinal [ICHD-IIIB 1.2.4], with brainstem 
aura [ICHD-IIIB 1.2.2], hemiplegic [ICHD-IIIB 1.2.3], status migrainosus [ICHD-IIIB 
1.4.1], other forms of complicated migraine, or secondary headaches 
• Subjects who have not responded to an adequate dose and appropriate duration of 
treatment with 2 or more triptans; 
• Subjects with known nasal obstruction, current uncontrolled nasopharyngeal illness, or 
known velum insufficiency (i.e., a cleft palate and/or structural abnormalities in the soft 
palate and nasopharynx) which may interfere with the proper use of study medication; 
• Subjects whose conditions in the investigator’s opinion may put the subject at significant 
safety risk or confound the study results. This include subjects who in the investigator’s 
opinion should not be enrolled in the study due to the risks described in the Warnings and 
Precautions or Contraindications sections of the ONZETRA Xsail Prescribing 
Information. 
A complete list of inclusion/exclusion criteria is presented in Section 4 of the study protocol. 
 
Study Design 
Design: This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
evaluating AVP-825 in adolescent subjects for the treatment of acute migraine with or without 
aura. This study includes 2 treatment phases; a single-blind placebo run-in phase and a 
 double-blind placebo-controlled treatment phase. A schematic of the study design is presented in 
Figure 1. 
Duration: Subjects will be enrolled in the study for up to approximately 28 weeks, with up to 12-
weeks in a single-blind placebo run-in period and up to 12-weeks in a double-blind treatment 
period, and an exit/early termination visit 10 days after treatment in the double-blind treatment 
phase. 
Study Treatment: The investigational product is ONZETRA Xsail 22 mg (AVP-825, sumatriptan 
nasal powder 11 mg per nosepiece). 
Control: The control treatment will be the same device as AVP-825 with matching placebo 
nosepieces containing capsules filled with lactose instead of sumatriptan. 
 Randomization/Stratification:   All eligible patients will treat one migraine attack of moderate to 
 severe pain intensity during the single-blind phase (Migraine Attack 1).   Placebo non-responders 
 (defined as subjects who are not headache pain free 2 hours post treatment of Migraine Attack 1) 


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who meet all inclusion/exclusion criteria will be randomized in a 1:1 ratio (active: placebo) to treat 
one migraine attack of moderate to severe pain intensity in the double-blind treatment phase 
(Migraine Attack 2).  Randomization will be stratified by age (12 to 14 years inclusive versus 15 to 
17 years inclusive).  Enrollment will be monitored to ensure that number of patients in either age 
group does not exceed 70% or drop below 30%. 
Dose Regimen: Study medication will be administered as soon as possible after the development 
of a migraine attack associated with moderate-to-severe headache pain during each phase, per the 
instructions for use (IFU) provided to the subject. 
Assessments and Visits 
There are up to 3 scheduled clinic visits including: screening/enrollment (Visit 1), randomization 
(Visit 2), and exit/early termination (Visit 3). Monthly follow-up phone calls will be made after 
Visits 1 and 2, up to 12 weeks after the visit depending on when Migraine Attacks 1 and 2 are 
treated. Study procedures will be performed at each visit as outlined in the Schedule of 
Evaluations and Visits (Table 1) and for each migraine attack (at 15, 30, 60, 120 minutes, and 24 
hour post dose) as outlined in Table 2. The randomization visit should occur approximately 10 
days after treatment of Migraine Attack 1. 
Outcome Measures 
 
Efficacy Endpoints and Patient Satisfaction Measures 
Primary efficacy endpoint: 
The primary endpoint of the study is headache pain-free at 120 minutes following treatment of 
Migraine Attack 2. 
Secondary efficacy endpoints (Migraine Attack 2): 
 
• Headache relief (defined as a reduction in pain intensity from moderate or severe [grade 2 
or 3] at baseline to none or mild [grade 0 or 1]) at 120 minutes 
• Headache pain-free by time (other than at 120 minutes) 
• Headache relief by time (other than at 120 minutes) 
• Change from baseline in headache severity by time 
• Sustained headache relief, defined as headache relief [headache severity mild (grade 1) or 
none (grade 0)] at 2 hours with no worsening of headache, use of a second dose of study 
medication, or rescue medication taken through 24 hours after dose 


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• Sustained pain freedom, defined as pain freedom [headache severity none (grade 0)] at 2 
hours with no recurrence of headache, use of a second dose of study medication or rescue 
medication taken through 24 hours after dose 
• Rescue medication use and time to rescue medication 
• Number of subjects with nausea, phonophobia, photophobia, or vomiting by time 
• Number of subjects who return to ‘normal’ functioning by time 
• Time to recurrence of headache defined as an increase from a headache severity score of 
0 (none) or 1 (mild) at 2 hours to 2 (moderate) or 3 (severe) within 24 hours 
Exploratory efficacy endpoints (Migraine Attack 2): 
 
• Sustained headache relief (1 to 2 hours), defined as headache relief [headache severity 
mild (grade 1) or none (grade 0)] at 60 minutes with no worsening of headache, use of a 
second dose of study medication, or rescue medication taken through 120 minutes after 
dose 
• Sustained pain freedom (1 to 2 hours), defined as pain freedom [headache severity none 
(grade 0)] at 60 minutes with no recurrence of headache, use of a second dose of study 
medication or rescue medication taken through 120 minutes after dose 
• Bilateral headache at predefined timepoints 
• Headache intensity increased by movement at predefined timepoints 
Safety 
• Adverse events 
• Physical and neurological examination 
• Vital signs 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
 
General Statistical Methods and Types of Analyses 
Analysis Populations 
Two analysis populations will be used; modified intent-to-treat (mITT) and safety. The mITT 
population includes all subjects randomized and treated for Migraine Attack 2 who have at least 
one post-baseline efficacy assessment and will be used for all analyses of efficacy. Subjects in 
the mITT population will be included in the treatment group to which they were randomized 


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regardless of treatment received. The safety population includes all subjects who received study 
treatment and will be used for all analyses of safety. Subjects will be included in the treatment 
group based on the actual treatment received. 
Efficacy Analyses 
The primary efficacy endpoint of the study is headache pain-free (no headache) at the 120- 
minutes following treatment of Migraine Attack 2. Treatment comparison will be performed by 
using the Cochran-Mantel-Haenszel (CMH) test stratified by age group (12-14 years or 15-17 
years) and baseline migraine pain severity (moderate or severe). Secondary efficacy endpoints 
will be analyzed similarly, or by appropriate statistical tests. Missing data will be imputed by 
treatment failure, i.e., headache pain-free equals no. 
Safety Analyses 
Safety measures will be summarized by treatment. 
Sample Size Calculation 
Power calculations are based on the results of the completed pivotal trial for adults (OPN-SUM- 
MIG-3301, Avanir data on file). The observed percentage (n) of subjects who are headache pain- 
free at 120 minutes was 34.3% (37) vs. 17.3% (18) for AVP-825 vs. placebo, respectively. For 
this study in adolescents with single-blind placebo run-in, if it is assumed that the percentage of 
subjects who are headache pain free at 120 minutes is 30% vs. 15%, a sample size of 236 
(118/arm) randomized and treated at Migraine Attack 2 would provide approximately 80% 
power with 2-sided α = 0.05. In consideration of the attrition rate during the run-in phase, it is 
estimated that approximately 420 subjects would be needed to enter the single-blind placebo 
run-in phase in order to have 236 subjects randomized and treated for Migraine Attack 2. 


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Figure 1  Study Schematic 
 
 


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Table 1 Schedule of Evaluations and Visits 
 
Screening/ 
Enrollment 
Single-Blind Placebo Run-in
(up to 12 weeks) 
Migraine Attack 1 
Randomization 
(Baseline) 
Double-Blind Treatment 
(up to 12 weeks) 
Migraine Attack 2 
Exit/ET 
Visit 
Visit 1 
Monthly phone call 
Visit 2 
Monthly phone call 
Visit 3 
Window 
Day -3 to 1 
Every 30 ± 3 days 
after Visit 1 
10 ± 4 days 
after Attack 1 
Every 30 ± 3 days 
after Visit 2 
10 ± 4 days 
after Attack 2 
Sign informed consent/minor assent 
X 
Medical and migraine history 
X 
X1 
Review of eligibility 
X 
X2 
Physical (including nasal examination) 
and neurological examination 
X 
X3 
X 
Randomization 
X 
Vital signs, height and weight 
X 
Urine drug screen 
X 
X 
X 
Urine pregnancy test4 
X 
X 
X 
C-SSRS 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Prior and concomitant medications 
X 
X 
X 
X 
X 
Training on use of study medication 
X 
X 
Provide/collect diary 
X 
X5 
X 
Access IWRS 
X 
X 
X 
Dispense and/or collect study medication 
X 
X 
X 
C-SSRS = Columbia-Suicide Severity Rating Scale; ET = early termination; IWRS = interactive web response system; 
Note: Subjects who do not have a migraine attack within 12 weeks of the screening/enrollment visit (single-blind phase) or randomization visit (double-blind 
treatment phase) may be granted another 12 weeks in each period based on sponsor approval. 
1 
Update any new information on medical and migraine history obtained since screening/enrollment. 
2 
A protocol eligibility form must be completed for subjects to be randomized. 
3. Nasal examination only should be performed before randomization 
4 
For females of childbearing potential only. 
5 
Diary will be reviewed and returned to the subjects who are eligible to continue in the study. 


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Table 2 Time and Event Schedule for Migraine Attacks 1 and 2 
 
Pre-Dose 
Dosing 
15 min 
30 min 
60 min 
120 min 
3 Hours 
4 Hours 
24 Hours 
Record efficacy assessments in diary: 
Pain free (Yes/No) 
X 
X 
X 
X 
X 
X 
X 
Headache severity score 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
Migraine symptoms (separate questions): 
Nausea, vomiting, photophobia, phonophobia 
X 
X 
X 
X 
X 
X 
Dose of study drug medication 
X 
Bilateral headache (Yes/No) 
X 
X1 
X1 
X1 
X1 
X1 
X1 
Intensity increased by movement (Yes/No) 
X 
X1 
X1 
X1 
X1 
X1 
X1 
Ability to function question 
X 
X 
X 
X 
X 
X 
Time of recurrence of headache 
X2 
X2 
Rescue medication 
X2 
X2 
Min = minutes;  
1 
Assessed only if response to pain free question is “No” 
2 
Assessment should be made after 120 minutes. 


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1 
BACKGROUND AND CLINICAL RATIONALE 
Migraine is a common disabling primary headache disorder in adults. Epidemiological studies 
have documented its high prevalence and high socioeconomic and personal impacts. An overall 
US prevalence of migraine has been reported to be 17.5% among females and 8.6% among 
males.1 Migraine attacks are recurrent and associated with moderate to severe headache that are 
usually associated with gastrointestinal, neurologic, and autonomic symptoms. Migraine attacks 
generally occur several times per month, typically last 4 to 72 hours, and are characterized by 
moderate to severe headaches, often unilateral, and with a pulsating quality. Migraines are often 
associated with nausea and/or vomiting, phonophobia, and/or photophobia. Approximately 30% 
of headaches also have associated aura, which is characterized by the transient focal neurological 
symptoms that usually precede or sometimes accompany the headache.2,3 
Migraine is the most common acute and recurrent headache syndrome in children. Prevalence 
data estimate that 3% to 23% of children and adolescents have migraines.4–8 Migraine in children 
and adolescents appears to be a similar nosological entity as migraine in adults with minor 
differences due to either different lifestyle (school/vacation) or due to incomplete neurological 
development.9–13  Although the clinical characteristics of migraine are similar to adults, some  
key differences have been noted in children and adolescents which can impact diagnosis and 
treatment, including shorter duration of the attacks, more frequent bilateral headaches, fewer  
aura symptoms, and prominent gastrointestinal symptoms.14 Along with the pain and associated 
symptoms, migraine in adolescents can result in decreased functional ability and a significant 
burden on quality of life. The impact of headaches on quality of life in this population is similar 
to that found for other chronic illness conditions such as childhood cancer, heart disease, and 
rheumatic disease.15 Migraine disability can lead to reduced school performance and missed 
school days, in addition to limiting participation in organized activities and socializing with 
friends.16 If uncontrolled, these effects of migraine may adversely affect the educational/social 
growth and development of adolescents with migraine. 
The management of migraine in children, as in adults, consists of general measures, abortive 
treatment, and prophylactic treatment. An individual patient may need all three 
approaches.6,7,17,18 Both prescription and over-the-counter (OTC) medications have been utilized 
in the treatment of migraines in pediatric patients and similar efficacy of such medicines in adult 
and pediatric migraineurs has been reported.19,20 However, the number of drugs studied and 
approved for the abortive treatment of migraine attacks in children and adolescents is limited 
compared with adults. This is due both to the practical challenges of conducting studies in 
children and the difficulty of demonstrating efficacy of treatments in young migraineurs due to 


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high placebo response.21,22 Non-prescription medications like acetaminophen and  ibuprofen  
have been shown to be safe and effective for acute migraine treatment in children.23,24 Triptans 
are the only class of medication developed specifically for the treatment of acute migraine, and 
there are three triptans and one triptan/nonsteroidal anti-inflammatory drug (NSAID) 
combination product which have been approved by the Food and Drug Administration (FDA) for 
acute migraine therapy in the pediatric population.25 In 2009, Almotriptan tablets became the  
first triptan approved for treatment in 12–17 year-olds,26 but the indication was only for pain and 
not migraine associated symptoms. Since then, rizatriptan tablets (6–17 year-olds),27 
sumatriptan/naproxen sodium tablets (12–17 year-olds)28 and zolmitriptan nasal spray (12–17 
year-olds)29 have been approved for the acute treatment of migraine in children and/or 
adolescents. 
There are 2 non-blinded, single-dose, single-center studies that examine the pharmacokinetics of 
intranasal sumatriptan in children aged 6 to 11 years (Study SUM40254)30 and in adolescents 
aged 12 to 17 years (Study SUMB1006).31 Both studies were conducted in patients diagnosed 
with migraine and demonstrated that pharmacokinetic parameters outside of a migraine attack in 
adolescents are similar to those previously reported in adults, suggesting that adolescents should 
be dosed similarly to adults. Given the dose adjustment scheme used in these studies based on 
age and bodyweight, there were no clinically significant differences in sumatriptan exposure 
between adults, adolescents, and children. Various doses and formulations of sumatriptan have 
been widely studied in adolescents, including subcutaneous,32,33 oral,34 and nasal spray 
formulations.35–38 Of the studies designed as placebo-controlled trials evaluating pain relief 
following treatment of a moderate-to-severe migraine attack, all failed to demonstrate efficacy 
for the primary endpoints, primarily due to high placebo response. For this reason, sumatriptan 
has not yet been approved by the FDA for use in adolescents with migraine. However, efficacy 
was demonstrated through secondary endpoints and pooled analysis suggesting a high probability 
of achieving pain freedom at 2 hours following treatment with 20 mg sumatriptan nasal spray. 
Based on these results, the 2004 American Academy of Neurology (AAN) Practice parameter on 
the pharmacologic treatment of migraine headache in children and adolescents concluded that 
sumatriptan nasal spray is effective and should be considered for the acute treatment of migraine 
in adolescents.7 
ONZETRA® Xsail® (AVP-825) is a novel intranasal delivery system containing low-dose 
sumatriptan powder, approved for the acute treatment of migraine with and without aura in 
adults (ONZETRA Xsail Prescribing Information, 2016). AVP-825 uses a Breath Powered® 
intranasal delivery system that widens nasal passages and naturally seals the soft palate, while 
using the patients’ exhaled air to propel sumatriptan-powder into the nostril and deliver drug 


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beyond the narrow nasal valve to the upper posterior nasal regions, an area of richly vascular 
mucosa conducive to rapid drug absorption into the systemic circulation.39 The recommended 
dose of AVP-825 is 22 mg sumatriptan nasal powder, administered as two nosepieces, one in 
each nostril, using the Breath Powered delivery system. Each nosepiece contains 11 mg 
sumatriptan nasal powder, and a full dose from two nosepieces delivers ~15-16 mg sumatriptan. 
Treatment with AVP-825 delivers sumatriptan powder efficiently across a significantly wider 
area of absorbent mucosa in the posterior nasal cavity, resulting in proven faster absorption of 
sumatriptan relative to traditional liquid nasal spray and oral tablets,40 with the potential for less 
drug swallowing and reduced first-pass hepatic metabolism due to closure of the soft palate. 
Treatment with AVP-825 is also associated with significantly lower overall systemic sumatriptan 
exposure versus oral tablet (100 mg) or subcutaneous injection (6 mg), which may lead to 
improved tolerability.40 Phase 2 and 3 placebo-controlled AVP-825 trials in the acute treatment 
of migraine in adults showed early onset of efficacy (significantly higher rates of pain relief as 
early as 30 minutes post-dose vs. placebo, and significantly higher rates of pain relief and pain 
freedom from 15 minutes compared to 100 mg oral sumatriptan in the Phase 3 trials) 
accompanied by sustained headache relief through 48 hours and a low level of triptan-related 
adverse effects.41–43 
The purpose of this study is to evaluate efficacy and safety of AVP-825 for the acute treatment of 
migraine with and without aura in adolescent subjects (age 12-17 years). Pharmacokinetic 
samples will also be collected to confirm there is no significant differences between this patient 
population and the adult patient population. In the pharmacokinetic study of intranasal 
sumatriptan in adolescents aged 12 to 17 years (Study SUMB1006),31 pharmacokinetic 
parameters for sumatriptan in adolescents were similar to those previously reported in adults  
with no clinically significant differences in sumatriptan exposure between adults and 
adolescents. A 22 mg dose of AVP-825 administered as two nosepieces offers efficient non-oral 
drug delivery, faster absorption of sumatriptan with low overall drug exposure and early onset of 
efficacy in adults. Therefore, AVP-825 may be an effective treatment for adolescents with 
migraine, where acute attacks may be shorter in duration and gastrointestinal symptoms may 
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2 
STUDY OBJECTIVES 
The objective of the study is to evaluate the safety and efficacy of ONZETRA Xsail (AVP-825) 
compared to placebo in the acute treatment of migraine in adolescent subjects, 12 through 17 
years of age. 


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3 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating 
AVP-825 for the acute treatment of migraine with or without aura in adolescent subjects (12 to 
17 years old). This study includes 2 treatment phases; a single-blind placebo run-in phase and a 
double-blind placebo-controlled treatment phase. A schematic of the study design is presented in 
Figure 1. 
Approximately 420 subjects will be enrolled in the single-blind placebo run in phase to obtain 
approximately 236 subjects randomized in the double-blind treatment phase. Subjects will be 
enrolled in the study for up to approximately 28 weeks; with up to 12-weeks in a single-blind 
placebo run-in period, and up to 12-weeks in a double-blind treatment period. An exit/early 
termination visit will occur 10 days after treatment of Migraine Attack 2. The investigational 
product in this study is ONZETRA Xsail 22 mg (AVP-825, sumatriptan nasal powder 11 mg per 
nosepiece) and the control treatment is the same device as AVP-825 with matching placebo 
nosepieces filled with lactose (i.e. contain no active drug). 
All eligible subjects will treat one migraine attack of moderate to severe intensity during the 
single-blind phase (Migraine Attack 1). Placebo non-responders (defined as subjects who are not 
headache pain free 2 hours after treatment of Migraine Attack 1) who meet all 
inclusion/exclusion criteria will be randomized in a 1:1 ratio (active: placebo) to treat one 
migraine attack of moderate to severe intensity in the double-blind treatment phase (Migraine 
Attack 2). Randomization will be stratified by age (12 to 14 years versus 15 to 17 years). 
Enrollment will be monitored to ensure that number of subjects in either age group does not 
exceed 70% or drop below 30%. Study medication will be administered as soon as possible after 
the development of a migraine attack associated with moderate-to-severe headache pain during 
each phase, per the instructions for use (IFU) provided to the subject, and relevant data will be 
collected in a subject diary. 
There are up to 3 scheduled clinic visits including: screening/enrollment (Visit 1), randomization 
(Visit 2), and exit/early termination (Visit 3). Monthly follow-up phone calls will be made after 
Visits 1 and 2 for up to 12 weeks after the visit, depending on when Migraine Attacks 1 and 2 are 
treated. 
The primary endpoint of the study is headache pain free at 120 minutes following treatment of 
Migraine Attack 2. Secondary efficacy endpoints include: headache relief at 120 minutes, 
headache pain-free by time (other than 120 minutes), headache relief by time (other than 120 
minutes), change from baseline in headache severity by time, sustained pain relief (2 to 24 
hours), sustained pain freedom (2 to 24 hours), rescue medication use and time to rescue 


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medication use, number of subjects with nausea, phonophobia, photophobia, or vomiting by  
time, number of subjects who return to ‘normal’ functioning at each timepoint, and time to 
recurrence of headache in 24 hours. Exploratory efficacy endpoints include sustained pain relief 
(1 to 2 hours), sustained pain freedom (1 to 2 hours), bilateral headache at predefined timepoints, 
and headache intensity increased by movement at predefined timepoints. The safety measures in 
this study are standard measures used for controlled trials and include adverse events reported, 
physical and neurological examination, vital signs, and the Columbia Suicide Severity Rating 
Scale (C-SSRS).   


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4 
STUDY POPULATION 
 
4.1 
Inclusion Criteria 
1. Male and females 12 to 17 years (inclusive) of age at the time of informed consent. 
2. Have a diagnosis of episodic migraine with or without aura according to International 
Classification of Headache Disorders-3rd edition, beta version (ICHD-IIIB, 1.2.1 or 1.1) 
criteria for at least 1 year prior to the screening/enrollment visit. 
3. Experienced migraine attacks of moderate-to-severe intensity and typically lasting ≥ 3 hours 
untreated, occurring at a frequency of ≥ 2 to ≤ 14 attacks per month for the past 6 months 
prior to the screening/enrollment visit. 
4. Subject’s parent or legal guardian must be willing to sign a copy of informed consent form 
(ICF) as well as documentation for Written Authorization for Use and Release of Health and 
Research Study Information, after the nature and risks of study participation have been fully 
explained. 
5. Subjects also must be willing to provide minor assent according to the state law and 
Institutional Review Board (IRB) requirements, after the nature and risks of study 
participation have been fully explained. 
6. Subjects must have a verified airflow through both nostrils and an ability to close the soft 
palate. 
7. Subjects must demonstrate the ability to use the Breath Powered delivery device correctly. 
8. Able and willing to read and comprehend written instructions and complete the diary. 
Subjects with ≥ 75% diary data entry for Migraine Attack 1 are eligible to be randomized. 
9. Female patients who are of childbearing potential (post-menarche) must: 
a. agree to practice a medically acceptable method of birth control during the entire 
study duration (oral contraceptive tablets, hormonal implant device, hormone patch, 
intrauterine device, diaphragm and contraceptive cream or foam, condom with 
spermicide, or abstinence) or be surgically sterile, and 
b. have a negative urine pregnancy test at screening/enrollment and baseline visits. 
 
4.2 
Exclusion Criteria 
1. Subjects who weigh less than 30 kg. 


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2. Subjects with a body mass index (BMI) of more than 40. 
3. Subjects with >15 headache days per month in total (migraine, probable migraine, or 
tension-type). 
4. Subjects with the following headache types: retinal [ICHD-IIIB 1.2.4], with brainstem aura 
[ICHD-IIIB 1.2.2], hemiplegic [ICHD-IIIB 1.2.3)], status migrainosus [ICHD-IIIB 1.4.1], 
other forms of complicated migraine, or secondary headaches. 
5. Subjects who have not responded to an adequate dose and appropriate duration of treatment 
with 2 or more triptans. 
6. Current use of medication for migraine prophylaxis that has not been stable or requires dose 
adjustment within 7 days prior to the screening/enrollment visit or if a dose adjustment is 
expected during the study. 
7. Received chronic opioid therapy for more than 3 consecutive days within the 30 days prior 
to the screening/enrollment visit. 
8. Current treatment with monoamine oxidase A (MAO-A) inhibitors or use within 4 weeks 
before the screening/enrollment visit. 
9. Subjects with known nasal obstruction, current uncontrolled nasopharyngeal illness, or 
known velum insufficiency (i.e., a cleft palate and/or structural abnormalities in the soft 
palate and nasopharynx) which may interfere with the proper use of study medication. 
10. History of clinically significant abnormality in electrocardiogram. 
11. History or current symptoms or signs of ischemic cardiac, cerebrovascular or peripheral 
vascular syndrome. 
12. Uncontrolled hypertension defined as systolic or diastolic blood pressure that exceeds the 
90th percentile for age and height (Appendix 1).44 
13. Any disease or condition which in the opinion of the investigator would contraindicate study 
participation such as a history of coronary artery disease, coronary vasospasm or a cardiac 
accessory conduction pathway disorder; a history of stroke, transient ischemic attack, or 
hemiplegic or basilar migraine; peripheral vascular disease; ischemic bowel disease; 
uncontrolled hypertension; severe hepatic impairment; epilepsy; drug or alcohol abuse; any 
systemic disease, neurological or psychiatric condition. 
14. Subjects who fail urine drug screen test at the screening/enrollment visit. 
15. Current suicide risk, as evidenced by any of the following: 
a. It is the judgment of the investigator that the subject may be at risk for suicide. 


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b. The subject is rated a “yes” to question 4 or question 5 on the C-SSRS at 
screening/enrollment or randomization visit, and the most recent episode occurred 
within the past 6 months prior to the screening/enrollment visit. 
c. The subject has attempted suicide within the past 12 months prior to the 
screening/enrollment visit. 
16. Hypersensitivity or intolerance to sumatriptan, any of its components, or sulphonamides. 
17. Subjects whose conditions in the investigator’s opinion may put the subject at significant 
safety risk or confound the study results. This include subjects who in the investigator’s 
opinion should not be enrolled in the study due to the risks described in Warnings and 
Precautions or Contraindications sections of the ONZETRA Xsail Prescribing Information. 
18. Have taken any investigational medication within 4 weeks before the screening/enrollment 
visit, or are scheduled to receive an investigational drug, other than sumatriptan for this 
study, while participating in the study. 
19. Females who are pregnant or breast-feeding. 
 
4.3 
Subject Withdrawal from the Study 
Subjects and their parent/legal guardian will be advised verbally and in the written ICF that they 
have the right to withdraw from the study at any time without prejudice or loss of benefits to 
which they are otherwise entitled. The investigator or sponsor may discontinue a subject from the 
study in the event of an intercurrent illness, adverse event, other reasons concerning the health or 
well-being of the subject, or in the case of lack of cooperation, non-compliance, protocol 
violation, or other administrative reasons. Subjects who are placebo responders (defined as 
subjects who are headache pain free 2 hours post treatment of Migraine Attack 1) will be 
withdrawn from the study and procedures specified at the exit/early termination visit (Visit 3) 
will be performed. Subjects who do not have a migraine attack within 12 weeks of the 
screening/enrollment visit (single-blind phase) or randomization (double-blind treatment phase) 
may be granted another 12 weeks in each period based on sponsor approval. If a subject does not 
return for a scheduled visit, every effort should be made to contact the subject. Regardless of the 
circumstance, every effort should be made to document subject outcome, if possible. The 
investigator should inquire about the reason for withdrawal, request the subject/parent/legal 
guardian to return all unused investigational product (IP), and follow-up with the subject and 


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their parent/legal guardian regarding any unresolved adverse events. 
If the subject and their parent/legal guardian withdraws from the study, and consent is withdrawn 
for disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. Subjects who withdraw from the study will not be 
replaced. 


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5 
STUDY TREATMENTS 
 
5.1 
Treatments Administered 
All medication used in this study will be prepared, packaged, and labeled in accordance with 
Good Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation 
(ICH) Good Clinical Practice (GCP) guidelines, and applicable laws and regulations. 
 
5.1.1 
Description and Composition of Study Medications 
Clinical study medication will be provided in individual cartons containing one dose. Each 
carton/dose will consist of one ONZETRA Xsail reusable device body, and one foil laminated 
pouch containing 2 single-use nosepieces, equivalent to one dose of study medication. Each 
nosepiece will contain sumatriptan succinate or placebo (lactose monohydrate) dry powder in a 
clear, size 3, hydroxypropyl methylcellulose (HPMC) inhalation capsule printed with black ink 
on the cap. 
Two different strengths of study medication will be provided as follows: 
• AVP-825 22 mg of sumatriptan; 2 nosepieces in a pouch with each nosepiece/capsule 
containing 11 mg sumatriptan (equivalent to 15.4 mg of sumatriptan succinate). 
• AVP-825 Placebo; 2 nosepieces in a pouch with each nosepiece/capsule containing 
lactose monohydrate. 
The composition of each nosepiece of the IP is shown in Table 3. 
 
Table 3 Composition of One Capsule/Nosepiece 
 
 
 
Ingredient 
AVP-825 11 mg 
(mg) 
Placebo 
(mg) 
Sumatriptan succinate, USP dry powder 
15.4 
0 
Lactose monohydrate, NF dry powder 
0 
30.01 
HPMC inhalation capsule 
45 
45 
HPMC = Hydroxypropyl methylcellulose; NF = National Formulary; USP = United States Pharmacopoeia 
1 Volume of 30 mg of lactose monohydrate is equivalent to the volume of 15.4 mg of sumatriptan succinate; volume 
of powder in a clear capsule shell is critical for blinding purpose 
 
Demonstration kits will be provided for training purposes. The demonstration kit will be clearly 
marked with the ONZETRA Xsail name and ‘demonstration kit contains no medication’. The kit 


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will consist of the reusable device body (the same device body as in the study medication kit but 
with a different label) and one foil laminated pouch containing 2 single-use nosepieces with the 
empty capsules marked with ‘demo’ on one side of the capsule. 
 
5.1.2 
Packaging 
The IP will be supplied as a blinded, pre-labeled, individually packaged drug device combination 
product kit. Each kit will contain a reusable device body, one pouch containing 2 nosepieces of 
active study medication or 2 nosepieces of placebo, and instructions for use. 
 
5.1.3 
Labeling 
All labels for the individual cartons will contain the protocol number, kit number, description of 
the content of the package, dosing instructions, an investigational drug warning, storage 
conditions, and the sponsor company name and address. It will also contain space to document 
subject number, site number, subject initial, and dosing period number or date dispensed. 
The carton label will consist of 2 panels, with 1 detachable panel that will be removed and kept 
with the site’s study records (e.g., affixed to the study medication dispensing log page or subject 
source records) at the time of dispensing. Space is provided on both panels of the card label to 
record subject number, dispensing date and assigned treatment period. All IP labels comply with 
all applicable federal and local regulations. 
 
5.1.4 
Storage of Clinical Supplies 
Clinical supplies must be stored in compliance with label requirements in a secure place and kept 
at room temperature; 20° - 25°C (68° -77°F) with excursions permitted to 15°C to 30°C (59°F-
86°F). The approved expiration date for ONZETRA Xsail is 36 months. 
 
5.1.5 
Study Medication Administration 
All subjects will receive AVP-825 or matching placebo according to the kit number assigned by 
an Interactive Web Response System (IWRS) randomization scheme. Designated staff at each 
site will dispense study medication and train subjects on the use of a drug device combination 
product using a demonstration kit clearly labelled as ‘demo kit’. The subject will self-administer 
the study medication following instruction for use provided in the study medication kit. 
 
5.2 
Accountability of Study Supplies 
Receipt of Supplies 


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The IP will be shipped by the sponsor directly to the study sites. 
The investigator is responsible for maintaining an inventory of each shipment of IP received and 
comparing it with the accompanying Drug Accountability Report/Material Shipping Form. The 
investigator will verify the accuracy of the information on the form, sign and date it, and return 
the form to the sponsor or its representative. All IP supplied is for use only in this study and 
should not be used for any other purpose. All study drug material kit numbers will also be 
recorded and tracked at the site using the Drug Accountability Log. 
Record of Dispensing 
Accurate records of all kits dispensed for individual subjects will be made in the appropriate 
section of the subject's drug accountability records. This document will contain the following 
information: (i) the subject number to whom the drug was dispensed; (ii) the date(s) and quantity 
of the drug dispensed to the subject; and (iii) the kit number assigned to the subject via IRT 
system. 
Additionally, the detachable panel of the 2-panel label from each kit will be removed and kept 
with the site’s study records (e.g., affixed to a study medication subject drug dispensing log page) 
at the time of dispensing. Space is provided on both panels of the kit label to record subject 
number, site number, subject initial, and dosing period number or date dispensed. 
Unused Supplies 
At the end of the study, all unused investigational supplies must be inventoried on the Drug 
Accountability Log and returned to the sponsor or its representative, along with a completed and 
signed Drug Accountability Report/Material Shipping Form. If any study medication is lost or 
damaged, it should be indicated on the form. 
 
5.3 
Subject Compliance 
At screening/enrollment (Visit1) and randomization (Visit 2), subjects will be trained on the use 
of the study medication and completion of the diary. Subjects will be instructed to treat their 
migraine headache as soon as it reaches an intensity of moderate to severe, and record 
information in the diary for each attack during the treatment phases. Subjects will be instructed 
to bring their diary and used study medication to the site at Visits 2 and 3 for review and 
compliance check. 
 
5.4 
Concomitant and Prohibited Medication 
All medications and other treatments taken by the subjects during the study, including those 
treatments initiated 30 days prior to the start of the study, must be recorded on the electronic 


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Case Report Form (eCRF). 
During the study, subjects will be permitted to continue to take migraine prophylactic 
medications they were taking at screening/enrollment provided they had been on a constant 
regimen for at least 7 days prior to screening/enrollment. The regimen is to remain constant 
throughout the study, except for necessary changes for medical or safety reasons. If a 
prophylactic regimen changes after screening/enrollment, then the subject is to postpone 
treatment of a migraine with investigational product until the new prophylactic regimen has been 
in place for at least 7 days. 
The following medications, OTC or prescription, are prohibited during the specified timeframe: 
• Any acute medications for migraine, including short acting NSAID-containing 
compound, other simple analgesics, as well as anti-emetic medications are prohibited for 
the following duration: 6 hours before dosing to 2 hours after treatment with 
investigational product. 
• Analgesics containing morphine, codeine, a barbiturate or an opioid derivative 24 hours 
before and 24 hours after taking investigational product. 
• Ergotamine containing drugs, ergotamine derivatives or any 5-hydroxytryptamine 1 (5-
HT1) agonist (including but not limited to sumatriptan, naratriptan, zolmitriptan, 
almotriptan, frovatriptan, eletriptan or rizatriptan) are also excluded within 24 hours 
before, and 24 hours after treatment with investigational product. 
• Monoamine oxidase-A (MAO-A) inhibitors are excluded for at least 4 weeks before 
screening/enrollment or at any time during the course of this study. 
• In addition, use of any investigational drug within 4 weeks prior to randomization or 
during the study is prohibited. 
 
5.5 
Rescue Medication 
Subjects are allowed to take recue medication 2 hours after taking the study treatment and after 
completing the 2-hour post-dose diary questions. The use of rescue medication will be recorded 
on the diary. Rescue medication may include the following: 
 
• OTC pain reliever – OTC monotherapy pain reliever such as acetaminophen or 
nonsteroidal anti-inflammatory drugs (NSAIDs), not exceeding the maximum 
recommended dose 
• Prescription NSAIDs – prescription NSAID monotherapy should be prescribed by the 


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investigator specifically for the subject for the acute treatment of migraine, and should be 
used according to the package insert 
• OTC anti-emetics – OTC anti-emetics commonly used to treat nausea symptoms during 
migraine attacks, not exceeding the maximum recommended dose 
• Prescription anti-emetics – prescription anti-emetics should be prescribed by the 
investigator specifically for the subject for the symptoms of migraine, and should be 
used according to the package insert 
For any questions regarding rescue medication, the Medical Monitor (MM) should be 
consulted. Rescue medications will not be supplied by the sponsor. 
 


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6 
STUDY ASSESSMENTS AND PROCEDURES 
 
6.1 
Efficacy Measures 
 
6.1.1 
Primary Measure 
Subjects will record in the diary if they are headache pain free for each migraine attack (1 and 2), 
at the following timepoints post dose: 15, 30, 60, 120 mins, 3, 4, and 24 hours. 
The primary endpoint is headache pain-free at 120 minutes following treatment of Migraine 
Attack 2. 
 
6.1.2 
Secondary Measures 
Subjects will record the following in the diary for each migraine attack (1 and 2) at the 
timepoints specified in Table 2: 
• Headache severity score (scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, 3 = 
severe) 
• Nausea, vomiting photophobia, phonophobia (yes/no for each symptom) 
• Ability to function (response to ‘how do you rate your ability to do school-work or 
perform your usual activities?’ on a 5-point scale [normal, mildly impaired, moderately 
impaired, severely impaired, I require bedrest]) 
• Time of recurrence of headache, defined as an increase from a headache severity score of 
0 (none) or 1 (mild) pain to 2 (moderate) or 3 (severe) 
• Use and time of rescue medication 
• Bilateral headache (yes/no) 
• Intensity increased by movement (yes/no) 
 
6.2 
Safety 
 
6.2.1 
Adverse Events 
 
6.2.1.1 
Definitions 
An adverse event (AE) is any untoward medical occurrence or unintended change (including 
physical, psychological, or behavioral) from the time ICF is signed, including inter-current 


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illness, which occurs during the course of a clinical trial after treatment has started, whether 
considered related to treatment or not. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. Changes associated with normal growth and development that do not vary in frequency 
or magnitude from that ordinarily anticipated clinically are not AEs (e.g., onset of menstruation 
occurring at a physiologically appropriate time). 
Clinical AEs should be described by diagnosis and not by symptoms when possible (e.g., cold, 
seasonal allergies, instead of “runny nose”). 
Migraine headache and associated symptoms (i.e., photophobia, phonophobia, nausea, vomiting) 
will not be captured as AEs unless the investigator feels they differ in frequency, intensity or 
duration from the subject’s baseline condition. 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol and higher than known therapeutic doses. It must be reported 
irrespective of outcome even if toxic effects were not observed. 
AEs will be graded on a 3-point scale and reported in detail as indicated on the eCRF: 
Mild:  easily tolerated, causing minimal discomfort and not interfering with normal 
everyday activities 
Moderate: sufficiently discomforting to interfere with normal everyday activities 
Severe:  incapacitating and/or preventing normal everyday activities 
The relationship of each AE to study medication should be determined by the investigator using 
the following explanations: 
Not related: the event is clearly related to other factors such as the subject’s clinical state, 
therapeutic interventions, or concomitant medications administered to the 
subject 
Unlikely related: the event is most likely produced by other factors such as the subject’s 
clinical state, therapeutic interventions, or concomitant medications 
administered to the subject; and does not follow a known response pattern to 
the study medication 
Possibly related: the event follows a reasonable temporal sequence from the time of drug 
administration; and/or follows a known response pattern to the study 
medication; but could have been produced by other factors such as the 
subject’s clinical state, therapeutic interventions, or concomitant medications 


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administered to the subject 
Related: the event follows a reasonable temporal sequence from the time of drug 
administration; and follows a known response pattern to the study 
medication; and cannot be reasonably explained by other factors such as the 
subject’s clinical state, therapeutic interventions, or concomitant medications 
administered to the subject 
6.2.1.2  
Serious Adverse Events 
A Serious Adverse Event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes: 
1. Death 
 
2. Life-threatening experience (one that places the subject, in the view of the initial reporter, at 
immediate risk of death from the AE as it occurred, i.e., it does not include an AE that, had  
it occurred in a more severe form, might have caused death) 
3. Persistent or significant disability/incapacity (disability is a substantial disruption of a 
person’s ability to conduct normal life functions) 
4. In-patient hospitalization or prolongation of hospitalization 
 
5. Congenital anomaly/birth defect 
 
Important medical events that may not result in death, or be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject or require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. 
The terms “cancer” and “overdose” are not considered to be SAEs, but if a subject experiences 
cancer or overdose, they are still reportable as AEs. 
Pregnancy is not considered to be an AE or an SAE, unless a complication occurs that meets the 
requirements for an AE or SAE but must be reported on a pregnancy report form. Women who 
are pregnant or likely to become pregnant are excluded from this study. In the event a subject 
becomes pregnant during the study, study medication must be discontinued, a pregnancy report 
form must be completed to capture potential drug exposure during pregnancy, and the pregnancy 
must be reported within 24 hours of notice. Any pregnant subject must be followed until the 
outcome of her pregnancy is known (i.e., normal delivery, abnormal delivery, 
spontaneous/voluntary/therapeutic abortion). The pregnancy (i.e., the mother and the fetus) must 
be followed up through delivery with regard to outcome. 


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A pregnancy report form must also be completed in the event that a female partner of a male 
subject becomes pregnant within 30 days after his last dose of study medication. 
The term ‘severe’ is a measure of intensity; thus, a severe AE is not necessarily serious. For 
example, nausea of several hours’ duration may be rated as severe but may not be clinically 
serious. 
 
6.2.1.3 
Reporting 
Subjects will be queried regarding AEs at all in-clinic visits and at follow-up phone calls during 
the single-blind placebo run-in phase and the double-blind phase. The investigator will assess 
and record all reported AEs. Any AE newly reported after receiving the last dose of study 
medication will be followed up until 30 days. 
A death occurring during the study, or which comes to the attention of the investigator within 30 
days after stopping the treatment whether considered treatment-related or not, must be reported 
to the sponsor. 
For all SAEs, including an abnormal laboratory test value, the investigator must inform the 
Medical Monitor (MM) by telephone no later than 24 hours after becoming aware of the event. 
Subsequently, the SAE must be assessed for the following details: seriousness of event, start date, 
stop date, intensity, frequency, relationship to study drug, action taken regarding study drug, 
treatment required, outcome to date, and other data as indicated on the SAE form. All details 
regarding the SAE must be recorded on the SAE form that is provided. The SAE reporting 
contact information is as follows: 
Medical Monitor 1-908-239-0292 (direct) or 1-732-589-2478 (mobile) and email everestsafety-
Vielight-P17.03@ecrscorp.com. Such preliminary reports will be followed by detailed 
descriptions later, which may include copies of hospital case reports, autopsy reports, and other 
related documents when requested. 
The IRB will be notified of such an event in writing as soon as is practical in compliance with 
federal and local regulations. 
6.2.1.4 Suspected Technical Device Issues 
If a device is suspected of having technical issues (e.g., damaged device, missing parts, 
inoperable device), the nature of the technical issue should be reviewed by the investigator to 
determine if the issue resulted in an AE or SAE and that this event is documented and reported 
appropriately. 
If the investigator suspects that a technical device issue does exist, then the issue must be 


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reported by the investigational staff within 1 working day of their knowledge of the event using 
the Technical Device Issue Notification Form. 
Unanticipated Adverse Device Effects 
The definition of unanticipated adverse device effects (UADEs), which are device effects that are 
reportable on an expedited basis in the United States is as follows: 
An UADE is defined as a serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the right, safety, or welfare of subjects. 
For investigational devices, sponsors are required to collect, track, and review all potential 
UADEs. 
1) Site collects all AEs on CRF form 
2) AEs that are deemed to be related to the investigational device are called adverse device 
effects (ADEs). ADEs require further review, typically done by the MM. 
3) The site would complete an ADE form (similar to an SAE form), submit to the contract 
research organization (CRO)/sponsor. Medical Monitor would review and determine if 
the ADE complies with the definition of a UADE. 
4) If the effect is indeed a UADE, the UADE is then reported to the FDA within 10 days of 
notification to sponsor. Reporting time is 5 days if remedial action is needed, such as 
changes to instructions for use of device, subject population or stopping clinical trial 
altogether. 
5) Anything reported to FDA must also be reported to IRBs. 
6.2.2 
Physical and Neurological Examination 
Physical and neurological examination will be performed at Visits 1 and 3, and will include 
assessments of head, eyes, ears, nose, throat, lymph nodes, skin, extremities, respiratory, 
gastrointestinal, musculoskeletal, cardiovascular, and nervous systems. A nasal examination 
using a speculum will be conducted at Visits 1, 2, and 3 to ensure that the subject does not have 
nasal obstruction due to nasal septum deviation, polyposis, severe mucosal swelling, or any other 
reason. The physical/neurological and nasal examinations should be performed by the same 
person each time, whenever possible. 


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Physical examination abnormalities determined by the investigator to be clinically significant at 
screening/enrollment should be recorded as medical history. Any clinically significant changes in 
physical examination findings from the screening examination should be recorded as AEs. 
 
6.2.3 
Vital Signs 
Vital signs, systolic and diastolic blood pressure (mm Hg), heart rate (beats/minute), respiratory 
rate (breaths/minute) and body temperature (ºF) should be recorded at Visit 1. 
Weight and height should be measured at Visit 1. 
 
6.2.4 
Urine Drug Screen Tests 
Urine samples will be analyzed at the study site at all clinic visits (Visit 1 to 3) for the following: 
marijuana, opiates, amphetamines, cocaine, phencyclidine, barbiturates, benzodiazepines and 
methadone. 
 
6.2.5 
Pregnancy Tests 
Urine pregnancy tests are to be performed for females of childbearing potential at all clinic visits 
(Visit 1 to 3). 
All female subjects of childbearing potential should be instructed to use appropriate birth control 
methods for up to 4 weeks following the last dose of study medication. 
 
6.2.6 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Appendix 3) is a low-burden measure of the spectrum of suicidal ideation and 
behavior that was developed by Columbia University researchers for the National Institute of 
Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track 
suicidal events through any treatment.46 It is a clinical interview providing a summary of both 
ideation and behavior that can be administered during any evaluation or risk assessment to 
identify the level and type of suicidality present. The C-SSRS can also be used during treatment 
to monitor for clinical worsening. 
The C-SSRS evaluation will be performed at all clinic visits (Visit 1 [‘baseline/screening’ 
version], Visit 2 and Visit 3 [‘since last visit’ version]). 
 
6.3 
Schedule of Evaluations and Procedures 
A schedule of evaluations and procedures by study visit is provided in Table 1. The schedule for 


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evaluations and their frequency during a migraine attack is provided in Table 2. 
 
6.3.1 
Description of Study Procedures 
 
6.3.1.1 
Visit 1 (Screening/Enrollment) 
The following procedures should be performed at screening/enrollment (Day -3 to 1) 
1. The investigator will provide the subject and their parent/legal guardian with assent /ICF 
and privacy documents for signature and will explain the rationale for the study, 
providing ample time for participants, and/or authorized representatives to ask questions 
2. Review and record medical and migraine history 
3. Review and record prior and concomitant medications 
4. Query subject on any adverse events 
5. Review eligibility (inclusion/exclusion criteria) 
6. Perform physical and neurological examination including nasal examination 
7. Measure and record vital signs, height and weight 
8. Collect urine specimen for drug screen 
9. Urine pregnancy test (for females of childbearing potential only) 
10. Administer the C-SSRS 
11. Train subject on the use of study medication 
12. Access IWRS to obtain assigned kit number for study medication 
13. Dispense diary and study medication 
Subjects will be instructed to treat one migraine headache of moderate to severe intensity in the 
subsequent 12 weeks (84 days) with the study medication and to respond to questions on the 
study diary. Diary should be used before taking the study treatment and at 15, 30, 60, 120 min, 3 
hours, 4 hours, and 24 hours after dosing. A monthly phone call to the subject or their 
parent/legal guardian will be placed by site personnel to inquire about any adverse events and to 
answer study question. 
 
Following treatment in the single-blind placebo run-in phase, the site will complete a protocol 
eligibility form and submit to the MM for approval. Subjects deemed eligible by the investigator 
and the MM will be enrolled into the study. 


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6.3.1.2 Visit 2 (Randomization) 
The following procedures should be performed at Visit 2 
1. Review and record medical and migraine history 
2. Review and record prior and concomitant medications 
3. Review eligibility (inclusion/exclusion criteria) 
4. Collect urine specimen for drug screen 
5. Urine pregnancy test (for females of childbearing potential only) 
6. Administer the C-SSRS 
7. Train subject on the use of study medication 
8. Query subject on any adverse events 
9. Perform nasal examination 
10. Review diary and return to subject 
11. Randomization 
12. Access IWRS to obtain assigned kit number for study medication 
13. Dispense study medication 
Subjects will be instructed to treat one migraine headache of moderate to severe intensity in the 
subsequent 12 weeks (84 days) with the study medication and to respond to questions on the 
study diary. Diary should be used before taking the study treatment and at 15, 30, 60, 120 min, 3 
hours, 4 hours, and 24 hours after dosing. A monthly phone call to the subject or their 
parent/legal guardian will be placed by site personnel to inquire about any adverse events or to 
answer study question. 
6.3.1.3  
Visit 3 (Exit/Early Termination) 
The following procedures should be performed at Visit 3. 
1. Review and record concomitant medications 
2. Perform physical and neurological examination including nasal examination 
3. Query subject on any adverse events 
4. Collect urine specimen for drug screen 
5. Urine pregnancy test (for females of childbearing potential only) 


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6. Administer the C-SSRS 
7. Collect diary and study medication 
8. Access IWRS to record subject exit 
6.3.1.4 
Follow-up Phone Visits 
The investigator will follow-up with monthly telephone calls after the screening/enrollment visit 
and after the randomization visit for up to 12 weeks depending on when a migraine attack is 
treated. During these phone visits, subjects will be queried on adverse events and any 
concomitant medications taken. 
6.3.1.5 
Procedures During Treatment 
Subjects will be instructed to administer their study medication at the onset of a migraine attack 
and enter the information in the diary. The schedule of procedures is outlined in Table 2. 
 


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7 
DATA MANAGEMENT 
 
7.1 
Data Collection 
The sponsor or designated representative (e.g., CRO) will perform the data management 
activities in accordance with the data management plan (DMP). The DMP will outline the 
systems and procedures to be used in the study. 
Clinical study data will be reported (captured) by study site personnel on eCRFs. An eCRF must 
be completed for every subject enrolled in the study. The eCRF data will be entered by trained 
study-site personnel and then reviewed for completeness and accuracy and electronically signed 
by the investigator or authorized designee. All study-site personnel must use a password-
protected user account to enter, review, or correct study data. Electronic signature procedures 
shall comply with the CFR Title 21 Part 11. Passwords will be strictly confidential. 
All eCRF data will be exported from the electronic data capture (EDC) system and transferred to 
the sponsor or representative. The sponsor or representative will also receive electronic transfers 
of non-eCRF data from third-party vendors as appropriate. The electronic data format of all 
transfers will be agreed upon with the sponsor or representative and documented in the DMP or 
vendor data transfer requirements document as appropriate.The clinical monitoring staff will 
perform source data verification (SDV) of the data recorded in the EDC system with source 
documents at the clinical study sites according to the data management plan and clinical 
monitoring plan. The data will be subjected to consistency and validation checks within the EDC 
system with supplemental data reviews performed outside of the EDC system. 
Medical history and adverse events will be coded using a current version of Medical Dictionary 
for Regulatory Activities (MedDRA), and concomitant medications using a current version of 
the World Health Organization (WHO) Drug Dictionary. The sponsor or representative will 
perform a medical safety review of the coding. 
Completed eCRF images with a date- and time-stamped electronic audit trail indicating the user, 
the data entered, and any reason for change (if applicable) will be archived at the investigator’s 
site and at the sponsor’s site. 
 


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8 
STATISTICAL METHODS 
 
8.1 
Analysis Populations 
Two analysis populations will be used; modified intent-to-treat (mITT) and safety. The mITT 
population includes all subjects randomized and treated for Migraine Attack 2 who have at least 
one post-baseline efficacy assessment and will be used for all analyses of efficacy. Subjects in 
the mITT population will be included in the treatment group to which they were randomized 
regardless of treatment received. The safety population includes all subjects who received study 
treatment and will be used for all analyses of safety. Subjects will be included in the treatment 
group based on the actual treatment received. 
 
8.2 
Efficacy Analysis 
The primary efficacy endpoint of the study is headache pain-free at 120 minutes following 
treatment of Migraine Attack 2. Treatment comparison will be performed by using the Cochran- 
Mantel-Haenszel (CMH) test stratified by age group (12-14 years or 15-17 years) and baseline 
migraine pain severity (moderate or severe). Secondary and exploratory efficacy endpoints will 
be analyzed similarly, or appropriate statistical tests will be used. Efficacy assessments after 
taking rescue medication will be set to missing. Missing data will be imputed by treatment 
failure, i.e., headache pain-free = no.Secondary efficacy endpoints (Migraine Attack 2): 
• Headache relief (defined as a reduction in pain intensity from moderate or severe [grade 2 
or 3] at baseline to none or mild [grade 0 or 1]) at 120 minutes 
• Headache pain-free by time (other than at 120 minutes) 
• Headache relief by time (other than at 120 minutes) 
• Change from baseline in headache severity by time 
• Sustained pain relief, defined as headache relief [headache severity mild (grade 1) or 
none (grade 0)] at 2 hours with no worsening of headache, use of a second dose of study 
medication, or rescue medication taken through 24 hours after dose 
• Sustained pain freedom, defined as pain freedom [headache severity none (grade 0)] at 2 
hours with no recurrence of headache, use of a second dose of study medication or rescue 
medication taken through 24 hours after dose 
• Rescue medication use and time to rescue medication 
• Number of subjects with nausea, phonophobia, photophobia, or vomiting by time 
• Number of subjects who return to ‘normal’ functioning by time 


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• Time to recurrence of headache defined as an increase from a headache severity score of 
0 (none) or 1 (mild) at 2 hours to 2 (moderate) or 3 (severe) within 24 hours 
Exploratory efficacy endpoints (Migraine Attack 2): 
• Sustained pain relief (1 to 2 hours), defined as headache relief [Headache severity mild 
(grade 1) or none (grade 0)] at 60 minutes with no worsening of headache, use of a 
second dose of study medication, or rescue medication taken through 120 minutes after 
dose 
• Sustained pain freedom (1 to 2 hours), defined as pain freedom [Headache severity none 
(grade 0)] at 60 minutes with no recurrence of headache, use of a second dose of study 
medication or rescue medication taken through 120 minutes after dose 
• Bilateral headache at predefined timepoints 
• 
Headache intensity increased by movement at predefined timepoints 
 
8.3 
Safety Analysis 
Safety will be assessed by the following measurements: AEs, physical examination, vital signs, 
and urine pregnancy test. All safety measures will be summarized by treatment. 
 
8.3.1 
Interim Analysis 
No interim analysis is planned. 
 
8.4 
Sample Size Calculations 
Power calculations are based on the results of the completed pivotal trial for adults (OPN-SUM- 
MIG-3301, Avanir data on file). The observed percentage (n) of subjects experiencing migraine 
headache pain free at 120 minutes was 34.3% (37) vs. 17.3% (18) for AVP-825 vs. placebo, 
respectively. For this study in adolescents with single-blind placebo run-in, if it is assumed that 
the percentage of subjects who are migraine headache pain free at 120 minutes is 30% vs. 15%, a 
sample size of 236 (118/arm) randomized and treated at Migraine Attack 2 would provide 
approximately 80% power with 2-sided α = 0.05. In consideration of the attrition rate during the 
run-in phase, it is estimated that 420 subjects would be needed to enter the single-blind placebo 
run-in phase in order to have approximately 236 subjects randomized and treated for Migraine 
Attack 2. 
 


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9 
ADMINISTRATIVE PROCEDURES 
 
9.1 
Institutional Review Board Approval 
Institutional Review Boards must meet the guidelines set out by the FDA and conform to local 
laws and customs where appropriate. Written IRB approval for the protocol and the signed ICF 
must be obtained and transmitted to Currax Pharmaceuticals or representative before the study 
can be initiated. The IRB must be informed of and approve all protocol amendments. The 
investigator will ensure that this study is conducted in full conformance with the laws and 
regulations of the US (see Appendix 4, Investigator Responsibilities). The complete text of the 
World Medical Association Declaration of Helsinki is given in Appendix 5. 
 
9.2 
Informed Consent Form 
The ICF will follow the principles outlined in the current version of the Declaration of Helsinki. 
For each patient found to be eligible for the study, informed assent/consent will be obtained from 
the patient and their parent/legal guardian. The patients and patient’s parent/legal guardian will 
be properly informed of the purpose of the study. A signed ICF will be obtained from all 
patient’s parent/legal guardian and an informed assent from all patients will be obtained prior to 
patient entry into this study. Patients and patient’s parent/legal guardian will be provided with a 
copy of their signed ICF/assent form. 
 
9.3 
Subject’s Diary 
Subjects will be provided with an electronic device (e-diary) to prompt and record subject 
responses at various intervals during a treated migraine attack. The subject’s e-diary will be 
reviewed by clinical study personnel at Visits 2 and 3, for confirmation of medication dosage, 
rescue medication taken, and subject responses. The study personnel are responsible for (i) 
ensuring that subjects are properly collecting data and recording it into the diaries; and (ii) 
transcribing the relevant diary recordings into the eCRF. 
 
9.4 
Electronic Case Report Forms 
For each subject enrolled who has given informed consent, an eCRF must be completed and 
electronically signed by the investigator to certify that the data within each eCRF are complete 
and correct. This also applies to those subjects who fail to complete the study. If a subject is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be made 
to document the outcome. 


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Any site personnel delegated responsibility for data entry, query resolution, or eCRF approval 
must complete training prior to accessing the eCRF. The electronic data capture (EDC) vendor 
will provide user-specific access to the live (production) eCRF once training completion has 
been confirmed and the account has been approved by the sponsor. Changes to the data once it 
has been initially saved will be tracked via audit trail and will require a reason for the change. 
The audit trail will also include who made the change and a date/time stamp. 
The eCRFs will be reviewed by the study monitor at the study site. Errors detected by 
subsequent in-house data review may necessitate clarification or correction of errors.  All 
changes will be documented and approved by the investigator. 
All investigators will be provided with copies of the eCRFs for their site on a CD-ROM at the 
end of the study. 
 
9.5 
Quality Assurance 
 
9.5.1 
Documentation 
For each process, evaluation, or test that generates study data but is not described in the protocol 
or eCRF, a written description of the data generation procedures shall be retained in the quality 
assurance section of the study files. In the case of routine clinical diagnostic procedures, only a 
copy of the relevant certification document is required. 
 
9.5.2 
Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator. This will include telephone calls and on-site visits. The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected. 
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol. As part of the data audit, source documents will be made available for review by the 
study monitor. The study monitor may periodically request review of the investigator study file 
to assure the completeness of documentation in all aspects of clinical study conduct. 
The study monitor will verify that each subject has proper consent documentation from the 
subject and subject’s authorized representative for study procedures and for the release of 
medical records to the sponsor, FDA, other regulatory authorities, and the IRB. The investigator 
or appointed delegate will receive the study monitor during these onsite visits and will cooperate 
in providing the documents for inspection and respond to inquiries. In addition, the investigator 
will permit inspection of the study files by authorized representatives of the regulatory agencies. 


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On completion of the study, the study monitor will arrange for a final review of the study files 
after which the files should be secured for the appropriate time period. 
 
9.6 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Currax, the investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records, e.g., CRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE 
forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, telephone call reports). 
The records should be retained by the investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever is longer. 
If the investigator is unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), Currax should be prospectively notified. The study records 
must be transferred to a designee acceptable by Currax, such as another investigator, another 
institution, or to Currax. The investigator must obtain Currax’s written permission before 
disposing of any records, even if retention requirements have been met. 
 
9.7 
Source Data 
The documents that will form the source data for the clinical study (e.g., patient charts, 
laboratory reports) must be defined and documented in the in-house study master file prior to the 
start of the study. Data on the eCRFs which will be checked against source data during 
monitoring visits must also be defined and documented in the in-house study master file 
including the percentage of each of the source data to be verified and the percentage of subjects’ 
eCRFs to be monitored. 
 
9.8 
Data Handling 
Data collected on the eCRFs will be entered into EDC system by trained site staff. Any queries 
arising from data entry will be checked with the investigator and changes approved. 
 
9.9 
Guidelines for Good Clinical Practice 
Standards for GCP must be adhered to for all study-based procedures. 
 
9.10 
Conditions for Amending the Protocol 
Protocol modification to the ongoing study which could potentially adversely affect the safety of 


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subjects or which alter the scope of the investigation, the scientific quality of the study, the 
experimental design, dosages, duration of therapy, assessment variables, the number of subjects 
treated, or subject selection criteria must be made only after appropriate consultation between an 
appropriate representative of Currax and the investigator. 
Protocol modifications must be prepared by a representative of Currax or the investigator and 
reviewed and approved by Currax. 
All protocol modifications must be reviewed and approved by the appropriate IRB in accordance 
with local requirements, before the revised edition can be implemented. Modifications which 
eliminate an apparent immediate hazard to subjects do not require pre-approval by the IRB. 
 
9.11 
Conditions for Terminating the Study 
Both Currax and the principal investigator reserve the right to terminate the study at the site at 
any time. Should this be necessary, the procedures to effect study termination will be arranged 
after review and consultation by both parties. In terminating the study, Currax and the 
investigator will assure that adequate consideration is given to the protection of the subject’s 
interests. 
 
9.12 
Confidentiality of Study Documents and Patient Records 
The investigator must assure that the subject’s anonymity will be maintained. On eCRFs or other 
documents submitted to Currax, subjects should not be identified by their names but by an 
identification code. 
The investigator should keep a separate log of subject’s codes, names, and addresses. Documents 
not for submission to Currax, for example, subjects signed ICFs, should be maintained by the 
investigator in strict confidence. 
 
9.13 
Reports 
At the completion of the study, the investigator shall provide the sponsor with an adequate report 
shortly after completion of the investigator's participation in the study as described in the Code 
of Federal Regulations (CFR) Title 21, Part 312.64. 
 
9.14 
Publications 
It is anticipated that a report of this study will be published in the scientific literature by the 
sponsor. The investigator will not seek to arrange for publication of any of the information or 
results from the study in any scientific journal, or other publication or by way of lecture without 


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Currax’s prior review and written consent. 
 
9.15 
Audits/Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel or designee(s) from Currax or to health authority 
inspectors after appropriate notification. The verification of the eCRF data may be by direct 
inspection of source documents (where permitted by law) or through an interview exchange. 
The inspector from the regulatory authority will be especially interested in the following items: 
• Visits from the sponsor’s representatives 
• IRB approval(s) 
• Study medication accountability 
• Study protocol and amendments 
• ICFs of the subject 
• Medical records supportive of eCRF data 
• Reports to the IRB and the sponsor 
• Record retention 
The sponsor will be available to help investigators prepare for an inspection. 


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10 
REFERENCES 
 
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Goadsby PJ. Pathophysiology of migraine. Neurologic clinics. 2009;27(2):335-60. 
3. 
The International Classification of Headache Disorders, 3rd edition (beta version). 
Cephalalgia. 2013;33(9):629-808. 
4. 
Wober-Bingol C. Pharmacological treatment of acute migraine in adolescents and 
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5. 
Eiland LS, Hunt MO. The use of triptans for pediatric migraines. Paediatr Drugs. 
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Lewis DW, Diamond S, Scott D, Jones V. Prophylactic treatment of pediatric migraine. 
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Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. Practice parameter: 
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Ozge A, Termine C, Antonaci F, Natriashvili S, Guidetti V, Wober-Bingol C. Overview 
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Linder SL. Treatment of childhood headache with dihydroergotamine mesylate. 
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Gelfand AA, Goadsby PJ. Treatment of pediatric migraine in the emergency room. 
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Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus 
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Tanen DA, Miller S, French T, Riffenburgh RH. Intravenous sodium valproate versus 
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Winner P, Wasiewski W, Gladstein J, Linder S. Multicenter prospective evaluation of 
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Powers SW, Patton SR, Hommel KA, Hershey AD. Quality of life in childhood 
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Powers SW, Hershey AD, Coffey CS, et al. The Childhood and Adolescent Migraine 
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O’Brien HL, Kabbouche MA, Hershey AD. Treating pediatric migraine: an expert 
opinion. Expert Opin Pharmacother. 2012;13(7):959-66. 
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El-Chammas K, Keyes J, Thompson N, Vijayakumar J, Becher D, Jackson JL. 
Pharmacologic treatment of pediatric headaches: a meta-analysis. JAMA Pediatr. 
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Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of 
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2001;41(7):646-57. 
20. 
Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and 
treatment: results from the American Migraine Study II. Headache. 2001;41(7):638-45. 
21. 
Sun H, Bastings E, Temeck J, et al. Migraine therapeutics in adolescents: a systematic 
analysis and historic perspectives of triptan trials in adolescents. JAMA Pediatr. 
2013;167(3):243-9. 
22. 
Lewis DW, Winner P, Wasiewski W. The placebo responder rate in children and 
adolescents. Headache. 2005;45(3):232-9. 
23. 
Metsahonkala L, Sillanpaa M, Tuominen J. Headache diary in the diagnosis of childhood 
migraine. Headache. 1997;37(4):240-4. 
24. 
Tfelt-Hansen P, De Vries P, Saxena PR. Triptans in migraine: a comparative review of 
pharmacology, pharmacokinetics and efficacy. Drugs. 2000;60(6):1259-87. 
25. 
Patniyot IR, Gelfand AA. Acute Treatment Therapies for Pediatric Migraine: A 
Qualitative Systematic Review. Headache. 2016;56(1):49-70. 
26. 
Linder SL, Mathew NT, Cady RK, Finlayson G, Ishkanian G, Lewis DW. Efficacy and 
tolerability of almotriptan in adolescents: a randomized, double-blind, placebo-controlled 
trial. Headache. 2008;48(9):1326-36. 
27. 
Ho TW, Pearlman E, Lewis D, et al. Efficacy and tolerability of rizatriptan in pediatric 
migraineurs: results from a randomized, double-blind, placebo-controlled trial using a 
novel adaptive enrichment design. 20121130, ed. Cephalalgia. 2012;32(10):750-65. 
28. 
Derosier FJ, Lewis D, Hershey AD, et al. Randomized trial of sumatriptan and naproxen 
sodium combination in adolescent migraine. Pediatrics. 2012;129(6):e1411-20. 
29. 
Winner P, Farkas V, Stillova H, et al. Efficacy and tolerability of zolmitriptan nasal spray 
for the treatment of acute migraine in adolescents: Results of a randomized, double-blind, 


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multi-center, parallel-group study (TEENZ). Headache. June 2016. 
30. 
Christensen ML, Mottern RK, Jabbour JT, Fuseau E. Pharmacokinetics of sumatriptan 
nasal spray in children. J Clin Pharmacol. 2004;44(4):359-67. 
31. 
Christensen ML, Mottern RK, Jabbour JT, Fuseau E. Pharmacokinetics of sumatriptan 
nasal spray in adolescents. J Clin Pharmacol. 2003;43(7):721-6. 
32. 
MacDonald JT. Treatment of juvenile migraine with subcutaneous sumatriptan. 
Headache. 1994;34(10):581-2. 
33. 
Linder SL. Subcutaneous sumatriptan in the clinical setting: the first 50 consecutive 
patients with acute migraine in a pediatric neurology office practice. Headache. 
1996;36(7):419-22. 
34. 
Hamalainen ML, Hoppu K, Santavuori P. Sumatriptan for migraine attacks in children: a 
randomized placebo-controlled study. Do children with migraine respond to oral 
sumatriptan differently from adults? Neurology. 1997;48(4):1100-3. 
35. 
Ueberall MA. W, Dieter. Intranasal sumatriptan for the acute treatment of migraine in 
children. Neurology. 1999:1506-11. 
36. 
Winner P, Rothner AD, Wooten JD, Webster C, Ames M. Sumatriptan nasal spray in 
adolescent migraineurs: a randomized, double-blind, placebo-controlled, acute study. 
Headache. 2006;46(2):212-22. 
37. 
Rothner AD, Winner P, Nett R, et al. One-year tolerability and efficacy of sumatriptan 
nasal spray in adolescents with migraine: results of a multicenter, open-label study. Clin 
Ther. 2000;22(12):1533-46. 
38. 
Ahonen K, Hamalainen ML, Rantala H, Hoppu K. Nasal sumatriptan is effective in 
treatment of migraine attacks in children: A randomized trial. Neurology. 
2004;62(6):883-7. 
39. 
Djupesland PG, Messina JC, Mahmoud RA. Breath powered nasal delivery: a new route 
to rapid headache relief. Headache. 2013;53 Suppl 2(SUPPL.2):72-84. 
40. 
Obaidi M, Offman E, Messina J, Carothers J, Djupesland PG, Mahmoud RA. Improved 
pharmacokinetics of sumatriptan with Breath Powered nasal delivery of sumatriptan 
powder. Headache. 2013;53(8):1323-33. 
41. 
Cady RK, McAllister PJ, Spierings ELH, et al. A randomized, double-blind, placebo- 
controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in 
the treatment of acute migraine (The TARGET Study). Headache. 2015;55(1):88-100. 
42. 
Djupesland PG, Docekal P. Intranasal sumatriptan powder delivered by a novel breath- 
actuated bi-directional device for the acute treatment of migraine: A randomised, 
placebo-controlled study. Cephalalgia. 2010;30(8):933-42. 
43. 
Tepper SJ, Cady RK, Silberstein S, et al. AVP-825 breath-powered intranasal delivery 
system containing 22 mg sumatriptan powder vs 100 mg oral sumatriptan in the acute 


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Version 2.0 
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across multiple attacks. Headache. 2015;55(5):621-35. 
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children and adolescents. Pediatrics. 2004;114(2 Suppl 4th Report):555-76. 
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CONFIDENTIAL AND PROPRIETARY 
Protocol 17-AVP-825-301 
CURRAX PHARMACEUTICALS LLC 
Version 2.0 
 
 
 
11 
APPENDICES 
Appendix 1: Blood Pressure Levels by Age and Height Percentile 
Appendix 2: Columbia Suicide Severity Rating Scale (C-SSRS) 
Appendix 3: Investigator Responsibilities 
Appendix 4: World Medical Association Declaration of Helsinki 


 
CONFIDENTIAL AND PROPRIETARY 
CURRAX PHARMACEUTICALS LLC 
Protocol 17-AVP-825-301 
Version 2.0 
 
 
Appendix 1: Blood Pressure Levels by Age and Height Percentile 
 
 
Reference: The fourth report on the diagnosis, evaluation, and treatment of high blood pressure 
in children and adolescents. Pediatrics. 2004;114(2 Suppl 4th Report):555-76. 


 
 
Blood Pressure Levels for Boys by Age and Height Percentile* 
 
 
Age 
BP 
(Year) Percentile 
Systolic BP (mmHg) 
← Percentile of Height → 
Diastolic BP (mmHg) 
 
 
← Percentile of Height → 
 
↓ 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
50th 
80 
81 
83 
85 
87 
88 
89
34 
35 
36 
37 
38 
39 
39 
90th 
94 
95 
97 
99 
100 
102 
103
49 
50 
51 
52 
53 
53 
54 
95th 
98 
99 
101 
103 
104 
106 
106
54 
54 
55 
56 
57 
58 
58 
99th 
105 
106 
108 
110 
112 
113 
114
61 
62 
63 
64 
65 
66 
66 
2 
50th 
84 
85 
87 
88 
90 
92 
92
39 
40 
41 
42 
43 
44 
44 
90th 
97 
99 
100 
102 
104 
105 
106
54 
55 
56 
57 
58 
58 
59 
95th 
101 
102 
104 
106 
108 
109 
110
59 
59 
60 
61 
62 
63 
63 
99th 
109 
110 
111 
113 
115 
117 
117
66 
67 
68 
69 
70 
71 
71 
3 
50th 
86 
87 
89 
91 
93 
94 
95
44 
44 
45 
46 
47 
48 
48 
90th 
100 
101 
103 
105 
107 
108 
109
59 
59 
60 
61 
62 
63 
63 
95th 
104 
105 
107 
109 
110 
112 
113
63 
63 
64 
65 
66 
67 
67 
99th 
111 
112 
114 
116 
118 
119 
120
71 
71 
72 
73 
74 
75 
75 
4 
50th 
88 
89 
91 
93 
95 
96 
97
47 
48 
49 
50 
51 
51 
52 
90th 
102 
103 
105 
107 
109 
110 
111
62 
63 
64 
65 
66 
66 
67 
95th 
106 
107 
109 
111 
112 
114 
115
66 
67 
68 
69 
70 
71 
71 
99th 
113 
114 
116 
118 
120 
121 
122
74 
75 
76 
77 
78 
78 
79 
5 
50th 
90 
91 
93 
95 
96 
98 
98
50 
51 
52 
53 
54 
55 
55 
90th 
104 
105 
106 
108 
110 
111 
112
65 
66 
67 
68 
69 
69 
70 
95th 
108 
109 
110 
112 
114 
115 
116
69 
70 
71 
72 
73 
74 
74 
99th 
115 
116 
118 
120 
121 
123 
123
77 
78 
79 
80 
81 
81 
82 
6 
50th 
91 
92 
94 
96 
98 
99 
100
53 
53 
54 
55 
56 
57 
57 
90th 
105 
106 
108 
110 
111 
113 
113
68 
68 
69 
70 
71 
72 
72 
95th 
109 
110 
112 
114 
115 
117 
117
72 
72 
73 
74 
75 
76 
76 
99th 
116 
117 
119 
121 
123 
124 
125
80 
80 
81 
82 
83 
84 
84 
7 
50th 
92 
94 
95 
97 
99 
100 
101
55 
55 
56 
57 
58 
59 
59 
90th 
106 
107 
109 
111 
113 
114 
115
70 
70 
71 
72 
73 
74 
74 
95th 
110 
111 
113 
115 
117 
118 
119
74 
74 
75 
76 
77 
78 
78 
99th 
117 
118 
120 
122 
124 
125 
126
82 
82 
83 
84 
85 
86 
86 
8 
50th 
94 
95 
97 
99 
100 
102 
102
56 
57 
58 
59 
60 
60 
61 
90th 
107 
109 
110 
112 
114 
115 
116
71 
72 
72 
73 
74 
75 
76 
95th 
111 
112 
114 
116 
118 
119 
120
75 
76 
77 
78 
79 
79 
80 
99th 
119 
120 
122 
123 
125 
127 
127
83 
84 
85 
86 
87 
87 
88 
9 
50th 
95 
96 
98 
100 
102 
103 
104
57 
58 
59 
60 
61 
61 
62 
90th 
109 
110 
112 
114 
115 
117 
118
72 
73 
74 
75 
76 
76 
77 
95th 
113 
114 
116 
118 
119 
121 
121
76 
77 
78 
79 
80 
81 
81 
99th 
120 
121 
123 
125 
127 
128 
129
84 
85 
86 
87 
88 
88 
89 
10 
50th 
97 
98 
100 
102 
103 
105 
106
58 
59 
60 
61 
61 
62 
63 
90th 
111 
112 
114 
115 
117 
119 
119
73 
73 
74 
75 
76 
77 
78 
95th 
115 
116 
117 
119 
121 
122 
123
77 
78 
79 
80 
81 
81 
82 
99th 
122 
123 
125 
127 
128 
130 
130
85 
86 
86 
88 
88 
89 
90 
 
10 
The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents 
T A B L E 3 


 
 
 
Age 
BP 
(Year) Percentile 
Systolic BP (mmHg) 
← Percentile of Height → 
Diastolic BP (mmHg) 
 
 
← Percentile of Height → 
 
↓ 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th
11 
50th 
99 
100 
102 
104 
105 
107 
107
59 
59 
60 
61 
62 
63 
63 
90th 
113 
114 
115 
117 
119 
120 
121
74 
74 
75 
76 
77 
78 
78 
95th 
117 
118 
119 
121 
123 
124 
125
78 
78 
79 
80 
81 
82 
82 
99th 
124 
125 
127 
129 
130 
132 
132
86 
86 
87 
88 
89 
90 
90 
12 
50th 
101 
102 
104 
106 
108 
109 
110
59 
60 
61 
62 
63 
63 
64 
90th 
115 
116 
118 
120 
121 
123 
123
74 
75 
75 
76 
77 
78 
79 
95th 
119 
120 
122 
123 
125 
127 
127
78 
79 
80 
81 
82 
82 
83 
99th 
126 
127 
129 
131 
133 
134 
135
86 
87 
88 
89 
90 
90 
91 
13 
50th 
104 
105 
106 
108 
110 
111 
112
60 
60 
61 
62 
63 
64 
64 
90th 
117 
118 
120 
122 
124 
125 
126
75 
75 
76 
77 
78 
79 
79 
95th 
121 
122 
124 
126 
128 
129 
130
79 
79 
80 
81 
82 
83 
83 
99th 
128 
130 
131 
133 
135 
136 
137
87 
87 
88 
89 
90 
91 
91 
14 
50th 
106 
107 
109 
111 
113 
114 
115
60 
61 
62 
63 
64 
65 
65 
90th 
120 
121 
123 
125 
126 
128 
128
75 
76 
77 
78 
79 
79 
80 
95th 
124 
125 
127 
128 
130 
132 
132
80 
80 
81 
82 
83 
84 
84 
99th 
131 
132 
134 
136 
138 
139 
140
87 
88 
89 
90 
91 
92 
92 
15 
50th 
109 
110 
112 
113 
115 
117 
117
61 
62 
63 
64 
65 
66 
66 
90th 
122 
124 
125 
127 
129 
130 
131
76 
77 
78 
79 
80 
80 
81 
95th 
126 
127 
129 
131 
133 
134 
135
81 
81 
82 
83 
84 
85 
85 
99th 
134 
135 
136 
138 
140 
142 
142
88 
89 
90 
91 
92 
93 
93 
16 
50th 
111 
112 
114 
116 
118 
119 
120
63 
63 
64 
65 
66 
67 
67 
90th 
125 
126 
128 
130 
131 
133 
134
78 
78 
79 
80 
81 
82 
82 
95th 
129 
130 
132 
134 
135 
137 
137
82 
83 
83 
84 
85 
86 
87 
99th 
136 
137 
139 
141 
143 
144 
145
90 
90 
91 
92 
93 
94 
94 
17 
50th 
114 
115 
116 
118 
120 
121 
122
65 
66 
66 
67 
68 
69 
70 
90th 
127 
128 
130 
132 
134 
135 
136
80 
80 
81 
82 
83 
84 
84 
95th 
131 
132 
134 
136 
138 
139 
140
84 
85 
86 
87 
87 
88 
89 
99th 
139 
140 
141 
143 
145 
146 
147
92 
93 
93 
94 
95 
96 
97 
 
BP, blood pressure 
* The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. For research purposes, 
the standard deviations in appendix table B–1 allow one to compute BP Z-scores and percentiles for boys with height percentiles given 
in table 3 (i.e., the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles). These height percentiles must be converted to height 
Z-scores given by (5% = -1.645; 10% = -1.28; 25% = -0.68; 50% = 0; 75% = 0.68; 90% = 1.28; 95% = 1.645) and then computed 
according to the methodology in steps 2–4 described in appendix B. For children with height percentiles other than these, follow steps 
1–4 as described in appendix B. 
 
 
 
 
 
 
Blood Pressure Tables 
11 


 
Blood Pressure Levels for Girls by Age and Height Percentile* 
Age 
BP 
(Year) Percentile 
Systolic BP (mmHg) 
← Percentile of Height → 
Diastolic BP (mmHg) 
← Percentile of Height → 
 
↓ 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
50th 
83 
84 
85 
86 
88 
89 
90
38 
39 
39 
40 
41 
41 
42 
90th 
97 
97 
98 
100 
101 
102 
103
52 
53 
53 
54 
55 
55 
56 
95th 
100 
101 
102 
104 
105 
106 
107
56 
57 
57 
58 
59 
59 
60 
99th 
108 
108 
109 
111 
112 
113 
114
64 
64 
65 
65 
66 
67 
67 
2 
50th 
85 
85 
87 
88 
89 
91 
91
43 
44 
44 
45 
46 
46 
47 
90th 
98 
99 
100 
101 
103 
104 
105
57 
58 
58 
59 
60 
61 
61 
95th 
102 
103 
104 
105 
107 
108 
109
61 
62 
62 
63 
64 
65 
65 
99th 
109 
110 
111 
112 
114 
115 
116
69 
69 
70 
70 
71 
72 
72 
3 
50th 
86 
87 
88 
89 
91 
92 
93
47 
48 
48 
49 
50 
50 
51 
90th 
100 
100 
102 
103 
104 
106 
106
61 
62 
62 
63 
64 
64 
65 
95th 
104 
104 
105 
107 
108 
109 
110
65 
66 
66 
67 
68 
68 
69 
99th 
111 
111 
113 
114 
115 
116 
117
73 
73 
74 
74 
75 
76 
76 
4 
50th 
88 
88 
90 
91 
92 
94 
94
50 
50 
51 
52 
52 
53 
54 
90th 
101 
102 
103 
104 
106 
107 
108
64 
64 
65 
66 
67 
67 
68 
95th 
105 
106 
107 
108 
110 
111 
112
68 
68 
69 
70 
71 
71 
72 
99th 
112 
113 
114 
115 
117 
118 
119
76 
76 
76 
77 
78 
79 
79 
5 
50th 
89 
90 
91 
93 
94 
95 
96
52 
53 
53 
54 
55 
55 
56 
90th 
103 
103 
105 
106 
107 
109 
109
66 
67 
67 
68 
69 
69 
70 
95th 
107 
107 
108 
110 
111 
112 
113
70 
71 
71 
72 
73 
73 
74 
99th 
114 
114 
116 
117 
118 
120 
120
78 
78 
79 
79 
80 
81 
81 
6 
50th 
91 
92 
93 
94 
96 
97 
98
54 
54 
55 
56 
56 
57 
58 
90th 
104 
105 
106 
108 
109 
110 
111
68 
68 
69 
70 
70 
71 
72 
95th 
108 
109 
110 
111 
113 
114 
115
72 
72 
73 
74 
74 
75 
76 
99th 
115 
116 
117 
119 
120 
121 
122
80 
80 
80 
81 
82 
83 
83 
7 
50th 
93 
93 
95 
96 
97 
99 
99
55 
56 
56 
57 
58 
58 
59 
90th 
106 
107 
108 
109 
111 
112 
113
69 
70 
70 
71 
72 
72 
73 
95th 
110 
111 
112 
113 
115 
116 
116
73 
74 
74 
75 
76 
76 
77 
99th 
117 
118 
119 
120 
122 
123 
124
81 
81 
82 
82 
83 
84 
84 
8 
50th 
95 
95 
96 
98 
99 
100 
101
57 
57 
57 
58 
59 
60 
60 
90th 
108 
109 
110 
111 
113 
114 
114
71 
71 
71 
72 
73 
74 
74 
95th 
112 
112 
114 
115 
116 
118 
118
75 
75 
75 
76 
77 
78 
78 
99th 
119 
120 
121 
122 
123 
125 
125
82 
82 
83 
83 
84 
85 
86 
9 
50th 
96 
97 
98 
100 
101 
102 
103
58 
58 
58 
59 
60 
61 
61 
90th 
110 
110 
112 
113 
114 
116 
116
72 
72 
72 
73 
74 
75 
75 
95th 
114 
114 
115 
117 
118 
119 
120
76 
76 
76 
77 
78 
79 
79 
99th 
121 
121 
123 
124 
125 
127 
127
83 
83 
84 
84 
85 
86 
87 
10 
50th 
98 
99 
100 
102 
103 
104 
105
59 
59 
59 
60 
61 
62 
62 
90th 
112 
112 
114 
115 
116 
118 
118
73 
73 
73 
74 
75 
76 
76 
95th 
116 
116 
117 
119 
120 
121 
122
77 
77 
77 
78 
79 
80 
80 
99th 
123 
123 
125 
126 
127 
129 
129
84 
84 
85 
86 
86 
87 
88 
 
12 
The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents
T A B L E 4 


 
Age 
(Years) 
BP 
Percentile 
Systolic BP (mmHg) 
 
Diastolic BP (mmHg) 
← Percentile of Height → 
← Percentile of Height → 
↓ 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
11 
50th 
100 
101 
102 
103 
105 
106 
107
60 
60 
60 
61 
62 
63 
63 
90th 
114 
114 
116 
117 
118 
119 
120
74 
74 
74 
75 
76 
77 
77 
95th 
118 
118 
119 
121 
122 
123 
124
78 
78 
78 
79 
80 
81 
81 
99th 
125 
125 
126 
128 
129 
130 
131
85 
85 
86 
87 
87 
88 
89 
12 
50th 
102 
103 
104 
105 
107 
108 
109
61 
61 
61 
62 
63 
64 
64 
90th 
116 
116 
117 
119 
120 
121 
122
75 
75 
75 
76 
77 
78 
78 
95th 
119 
120 
121 
123 
124 
125 
126
79 
79 
79 
80 
81 
82 
82 
99th 
127 
127 
128 
130 
131 
132 
133
86 
86 
87 
88 
88 
89 
90 
13 
50th 
104 
105 
106 
107 
109 
110 
110
62 
62 
62 
63 
64 
65 
65 
90th 
117 
118 
119 
121 
122 
123 
124
76 
76 
76 
77 
78 
79 
79 
95th 
121 
122 
123 
124 
126 
127 
128
80 
80 
80 
81 
82 
83 
83 
99th 
128 
129 
130 
132 
133 
134 
135
87 
87 
88 
89 
89 
90 
91 
14 
50th 
106 
106 
107 
109 
110 
111 
112
63 
63 
63 
64 
65 
66 
66 
90th 
119 
120 
121 
122 
124 
125 
125
77 
77 
77 
78 
79 
80 
80 
95th 
123 
123 
125 
126 
127 
129 
129
81 
81 
81 
82 
83 
84 
84 
99th 
130 
131 
132 
133 
135 
136 
136
88 
88 
89 
90 
90 
91 
92 
15 
50th 
107 
108 
109 
110 
111 
113 
113
64 
64 
64 
65 
66 
67 
67 
90th 
120 
121 
122 
123 
125 
126 
127
78 
78 
78 
79 
80 
81 
81 
95th 
124 
125 
126 
127 
129 
130 
131
82 
82 
82 
83 
84 
85 
85 
99th 
131 
132 
133 
134 
136 
137 
138
89 
89 
90 
91 
91 
92 
93 
16 
50th 
108 
108 
110 
111 
112 
114 
114
64 
64 
65 
66 
66 
67 
68 
90th 
121 
122 
123 
124 
126 
127 
128
78 
78 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
128 
130 
131 
132
82 
82 
83 
84 
85 
85 
86 
99th 
132 
133 
134 
135 
137 
138 
139
90 
90 
90 
91 
92 
93 
93 
17 
50th 
108 
109 
110 
111 
113 
114 
115
64 
65 
65 
66 
67 
67 
68 
90th 
122 
122 
123 
125 
126 
127 
128
78 
79 
79 
80 
81 
81 
82 
95th 
125 
126 
127 
129 
130 
131 
132
82 
83 
83 
84 
85 
85 
86 
99th 
133 
133 
134 
136 
137 
138 
139
90 
90 
91 
91 
92 
93 
93 
 
BP, blood pressure 
* The 90th percentile is 1.28 SD, 95th percentile is 1.645 SD, and the 99th percentile is 2.326 SD over the mean. For research purposes, 
the standard deviations in appendix table B–1 allow one to compute BP Z-scores and percentiles for girls with height percentiles given in 
table 4 (i.e., the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles). These height percentiles must be converted to height Z-scores 
given by (5% = -1.645; 10% = -1.28; 25% = -0.68; 50% = 0; 75% = 0.68; 90% = 1.28; 95% = 1.645) and then computed according to 
the methodology in steps 2–4 described in appendix B. For children with height percentiles other than these, follow steps 1–4 as 
described in appendix B. 
 
 
 
Blood Pressure Tables 
13 


 
CONFIDENTIAL AND PROPRIETARY 
CURRAX PHARMACEUTICALS LLC 
Protocol 17-AVP-825-301 
Version 2.0 
 
 
Appendix 2: 
Columbia Suicide Severity Rating Scale (C-SSRS) 


 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
 
Visit 2 and Visit 3 Exit/Early Termination Visit 
 
 
SITE 
NUMBER 
PATIENT 
NUMBER 
PATIENT 
INITIALS 
VISIT 
NUMBER 
VISIT 
DATE 
EXAMINER 
INITIALS 
 
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 
 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
 
 
 
Page 1 of 3 


© 2008 Research Foundation for Mental Hygiene, Inc. 
Page 2 of 3 
C-SSRS—Screening (Version 1/14/09) 
 
 
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? 
If yes, describe: 
Yes 
No 
□ □ 
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 
and to end/stop the pain 
 
living with the pain or how you were feeling) 
(0) Does not apply 
 
 


© 2008 Research Foundation for Mental Hygiene, Inc. 
Page 3 of 3 
C-SSRS—Screening (Version 1/14/09) 
 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
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. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
Yes 
No 
□ □ 
Total # of 
interrupted 
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. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
Yes 
No 
□ □ 
Total # of 
aborted 
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). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
Yes 
No 
□ □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes 
No 
□ □ 
Suicide: 
Yes   No 
□ □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
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). 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
 


 
CONFIDENTIAL AND PROPRIETARY 
CURRAX PHARMACEUTICALS, INC 
Protocol 17-AVP-825-301 
Version 2.0 
 
 
Appendix 3: 
Investigator Responsibilities 


Guidance for Industry 
E6 Good Clinical Practice: 
Consolidated Guidance 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICH 
April 1996 


Guidance for Industry 
E6 Good Clinical Practice: 
Consolidated Guidance 
 
 
 
 
 
 
 
 
 
 
Additional copies are available from: 
the Drug Information Branch (HFD-210), 
Center for Drug Evaluation and Research (CDER), 
5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573 
http://www.fda.gov/cder/guidance/index.htm 
or 
Office of Communication, 
Training, and Manufacturers Assistance (HFM-40) 
Center for Biologics Evaluation and Research (CBER) 
1401 Rockville Pike, Rockville, MD 20852-1448, 
http://www.fda.gov/cber/guidelines.htm 
(Fax) 888-CBERFAX or 301-827-3844 
(Voice Information) 800-835-4709 or 301-827-1800 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
April 1996 
ICH 


13 
 
 
(b) Changes increasing the risk to subjects and/or affecting significantly the 
conduct of the trial (see section 4.10.2). 
 
(c) All adverse drug reactions (ADRs) that are both serious and 
unexpected. 
 
(d) New information that may affect adversely the safety of the subjects or 
the conduct of the trial. 
 
3.3.9 Ensuring that the IRB/IEC promptly notify in writing the 
investigator/institution concerning: 
 
(a) Its trial-related decisions/opinions. 
(b) The reasons for its decisions/opinions. 
(c) Procedures for appeal of its decisions/opinions. 
 
3.4 
Records 
 
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, 
lists of occupations/affiliations of members, submitted documents, minutes of meetings,  
and correspondence) for a period of at least 3 years after completion of the trial and make 
them available upon request from the regulatory authority(ies). 
 
The IRB/IEC may be asked by investigators, sponsors, or regulatory authorities to provide 
copies of its written procedures and membership lists. 
 
 
4. 
INVESTIGATOR 
 
4.1 
Investigator's Qualifications and Agreements 
 
4.1.1 The investigator(s) should be qualified by education, training, and 
experience to assume responsibility for the proper conduct of the trial, should meet 
all the qualifications specified by the applicable regulatory requirement(s), and 
should provide evidence of such qualifications through up-to-date curriculum vitae 
and/or other relevant documentation requested by the sponsor, the IRB/IEC, 
and/or the regulatory authority(ies). 
 
4.1.2 The investigator should be thoroughly familiar with the appropriate use of 
the investigational product(s), as described in the protocol, in the current 
Investigator's Brochure, in the product information, and in other information 
sources provided by the sponsor. 


14 
 
 
4.1.3 The investigator should be aware of, and should comply with, GCP and the 
applicable regulatory requirements. 
 
4.1.4 The investigator/institution should permit monitoring and auditing by the 
sponsor, and inspection by the appropriate regulatory authority(ies). 
 
4.1.5 The investigator should maintain a list of appropriately qualified persons to 
whom the investigator has delegated significant trial-related duties. 
 
4.2 
Adequate Resources 
 
4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective 
data) a potential for recruiting the required number of suitable subjects within the 
agreed recruitment period. 
 
4.2.2 The investigator should have sufficient time to properly conduct and 
complete the trial within the agreed trial period. 
 
4.2.3 The investigator should have available an adequate number of qualified staff 
and adequate facilities for the foreseen duration of the trial to conduct the trial 
properly and safely. 
 
4.2.4 The investigator should ensure that all persons assisting with the trial are 
adequately informed about the protocol, the investigational product(s), and their 
trial-related duties and functions. 
 
4.3 
Medical Care of Trial Subjects 
 
4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator 
or a sub-investigator for the trial, should be responsible for all trial-related 
medical (or dental) decisions. 
 
4.3.2 During and following a subject's participation in a trial, the 
investigator/institution should ensure that adequate medical care is provided to a 
subject for any adverse events, including clinically significant laboratory values, 
related to the trial. The investigator/institution should inform a subject when 
medical care is needed for intercurrent illness(es) of which the investigator 
becomes aware. 
 
4.3.3 It is recommended that the investigator inform the subject's primary 
physician about the subject's participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 


15 
 
 
4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing 
prematurely from a trial, the investigator should make a reasonable effort to 
ascertain the reason(s), while fully respecting the subject's rights. 
 
4.4 
Communication with IRB/IEC 
 
4.4.1 Before initiating a trial, the investigator/institution should have written and 
dated approval/favorable opinion from the IRB/IEC for the trial protocol, written 
informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements), and any other written information to be provided to 
subjects. 
 
4.4.2 As part of the investigator's/institution’s written application to the IRB/IEC, 
the investigator/institution should provide the IRB/IEC with a current copy of the 
Investigator's Brochure. If the Investigator's Brochure is updated during the trial, 
the investigator/institution should supply a copy of the updated Investigator’s 
Brochure to the IRB/IEC. 
 
4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all 
documents subject to its review. 
 
4.5 
Compliance with Protocol 
 
4.5.1 The investigator/institution should conduct the trial in compliance with the 
protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), 
and which was given approval/favorable opinion by the IRB/IEC. The 
investigator/institution and the sponsor should sign the protocol, or an alternative 
contract, to confirm their agreement. 
 
4.5.2 The investigator should not implement any deviation from, or changes of, 
the protocol without agreement by the sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where 
necessary to eliminate an immediate hazard(s) to trial subjects, or when the 
change(s) involves only logistical or administrative aspects of the trial (e.g., 
change of monitor(s), change of telephone number(s)). 
 
4.5.3 The investigator, or person designated by the investigator, should document 
and explain any deviation from the approved protocol. 
 
4.5.4 The investigator may implement a deviation from, or a change in, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior 
IRB/IEC approval/favorable opinion. As soon as possible, the implemented 


16 
 
 
deviation or change, the reasons for it, and, if appropriate, the proposed protocol 
amendment(s) should be submitted: 
 
(a) To the IRB/IEC for review and approval/favorable opinion; 
(b) To the sponsor for agreement and, if required; 
(c) To the regulatory authority(ies). 
 
4.6 
Investigational Product(s) 
 
4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) 
rests with the investigator/institution. 
 
4.6.2 Where allowed/required, the investigator/institution may/should assign some 
or all of the investigator's/institution’s duties for investigational product(s) 
accountability at the trial site(s) to an appropriate pharmacist or another 
appropriate individual who is under the supervision of the investigator/institution. 
 
4.6.3 The investigator/institution and/or a pharmacist or other appropriate 
individual, who is designated by the investigator/institution, should maintain 
records of the product's delivery to the trial site, the inventory at the site, the use 
by each subject, and the return to the sponsor or alternative disposition of unused 
product(s). These records should include dates, quantities, batch/serial numbers, 
expiration dates (if applicable), and the unique code numbers assigned to the 
investigational product(s) and trial subjects. Investigators should maintain records 
that document adequately that the subjects were provided the doses specified by 
the protocol and reconcile all investigational product(s) received from the sponsor. 
 
4.6.4 The investigational product(s) should be stored as specified by the sponsor 
(see sections 5.13.2 and 5.14.3) and in accordance with applicable regulatory 
requirement(s). 
 
4.6.5 The investigator should ensure that the investigational product(s) are used 
only in accordance with the approved protocol. 
 
4.6.6 The investigator, or a person designated by the investigator/institution, 
should explain the correct use of the investigational product(s) to each subject and 
should check, at intervals appropriate for the trial, that each subject is following 
the instructions properly. 
 
4.7 
Randomization Procedures and Unblinding 
 
The investigator should follow the trial's randomization procedures, if any, and should 
ensure that the code is broken only in accordance with the protocol. If the trial is blinded, 


17 
 
 
the investigator should promptly document and explain to the sponsor any premature 
unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the 
investigational product(s). 
 
4.8 
Informed Consent of Trial Subjects 
 
4.8.1 In obtaining and documenting informed consent, the investigator should 
comply with the applicable regulatory requirement(s) and should adhere to GCP 
and to the ethical principles that have their origin in the Declaration of Helsinki. 
Prior to the beginning of the trial, the investigator should have the IRB/IEC's 
written approval/favorable opinion of the written informed consent form and any 
other written information to be provided to subjects. 
 
4.8.2 The written informed consent form and any other written information to be 
provided to subjects should be revised whenever important new information 
becomes available that may be relevant to the subject’s consent. Any revised 
written informed consent form, and written information should receive the 
IRB/IEC's approval/favorable opinion in advance of use. The subject or the 
subject’s legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this 
information should be documented. 
 
4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence 
a subject to participate or to continue to participate in a trial. 
 
4.8.4 None of the oral and written information concerning the trial, including the 
written informed consent form, should contain any language that causes the subject 
or the subject's legally acceptable representative to waive or to appear to waive 
any legal rights, or that releases or appears to release the investigator, the 
institution, the sponsor, or their agents from liability for negligence. 
 
4.8.5 The investigator, or a person designated by the investigator, should fully 
inform the subject or, if the subject is unable to provide informed consent, the 
subject's legally acceptable representative, of all pertinent aspects of the trial 
including the written information given approval/favorable opinion by the 
IRB/IEC. 
 
4.8.6 The language used in the oral and written information about the trial, 
including the written informed consent form, should be as nontechnical as practical 
and should be understandable to the subject or the subject's legally acceptable 
representative and the impartial witness, where applicable. 


18 
 
 
4.8.7 Before informed consent may be obtained, the investigator, or a person 
designated by the investigator, should provide the subject or the subject's legally 
acceptable representative ample time and opportunity to inquire about details of 
the trial and to decide whether or not to participate in the trial. All questions 
about the trial should be answered to the satisfaction of the subject or the subject's 
legally acceptable representative. 
 
4.8.8 Prior to a subject’s participation in the trial, the written informed consent 
form should be signed and personally dated by the subject or by the subject's 
legally acceptable representative, and by the person who conducted the informed 
consent discussion. 
 
4.8.9 If a subject is unable to read or if a legally acceptable representative is 
unable to read, an impartial witness should be present during the entire informed 
consent discussion. After the written informed consent form and any other written 
information to be provided to subjects is read and explained to the subject or the 
subject’s legally acceptable representative, and after the subject or the subject’s 
legally acceptable representative has orally consented to the subject’s participation 
in the trial, and, if capable of doing so, has signed and personally dated the 
informed consent form, the witness should sign and personally date the consent 
form. By signing the consent form, the witness attests that the information in the 
consent form and any other written information was accurately explained to, and 
apparently understood by, the subject or the subject's legally acceptable 
representative, and that informed consent was freely given by the subject or the 
subject’s legally acceptable representative. 
 
4.8.10 Both the informed consent discussion and the written informed consent 
form and any other written information to be provided to subjects should include 
explanations of the following: 
 
(a) That the trial involves research. 
 
(b) The purpose of the trial. 
 
(c) The trial treatment(s) and the probability for random assignment to 
each treatment. 
 
(d) The trial procedures to be followed, including all invasive procedures. 
 
(e) The subject's responsibilities. 
 
(f) Those aspects of the trial that are experimental. 


19 
 
 
(g) The reasonably foreseeable risks or inconveniences to the subject and, 
when applicable, to an embryo, fetus, or nursing infant. 
 
(h) The reasonably expected benefits. When there is no intended clinical 
benefit to the subject, the subject should be made aware of this. 
 
(i) The alternative procedure(s) or course(s) of treatment that may be 
available to the subject, and their important potential benefits and risks. 
 
(j) The compensation and/or treatment available to the subject in the event 
of trial-related injury. 
 
(k) The anticipated prorated payment, if any, to the subject for 
participating in the trial. 
 
(l) The anticipated expenses, if any, to the subject for participating in the 
trial. 
 
(m) That the subject's participation in the trial is voluntary and that the 
subject may refuse to participate or withdraw from the trial, at any time, 
without penalty or loss of benefits to which the subject is otherwise 
entitled. 
 
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory 
authority(ies) will be granted direct access to the subject's original medical 
records for verification of clinical trial procedures and/or data, without 
violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations and that, by signing a written informed 
consent form, the subject or the subject's legally acceptable representative 
is authorizing such access. 
 
(o) That records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws and/or regulations, will not be made 
publicly available. If the results of the trial are published, the subject’s 
identity will remain confidential. 
 
(p) That the subject or the subject's legally acceptable representative will 
be informed in a timely manner if information becomes available that may 
be relevant to the subject's willingness to continue participation in the trial. 
 
(q) The person(s) to contact for further information regarding the trial and 
the rights of trial subjects, and whom to contact in the event of trial-related 
injury. 


20 
 
 
(r) The foreseeable circumstances and/or reasons under which the subject's 
participation in the trial may be terminated. 
 
(s) The expected duration of the subject's participation in the trial. 
 
(t) The approximate number of subjects involved in the trial. 
 
4.8.11 Prior to participation in the trial, the subject or the subject's legally 
acceptable representative should receive a copy of the signed and dated written 
informed consent form and any other written information provided to the subjects. 
During a subject’s participation in the trial, the subject or the subject’s legally 
acceptable representative should receive a copy of the signed and dated consent 
form updates and a copy of any amendments to the written information provided 
to subjects. 
 
4.8.12 When a clinical trial (therapeutic or nontherapeutic) includes subjects who 
can only be enrolled in the trial with the consent of the subject’s legally acceptable 
representative (e.g., minors, or patients with severe dementia), the subject should 
be informed about the trial to the extent compatible with the subject’s 
understanding and, if capable, the subject should assent, sign and personally date 
the written informed consent. 
 
4.8.13 Except as described in 4.8.14, a nontherapeutic trial (i.e., a trial in which 
there is no anticipated direct clinical benefit to the subject) should be conducted in 
subjects who personally give consent and who sign and date the written informed 
consent form. 
 
4.8.14 Nontherapeutic trials may be conducted in subjects with consent of a 
legally acceptable representative provided the following conditions are fulfilled: 
 
(a) The objectives of the trial cannot be met by means of a trial in subjects 
who can give informed consent personally. 
 
(b) The foreseeable risks to the subjects are low. 
 
(c) The negative impact on the subject’s well-being is minimized and low. 
 
(d) The trial is not prohibited by law. 
 
(e) The approval/favorable opinion of the IRB/IEC is expressly sought on 
the inclusion of such subjects, and the written approval/favorable opinion 
covers this aspect. 


21 
 
 
Such trials, unless an exception is justified, should be conducted in patients having 
a disease or condition for which the investigational product is intended. Subjects 
in these trials should be particularly closely monitored and should be withdrawn if 
they appear to be unduly distressed. 
 
4.8.15 In emergency situations, when prior consent of the subject is not possible, 
the consent of the subject's legally acceptable representative, if present, should be 
requested. When prior consent of the subject is not possible, and the subject’s 
legally acceptable representative is not available, enrollment of the subject should 
require measures described in the protocol and/or elsewhere, with documented 
approval/favorable opinion by the IRB/IEC, to protect the rights, safety, and well- 
being of the subject and to ensure compliance with applicable regulatory 
requirements. The subject or the subject's legally acceptable representative should 
be informed about the trial as soon as possible and consent to continue and other 
consent as appropriate (see section 4.8.10) should be requested. 
 
4.9 
Records and Reports 
 
4.9.1 The investigator should ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required 
reports. 
 
4.9.2 Data reported on the CRF, which are derived from source documents, 
should be consistent with the source documents or the discrepancies should be 
explained. 
 
4.9.3 Any change or correction to a CRF should be dated, initialed, and explained 
(if necessary) and should not obscure the original entry (i.e., an audit trail should 
be maintained); this applies to both written and electronic changes or corrections 
(see section 5.18.4(n)). Sponsors should provide guidance to investigators and/or 
the investigators' designated representatives on making such corrections. Sponsors 
should have written procedures to assure that changes or corrections in CRFs 
made by sponsor's designated representatives are documented, are necessary, and 
are endorsed by the investigator. The investigator should retain records of the 
changes and corrections. 
 
4.9.4 The investigator/institution should maintain the trial documents as specified 
in Essential Documents for the Conduct of a Clinical Trial (see section 8.) and as 
required by the applicable regulatory requirement(s). The investigator/institution 
should take measures to prevent accidental or premature destruction of these 
documents. 


22 
 
 
4.9.5 Essential documents should be retained until at least 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. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained 
(see section 5.5.12). 
 
4.9.6 The financial aspects of the trial should be documented in an agreement 
between the sponsor and the investigator/institution. 
 
4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 
investigator/institution should make available for direct access all requested trial- 
related records. 
 
4.10 
Progress Reports 
 
4.10.1 Where required by the applicable regulatory requirements, the investigator 
should submit written summaries of the trial’s status to the institution. The 
investigator/institution should submit written summaries of the status of the trial to 
the IRB/IEC annually, or more frequently, if requested by the IRB/IEC. 
 
4.10.2 The investigator should promptly provide written reports to the sponsor, 
the IRB/IEC (see section 3.3.8), and, where required by the applicable regulatory 
requirements, the institution on any changes significantly affecting the conduct of 
the trial, and/or increasing the risk to subjects. 
 
4.11 
Safety Reporting 
 
4.11.1 All serious adverse events (SAEs) should be reported immediately to the 
sponsor except for those SAEs that the protocol or other document (e.g., 
Investigator's Brochure) identifies as not needing immediate reporting. The 
immediate reports should be followed promptly by detailed, written reports. The 
immediate and follow-up reports should identify subjects by unique code numbers 
assigned to the trial subjects rather than by the subjects' names, personal 
identification numbers, and/or addresses. The investigator should also comply 
with the applicable regulatory requirement(s) related to the reporting of 
unexpected serious adverse drug reactions to the regulatory authority(ies) and the 
IRB/IEC. 


23 
 
 
4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as 
critical to safety evaluations should be reported to the sponsor according to the 
reporting requirements and within the time periods specified by the sponsor in the 
protocol. 
 
4.11.3 For reported deaths, the investigator should supply the sponsor and the 
IRB/IEC with any additional requested information (e.g., autopsy reports and 
terminal medical reports). 
 
4.12 
Premature Termination or Suspension of a Trial 
 
If the trial is terminated prematurely or suspended for any reason, the 
investigator/institution should promptly inform the trial subjects, should assure appropriate 
therapy and follow-up for the subjects, and, where required by the applicable regulatory 
requirement(s), should inform the regulatory authority(ies). In addition: 
 
4.12.1 If the investigator terminates or suspends a trial without prior agreement of 
the sponsor, the investigator should inform the institution, where required by the 
applicable regulatory requirements, and the investigator/institution should 
promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and 
the IRB/IEC a detailed written explanation of the termination or suspension. 
 
4.12.2 If the sponsor terminates or suspends a trial (see section 5.21), the 
investigator should promptly inform the institution, where required by the 
applicable regulatory requirements, and the investigator/institution should 
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written 
explanation of the termination or suspension. 
 
4.12.3 If the IRB/IEC terminates or suspends its approval/favorable opinion of a 
trial (see sections 3.1.2 and 3.3.9), the investigator should inform the institution, 
where required by the applicable regulatory requirements, and the 
investigator/institution should promptly notify the sponsor and provide the sponsor 
with a detailed written explanation of the termination or suspension. 
 
4.13 
Final Report(s) by Investigator/Institution 
 
Upon completion of the trial, the investigator should, where required by the applicable 
regulatory requirements, inform the institution, and the investigator/institution should 
provide the sponsor with all required reports, the IRB/IEC with a summary of the trial’s 
outcome, and the regulatory authority(ies) with any report(s) they require of the 
investigator/institution. 


 
CONFIDENTIAL AND PROPRIETARY 
CURRAX PHARMACEUTICALS LLC 
Protocol 17-AVP-825-301 
Version 2.0 
 
 
Appendix 4 
World Medical Association Declaration of Helsinki 


Copyright 2013 American Medical Association. All rights reserved. 
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Special Communication 
World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research 
Involving Human Subjects 
World Medical Association 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 
Preamble 
1. The World Medical Association (WMA) has developed the Dec- 
laration of Helsinki as a statement of ethical principles for medi- 
cal research involving human subjects, including research on 
identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of 
its constituent paragraphs should be applied with consider- 
ation of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is ad- 
dressed primarily to physicians. The WMA encourages others 
who are involved in medical research involving human subjects 
to adopt these principles. 
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with 
the words, “The health of my patient will be my first consider- 
ation,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when provid- 
ing medical care.” 
 
4. It is the duty of the physician to promote and safeguard the 
health, well-being and rights of patients, including those who are 
involved in medical research. The physician's knowledge and con- 
science are dedicated to the fulfilment of this duty. 
 
5. Medical progress is based on research that ultimately must in- 
clude studies involving human subjects. 
 
6. The primary purpose of medical research involving human sub- 
jects is to understand the causes, development and effects of 
diseases and improve preventive, diagnostic and therapeutic in- 
terventions (methods, procedures and treatments). Even the 
 
best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, 
accessibility and quality. 
 
7. Medical research is subject to ethical standards that promote 
and ensure respect for all human subjects and protect their 
health and rights. 
 
8. While the primary purpose of medical research is to generate new 
knowledge, this goal can never take precedence over the rights 
and interests of individual research subjects. 
 
9. It is the duty of physicians who are involved in medical research 
to protect the life, health, dignity, integrity, right to self- 
determination, privacy, and confidentiality of personal informa- 
tion of research subjects. The responsibility for the protection 
of research subjects must always rest with the physician or other 
health care professionals and never with the research subjects, 
even though they have given consent. 
 
10. Physicians must consider the ethical, legal and regulatory norms 
and standards for research involving human subjects in their own 
countries as well as applicable international norms and stan- 
dards. No national or international ethical, legal or regulatory re- 
quirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that mini- 
mises possible harm to the environment. 
 
12. Medical research involving human subjects must be conducted 
only by individuals with the appropriate ethics and scientific edu- 
cation, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care profes- 
sional. 
 
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13. Groups that are underrepresented in medical research should 
be provided appropriate access to participation in research. 
 
14. Physicians who combine medical research with medical care 
should involve their patients in research only to the extent that 
this is justified by its potential preventive, diagnostic or thera- 
peutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the 
health of the patients who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are 
harmed as a result of participating in research must be en- 
sured. 
 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions 
involve risks and burdens. 
 
Medical research involving human subjects may only be con- 
ducted if the importance of the objective outweighs the risks and 
burdens to the research subjects. 
 
17. All medical research involving human subjects must be pre- 
ceded by careful assessment of predictable risks and burdens 
to the individuals and groups involved in the research in com- 
parison with foreseeable benefits to them and to other individu- 
als or groups affected by the condition under investigation. 
 
Measures to minimise the risks must be implemented. The risks 
must be continuously monitored, assessed and documented by 
the researcher. 
 
18. Physicians may not be involved in a research study involving hu- 
man subjects unless they are confident that the risks have been 
adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or 
when there is conclusive proof of definitive outcomes, physi- 
cians must assess whether to continue, modify or immediately 
stop the study. 
 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may 
have an increased likelihood of being wronged or of incurring ad- 
ditional harm. 
 
All vulnerable groups and individuals should receive specifi- 
cally considered protection. 
 
20. Medical research with a vulnerable group is only justified if the 
research is responsive to the health needs or priorities of this 
group and the research cannot be carried out in a non- 
vulnerable group. In addition, this group should stand to ben- 
efit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to gen- 
erally accepted scientific principles, be based on a thorough 
knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, ani- 
mal experimentation. The welfare of animals used for research 
must be respected. 
 
22. The design and performance of each research study involving 
human subjects must be clearly described and justified in a re- 
search protocol. 
 
The protocol should contain a statement of the ethical consid- 
erations involved and should indicate how the principles in this 
Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affilia- 
tions, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compen- 
sating subjects who are harmed as a consequence of participa- 
tion in the research study. 
 
In clinical trials, the protocol must also describe appropriate ar- 
rangements for post-trial provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, com- 
ment, guidance and approval to the concerned research ethics 
committee before the study begins. This committee must be 
transparent in its functioning, must be independent of the re- 
searcher, the sponsor and any other undue influence and must 
be duly qualified. It must take into consideration the laws and 
regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate 
any of the protections for research subjects set forth in this Dec- 
laration. 
 
The committee must have the right to monitor ongoing stud- 
ies. The researcher must provide monitoring information to the 
committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of 
the study, the researchers must submit a final report to the com- 
mittee containing a summary of the study’s findings and con- 
clusions. 
 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of re- 
search subjects and the confidentiality of their personal infor- 
mation. 
 
Informed Consent 
25. Participation by individuals capable of giving informed consent 
as subjects in medical research must be voluntary. Although it 
 
 
 
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may be appropriate to consult family members or community 
leaders, no individual capable of giving informed consent may 
be enrolled in a research study unless he or she freely agrees. 
 
26. In medical research involving human subjects capable of giving 
informed consent, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any pos- 
sible conflicts of interest, institutional affiliations of the re- 
searcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, post-study provisions and any 
other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or 
to withdraw consent to participate at any time without repri- 
sal. Special attention should be given to the specific informa- 
tion needs of individual potential subjects as well as to the meth- 
ods used to deliver the information. 
 
After ensuring that the potential subject has understood the in- 
formation, the physician or another appropriately qualified in- 
dividual must then seek the potential subject’s freely-given in- 
formed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally 
documented and witnessed. 
 
All medical research subjects should be given the option of being 
informed about the general outcome and results of the study. 
 
27. When seeking informed consent for participation in a research 
study the physician must be particularly cautious if the poten- 
tial subject is in a dependent relationship with the physician or 
may consent under duress. In such situations the informed con- 
sent must be sought by an appropriately qualified individual who 
is completely independent of this relationship. 
 
28. For a potential research subject who is incapable of giving in- 
formed consent, the physician must seek informed consent from 
the legally authorised representative. These individuals must not 
be included in a research study that has no likelihood of benefit 
for them unless it is intended to promote the health of the group 
represented by the potential subject, the research cannot in- 
stead be performed with persons capable of providing in- 
formed consent, and the research entails only minimal risk and 
minimal burden. 
 
29. When a potential research subject who is deemed incapable of 
giving informed consent is able to give assent to decisions about 
participation in research, the physician must seek that assent in 
addition to the consent of the legally authorised representa- 
tive. The potential subject’s dissent should be respected. 
 
30. Research involving subjects who are physically or mentally in- 
capable of giving consent, for example, unconscious patients, 
may be done only if the physical or mental condition that pre- 
vents giving informed consent is anecessary characteristic of the 
research group. In such circumstances the physician must seek 
informed consent from the legally authorised representative. If 
no such representative is available and if the research cannot be 
delayed, the study may proceed without informed consent pro- 
vided that the specific reasons for involving subjects with a con- 
dition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been ap- 
proved by a research ethics committee. Consent to remain in the 
research must be obtained as soon as possible from the subject 
or a legally authorised representative. 
 
31. The physician must fully inform the patient which aspects of their 
care are related to the research. The refusal of a patient to par- 
ticipate in a study or the patient’s decision to withdraw from the 
study must never adversely affect the patient-physician rela- 
tionship. 
 
32. For medical research using identifiable human material or data, 
such as research on material or data contained in biobanks or 
similar repositories, physicians must seek informed consent for 
its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracti- 
cable to obtain for such research. In such situations the re- 
search may be done only after consideration and approval of a 
research ethics committee. 
 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new inter- 
vention must be tested against those of the best proven inter- 
vention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no 
intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological 
reasons the use of any intervention less effective than the best 
proven one, the use of placebo, or no intervention is necessary 
to determine the efficacy or safety of an intervention 
 
and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be sub- 
ject to additional risks of serious or irreversible harm as a result 
of not receiving the best proven intervention. 
 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. Inadvance of a clinical trial, sponsors, researchers and host coun- 
try governments should make provisions for post-trial access for 
all participants who still need an intervention identified as ben- 
eficial in the trial. This information must also be disclosed to par- 
ticipants during the informed consent process. 
 
Research Registration and Publication and Dissemination 
of Results 
35. Every research study involving human subjects must be regis- 
tered in a publicly accessible database before recruitment of the 
first subject. 
 
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36. Researchers, authors, sponsors, editors and publishers all have 
ethical obligations with regard to the publication and dissemi- 
nation of the results of research. Researchers have a duty to make 
publicly available the results of their research on human sub- 
jects and are accountable for the completeness and accuracy of 
their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as posi- 
tive results must be published or otherwise made publicly avail- 
able. Sources of funding, institutional affiliations and conflicts 
of interest must be declared in the publication. Reports of re- 
search not in accordance with the principles of this Declaration 
should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven inter- 
ventions do not exist or other known interventions have been 
ineffective, the physician, after seeking expert advice, with in- 
formed consent from the patient or a legally authorised repre- 
sentative, may use an unproven intervention if in the physi- 
cian's judgement it offers hope of saving life, re-establishing 
health or alleviating suffering. This intervention should subse- 
quently be made the object of research, designed to evaluate 
its safety and efficacy. In all cases, new information must be re- 
corded and, where appropriate, made publicly available. 
 
 
 
ARTICLE INFORMATION 
Corresponding Author: World Medical 
Association, 13, ch. du Levant, CIB - Bâtiment A, 
01210 Ferney-Voltaire, France; wma@wma.net. 
Published Online: October 19, 2013. 
doi:10.1001/jama.2013.281053. 
Disclaimer: ©2013 World Medical Association, Inc. 
All Rights Reserved. All intellectual property rights 
in the Declaration of Helsinki are vested in the 
World Medical Association. The WMA has granted 
JAMA exclusive rights to publish the 
English-language version of the Declaration 
through December 31, 2013. 
Online-Only Content: Audio podcast is available at 
www.jama.com. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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