Clinical Evaluation of Avulux® Lenses as an Aid in Reducing the Impact of Migraine Headaches
Phase: NA
Conditions: Migraine
Sponsor: Avulux, Inc.

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Clinical Evaluation of Avulux® Lenses as an Aid in 
Reducing the Impact of Migraine Headaches 
 
 
Protocol # AVU-02 Version 1 
February 21, 2020 
 
 
 
 
 
 
Sponsor:   
MATAP II LLC 
#245 -2901 Clint Moore Road 
Boca Raton, FL 33496 
 
 

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Statement of Compliance  
 
 
The trial will be conducted in accordance with the Clinical Study Protocol, requirements of the 
IRB, the Investigator Agreement, and the following Code of Federal Regulations: 21 CFR 812, 21 
CFR 50, 21 CFR 54, 21 CFR 56, and 21 CFR 11.  
 
I hereby confirm that I approve of this Clinical Study Protocol and agree to comply with its 
terms as laid out in this document. I agree to ensure that all staff members involved in the 
conduct of this study are informed about their obligations in meeting the above commitments.  
 
 
 
Principal Investigator:  
 
 
______________________________________  
(Print/Type Name) 
 
 
Signed: ________________________________  
 
 
Date: _________________________________ 
 
 
 

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Table of Contents 
 
1. 
Study Scope ............................................................................................................................ 5 
2. 
Principle of the Device............................................................................................................ 5 
3. 
Study Objectives ..................................................................................................................... 5 
3.1 
Primary Objective ............................................................................................................ 5 
3.2 
Secondary Objective ........................................................................................................ 5 
3.3 
Exploratory Objectives ..................................................................................................... 6 
4. 
Study Endpoints ...................................................................................................................... 6 
4.1 
Primary Endpoint ............................................................................................................. 6 
4.2 
Secondary Endpoint ......................................................................................................... 6 
4.3 
Exploratory Endpoints...................................................................................................... 6 
5. 
Inclusion/Exclusion Criteria ................................................................................................... 7 
5.1 
Inclusion Criteria .............................................................................................................. 7 
5.2 
Exclusion Criteria ............................................................................................................. 7 
6. 
Study Procedures .................................................................................................................... 7 
6.1 
Consent Procedures .......................................................................................................... 7 
6.2 
Enrollment and Randomization of Study Subjects .......................................................... 8 
6.3 
Pain Scale ......................................................................................................................... 8 
6.4 
Procedures and Assessments ............................................................................................ 8 
7. 
Safety Reporting ..................................................................................................................... 9 
7.1 
Adverse Events ................................................................................................................. 9 
7.2 
Serious Adverse Events .................................................................................................... 9 
7.3 
Reporting of Events ........................................................................................................ 10 
7.3.1 
Adverse Events ....................................................................................................... 10 
7.3.2 
Serious Adverse Events .......................................................................................... 10 
8. 
Risk/Benefit Analysis ........................................................................................................... 10 
8.1 
Risks ............................................................................................................................... 10 
8.2 
Benefits........................................................................................................................... 10 
9. 
Subject Withdrawal ............................................................................................................... 10 

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10. 
Administrative Considerations........................................................................................... 11 
10.1 
Prior to Study Initiation .............................................................................................. 11 
10.2 
Amendments ............................................................................................................... 11 
10.3 
Financial Disclosure of Clinical Investigators ............................................................ 11 
10.4 
Subject Informed Consent .......................................................................................... 12 
10.5 
Subject Confidentiality ............................................................................................... 12 
10.6 
Study Registration ...................................................................................................... 13 
10.7 
Source Documents ...................................................................................................... 13 
10.8    
 Device Accountability ............................................................................................... 13 
10.9 
Device Labeling .......................................................................................................... 13 
10.10 
Study Monitoring ........................................................................................................ 13 
10.11  
Retention of Study Records ........................................................................................ 14 
10.12 
Protocol Termination .................................................................................................. 14 
11. 
Data Analysis ..................................................................................................................... 14 
11.1 
Sample Size Justification ............................................................................................ 14 
11.2 
Proposed Analyses ...................................................................................................... 15 
11.2.1 Analysis Populations ............................................................................................... 15 
11.2.2 Subject Accountability ............................................................................................ 16 
11.2.3 Handling of Missing Data ....................................................................................... 16 
11.2.4 Demographic and Baseline Characteristics ............................................................ 16 
11.2.5 Analysis of Primary Endpoint ................................................................................. 16 
11.2.6 Analysis of Secondary Endpoint ............................................................................. 17 
11.2.7 Analysis of Exploratory Endpoints ......................................................................... 17 
11.2.8 Blinding Assessment ............................................................................................... 18 
11.2.9 Adverse Event Data ................................................................................................ 18 
 
 
 

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1. Study Scope 
This study is a prospective, multi-center, randomized, placebo-controlled study.  A minimum of 
68 subjects who suffer from acute migraine headaches and who provide written informed 
consent will be enrolled at a minimum of 3 clinical sites.  Subjects will be randomized into one 
of two treatment groups (i.e. Avulux® device vs. control/sham device) in a one-to-one ratio.   
Subjects will participate in the study for a maximum of four (4) weeks after enrollment.  
Subjects will be directed to apply the study device specific to their study arm as soon as 
possible once they experience symptoms consistent with the onset of a migraine attack.  
Subjects will be asked to assess the severity of each headache using a pain score just prior to 
the application of the study device, and 2- and 4-hours following application of the device, for 
all severe or very severe migraine headaches that they experience while enrolled in the study.   
 
This study will be conducted upon execution of a clinical study agreement and receipt of 
Institutional Review Board or Ethics Committee (IRB/EC) approval from each participating site.   
 
2. Principle of the Device 
Avulux® is intended to reduce the severity of headache pain in adult patients diagnosed with 
episodic migraine headache.  In this study, the investigative Avulux® device shall consist of a 
pair of optical filters in the form of spectacle lenses, provided in a standard spectacle frame; the 
lenses contain a dye that effectively blocks light at specified wavelength ranges while 
minimizing distortion of the visible spectrum. The optical filters block a portion of the optical 
spectrum that is suspected to stimulate photophobic responses that trigger some, and 
exacerbate most, migraines.  
 
The control/sham device for this study shall be a pair of plastic lenses provided in a standard 
spectacle frame, which will have negligible light-blocking properties at the optical wavelengths 
which are blocked by the Avulux® device. 
  
3. Study Objectives 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of the Avulux® device in reducing 
the impact of migraine headaches, as measured by improvement in an 11-point pain scale after 
2 hours of device application, when compared to a control/sham device.  
 
3.2 
Secondary Objective 
The secondary objective of this study is to evaluate the efficacy of the Avulux® device in 
reducing the impact of migraine headaches, as measured by improvement in an 11-point pain 
scale after 4 hours of device application, when compared to a control/sham device.  
 

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3.3 
Exploratory Objectives 
Exploratory objectives for this study are: 
• To compare the proportion of subjects who show quantifiable improvement in overall 
migraine impact (as measured by a change in migraine pain from severe to mild/no 
pain) when using the Avulux® device vs. a control/sham device; 
• To compare the proportion of subjects who require adjunctive medication to control 
their migraine headache when using the Avulux® device vs. a control/sham device; and 
• To compare the proportion of subjects suffering from light sensitivity as a result of their 
migraine headache when using the Avulux® device vs. a control/sham device.    
 
4. 
Study Endpoints 
4.1 
Primary Endpoint   
The primary endpoint variable is the change in migraine pain as measured on an eleven-point 
pain scale, defined as the pain score after an elapsed time of 2 hours following application of 
the device minus the pain score at onset of migraine symptoms, with respect to the first severe 
or very severe migraine headache (defined as a pain score of 6 or greater at onset of migraine 
symptoms) experienced by an enrolled subject. 
 
4.2 
Secondary Endpoint 
The secondary endpoint variable is the change in migraine pain as measured on an eleven-point 
pain scale, defined as the pain score after an elapsed time of 4 hours following application of 
the device minus the pain score at onset of migraine symptoms, with respect to the first severe 
or very severe migraine headache (defined as a pain score of 6 or greater at onset of migraine 
symptoms) experienced by an enrolled subject. 
 
4.3 
Exploratory Endpoints 
Exploratory endpoint variables are:  
• The proportion of subjects who report mild or no symptoms (defined as a pain score of 
3 or less) after an elapsed time of 2 hours following application of the device, with 
respect to their first severe or very severe migraine headache;  
• The proportion of subjects who require abortive medication to control their first severe 
or very severe migraine headache within 8 hours following application of the device; 
and 
• The proportion of subjects who report sensitivity to light after elapsed times of 2 hours 
and 4 hours following application of the device, with respect to their first severe or very 
severe migraine headache.   
 

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5. Inclusion/Exclusion Criteria 
5.1 
Inclusion Criteria 
All enrolled patients must meet all of the following inclusion criteria: 
• Subject is 18 years or older; 
• Subject is willing and able to provide written informed consent; 
• Diagnosis of migraine, based on a history of at least 5 attacks per month with the 
following primary headache characteristics: 
o Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated); 
o Headache has at least two of the following characteristics:  
 unilateral location;  
 pulsating quality;  
 moderate or severe pain intensity;  
 aggravation by or causing avoidance of routine physical activity (e.g. 
walking or climbing stairs); 
o Headache occurs with at least one of the following symptoms:  
 nausea and/or vomiting;  
 photophobia and phonophobia; 
• Subject has experienced at least 4 migraine attacks in the last month, with at least two 
migraine attacks resulting in severe pain prior to the use of any abortive medications; 
• Migraines are not attributed to another disorder.  
 
5.2 
Exclusion Criteria 
All enrolled patients must meet none of the following exclusion criteria: 
• Subjects participating in another prospective, interventional clinical study; 
• Subjects with other light sensitive conditions, such as iritis;  
• Subjects who have less than 4 headache days per month with the above characteristics;  
• Chronic migraine subjects (defined as subjects who experience a minimum of 15 
headache days per month);  
• Subjects with headaches due to medication overuse (defined as regular use of headache 
medication for a minimum of 10 days per month, for a minimum period of 3 months); 
• Subjects who have had any change in their migraine treatment within 4 weeks prior to 
study enrollment.   
• Subjects whose family members are currently participating in this study, or are 
employees of the study site, Avulux, or the coordinating CRO. 
 
6. Study Procedures 
6.1 
Consent Procedures 
After Institutional Review Board/Ethics Committee (IRB/EC) approval for the study is obtained 
at a given clinical site, the investigator (or appropriate designee) at the site will identify 

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potential subjects for the study, based on the inclusion/exclusion criteria outlined in Section 4.  
Eligible subjects will be asked to provide written informed consent. The informed consent 
process will be documented for each subject and will include a thorough discussion of study 
procedures involved.  Each subject participating in the study shall sign and date the consent 
form prior to the initiation of any study procedures.   
6.2 
Enrollment and Randomization of Study Subjects 
Subjects will be asked to provide demographic information (date of birth, gender, 
race/ethnicity) and relevant medical history related to migraine headaches.  Subjects who meet 
all inclusion criteria and none of the exclusion criteria, and who provide written informed 
consent, will be enrolled in the study.  Enrolled subjects will then be randomized to the Avulux® 
study glasses vs. control/sham study arm, with allocation on a 1:1 basis; subjects will be 
provided with the device specific to their assigned study arm.  Subjects will be blinded to the 
type of device being assessed (both the blocking abilities when worn).   
 
6.3 
Pain Scale 
Subjects will be asked to rate their headache pain using an 11-point scale, i.e. on an integer 
scale from 0 to 10 inclusive, with 0 indicating no pain and 10 indicating the worst pain 
imaginable.  The scale can be interpreted clinically as follows:   
• 10:   worst pain imaginable; 
• 8-9:  very severe pain; 
• 6-7:  severe pain;  
• 4-5:  moderate pain; 
• 1-3:  mild pain;  
• 0:      no pain. 
The 11-point pain scale has been validated for use in migraine headache evaluations.1 
 
6.4 
Procedures and Assessments 
Subjects will be directed to: 
• apply the study glasses at the first onset of aura, or as soon as possible once they 
experience symptoms consistent with the onset of a migraine attack.   
• avoid taking abortive medication for the first four hours of a migraine attack. If abortive 
medications cannot be avoided, the subject should document use. 
• record the following information for the first (and all subsequent) severe or very severe 
migraine headaches that they experience while enrolled in the study: 
o The date and time of symptom onset;  
 
1 Kwong WJ and Pathak DS. Validation of the eleven-point pain scale in the measurement of migraine headache 
pain.  Cephalgia 2007; 27:  336-342. 

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o The pain score (as assessed on the 11-point pain scale) just prior to the 
application of the study glasses (score needs to be greater than or equal to 6 to 
qualify as a severe or very severe headache); 
o The time at which the study glasses are applied;  
o Whether the subject was wearing prescription eyewear in addition to the study 
glasses, or whether the study glasses alone were worn; 
o The pain score (as assessed on the eleven-point pain scale) 2 hours after the 
study glasses are applied;  
o The pain score (as assessed on the eleven-point pain scale) 4 hours after the 
study glasses are applied;  
o The type of abortive medication taken (if any) to control headache symptoms, 
the dosage taken, and the time at which the medication is taken; and  
o Any experience of light sensitivity within 4 hours after the study glasses are 
applied, and the time at which light sensitivity is first experienced. 
Subjects will participate in the study for a maximum of four (4) weeks ± 3 days after enrollment; 
if a given subject does not experience a severe or very severe migraine headache within four (4) 
weeks, that subject will not be included in the evaluable study population.  
 
Study coordinators will contact subjects once per week to ensure they are wearing the study device 
as instructed, and that they are recording the requested information related to their headaches. 
These weekly contacts will also enable coordinators to identify and address any barriers to 
adherence with the protocol.  
 
After completion of study activities, subjects will return the glasses specific to their study arm, 
and be asked to complete a study questionnaire, to provide feedback regarding the wearability 
and ease of use of the glasses.   Subjects will also be asked to provide an opinion as to which 
type of device they believe they were assigned to (Avulux® vs. control/sham vs. do not know). 
 
7. Safety Reporting 
7.1 
Adverse Events 
An adverse event (AE) is defined as an undesirable physical, psychological, or behavioral effect 
experienced by a subject related to headaches in conjunction with his/her participation in the 
clinical study, whether or not device related.  Any subject may experience adverse events or 
complications while enrolled in the study.  Should they occur, these events will be reported to 
the sponsor as detailed in section 7.3.1.  
 
7.2 
Serious Adverse Events 
A serious adverse event (SAE), as defined by the International Conference on Harmonization 
(ICH) guidelines, is any adverse event that results in any of the following outcomes: 
1. 
Death; 

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2. 
Life-threatening outcome (i.e. immediate risk of death from the reaction as it occurred); 
3. 
Inpatient hospitalization or prolongation of existing hospitalization; 
4. 
Persistent or significant disability or incapacity; or 
5. 
Congenital anomaly. 
 
7.3 
Reporting of Events 
7.3.1 Adverse Events 
Adverse events will be reported to the sponsor in a timely manner.  A case report form shall be 
completed for each event, with description of the event, onset date, end date, relation to study 
device, any treatment rendered and the outcome. 
 
7.3.2 Serious Adverse Events 
Serious adverse events should be reported to the sponsor within 24 hours of awareness of the 
event. The investigator or designee should report the event via telephone, email or fax with 
details describing the event, onset date, end date, severity of event, relation to study device 
treatment and outcome. If all details are not known at the time of reporting, an initial report is 
filed followed by a detailed report within 7 working days. It is the responsibility of the 
investigator to inform the IRB/EC as applicable according to their IRB/EC policies. It is the 
responsibility of the sponsor to inform the other sites of the event.  
 
8. Risk/Benefit Analysis 
8.1 
Risks 
There are no anticipated risks to study subjects as a result of application of the device. Any 
potential discomfort experienced from use of the device would be mitigated by removal of the 
device.   
 
8.2 
Benefits 
The anticipated benefit of the device is the reduction in headache severity in patients with 
migraine headaches.  Information gained from this study may aid in the future management of 
patients with episodic migraine headaches.   
 
9. Subject Withdrawal 
In accordance with Good Clinical Practice (GCP) guidelines, subjects who have consented to 
participate in the study are free to withdraw consent and discontinue participation in the study 
at any time, and without prejudice to further treatment as required for their condition.   
If a subject decides to discontinue participation in the study, the investigator will note the 
reason for the discontinuation (and any potential AEs) on the applicable case report form. 

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10. Administrative Considerations 
This protocol was designed and will be conducted, recorded, and reported in compliance with 
Good Clinical Practice (GCP) guidelines and with applicable U.S. Food and Drug Administration 
(FDA) Investigational Device Exemption (IDE) regulations.    
 
10.1 Prior to Study Initiation 
The following will be provided to the sponsor from the study site, prior to study initiation: 
• Curriculum Vitae of the investigator; 
• The “Statement of Compliance” page of the protocol, signed and dated by the 
investigator; 
• An independent IRB/EC membership list current at the time of the review of this 
protocol; 
• Financial Disclosure Form, signed and dated by the investigator;  
• Written verification of IRB/EC approval for the study; and 
• A duly executed clinical study agreement.   
10.2 Amendments  
Amendments to this study protocol must be agreed upon in writing between the investigator 
and the sponsor.  Written verification of IRB/EC approval will be obtained before any 
amendment is implemented which affects subject safety or materially alters the study design.  
Modifications of the protocol which are administrative in nature do not require IRB/EC 
approval, but will be submitted to the IRB/EC for informational purposes.   
If there are changes to the informed consent form utilized by a site, written verification of 
IRB/EC approval of the new form must be forwarded to the sponsor, along with a copy of the 
new form. If the changes in the content of the consent form are directly related to information 
that may influence the subject’s decision to participate in the study, the subject may need to be 
reconsented. 
 
10.3 Financial Disclosure of Clinical Investigators 
The clinical investigator(s) participating in this study shall complete a financial disclosure form, 
so as to provide sufficient and accurate financial information to the sponsor pertaining to: 
• Any arrangements between the sponsor and clinical investigator whereby the value of 
compensation to the investigator for conducting the study could be influenced by the 
outcome of the study; 
• Any significant payments or other forms of compensation from the sponsor, such as 
grants to fund ongoing research, compensation in the form of equipment, retainers for 
ongoing consultation, or honoraria;  

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• Any proprietary interest in the product to be developed and held by the investigator 
involved in the study; and 
• Any significant equity interest in the sponsor held by the investigator, his/her spouse or 
dependent children. 
 
10.4 Subject Informed Consent  
This study will be conducted in compliance with the principles of ‘Informed Consent’ described 
in the Declaration of Helsinki and FDA 21 CFR Part 50.  It is the responsibility of the investigator, 
or designee, to obtain written informed consent from each subject prior to the subject’s 
inclusion in the study. 
The sponsor will provide each investigator with a sample informed consent document that the 
site may modify to meet individual IRB/EC requirements.  The investigator should provide the 
sponsor with a copy of the proposed consent form, preferably prior to submitting it to the 
IRB/EC, so that the sponsor may ensure that all appropriate and required elements are 
incorporated into the document. 
Prior to study initiation, the investigator must provide the sponsor with a copy of the informed 
consent form approved by the IRB/EC, and a copy of the IRB/EC letter stating that formal 
approval has been granted by the institution. 
Study subjects must provide written consent using the IRB/EC-approved informed consent form 
in effect at the time of presentation of the subject to the study site.  Participating subjects in 
the State of California will also be provided with the Experimental Subject’s Bill of Rights as part 
of the informed consent form. 
 
A copy of the IRB/EC-approved informed consent form and a copy of each subject’s signed 
consent form will be maintained by each investigator in the site’s study file.  A copy of the 
signed and dated informed consent form must be given to each study subject.  The original 
informed consent form for each subject must be kept on file at each of the participating study 
sites for a minimum retaining period, in accordance with applicable regulatory authority 
recommendations (refer to section 10.10). 
 
10.5 Subject Confidentiality  
The sponsor and the study investigators shall make every effort to protect the confidentiality of 
subjects participating in the study.  All study information and data with respect to individual 
study subjects will be considered confidential.  Only authorized personnel will have access to 
this confidential information.   
Subject specimens will be identified using a unique identifier.  All data used in the analysis and 
reporting of this evaluation will be without identifiable reference to the subjects.   

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10.6 Study Registration 
Study information and final study results will be entered in the ClinicalTrials.gov registry 
database in compliance with the FDA Modernization Act of 1997 and the FDA Amendments Act 
of 2007.   
10.7 Source Documents 
The subject’s site visit must be fully documented on source document worksheets or in the 
subject’s medical records, or a combination of both.   
During the monitoring process, information entered into the study case report forms will be 
verified against the source worksheets or subject medical records.  
10.8     Device Accountability 
Only the investigator and study staff identified in the clinical research agreement and/or study 
logs on file with the sponsor and at the study site may have access to the investigational device. 
The investigator must maintain a full accountability for any devices received.  An accountability 
log will be provided to maintain current and accurate inventory records covering the receipt 
and return of the devices.     
 
At the conclusion of the study, the site will return the devices to the sponsor.  The site shall 
retain a copy of the accountability log for its study files. 
10.9 Device Labeling 
The study glasses and sham glasses will be labeled in accordance with U.S. federal regulations 
applicable to an investigational device.  All device labeling, operating instructions, device 
warnings or precautions, and informational materials will include the following statement: 
 
CAUTION - THIS IS AN INVESTIGATIONAL DEVICE. 
LIMITED BY FEDERAL (OR U.S.) LAW TO INVESTIGATIONAL USE. 
 
 
10.10 Study Monitoring  
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported study data are accurate, complete, and verifiable, and that the 
conduct of the trial is compliant with federal regulations, agreements with the sponsor, the 
currently approved protocol, and with any requirements imposed by the IRB/EC.  
 
Site monitoring will be performed by a third-party contract research organization (CRO) 
working on behalf of the sponsor.  A Clinical Monitoring Plan (CMP) will be developed to 
establish the plan for study oversight.  

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On-site monitoring is anticipated throughout the course of the study. The sponsor will be 
provided with written reports of these visits, and the sites will be provided with a follow-up 
letter describing the findings and defining any outstanding issues or action items required.   
 
10.11  Retention of Study Records  
The investigator will maintain adequate records for the study including informed consent 
forms, source documents (as applicable), medical records, safety reports (as applicable), and 
other pertinent study data.   
For participating U.S. study sites, all records for this study must be retained by the Investigator 
for a minimum period of: 
• two (2) years after the FDA approves the marketing notification for the product, or 
 
• two (2) years following termination of the study if no marketing notification is ever 
sought or approved, 
whichever is the longer elapsed time.     
To avoid any possible misunderstandings, the investigator will contact the sponsor prior to the 
planned destruction of any study records, or if the investigator leaves the institution where the 
study was conducted.  The investigator will notify the sponsor in the event of accidental loss or 
destruction of any study records. 
10.12 Protocol Termination 
Both the sponsor and the investigator have the right to terminate the study at their discretion, 
with written notice to the other party.  This action should be taken only after appropriate 
consultation between the sponsor and investigator or institution.  Termination of the study 
shall not affect the rights and obligations of either of the parties prior to the date of 
termination. 
 
11.  Data Analysis 
11.1 Sample Size Justification 
A pilot evaluation of the Avulux® and control/sham devices (n = 10 subjects using each type of 
device) demonstrated that users of the Avulux® device reported a mean decrease of 4.1 points 
in pain score (standard deviation = 1.9 points) after an elapsed time of 2 hours, and users of the 
placebo device reported a mean decrease of 1.9 points in pain score (standard deviation = 1.5 
points) after an elapsed time of 2 hours.  The difference between the performance of the two 
devices was statistically significant (p = 0.004).   
 
Assuming that subjects with severe or very severe migraine headaches achieve a mean 4-point 
improvement in pain score when using the investigative device and at most a mean 2-point 
improvement when using the control/sham device, and assuming a standard deviation of at 

15 
 
most 2.0 points when estimating the mean difference in pain scores in individual study subjects 
after application of either device, a sample size of 27 subjects per study arm provides a 
minimum statistical power of 95% to detect a significant difference in mean results for the 
primary endpoint variable between the two (2) device types, at a significance level of α = 0.05. 
Given an estimated dropout rate of up to 20% in each study arm, a minimum of 34 subjects per 
arm (or 68 total subjects) are required to be enrolled in this study.   
 
The above assumptions imply that the mean improvement in pain score after 2 hours will be at 
least 2 points higher for the Avulux® device than for the control/sham device.  Meta-analyses 
have shown that the minimal clinically important difference (MCID) to detect changes in acute 
pain as measured on the 11-point pain scale is 1.7 points;2,3 therefore, a 2-point difference in 
mean improvement between study devices is considered to be clinically meaningful.   
 
11.2 Proposed Analyses 
A statistical analysis plan, containing detailed information regarding the proposed statistical 
analyses of study data, will be created and approved prior to database lock. 
 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a 
significance level of α = 0.05. 
 
11.2.1 Analysis Populations 
The intention-to-treat (ITT) population shall be defined as the population of all enrolled subjects 
who were assigned to a study group and who experienced a minimum of one severe or very 
severe headache within 4 weeks of enrollment. This population shall include subjects who were 
non-compliant with study procedures, and subjects who were assigned to the incorrect device 
specific to their study group.   
 
The per-protocol population shall be defined as the population of all enrolled subjects who 
were assigned to the correct device specific to their study group, who experienced a minimum 
of one severe or very severe headache within 4 weeks of enrollment, and who were compliant 
with study procedures throughout the duration of their enrollment in the study.    
 
Analyses of the primary and secondary endpoints shall be conducted using data from intention-
to-treat population.  Analyses of exploratory endpoints shall be conducted using data from the 
per-protocol population.  
 
 
2 Olsen MF, Bjerre E, Hansen MD et al. Pain relief that matters to patients:  systematic review of empirical studies 
assessing the minimum clinically important difference in acute pain.  BMC Medicine 2017, 15:  35. 
3 Farrar JT, Young JP Jr., LaMoreaux L et al.  Clinical importance of changes in chronic pain intensity measured on 
an 11-point numerical pain rating scale.  Pain 2001, 94:  149-158. 

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11.2.2 Subject Accountability 
All subjects who provided informed consent (screened subjects) will be included in a summary 
of subject accountability. The number of subjects screened, the number and percentage of 
subjects who were screen failures, and the number and percentage of subjects who were 
enrolled in the study will be summarized by investigational site and overall. The reasons for 
screen failure will also be tabulated.  
 
11.2.3 Handling of Missing Data 
In the intention-to-treat population, any missing pain scores at time points of 2 and 4 hours 
after application of the device shall be imputed using a multiple imputation procedure, with 
study arm, age, sex, baseline pain score, number of severe or very severe headaches 
experienced while enrolled in the study, and pain scores at 2 and 4 hours after application of 
the device for subsequent severe or very severe headaches experienced while enrolled in the 
study as predictors.  Imputation procedures shall utilize predictive mean matching.4  A total of 
50 sets of multiple imputations shall be generated; the analysis of the primary endpoint shall be 
conducted for each set, and a pooled estimate of the difference in mean improvement between 
the two devices will be computed, along with a 95% interval estimate and p-value associated 
with the null hypothesis.   
 
In the per-protocol population, subjects with a missing value of an exploratory endpoint will not 
be included in the evaluable population for that endpoint.  
 
11.2.4 Demographic and Baseline Characteristics 
Descriptive statistics of demographic variables (sex, age, race/ethnicity) will be presented for all 
enrolled study subjects, and for subjects stratified by study site and by assigned study arm. 
 
Continuous variables as a minimum will be described by number of non-missing observations 
(n), arithmetic mean, standard deviation (SD), minimum, median, and maximum. Categorical 
variables will be presented using the number of observations in each category, and 
corresponding proportions (expressed as percentages).  
 
11.2.5 Analysis of Primary Endpoint 
The null hypothesis to be tested is  
Ho:  DA – DC/S = 0,  
where DA is the change in pain score after an elapsed time of 2 hours using the active device, 
and DC/S is the change in pain score after an elapsed time of 2 hours using the control/sham 
device.   
 
 
4 Van Buuren S and Goothius-Oudshoorn K.  mice:  Multivariate imputation by chained equations.  Journal of 
Statistical Science 2011, 45:  1-67. 

17 
 
In order to assess whether there is a possible baseline effect, the mean baseline pain score (i.e. 
mean pain score at symptom onset) using the active device shall be statistically compared to 
the mean baseline pain score using the active/sham device, using a two-sample t-test at a 
significance level of α = 0.05.  
 
In order to assess whether there is a possible effect of rescue medications on the primary 
endpoint, the proportion of subjects using rescue medications within 2 hours of symptom onset 
will be statistically compared between the two study arms, using Fisher’s exact test at a 
significance level of α = 0.05.  
 
If there is no significant difference in baseline pain scores and no significant difference in early 
use of rescue medications between the two device types, the null hypothesis will be tested 
using the difference between the change in pain scores after 2 hours using the active device 
and the change in pain scores after 2 hours using the control/sham device.   
 
The distributions of these differences will be tested for normality using the Shapiro-Wilk test at 
a significance level of α = 0.05. If the distributions are consistent with a hypothesis of normality, 
the above null hypothesis will be tested using a two-sample t-test; otherwise, the null 
hypothesis will be tested using a non-parametric Mann-Whitney test.  The mean and associated 
95% confidence interval for the true difference between the two devices will be computed, 
along with the p-value associated with the null hypothesis.   
 
If there is a significant difference in baseline pain scores and/or early use of rescue medications 
between the two study arms, an analysis of covariance (ANCOVA) model shall be fitted to the 
data, relating the difference in pain scores after 2 hours to the device type (active vs. 
control/sham), while controlling for any significant covariates.  A p-value associated with the 
test of the hypothesis of no effect of the active device on change in pain score after 2 hours will 
be computed. 
 
11.2.6 Analysis of Secondary Endpoint 
In order to compare the mean change in pain score after an elapsed time of 4 hours using the 
active device to the mean change in pain score after an elapsed time of 4 hours using the 
control/sham device, the analyses as described in section 10.2.5 for the primary endpoint shall 
be followed.   
 
11.2.7 Analysis of Exploratory Endpoints 
In order to compare the proportion of subjects who report mild or no symptoms after an 
elapsed time of 2 hours using the active device to the corresponding proportion using the 
control/sham device, subjects will be stratified into two categories within each study arm, using 
the baseline pain score (6-7 vs. 8-10) as the basis for stratification.  Within each of the two 
strata, the number of subjects with a pain score of ≤ 3 after 2 hours and the number of subjects 
with a pain score of > 3 after 2 hours shall be tabulated for both the active device and for the 

18 
 
control/sham device; results for each stratum shall be displayed in a 2 x 2 table. A Cochran-
Mantel-Haenszel test shall be conducted to test the hypothesis of lack of association between 
the proportion of subjects reporting mild or no symptoms after 2 hours and the type of device, 
across all strata. An estimate of the pooled odds ratio and the associated exact 95% confidence 
interval will be computed, along with the p-value associated with the test of the null 
hypothesis. 
 
The procedures described above shall also be conducted in order to compare the proportion of 
subjects who require abortive medication to control their migraine headache within 8 hours 
between the two device types, and to compare the proportion of subjects who report 
sensitivity to light after elapsed times of 2 hours and 4 hours between the two device types.  
 
11.2.8 Blinding Assessment 
As described in section 5.4, subjects who complete all study procedures will be asked at the 
final site visit to provide an opinion as to which type of device they believe they were assigned 
to (Avulux® vs. control/sham vs. do not know).  Blinding assessments shall be performed on the 
resulting data, following procedures as described in James et al.5 and in Bang et al.6 
 
11.2.9 Adverse Event Data 
Analyses of adverse event data shall be conducted with respect to all enrolled subjects who 
participated in the use of either the active device or the control/sham device during study 
procedures. 
 
For each study device, the number of adverse events (AEs) shall be tabulated, and descriptive 
statistics shall be utilized to summarize the severity of AEs and their relationship to study 
procedures for each device.   
 
All serious adverse events (SAEs) will be listed individually.   
 
 
 
 
5 James KE, Bloch DA, Lee KK et al.  An index for assessing blindness in a multi-centre clinical trial:  disulfiram 
for alcohol cessation – a VA cooperative study.  Stat Med 1996, 15:  1421-1434. 
6 Bang H, Ni L and Davis CE.  Assessment of blinding in clinical trials.  Control Clin Trials 2004, 25:  143-156.