Optical Treatment of Migraines Clinical Study
Phase: NA
Conditions: Migraine
Sponsor: Avulux, Inc.

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 1  
 
 
 
 
Optical Treatment of Migraines 
Study Protocol 
 
Version 1.0 
 
 
 
 
 
 
 
 
 
 
 
February 28, 2019 
 
 
 
Sponsor: 
 
Avulux 
 
2901 Clint Moore Road #245 
Boca Raton, FL 33496 
 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 2  
 
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: _________________________________ 
 
 
 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 3  
 
Table of Contents 
Background and Introduction: ...................................................................................... 4 
Investigational Device .................................................................................................. 5 
Objectives: ................................................................................................................... 6 
Anticipated Clinical Benefits ........................................................................................ 6 
Anticipated Risks ......................................................................................................... 6 
Study Design: .............................................................................................................. 6 
Patient Recruitment and Screening ............................................................................. 7 
Enrollment Criteria ....................................................................................................... 7 
Inclusion Criteria: ..................................................................................................... 7 
Exclusion Criteria: .................................................................................................... 7 
Study Procedures ........................................................................................................ 8 
Patient Reported Outcome Data .............................................................................. 8 
Patient Withdrawal or Termination ........................................................................... 9 
Standard of Care vs. Research-Related Procedures: .............................................. 9 
Study Oversight ........................................................................................................... 9 
Safety Committees ................................................................................................... 9 
Study Monitoring ...................................................................................................... 9 
Statistical Methods, Data Analysis and Interpretation .................................................. 9 
Preliminary Analyses ................................................................................................ 9 
Primary Outcome ................................................................................................... 10 
Required Sample Size ........................................................................................... 10 
Secondary Outcome .............................................................................................. 10 
Exploratory Outcomes ............................................................................................ 10 
Control of Investigational Devices/Drugs: .............................................................. 11 
Abbreviated Device Regulations for Nonsignificant Risk (NSR) Devices: .................. 11 
Nonsignificant risk determination ........................................................................... 11 
References: ............................................................................................................... 15 
APPENDIX A: Revised International Headache Society criteria for migraine headache
................................................................................................................................... 16 
APPENDIX B: HEADACHE IMPACT TEST (HIT-6) .................................................. 26 
 
 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 4  
 
Background and Introduction:  
Approximately 9% of men and 18% of women are afflicted with migraines. (Stovner, 2006) Over 
90% of patients with migraines report a sensitivity to light (photophobia) during headaches. 
(Evans, 2008) Some migraine sufferers report that light can trigger a migraine and some have a 
chronic sensitivity to light. (Main, 1997) Migraineurs are especially sensitive to non-
incandescent lighting sources such as fluorescent lights, computer monitors, and gas-vapor 
lamps.  
The pathway that mediates photophobia appears to involve intrinsically photosensitive retinal 
ganglion cells (IPRGCs, Hattar, 2002) and trigeminal afferents (Noseda, 2010; Digre and 
Brennan, 2012). These retinal cells do not require input from photoreceptors to be activated by 
light, and they have been shown to be responsible for circadian rhythm entrainment and the 
pupillary light reflex. As such, these cells constitute a pathway separate from that of the visual 
pathway (Güler, 2008). IPRGCs contain the chromophore melanopsin.  Unlike rhodopsin, the 
photosensitive molecule found in rods and cones, melanopsin is a bi-stable molecule. Although 
melanopsin is related to rhodopsin, it shares more similarities with the photosensitive 
molecules found in invertebrate photoreceptors (Mure, 2009). Bi-stable pigments such as 
melanopsin have two stable isoforms that are spectrally distinct (Figure 1). One isoform is 
active and can elicit a physiologic response; the other is inactive. Different wavelengths of light 
(1 and 2) trigger a conformational change between the two isoforms. In the case of 
melanopsin, it is 480 nm light that isomerizes melanopsin from its active to its inactive state 
and triggers the phototransduction cascade in the IPRGC. In addition to a possible natural slow 
thermal relaxation back to the cis state, exposure to 590 nm light drives melanopsin from its 
inactive, all-trans isoform to its active, 11-cis isoform. Although 590 nm light isomerizes 
melanopsin, it does not activate the cell. 
In a previous study, Subhash and Hoggan designed thin-film optical filters for spectacles lenses 
that blocked light around 480 and 620 nm. Patients with chronic migraines experienced 
statistically and clinically significant reductions in headache impact as measured by the 
Headache Impact Test (HIT-6TM) while wearing these filters. However, this study lacked an 
adequate control intervention. 
We hypothesize that if we could selectively block this portion of the visible spectrum, we could 
reduce the severity of headaches in migraine patients. The objective of this study is to develop 
optical filters that can be applied to spectacle lenses, contact lenses, and light sources that will 
block the target wavelengths. The filters will then be tested in a cohort of adult patients with 
migraines.  If successful, these filters could be a novel, non-invasive adjuvant in the treatment 
of migraines and light sensitivity. 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 5  
 
Investigational Device 
Avulux™ is intended to decrease the impact of headache and migraine on normal daily life and 
the ability to function, and reduce the frequency and severity of headache, in adult patients 
diagnosed with episodic migraine headache or chronic migraine. 
 
Avulux™ consists of a pair of optical filters in the form of spectacle lenses, provided in standard 
spectacle frames or as clip-on units, coated with a thin film 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.  
 
Our active and sham lenses will have tints calibrated such that the optical density, that is the 
overall “darkness” of all study lenses, will be the same. All study lenses will appear to have the 
same overall light-blocking effect to study subjects. The optical properties of the two lenses are 
demonstrated in Figure 1.   
 
Figure 1. Optical properties of study lenses (black) and sham lenses (blue) 
The study spectacles will be fitted with “wear over” frames that can be worn easily by study 
subjects who wear no corrective lenses, those who wear contacts, or those who normally wear 
corrective prescription lenses, as noted in the photo below. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 6  
 
 
Objectives:  
The long-term goal of the project is to reduce the impact of headaches in patients with 
migraine headaches. The goal of this study is to test optical filters that block light at 480 nm and 
590 nm. These wavelengths of light are known to activate IPRGCs. IPRGCs are part of the neural 
mechanism responsible for light-induced pain associated with migraines. 
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 Headache Impact Test (HIT-
6TM) scores at three weeks when compared to a control/sham device. 
Due to the minimal risk of adverse events while using the device, no safety objective is planned 
for this study, although adverse events (if any) will be recorded and reported. 
Anticipated Clinical Benefits 
The anticipated benefit of this device is to reduce the impact of headaches in patients with 
migraine headaches. 
Anticipated Risks  
There are no anticipated risks from the study or the device, since any potential discomfort 
experienced from use of the device would be mitigated by removal of the glasses. 
Study Design:  
This study is a prospective, multi-center, randomized, placebo-controlled, crossover trial. A 
total of 50 subjects will be randomized into one of two treatment groups in a one-to-one ratio. 
After three weeks, and following a one-week washout period, subjects will be given spectacles 
from the other treatment group. 
 
Subjects will be enrolled and followed at a maximum of three clinical sites. It is anticipated each 
clinical site will enroll 20 to 30 eligible study subjects who have provided written informed 
consent.  
 
Each principal investigator will be responsible for obtaining Institutional Review Board (IRB) 
approval prior to conducting this research. All potential subjects will be required to participate 
in an informed consent process and sign an IRB-approved written informed consent prior to 
study enrollment. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 7  
 
Patient Recruitment and Screening 
Suitable patients may be contacted and pre-screened prior to study commencement, but no 
study-related procedures are to be undertaken prior to IRB approval, eligibility confirmation, 
and informed consent. 
Enrollment Criteria 
The study population will be comprised of up to 50 subjects with a confirmed diagnosis of non-
chronic migraines. Subjects will be enrolled at up to three clinical sites. The frequency of 
migraine headache in females is roughly twice that in males and it is expected that the study 
population will reflect this gender disparity. Subjects must be geographically accessible 
throughout the study and be willing and able to attend required follow-up appointments.  
 
Candidates who express interest in study participation will be evaluated for enrollment based 
upon the following inclusion/exclusion criteria and will be offered informed consent. 
Inclusion Criteria: 
1. Patient is 18 years or older  
2. Patient is willing and able to provide written informed consent 
3. Patient is willing and able to complete all scheduled study visits 
4. Diagnosis of migraine, based on the following primary headache characteristics (based 
on the Revised International Headache Society criteria for migraine headache provided 
in Appendix A): 
A. At least 5 attacks fulfilling criteria B-D 
B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) 
C. Headache has at least two of the following characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (eg, walking or 
climbing stairs) 
D. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not attributed to another disorder 
Exclusion Criteria: 
1. Patients with other light sensitive conditions, such as iritis.  
2. Patients who have less than 4 headache days per month 
3. Patients who have chronic daily headaches.  
4. Patients who have had any change in their migraine treatment within the 4 weeks prior 
to the trial onset. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 8  
 
For the purposes of this study, patients will be considered enrolled (study subjects) following 
informed consent. 
Study Procedures 
 
Visit 1: 
At the enrollment visit, each subject will complete an initial/baseline HIT-6 inventory. They will 
then be randomized to receive spectacles having either the optical filter or a conventional tint. 
A randomized permuted block randomization will be employed.  
 
All spectacles will have the same overall optical density across the visible spectrum. This 
statement means that all study eyewear will appear to have the same amount of “darkness” to 
the subject. Subjects will be instructed to use the spectacles for three weeks. They will be 
instructed to put the spectacles on at the first signs or symptoms of their migraine attacks. This 
could be their usual aura, or the first signs of their headache commencing, and to keep the 
spectacles on until their headache has resolved. 
 
The study spectacles will be fitted with “wear over” frames that can be worn easily by study 
subjects who wear no corrective lenses, those that wear contacts, or those that normally wear 
corrective prescription lenses.   
 
Visit 2 (3 weeks ± 2 days): 
After three weeks they will return to the study site to complete the HIT-6 inventory and turn in 
their glasses. They will then undergo a washout period for 7 days. During the washout period 
subjects will have no access to study glasses, but will be expected to take their current migraine 
medications as needed/prescribed.  
 
Visit 3 (4 weeks ±2 days): 
After the washout period, subjects will return to the study site to receive new spectacles from 
the opposite treatment group, complete another HIT-6 inventory and then repeat the three 
week treatment period with the other lenses.  
 
Visit 4 (7 weeks ± 3 days): 
After the second treatment period, the subjects will return to the study site to turn in their 
spectacles and complete the final HIT-6 inventory. 
Patient Reported Outcome Data 
Subjects will be asked to complete the 6-item Headache Impact Test (HIT-6TM) inventory at 
baseline, week 3, week 4 and week 7. A copy of the HIT-6 TM is attached. Subjects will also be 
asking to keep daily diaries throughout the 8-week study detailing the frequency and severity of 
their headaches, a numerical pain score of their headaches, and their need for abortive 
medications in addition to the use of the spectacles.  
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 9  
 
Study coordinators will contact subjects once per week to insure they are completing their 
diaries and wearing their study-related spectacles. These weekly contacts will also enable 
coordinators to identify and address any barriers to adherence with the protocol. These 
contacts will help maximize retention and minimize loss to follow-up.  
Patient Withdrawal or Termination 
Study participants can choose to withdraw from participation in the study at any time during 
the process for any reason upon request. Additionally, subjects may be removed from the study 
at any point if the Investigator determines that the patient should be discontinued. 
Standard of Care vs. Research-Related Procedures:   
All procedures are research-related. 
Study Oversight 
Safety Committees  
This protocol does not pose any significant risk to subjects. Third-party safety committees (i.e., 
clinical events committees or data safety and monitoring boards) are not included. 
Study Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with federal regulations, agreements with the sponsor, the 
currently approved protocol, and with any requirements imposed by the IRB. 
 
1. Site monitoring will be performed by a third party CRO working on behalf of Avulux, Inc. 
2. Monitors will be qualified by training and experience to monitor the study. 
3. A Clinical Monitoring Plan (CMP) will be developed to establish the plan for study oversight.  
4. On-site monitoring is anticipated throughout the course of the study. 
5. 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 
Statistical Methods, Data Analysis and Interpretation 
Preliminary Analyses 
Baseline characteristics will be summarized by randomized treatment group with standardized 
differences between treatment groups used to assess the balance of patient characteristics 
between the two groups. Univariate summaries will also be performed at baseline and follow-
up for the primary and secondary outcome variables. If quantitative outcome variables exhibit 
substantial skewness, transformations may be sought to better approximate normality.  
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 10  
 
Primary Outcome 
The primary outcome measure is the HIT-6 Total Score. Additionally, we will focus on the first 
two questions of the HIT-6 which relate specifically to the severity of the migraine and its effect 
on activities of daily living.  
 
Required Sample Size 
In a preceding crossover trial, the pooled cross-sectional SD for the follow-up HIT values across 
the two periods was 7.60. Assuming a SD in the HIT-6 score of 7.6 points, and allowing for 10% 
loss-to-follow-up, 50 randomized crossover subjects  will provide 80% power with 2-sided 
α=0.05 to detect a mean difference in HIT score of 3.5 points. The effect size of 3.5 points is just 
under half the SD of 7.6 points assumed in our power calculations, and thus represents a 
moderate effect size.    
Secondary Outcome 
To measure effects on the number and severity of headaches, we will use the subjects’ daily 
diaries to count the number of days with headache that either a) made activity difficult, b) 
caused activity changes, or c) caused patient to go to bed. We will then compare the proportion 
of days with headaches that met one of these criteria for the 4-week baseline period and the 3-
week intervention. 
Exploratory Outcomes 
1. Proportion of subjects who were able to move out of the “very severe impact” category 
of the HIT-6 during the 3-week intervention. 
2. Proportion of patients who experienced at least a 5-point improvement in their HIT-6 
score during the 3-week intervention. 
3. Proportion of days with headaches which lead to use of medications to control the 
headache over the 3-week intervention. 
4. Proportion of days with light sensitivity over the 3-week intervention. 
5. Average Number of Hours Slept over the 3-week intervention. 
Analysis Plan for Secondary and Exploratory Outcomes 
Based on the initial descriptive summaries, each of the above secondary outcomes will be 
classified into one of the following categories: 
 
a) Numeric outcomes which are approximately normally distributed. 
b) Numeric outcomes which can be transformed to approximate normal distributions.  
c) Numeric outcomes which deviate substantially from normality and will be analyzed non-
parametrically. 
d) Numeric outcomes with substantial floor or ceiling effects that will be analyzed as 
dichotomous outcomes. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 11  
 
Numeric outcomes that can be transformed to approximate normality. All the secondary and 
exploratory outcomes assigned to categories (a) or (b) will be analyzed using analyses of 
covariance (ANCOVAs) to compare the outcomes between the treatment and control groups 
after controlling for the corresponding outcomes during the baseline phase of the study.  
 
Nonparametric Analyses. Secondary outcomes assigned to category (c) will be analyzed by 
comparing the changes from baseline to the 4-week follow-up assessment between the 
treatment groups using Wilxocon rank sums tests.  
 
Binary Outcomes. Outcomes assigned to category (d) will be analyzed by applying exact Mantel-
Haenszel tests to compare the 4-week follow-up values between the treatment groups, with 
stratification for the baseline level of each outcome. Baseline levels will be stratified by tertiles.  
 
Multiple comparisons. Multiple comparisons. The secondary outcome will be compared 
between the randomized groups using a 2-sided α level of 0.05, without adjustment for 
multiple comparisons.  The exploratory outcomes will also be compared between the 
treatment groups using a 2-sided α level of 0.05, without adjustment for multiple comparisons. 
However, interpretation of results for the exploratory outcomes will take into account the risk 
of Type 1 errors resulting from multiple hypothesis tests.  
 
Missing Data. The analysis of the primary outcome as well as other outcomes using linear 
mixed effects models will be approximately unbiased so long as the pattern of missing data is 
missing at random, meaning that the probability that an outcome measurement is missing may 
depend on the values of other non-missing measurements, but not on the value of the missing 
measurement itself. Should the fraction of missing measurements for the primary outcome 
exceed 10%, sensitivity analyses will be performed in which multiple imputation is used to 
impute missing data.  
Control of Investigational Devices/Drugs:  
Avulux, Inc. will maintain ownership of all devices provided to sites for testing. Clinical sites are 
expected to ensure the device is stored securely, yet available to study staff authorized to 
dispense the devices to study subjects. At the end of the study, sites will be asked to return any 
and all received devices back to Avulux. 
 
All study lenses will be numbered and stored in a locked cabinet. Only authorized study staff 
will have access to spectacles. Devices will be tracked on provided inventory logs. 
 
Abbreviated Device Regulations for Nonsignificant Risk (NSR) Devices:  
Nonsignificant risk determination 
21 CFR 812.3 contains the following definition of “Significant risk device”: 
(m) Significant risk device means an investigational device that: 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 12  
 
(1) Is intended as an implant and presents a potential for serious risk to the health, 
safety, or welfare of a subject; 
(2) Is purported or represented to be for a use in supporting or sustaining human life 
and presents a potential for serious risk to the health, safety, or welfare of a subject; 
(3) Is for a use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health and presents a potential 
for serious risk to the health, safety, or welfare of a subject; or 
(4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a 
subject. 
The FDA guidance document concerning significant and nonsignificant risk assessments 
(“Information Sheet Guidance For IRBs, Clinical Investigators, and Sponsors Significant Risk and 
Nonsignificant Risk Medical Device Studies”; US Department of Health and Human Services, 
Food and Drug Administration; January 2006.) contains the following information: 
 
A. What is a Significant Risk Device Study?  
Under 21 CFR 812.3(m), an SR device means an investigational device that:  
Is intended as an implant and presents a potential for serious risk to the health, safety, or 
welfare of a subject;  
Is purported or represented to be for use supporting or sustaining human life and presents a 
potential for serious risk to the health, safety, or welfare of a subject;  
Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or 
otherwise preventing impairment of human health and presents a potential for serious risk to 
the health, safety, or welfare of a subject; or  
Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.  
 
B. What is a Nonsignificant Risk Device Study?  
An NSR device study is one that does not meet the definition for an SR device study. 
 
C. Who Decides Whether A Device Study is SR or NSR?  
Sponsors are responsible for making the initial risk determination and presenting it to the IRB. 
FDA is also available to help the sponsor, clinical investigator, and IRB in making the risk 
determination. 
 
X. EXAMPLES OF NSR AND SR DEVICES  
The following examples may help sponsors and IRBs in making SR and NSR determinations. The 
list includes many commonly studied medical devices. Inclusion of a device in the NSR list is not 
a final determination because the evaluation of risk must reflect the proposed use of a device in 
a study.  
A. Nonsignificant Risk Devices  
• Caries Removal Solution  
• Contact Lens Solutions intended for use directly in the eye (e.g., lubricating/rewetting 
solutions) using active ingredients or preservation systems with a history of prior 
ophthalmic/contact lens use or generally recognized as safe for ophthalmic use  

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 13  
 
• Conventional Gastroenterology and Urology Endoscopes and/or Accessories  
• Conventional General Hospital Catheters (long-term percutaneous, implanted, 
subcutaneous and intravascular)  
• Conventional Implantable Vascular Access Devices (Ports)  
• Conventional Laparoscopes, Culdoscopes, and Hysteroscopes  
• Daily Wear Contact Lenses and Associated Lens Care Products not intended for use 
directly in the eye (e.g., cleaners; disinfecting, rinsing and storage solutions)  
• Dental Filling Materials, Cushions or Pads made from traditional materials and designs  
• Denture Repair Kits and Realigners  
• Digital Mammography  
• Electroencephalography (e.g., new recording and analysis methods, enhanced 
diagnostic capabilities, measuring depth of anesthesia if anesthetic administration is not 
based on device output)  
• Externally Worn Monitors for Insulin Reactions  
• Functional Non-Invasive Electrical Neuromuscular Stimulators  
• General Biliary Catheters  
• General Urological Catheters (e.g., Foley and diagnostic catheters) for short term use (< 
28 days)  
• Jaundice Monitors for Infants  
• Low Power Lasers for treatment of pain  
• Magnetic Resonance Imaging (MRI) Devices within FDA specified parameters  
• Manual Image Guided Surgery  
• Menstrual Pads (Cotton or Rayon, only)  
• Menstrual Tampons (Cotton or Rayon, only)  
• Nonimplantable Electrical Incontinence Devices  
• Nonimplantable Male Reproductive Aids with no components that enter the vagina  
• Ob/Gyn Diagnostic Ultrasound within FDA approved parameters  
• Partial Ossicular Replacement Prosthesis (PORP)  
• Total Ossicular Replacement Prosthesis (TORP)  
• Transcutaneous Electric Nerve Stimulation (TENS) Devices for treatment of pain (except 
for chest pain/angina)  
• Ureteral Stents  
• Urethral Occlusion Device for less than 14 days  
• Wound Dressings, excluding absorbable hemostatic devices and dressings (also 
excluding Interactive Wound and Burn Dressings that aid or are intended to aid in the 
healing process)  
 
The Avulux study will follow abbreviated requirements from 21 CFR 812.2: 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 14  
 
(b) Abbreviated requirements. The following categories of investigations are considered to have 
approved applications for IDE's, unless FDA has notified a sponsor under 812.20(a) that 
approval of an application is required: 
(1) An investigation of a device other than a significant risk device, if the device is not a banned 
device and the sponsor: 
(i) Labels the device in accordance with 812.5; 
(ii) Obtains IRB approval of the investigation after presenting the reviewing IRB with a brief 
explanation of why the device is not a significant risk device, and maintains such approval; 
(iii) Ensures that each investigator participating in an investigation of the device obtains from 
each subject under the investigator's care, informed consent under part 50 and documents it, 
unless documentation is waived by an IRB under 56.109(c). 
(iv) Complies with the requirements of 812.46 with respect to monitoring investigations; 
(v) Maintains the records required under 812.140(b) (4) and (5) and makes the reports required 
under 812.150(b) (1) through (3) and (5) through (10); 
(vi) Ensures that participating investigators maintain the records required by 812.140(a)(3)(i) 
and make the reports required under 812.150(a) (1), (2), (5), and (7); and 
(vii) Complies with the prohibitions in 812.7 against promotion and other practices. 
 
 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 15  
 
References: 
Blackburn MK, Lamb RD, Digre KB, Smith AG et al. FL-41 tint improves blink frequency, light 
sensitivity, and functional limitations in patients with benign essential blepharospasm. 
Ophthalmology. 2009. 116:997-1001. 
Digre KB, Brennan KC. Shedding light on photophobia. J Neuroophthalmol 2012. 32:68-81. 
Evans RW, Seifert T, Kailasam J, Mathew NT. The use of questions to determine the presence of 
photophobia and phonophobia during migraine. Headache 2008;48:395-7. 
Good PA, Taylor RH, Mortimer MJ. The use of tinted glasses in childhood migraine. Headache. 
1991. 31:533-6. 
Güler AD, Ecker JL, Lall GS, et al. Melanopsin cells are the principal conduits for rod-cone input 
to non-image-forming vision. Nature. 2008. 453:102-5. 
Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsin-containing retinal ganglion cells: 
architecture, projections, and intrinsic photosensitivity. Science. 2002. 295:1065-70. 
Main A, Dowson A, Gross M. Photophobia and phonophobia in migraineurs between attacks. 
Headache 1997;37:492-5. 
Mure LS, Cornut PL, Rieux C, Drouyer E, Denis P, Gronfier C, Cooper HM. 
Melanopsin bistability: a fly's eye technology in the human retina. PLoS One. 2009. 4(6):e5991. 
Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism 
for exacerbation of headache by light. Nat Neurosci. 2010. 13:239-45. 
Stovner LJ, Zwart JA, Hagen K, Terwindt GM, Pascual J. Epidemiology of headache in Europe. Eur 
J Neurol 2006 13:333.345. 
Hoggan, RN, Subhash A et al. Thin-film optical notch filter spectacle coatings for the treatment 
of migraine and photophobia. J Clin Neurosci 2016 June 28: 71-76 
 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 16  
 
APPENDIX A: Revised International Headache Society criteria for migraine headache  
(Source: http://ihs-classification.org/en/02_klassifikation/05_anhang/01.05.01_anhang.html).  
 
1.1 Migraine without aura 
Description: 
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics of the 
headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine 
physical activity and association with nausea and/or photophobia and phonophobia 
Diagnostic criteria: 
F. 
At least 5 attacks1 fulfilling criteria B-D 
G. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)2;3;4 
H. Headache has at least two of the following characteristics: 
5. 
unilateral location5;6 
6. 
pulsating quality7 
7. 
moderate or severe pain intensity 
8. 
aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) 
I. 
During headache at least one of the following: 
1. 
nausea and/or vomiting 
2. 
photophobia and phonophobia8 
J. 
Not attributed to another disorder9 
 
Notes: 
1. 
Differentiating between 1.1 Migraine without aura and 2.1 Infrequent episodic tension-type 
headache may be difficult. Therefore at least 5 attacks are required. Individuals who otherwise 
meet criteria for 1.1 Migraine without aura but have had fewer than 5 attacks should be coded 
1.6.1 Probable migraine without aura. 
2. 
When the patient falls asleep during migraine and wakes up without it, duration of the attack is 
reckoned until the time of awakening. 
3. 
In children, attacks may last 1-72 hours (although the evidence for untreated durations of less than 
2 hours in children requires corroboration by prospective diary studies). 
4. 
When attacks occur on ≥15 days/month for >3 months, code as 1.1 Migraine without aura and 
as 1.5.1 Chronic migraine. 
5. 
Migraine headache is commonly bilateral in young children; an adult pattern of unilateral pain 
usually emerges in late adolescence or early adult life. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 17  
 
6. 
Migraine headache is usually frontotemporal. Occipital headache in children, whether unilateral or 
bilateral, is rare and calls for diagnostic caution; many cases are attributable to structural lesions. 
7. 
Pulsating means throbbing or varying with the heartbeat. 
8. 
In young children, photophobia and phonophobia may be inferred from their behaviour. 
9. 
9. History and physical and neurological examinations do not suggest any of the disorders listed in 
groups 5-12, or history and/or physical and/or neurological examinations do suggest such disorder 
but it is ruled out by appropriate investigations, or such disorder is present but attacks do not occur 
for the first time in close temporal relation to the disorder. 
 
1.2 Migraine with aura 
Description: 
Recurrent disorder manifesting in attacks of reversible focal neurological symptoms that usually 
develop gradually over 5-20 minutes and last for less than 60 minutes. Headache with the features 
of migraine without aura usually follows the aura symptoms. Less commonly, headache lacks 
migrainous features or is completely absent. 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criterion B 
B. Migraine aura fulfilling criteria B and C for one of the subforms 1.2.1-1.2.6 
C. Not attributed to another disorder1 
Note: 
1. History and physical and neurological examinations do not suggest any of the disorders listed in 
groups 5-12, or history and/or physical and/or neurological examinations do suggest such 
disorder but it is ruled out by appropriate investigations, or such disorder is present but attacks 
do not occur for the first time in close temporal relation to the disorder. 
Comments: 
The aura is the complex of neurological symptoms that occurs just before or at the onset of migraine 
headache. Most patients with migraine have exclusively attacks without aura. Many patients who 
have frequent attacks with aura also have attacks without aura (code as 1.2 Migraine with aura and 
1.1 Migraine without aura). 
Premonitory symptoms occur hours to a day or two before a migraine attack (with or without aura). 
They include various combinations of fatigue, difficulty in concentrating, neck stiffness, sensitivity to 
light or sound, nausea, blurred vision, yawning and pallor. The terms prodrome and warning 
symptoms gare best avoided because they are often mistakenly used to include aura. 
The majority of migraine auras are associated with headache fulfilling criteria for 1.1 Migraine 
without aura. For this reason the entity 1.2.1 Typical aura with migraine headache has been singled 
out below. Migraine aura is sometimes associated with a headache that does not fulfil criteria for 
migraine without aura and, in other cases, migraine aura may occur without headache. These two 
subforms are also now distinguished. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 18  
 
Aura with similar features has also been described in association with other well-defined headache 
types, including cluster headache; the relationships between aura and headache are not fully 
understood. 
Before or simultaneously with the onset of aura symptoms, regional cerebral blood flow is 
decreased in cortex corresponding to the clinically affected area and often including an even wider 
area. Blood flow reduction usually starts posteriorly and spreads anteriorly and is usually above the 
ischaemic threshold. After one to several hours, gradual transition into hyperaemia occurs in the 
same region. Cortical spreading depression of Leão has been implicated. 
Systematic studies have demonstrated that many patients with visual auras occasionally have 
symptoms in the extremities. Conversely patients with symptoms in the extremities virtually always 
also suffer visual aura symptoms. A distinction between migraine with visual aura and 
hemiparaesthetic migraine is probably artificial and therefore is not recognised in this classification. 
Patients with motor weakness are classified separately because of the dominantly inherited form, 
1.2.4 Familial hemiplegic migraine, and because of clinical differences. The genetic relationship 
between migraine with aura and familial hemiplegic migraine has not been established. 
The previously-defined syndromes migraine with prolonged aura and migraine with acute-onset 
aura have been abandoned. The great majority of patients with such attacks have other attacks that 
fulfil criteria for one of the subforms of 1.2 Migraine with aura and should be coded to that 
diagnosis. The rest should be coded to 1.6.2 Probable migraine with aura specifying the atypical 
feature (prolonged aura or acute-onset aura) in parenthesis. 
 
1.2.1 
Typical aura with migraine headache 
Description: 
Recurrent disorder manifesting in attacks of reversible focal neurological symptoms that usually 
develop gradually over 5-20 minutes and last for less than 60 minutes. Headache with the 
features of migraine without aura usually follows the aura symptoms. Less commonly, headache 
lacks migrainous features or is completely absent. 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criterion B 
B. Migraine aura fulfilling criteria B and C for one of the subforms 1.2.1-1.2.6 
C. Not attributed to another disorder1 
Note: 
History and physical and neurological examinations do not suggest any of the disorders listed in 
groups 5-12, or history and/or physical and/or neurological examinations do suggest such 
disorder but it is ruled out by appropriate investigations, or such disorder is present but attacks 
do not occur for the first time in close temporal relation to the disorder. 
Comments: 
The aura is the complex of neurological symptoms that occurs just before or at the onset of 
migraine headache. Most patients with migraine have exclusively attacks without aura. Many 
patients who have frequent attacks with aura also have attacks without aura (code as 
1.2 Migraine with aura and 1.1 Migraine without aura). 
Premonitory symptoms occur hours to a day or two before a migraine attack (with or without 
aura). They include various combinations of fatigue, difficulty in concentrating, neck stiffness, 
sensitivity to light or sound, nausea, blurred vision, yawning and pallor. The terms prodrome 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 19  
 
and warning symptoms gare best avoided because they are often mistakenly used to include 
aura. 
The majority of migraine auras are associated with headache fulfilling criteria for 1.1 Migraine 
without aura. For this reason the entity 1.2.1 Typical aura with migraine headache has been 
singled out below. Migraine aura is sometimes associated with a headache that does not fulfil 
criteria for migraine without aura and, in other cases, migraine aura may occur without 
headache. These two subforms are also now distinguished. 
Aura with similar features has also been described in association with other well-defined 
headache types, including cluster headache; the relationships between aura and headache are 
not fully understood. 
Before or simultaneously with the onset of aura symptoms, regional cerebral blood flow is 
decreased in cortex corresponding to the clinically affected area and often including an even 
wider area. Blood flow reduction usually starts posteriorly and spreads anteriorly and is usually 
above the ischaemic threshold. After one to several hours, gradual transition into hyperaemia 
occurs in the same region. Cortical spreading depression of Leão has been implicated. 
Systematic studies have demonstrated that many patients with visual auras occasionally have 
symptoms in the extremities. Conversely patients with symptoms in the extremities virtually 
always also suffer visual aura symptoms. A distinction between migraine with visual aura and 
hemiparaesthetic migraine is probably artificial and therefore is not recognised in this 
classification. Patients with motor weakness are classified separately because of the dominantly 
inherited form, 1.2.4 Familial hemiplegic migraine, and because of clinical differences. The 
genetic relationship between migraine with aura and familial hemiplegic migraine has not been 
established. 
The previously-defined syndromes migraine with prolonged aura and migraine with acute-
onset aura have been abandoned. The great majority of patients with such attacks have other 
attacks that fulfil criteria for one of the subforms of 1.2 Migraine with aura and should be coded 
to that diagnosis. The rest should be coded to 1.6.2 Probable migraine with aura specifying the 
atypical feature (prolonged aura or acute-onset aura) in parenthesis. 
1.2.2 
Typical aura with non-migraine headache 
Description: 
Typical aura consisting of visual and/or sensory and/or speech symptoms. Gradual development, 
duration no longer than one hour, a mix of positive and negative features and complete 
reversibility characterise the aura which is associated with a headache that does not fulfil 
criteria for 1.1 Migraine without aura. 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criteria B-D 
B. Aura consisting of at least one of the following, but no motor weakness: 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 20  
 
1. 
fully reversible visual symptoms including positive features (eg, flickering lights, spots or 
lines) and/or negative features (ie, loss of vision) 
2. 
fully reversible sensory symptoms including positive features (ie, pins and needles) and/or 
negative features (ie, numbness) 
3. 
fully reversible dysphasic speech disturbance 
C. At least two of the following: 
1. 
homonymous visual symptoms1 and/or unilateral sensory symptoms 
2. 
at least one aura symptom develops gradually over ≥5 minutes and/or different aura 
symptoms occur in succession over ≥5 minutes 
3. 
each symptom lasts ≥5 and ≤60 minutes 
D. Headache that does not fulfil criteria B-D for 1.1 Migraine without aurabegins during the aura 
or follows aura within 60 minutes 
E. 
Not attributed to another disorder2 
Notes: 
1. 
Additional loss or blurring of central vision may occur. 
2. 
History and physical and neurological examinations do not suggest any of the disorders listed in 
groups 5-12, or history and/or physical and/or neurological examinations do suggest such 
disorder but it is ruled out by appropriate investigations, or such disorder is present but attacks 
do not occur for the first time in close temporal relation to the disorder. 
Comment: 
In the absence of headache fulfilling criteria for 1.1 Migraine without aura, precise diagnosis of 
aura and its distinction from mimics that may signal serious disease (eg, transient ischaemic attack) 
become much more important. 
1.2.3 
Typical aura without headache 
Description: 
Typical aura consisting of visual and/or sensory symptoms with or without speech symptoms. 
Gradual development, duration no longer than one hour, a mix of positive and negative features 
and complete reversibility characterise the aura which is not associated with headache. 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criteria B-D 
B. Aura consisting of at least one of the following, with or without speech disturbance but no 
motor weakness: 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 21  
 
1. fully reversible visual symptoms including positive features (eg, flickering lights, spots or 
lines) and/or negative features (ie, loss of vision) 
2. fully reversible sensory symptoms including positive features (ie, pins and needles) 
and/or negative features (ie, numbness) 
C. At least two of the following: 
1. homonymous visual symptoms1 and/or unilateral sensory symptoms 
2. at least one aura symptom develops gradually over ≥5 minutes and/or different aura 
symptoms occur in succession over ≥5 minutes 
3. each symptom lasts ≥5 and ≤60 minutes 
D. Headache does not occur during aura nor follow aura within 60 minutes 
E. Not attributed to another disorder2 
Notes: 
1. Additional loss or blurring of central vision may occur. 
2. History and physical and neurological examinations do not suggest any of the disorders 
listed in groups 5-12, or history and/or physical and/or neurological examinations do 
suggest such disorder but it is ruled out by appropriate investigations, or such disorder is 
present but attacks do not occur for the first time in close temporal relation to the disorder. 
Comments: 
In some patients a typical aura is always followed by migraine headache, but many patients 
have, in addition, attacks with aura followed by non-migraine headache or even without 
headache. A small number of patients have 1.2.3 Typical aura without headache exclusively. 
More commonly, as patients with 1.2.1 Typical aura with migraine headache become older, 
their headache may lose migraine characteristics or disappear completely even though auras 
continue. Some individuals, primarily males, have 1.2.3 Typical aura without headache from 
onset. 
In the absence of headache fulfilling criteria for 1.1 Migraine without aura, precise diagnosis of 
aura and its distinction from mimics that may signal serious disease (eg, transient ischaemic 
attack) become much more important. This distinction may require investigation. Especially if 
aura begins after age 40, if negative features (eg, hemianopia) are predominant, or if aura is 
prolonged or very short, other causes should be ruled out. 
1.2.4 
Familial hemiplegic migraine (FHM) 
Description: 
Migraine with aura including motor weakness and at least one first- or second-degree relative 
has migraine aura including motor weakness. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 22  
 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criteria B and C 
B. Aura consisting of fully reversible motor weakness and at least one of the following: 
1. fully reversible visual symptoms including positive features (eg, flickering lights, spots or 
lines) and/or negative features (ie, loss of vision) 
2. fully reversible sensory symptoms including positive features (ie, pins and needles) 
and/or negative features (ie, numbness) 
3. fully reversible dysphasic speech disturbance 
C. At least two of the following: 
1. at least one aura symptom develops gradually over ≥5 minutes and/or different aura 
symptoms occur in succession over ≥5 minutes 
2. each aura symptom lasts ≥5 minutes and < 24 hours 
3. headache fulfilling criteria B-D for 1.1 Migraine without aurabegins during the aura or 
follows onset of aura within 60 minutes 
D. At least one first- or second-degree relative has had attacks fulfilling these criteria A-E 
E. Not attributed to another disorder1 
Note: 
1. History and physical and neurological examinations do not suggest any of the disorders 
listed in groups 5-12, or history and/or physical and/or neurological examinations do 
suggest such disorder but it is ruled out by appropriate investigations, or such disorder is 
present but attacks do not occur for the first time in close temporal relation to the disorder. 
Comments: 
It may be difficult to distinguish weakness from sensory loss. 
New genetic data have allowed a more precise definition of FHM than previously. Specific 
genetic subtypes of 1.2.4 Familial hemiplegic migraine have been identified: in FHM1 there are 
mutations in the CACNA1A gene on chromosome 19, and in FHM2 mutations occur in the 
ATP1A2 gene on chromosome 1. If genetic testing is done, the genetic subtype should be 
specified parenthetically. 
It has been shown that FHM1 very often has basilar-type symptoms in addition to the typical 
aura symptoms and that headache is virtually always present. During FHM1 attacks, 
disturbances of consciousness (sometimes including coma), fever, CSF pleocytosis and confusion 
can occur. FHM1 attacks can be triggered by (mild) head trauma. In approximately 50% of FHM1 
families, chronic progressive cerebellar ataxia occurs independently of the migraine attacks. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 23  
 
FHM is very often mistaken for epilepsy, and (unsuccessfully) treated as such. 
1.2.5 
Sporadic hemiplegic migraine 
Description: 
Migraine with aura including motor weakness but no first- or second-degree relative has aura 
including motor weakness. 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criteria B and C 
B. Aura consisting of fully reversible motor weakness and at least one of the following: 
1. fully reversible visual symptoms including positive features (eg, flickering lights, spots or 
lines) and/or negative features (ie, loss of vision) 
2. fully reversible sensory symptoms including positive features (ie, pins and needles) 
and/or negative features (ie, numbness) 
3. fully reversible dysphasic speech disturbance 
C. At least two of the following: 
1. at least one aura symptom develops gradually over ≥5 minutes and/or different aura 
symptoms occur in succession over ≥5 minutes 
2. each aura symptom lasts ≥5 minutes and <24 hours 
3. headache fulfilling criteria B-D for 1.1 Migraine without aura begins during the aura or 
follows onset of aura within 60 minutes 
D. No first- or second-degree relative has attacks fulfilling these criteria A-E 
E. Not attributed to another disorder1 
Note: 
1. History and physical and neurological examinations do not suggest any of the disorders 
listed in groups 5-12, or history and/or physical and/or neurological examinations do 
suggest such disorder but it is ruled out by appropriate investigations, or such disorder is 
present but attacks do not occur for the first time in close temporal relation to the disorder. 
Comments: 
Epidemiological studies have shown that sporadic cases occur with approximately the same 
prevalence as familial cases. The attacks have the same clinical characteristics as those in 
1.2.4 Familial hemiplegic migraine. 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 24  
 
Sporadic cases always require neuroimaging and other tests to rule out other cause. A lumbar 
puncture is also necessary to rule out pseudomigraine with temporary neurological symptoms 
and lymphocytic pleocytosis. This condition is more prevalent in males and often associated 
with transient hemiparesis and aphasia. 
1.2.6 
Basilar-type migraine 
Description: 
Migraine with aura symptoms clearly originating from the brainstem and/or from both 
hemispheres simultaneously affected, but no motor weakness. 
Diagnostic criteria: 
A. At least 2 attacks fulfilling criteria B-D 
B. Aura consisting of at least two of the following fully reversible symptoms, but no motor 
weakness: 
1. dysarthria 
2. vertigo 
3. tinnitus 
4. hypacusia 
5. diplopia 
6. visual symptoms simultaneously in both temporal and nasal fields of both eyes 
7. ataxia 
8. decreased level of consciousness 
9. simultaneously bilateral paraesthesias 
C. At least one of the following: 
1. at least one aura symptom develops gradually over ≥5 minutes and/or different aura 
symptoms occur in succession over ≥5 minutes 
2. each aura symptom lasts ≥5 and ≤60 minutes 
D. Headache fulfilling criteria B-D for 1.1 Migraine without aura begins during the aura or 
follows aura within 60 minutes 
E. Not attributed to another disorder1 
Note: 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 25  
 
1. History and physical and neurological examinations do not suggest any of the disorders 
listed in groups 5-12, or history and/or physical and/or neurological examinations do 
suggest such disorder but it is ruled out by appropriate investigations, or such disorder is 
present but attacks do not occur for the first time in close temporal relation to the disorder. 
Comments: 
Basilar-type attacks are mostly seen in young adults. Many patients who have basilar-type 
attacks also report attacks with typical aura (code for both disorders). 
If motor weakness is present, code as 1.2.4 Familial hemiplegic migraine or 1.2.5 Sporadic 
hemiplegic migraine. Patients with 1.2.4 Familial hemiplegic migraine have basilar-type 
symptoms in 60% of cases. Therefore, 1.2.6 Basilar-type migraine should be diagnosed only 
when no motor weakness occurs. 
Many of the symptoms listed under criterion B are subject to misinterpretation as they may 
occur with anxiety and hyperventilation. 
Originally the terms basilar artery migraine or basilar migraine were used but, since 
involvement of the basilar artery territory is uncertain (ie,the disturbance may be 
bihemispheric), the term basilar-type migraine is preferred. 
 
 
 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 26  
 
APPENDIX B: HEADACHE IMPACT TEST (HIT-6) 
 
 

Avulux 
Optical Treatment of Migraines Clinical Study 
Version 1.0 
Page 27