A Prospective, Double-blind, Sham-controlled, Randomized Clinical Trial to Assess the Safety and Efficacy of the Mi-Helper Device for Acute Treatment of Migraine in an At Home Setting.
Phase: NA
Conditions: Migraine With or Without Aura, Migraine, Migraine Headache
Sponsor: Mi-Helper, Inc.

 
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PROTOCOL 
A prospective, double-blind, sham-controlled, randomized clinical trial to assess 
the safety and efficacy of the mi-helper device for acute treatment of migraine in 
an at home setting 
Short Title:  
  
Cooling to Alleviate Migraine #3 (CALM-3) 
Protocol No.: 
  
COT-004  
Test Article: 
  
Mi-Helper Device 
Sponsor: 
  
Mi-Helper Inc. 
 
  
101 West Dickman St, Suite 1050B 
 
  
Baltimore, MD, 21230 
Phase of Study: 
 
 
N/A 
 
Principal Investigator:  
Jessica Ailani, MD 
Study Design: 
 
A prospective, double-blind, sham-controlled, randomized  
study 
Country of Implementation: United States 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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INVESTIGATOR’S SIGNATURE PAGE 
 
Protocol Number: COT-004  
Version: 3.0 
Date: 27 May 2025 
 
 
INVESTIGATOR’S SIGNATURE 
 
I have read the protocol specified above and agree to participate in and comply with the 
procedures, as outlined herein for the conduct of this clinical trial.  I also agree to comply with 
the applicable US Food and Drug Administration (FDA) regulations, local regulations as well 
as Investigational Review Board (IRB) requirements for testing on human participants.  I agree 
to ensure that the requirements for obtaining informed consent are met. 
 
 
___________________________________________________  
________________ 
Investigator’s Signature  
 
 
 
 
          Date 
 
 
 
______ __________________________ 
Printed Name 
 
 
 
 
 
 
 
 
 

 
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STUDY TEAM INFORMATION 
Sponsor:  
 
 
Mi-Helper Inc. 
 
 
 
 
101 West Dickman St, Suite 1050B 
 
 
 
 
Baltimore, MD, 21230 
Sponsor  
Project Manager:  
Joy Holland 
 
 
 
 
T: 570-228-8140 
 
 
 
 
E: jholland@cooltechcorp.com 
 
Principal Investigator:  Jessica Ailani, MD 
 
 
 
 
T:  703-288-6931 
 
 
 
 
E: jessica.ailani@gunet.georgetown.edu 
 
CRO:   
 
 
SPRIM PRO  
274 E. Eau Gallie Blvd., #361 
Indian Harbour Beach, FL 32937 
 
Medical Monitor:  
MaryAnn Mays, MD 
 
 
 
 
T: +1-216-312-4044 
 
 
 
 
E:  maysm@ccf.org 
 
CRO Project Manager: 
Molly Moore 
 
 
 
 
T: 412-527-6765 
 
 
 
 
E: molly.moore@sprim.net 
 
 

 
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AMENDMENTS AND SUMMARY OF CHANGES 
Document History 
DOCUMENT 
VERSION 
SUMMARY OF CHANGES 
Protocol  
1.0 
20-Dec-2024 
Original version.  
Amendment 1 
2.0 
03Feb2025  
Amendments include changes to the inclusion and exclusion criteria, 
addition of several secondary endpoints, updates to text for further 
clarity, and general administrative updates.   
Amendment 2 
3.0  
27 May 2025 
Amendments include, an update to exclusion criteria 14, removal of 
select study endpoints, addition of several exploratory endpoints 
,reordering of  existing study endpoints, redefinition of study 
populations and  additional descriptive text in section “11.Statistical 
Analysis”, and other updates to text for further description and clarity  
 
Amendment 1 
SECTION # & NAME 
DESCRIPTION OF CHANGE 
Title Page 
Removal of the word “episodic” from the study title. 
Section 2 Protocol Synopsis  
 
Section 4 Study Objectives and 
Endpoints 
Added new secondary efficacy endpoint (Sustained Pain Relief from 2 
to 24 hours post treatment) 
Section 2 Protocol Synopsis  
 
Section 4 Study Objectives and 
Endpoints 
Added definition of success criteria for secondary endpoint on 
participant’s global impression of acute treatment effect  
Section 2 Protocol Synopsis  
 
Section 4 Study Objectives and 
Endpoints 
 
Section 11.5.2 Secondary 
Endpoints 
Added new exploratory endpoint (Sustained Pain Relief (SPR) from 2 
to 48 hours post treatment) 
 
 
Section 2 Protocol Synopsis 
 
Section 11.5.2 Secondary 
Endpoints 
Added Most Bothersome Symptom (MBS) relief immediately post 
treatment and MBS freedom immediately post treatment as 
secondary endpoints.  
 
 
 
Section 2 Protocol Synopsis 
 
Section 11.5.2 Secondary 
Endpoints 
Added freedom from migraine associated symptoms (nausea, 
photophobia, phonophobia) immediately following treatment 
completion and at 2 hours post treatment completion as secondary 
endpoints.  
 
Section 2 Protocol Synopsis  
 
Inclusion criterion 1 updated to increase the upper age limit for 
participation 

 
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DESCRIPTION OF CHANGE 
Section 6.1 Inclusion Criteria 
 
Section 5 Study Design 
 
Original text: Age of 18 to 65 years, inclusive, of either sex at birth 
 
Revised text: Age of 18 to 70 years, inclusive, of either sex at birth 
Section 2 Protocol Synopsis  
 
Section 6.1 Inclusion Criteria 
 
Section 5 Study Design 
(Overview) 
Inclusion criterion 4 updated to remove the word “episodic,” and 
removed an erroneous word. 
 
Original text: Individual has had a diagnosis of episodic migraine with 
or without aura over for at least 1 year. 
 
Revised text: Individual has had a diagnosis of migraine with or 
without aura for at least 1 year. 
Section 2 Protocol Synopsis  
 
Section 6.1 Inclusion Criteria 
 
Removed inclusion criterion 6 requiring that “Individual has been 
prescribed at least one acute treatment (drug or device) for their 
migraines 
Section 2 Protocol Synopsis  
 
Section 6.2 Exclusion Criteria 
 
Exclusion criterion 4 updated to add exclusion for sphenopalatine 
ganglion (SPG) blocks 
 
Original text: Participant has received Botox treatment, barbiturates, 
nerve blocks or trigger point injections in the head or neck within the 
last 4 weeks of screening. 
 
Revised text: Participant has received Botox treatment, barbiturates, 
SPG block, nerve blocks or trigger point injections in the head or 
neck within the last 4 weeks of screening. 
Section 2 Protocol Synopsis  
 
Section 6.2 Exclusion Criteria 
 
Exclusion criterion 17 updated to exclude previous study 
participation for 3 months prior to screening instead of 6 months. 
 
Original text: Prospective participant has participated in a migraine 
study or any interventional clinical study within the 6 months prior to 
screening. 
 
Revised text: Participation in a migraine study or any interventional 
clinical study within the 3 months prior to screening. 
Section 2 Protocol Synopsis  
 
Section 6.2 Exclusion Criteria 
 
Removed exclusion criterion 18 “Participant does not take acute 
medications to relieve their migraine attacks or symptoms.” 
Section 5 Study Design (Run-In 
Procedures) 
 
Corrected the name of the Milliman health data platform  
Section 5 Study Design 
(Randomization Procedures) 
 
Updated qualifying migraine criteria to include types of rescue 
medications that should not be taken in the 48 hours prior to 
treatment 
 
Original text: Participant did not take any migraine rescue 
medications in the 48 hours prior to the migraine attack 
 

 
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Revised text: Participant did not take any migraine rescue 
medications in the 48 hours prior to the migraine attack, such as 
tripans, NSAIDs, or gepants used for acute treatment. 
 
Section 5 Study Design 
(Randomization Procedures) 
 
Section 9.1 Participant 
Completion and Withdrawal 
 
Updated number of days that a participant has to treat a qualifying 
migraine attack with the study device. 
 
Original text: Participants will have up to 45 days to complete the 
treatment session after receiving the device. 
 
Revised text: Participants will have up to 35 days to complete the 
treatment session after receiving the device. 
Section 7.1 Study Product 
Description 
Updated the weight of the Mi-Helper device for accuracy 
 
Original text: The Mi-Helper device is small and lightweight, weighing 
10 lbs. 
Revised text: The Mi-Helper device is small and lightweight, weighing 
7 lbs. 
Section 7.3 Study Product 
Handling, Storage, & 
Accountability 
Added language describing what to do if a subject needs a supply 
reshipment due to a device technical issue at the end of their 35 day 
treatment window. 
Section 11.2 Randomization 
Added language to indicate that randomization will be stratified 
based on sex at birth.  
 
Amendment 2 
SECTION # & NAME 
DESCRIPTION OF CHANGE 
2. Protocol Synopsis 
4. Study Objectives and 
Endpoints  
 
Addition of the following exploratory endpoints: 
 
• 
Use of rescue medication before 2 hours post treatment 
completion. 
• 
Pain freedom (PF) at immediately post-treatment 
completion (defined as reduction in headache severity 
from mild/moderate/severe pain at baseline to no pain 
immediately after treatment completion).  
• 
Freedom from MBS immediately following treatment 
completion  
 
 

 
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DESCRIPTION OF CHANGE 
2. Protocol Synopsis 
4. Study Objectives and 
Endpoints  
 
Removal of the Following secondary endpoint: 
 
Tolerability of the Mi-Helper device based on percent of 
subjects to who fail to complete the full treatment session due 
to discomfort 
 
 
Removal of the fFollowing secondary objective: 
 
To assess the tolerability of the Mi-Helper device, based on the 
percentage of participants who fail to complete a full treatment 
session 
 
 
 
2. Protocol Synopsis 
4. Study Objectives and 
Endpoints  
 
Removal of the following exploratory endpoint: 
 
To assess whether blinding was maintained from a participant’s 
perspective  
 
Removal of the following exploratory objective: 
 
Participants belief of which treatment is received( blinding 
assessment) 
 
2. Protocol Synopsis 
4. Study Objectives and 
Endpoints  
11. Statistical Analysis 
Reordering of remaining Secondary and Exploratory Endpoints 
and Objectives to align with FDA Guidance on Multiplicity of 
endpoints 
1. List of Abbreviations 
Addition of PGIC( Patient Global Impression of Change) 
 
2. Protocol Synopsis  
6. Study Population 
 
Removal of conditions for Exclusion Criterion 14: 
 
Original Text: Participant with severe uncontrolled psychiatric 
conditions (such as major depressive episode, bipolar disorder, 
major depressive disorder, schizophrenia), dementia, or 
significant neurological disorders (other than migraine) that, in 
the Investigator’s opinion, might interfere with study 
assessments. 
 
Revised Text: Participant with severe uncontrolled psychiatric 
conditions or significant neurological disorders (other than 
migraine) that, in the Investigator’s opinion, might interfere with 
study assessments. 
 

 
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DESCRIPTION OF CHANGE 
5. Study Design 
Addition of clarifying text in overview 
 
Original Text: Blinding for this study will be applied to the PI 
and the study team. 
 
Revised Text: Treatment Assignment Blinding for this study will 
be applied to the PI and the study team. 
5. Study Design 
Modification of text explaining Run-In Procedures 
 
Original Text: If the subject passes the e-Diary, the Study Team 
will confirm their migraine diagnosis using the Milliman IRIX 
platform. If diagnosis history cannot be retrieved through IRIX, 
the participant will have the opportunity to supply evidence of 
their migraine diagnosis themselves. 
 
 
Revised Text: During the run in period ,the Study Team  use the 
Milliman IRIX platform to confirm a diagnosis of migraine and 
review additional eligibility criteria.... If the subject is unable to 
provide evidence of diagnosis, they will be unable to continue 
in the study. 
 
5. Study design 
 
Modification of Descriptive text explaining randomization  
procedures to include investigator review: 
 
Original text:  Once a participant meets all eligibility criteria 
they will be randomized, and the device shipment will occur 
thereafter. Participants will need to watch a video on how to set-
up and use the Mi-Helper device. Once the training is 
completed, the participant will be able to review the study 
training video at any time within the Study App. 
 
Revised Text: 
 
If the participant’s migraine e-diary and diagnosis confirmation 
are sufficient for enrollment, the virtual study team will conduct 
the end of run in call to review information submitted during 
screening and run-in period. The participant record will then be 
reviewed by an Investigator and, if eligible, will be randomized; 
the device shipment will occur thereafter.  
When the device kit is received, the participant will need to watch 
a series of videos on how to set-up and use the Mi-Helper device. 
Once the training is completed, they will complete a 

 
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comprehension quiz.  The participant will be able to review the 
study training video at any time within the Study App.   
 
10. Data management 
10.1 Data collection 
Additional Clarifying language added 
 
Original text: All data points except flow rate will be entered 
into the ClinicalOne EDC. 
 
Revised Text: . All data points except flow rate will be entered 
into the ClinicalOne EDC by an unblinded study team member. 
10.2 Data Handling 
Removal of WHO drug coding 
 
Original text: AEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA).) and any concomitant 
medications terms (if applicable) using a validated medication 
dictionary, WHODrug. 
 
Revised text: AEs will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA). 
 
11. Statistical Analysis 
 
11.2 Randomization 
Updated text to indicate that randomization will be stratified by 
gender instead of sex at birth 
 
Original Text: Subjects will be randomized in a 1:1 fashion, with 
stratification for sex at birth  . 
 
Revised Text: Subjects will be randomized in a 1:1 fashion, with 
stratification for gender. 
11.3 Populations for analyses  
Removal of Safety Population and Modification to Per 
Protocol(PP) Population: 
 
 
Original Text: Per Protocol (PP) Population – all randomized 
participants who do not have a major protocol deviation related 
to primary endpoint(s) and complete the treatment in 
compliance with the protocol, with group assignment as 
treated, and have no use of rescue medication within 2 hours 
post treatment who complete the primary endpoint(s) within the 
protocol-specified window, have completed full administration 
of treatment according to device data or subject reported 
completion of treatment if device data is not available, whose 
devices demonstrate adequate randomization (i.e. flow rate 
matches designated treatment group per randomization 

 
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schema), have no use of rescue medication within 2 hours prior 
to treatment, and have no use of rescue medication within 2 
hours post treatment. 
 
 
Revised Text: Per Protocol (PP) Population – all participants in 
the mITT population who do not have a major protocol 
deviation related to primary endpoint and complete the 
treatment in compliance with the protocol, with group 
assignment as treated, and have no use of rescue medication 
within 2 hours post treatment. 
 
11.3 Populations for Analyses 
Modified populations for safety, efficacy, and sensitivity analyses 
 
Original Text: Primary efficacy analyses will be performed on 
the mITT and PP Populations. Secondary and exploratory 
analyses will be performed on the mITT population. Safety 
analyses will be performed on the safety population 
 
Revised Text: The ITT analysis set will serve as the main analysis 
set for all safety evaluations. 
The mITT analysis set will be the primary population used for 
efficacy analyses in this study.  
The primary and secondary efficacy assessments will also be 
performed on the PP and the ITT analysis sets as a sensitivity 
analysis 
 
 
 

 
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Contents 
1. 
LIST OF ABBREVIATIONS..................................................................................... 13 
2. 
PROTOCOL SYNOPSIS ........................................................................................ 14 
2.1 
Table 1: Schedule of Events ................................................................................................. 20 
3. 
INTRODUCTION AND BACKGROUND ................................................................. 22 
3.1 
Study Rationale ...................................................................................................................... 22 
3.2 
Background ............................................................................................................................ 23 
3.3 
Risk/Benefit Assessment ....................................................................................................... 26 
3.3.1 
Known Potential Risks ................................................................................................................. 26 
3.3.2 
Known Potential Benefits............................................................................................................ 26 
3.3.3 
Assessment of Potential Risks and Benefits .............................................................................. 27 
4. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 27 
5. 
STUDY DESIGN .................................................................................................... 29 
6. 
STUDY POPULATION ........................................................................................... 32 
6.1 
Inclusion Criteria .................................................................................................................... 32 
6.2 
Exclusion Criteria ................................................................................................................... 32 
6.3 
Screen Failures....................................................................................................................... 33 
6.4 
Recruitment and Retention................................................................................................... 33 
7. 
STUDY INTERVENTION ........................................................................................ 34 
7.1 
Study Product Description ................................................................................................... 34 
7.1.1 
Test and Sham Device Description ........................................................................................... 34 
7.1.2 
Formulation, Appearance, Packaging, & Labeling .................................................................. 35 
7.2 
Study Product Administration .............................................................................................. 38 
7.3 
Study Product Handling, Storage, & Accountability ......................................................... 38 
7.4 
Concomitant Diets, Treatments, and Medications ............................................................ 38 
8. 
SAFETY AND ADVERSE EVENTS MANAGEMENT ................................................. 39 
8.1 
Adverse Events ...................................................................................................................... 39 
8.1.1 
Definition of Adverse Events ...................................................................................................... 39 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................................. 39 
8.1.3 
Adverse Event Reporting ........................................................................................................... 39 
8.1.4 
Anticipated Adverse Events ....................................................................................................... 40 
8.1.5 
Adverse Event Severity and Causality Assessments ................................................................ 40 
8.1.6 
Unanticipated Problems ............................................................................................................. 41 

 
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8.1.7 
Serious Adverse Event Reporting and Follow-Up ................................................................... 42 
8.1.8 
Pregnancy Reporting .................................................................................................................. 43 
9. 
PARTICIPANT COMPLETION AND WITHDRAWAL ............................................... 43 
9.1 
Participant Completion and Withdrawal ............................................................................ 43 
10. 
DATA MANAGEMENT .......................................................................................... 43 
10.1 
Data Collection .................................................................................................................. 43 
10.2 
Data Handling .................................................................................................................... 44 
10.3 
Computerized Edit Checks ............................................................................................... 44 
10.4 
Audit Trail ........................................................................................................................... 44 
11. 
STATISTICAL ANALYSIS ....................................................................................... 44 
11.1 
Determination of Sample Size .......................................................................................... 44 
11.2 
Randomization ................................................................................................................... 45 
11.3 
Populations for Analyses................................................................................................... 45 
11.4 
General Considerations .................................................................................................... 45 
11.5 
Significance Level and Handling of Type I Error ............................................................ 46 
11.6 
Efficacy Analysis ................................................................................................................. 46 
11.6.1 
Primary Endpoint(s)..................................................................................................................... 46 
11.6.2 
Secondary Endpoint(s) ............................................................................................................... 47 
11.7 
Safety Analysis .................................................................................................................... 47 
11.8 
Exploratory Analysis .......................................................................................................... 47 
......................................................................................................................... Blinding Assessment
............................................................................................................................................................. 47 
11.9 ..................................................................................................................................................... 47 
12. 
QUALITY CONTROL AND ASSURANCE................................................................ 47 
12.1 
Acceptability of Case Report Forms (Source Documents) ........................................... 48 
12.2 
Modification of Protocol ................................................................................................... 48 
12.3 
Reporting Protocol Deviations ......................................................................................... 49 
13. 
ETHICS AND REGULATORY REQUIREMENTS ...................................................... 50 
13.1 
Institutional Review Board/Independent Ethics Committee ........................................ 50 
13.2 
Investigator Responsibilities ............................................................................................. 50 
13.3 
Informed Consent Process ............................................................................................... 51 

 
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14. 
STUDY CLOSURE ................................................................................................. 51 
15. 
PUBLICATION & DATA SHARING POLICY ............................................................ 51 
16. 
REFERENCES ....................................................................................................... 53 
17. 
APPENDICES ....................................................................................................... 54 
17.1 
Appendix 1: Device Packaging ........................................................................................ 54 
 
1. List of Abbreviations 
TERM 
DEFINITION 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
app 
Application 
CFR 
Code of Federal Regulations 
CPM 
Clinical Project Manager 
CRPS 
Complex Regional Pain Syndrome 
DMS 
Data Management System 
EC 
Ethics Committee 
ED 
Emergency department 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Forms 
eIC 
Electronic Informed Consent 
ePRO 
Electronic Patient Reported Outcomes 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
 
 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council of Harmonization  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
lbs 
Pounds 
LPM 
Liters per minute 
MBS 
Most bothersome symptom 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIH  
National Institutes of Health 
NSAID 
Non-steroidal anti-inflammatory drugs 
NSR 
Non-Significant Risk 
OTC 
Over the counter 
PF 
Pain Freedom 
PGIC 
Patient Global Impression of Change 
PI 
Principal Investigator 
PP 
Per Protocol 

 
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PR 
Pain Relief 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPF 
Sustained Pain Freedom 
SPR 
Sustained Pain Relief 
SPG 
Sphenopalatine ganglion 
USA 
United States of America 
VRS 
Verbal Rating Scale  
WHO 
World Health Organization  
woRM 
without Rescue Medication 
 
2. Protocol Synopsis 
Title 
A prospective, double-blind, sham-controlled, randomized clinical trial 
to assess the safety and efficacy of the Mi-Helper Device for acute 
treatment of  migraine in an at home setting. 
Short Title 
Cooling to Alleviate Migraine #3 (CALM-3) 
Clinical Study 
Type 
Non-Significant Risk (NSR) Device Study 
Product Name 
Mi-Helper Device 
Study Duration 
~7 months 
Country of 
Implementation 
USA 
 
Description of 
Sites 
One decentralized site 
Study Objectives 
Primary Objectives: 
• 
To determine the safety and efficacy of one dose of Mi-Helper 
therapy compared to sham for the acute treatment of a single 
migraine attack. 
 
Secondary Objectives: 
• 
To assess the tolerability of the Mi-Helper device, based on the 
percentage of participants who fail to complete the full 
treatment session. 
• 
To assess sustained pain freedom between 2 and 24 hours post 
treatment completion without the use of rescue medication.  

 
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• 
To determine the proportion of participants reporting pain relief 
after Mi-Helper therapy without the use of rescue medication. 
• 
To determine the effect of Mi-Helper therapy on the most 
bothersome symptom (MBS) other than headache post 
treatment completion. 
 
Exploratory Objectives: 
• 
To explore the use of rescue medication following a single 
therapeutic treatment. 
• 
To assess whether blinding was maintained from a participant’s 
perspective. 
• 
To assess sustained pain freedom and sustained pain relief from 
2 to 48 hours post treatment completion without the use of 
rescue medication.  
Study Endpoints 
Primary Efficacy Endpoint 
• 
Pain freedom (PF) at 2 hours post-treatment completion (defined as 
reduction in headache severity from mild/moderate/severe pain at 
baseline to no pain at 2 hours after treatment completion). Use of 
rescue medication prior to 2 hours post treatment completion will 
be considered a failure for this endpoint (i.e. patient will be 
assigned the status of no reduction). 
 
Safety Endpoint 
• 
Safety of the Mi-Helper device following study treatment, 
measured by the incidence of adverse events related to the 
study device for 48 hours post treatment completion. 
 
Secondary Efficacy Endpoints 
• 
Freedom from MBS at 2 hours post-treatment completion  
• 
Sustained Pain Freedom (SPF) from 2 to 24 hours after treatment 
completion (defined as pain freedom with no administration of 
rescue medication and with no recurrence of a 
mild/moderate/severe headache). 
• 
Pain relief (PR) at 2 hours post-treatment completion (defined as 
the reduction of severe or moderate pain at baseline to mild or 
no pain at 2 hours post treatment completion, or from mild pain 
at baseline to no pain at 2 hours after treatment completion). 
• 
Participants’ global impression of acute treatment effect, as 
measured by the Patient Global Impression of Change (PGIC), 
which utilizes a 7-point scale, where 1=very much improved to 
7=very much worse. A score of 1 or 2 will be considered a 
success. 

 
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Exploratory Endpoints 
• 
Use of rescue medication before 2 hours post treatment 
completion. 
• 
Pain relief immediately post treatment completion (defined as 
the reduction of severe or moderate pain at baseline to mild or 
no pain, or from mild pain at baseline to no pain immediately 
post treatment completion). 
• 
Sustained pain freedom (SPF) from 2 to 48 hours after the initial 
dose (defined as pain freedom with no administration of either 
rescue medication and with no recurrence of a 
mild/moderate/severe headache). 
• 
Use of rescue medication between 2-48 hours post-treatment 
completion. 
• 
Relief from MBS immediately following treatment completion 
and at 2 hours post-treatment completion (defined as severe or 
moderate at baseline to mild or none, or from mild at baseline 
to none). MBS may be nausea, photophobia, or phonophobia as 
defined by each participant at baseline.  
• 
Freedom from migraine associated symptoms (nausea, 
photophobia, and phonophobia) immediately following 
treatment completion and at 2 hours post-treatment completion.  
 
Study Population Male and Female participants, 18 to 70 years of age, inclusive, who 
have had a diagnosis of migraine (with or without aura) for at least 1 
year will be invited to participate in this study.  
Approximately 156 English-speaking participants will be recruited for 
this study. 
Participant 
Duration 
Participants will each receive a single treatment (active or sham 
[control]) and will be required to complete post-treatment assessments 
at scheduled timepoints.  
Description of 
Study 
Intervention 
The Mi-Helper Neuromodulation Device is intended for acute treatment 
of migraine, with or without aura, in adults. Mi-Helper has been 
designed for use in an at-home setting whenever the afflicted individual 
feels the onset of migraine-related head pain. The device delivers a 
controlled stream of dehumidified air into the nose. The air is mixed 
with a fine saline mist for added comfort and cooling efficiency. The 
device is lightweight and low-cost with an integrated hand-held 
nebulizer. 
Study 
Implementation 
Digital and social media advertisements approved by the Institutional 
Review Board (IRB) will be used to recruit participants. Participants who 

 
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complete the pre-screening questionnaire and are eligible to take part 
in the study will be sent a link via email to download the study app and 
complete the registration process. Adult participants who download 
the study app to their personal mobile smartphone devices and 
provide electronic Informed Consent (eIC) will be enrolled and 
randomized, if eligible. eIC will include acknowledgement that the 
participant will be using the supplied device for one treatment only and 
that they agree to return the device and associated equipment shortly 
after its use. 
 
A total of 156 participants will be randomized equally between two 
groups: 
• 
Group I (active treatment): 10 Liters per minute (LPM), 
dehumidified air, 15 minutes total 
• 
Group II (sham [control] treatment): 2 LPM, ambient air 
administered intermittently via Mi-Helper, 15 minutes total 
After randomization, the Mi-Helper device will be shipped to the 
participant’s address. Participants will need to confirm receipt of the 
device through the study app prior to continuing in the study.  
Participants will receive training on how to set up and use the Mi-Helper 
device and associated supplies, and appropriately complete all study-
related procedures, including completion of the migraine eDiary. 
The training will also instruct the participants that the device may only 
be used ‘once’ during a qualifying migraine attack. A qualifying 
migraine attack must meet the following criteria based on responses to 
the Baseline Questionnaire: 
• 
Migraine head pain is at least mild intensity (score of 1, 2, or 3 on 
the 4-point VRS) 
• 
Onset of migraine head pain was no more than one hour prior to 
treatment 
• 
Participant did not wake up with the migraine attack 
• 
Participant is not experiencing severe sinus congestion 
• 
Participant did not have migraine related pain in the 48 hours prior 
to the migraine attack 
• 
Participant did not take any migraine rescue medications in the 48 
hours prior to the migraine attack 
Inclusion Criteria 
Individuals must meet all the following criteria to be eligible to 
participate in the study: 
1. Age of 18 to 70 years, inclusive, of either sex at birth. 
2. Lives in the contiguous United States. 

 
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3. Self-reported to be able to read and understand English 
sufficiently to provide electronic Informed Consent. 
4. Documented Diagnosis of migraine with or without aura for at 
least 1 year. 
5. Individual experiences 2 to 8 migraine attacks per month 
documented via migraine eDiary during screening. 
6. Migraine onset before 50 years of age, self-reported during 
screening. 
7. Migraine preventive medication unchanged for 4 weeks prior to 
study enrollment. 
8. Stated willingness to comply with all study procedures and 
availability for the duration of the study. 
9. Individuals that own a functioning smartphone device, internet 
connection (Wi-Fi or data plan) and are willing to download the 
study app. 
Exclusion 
Criteria 
Individuals that meet any one of the following criteria will be excluded 
from the study: 
1. Participant has difficulty distinguishing his or her migraine 
attacks from other types of headaches such as tension, exertion, 
cluster, hormonal or sinus headaches. 
2. Participant has 15 or more headache days per month reported 
via migraine eDiary and during screening. 
3. Participant using any opioid medication at the time of screening. 
4. Participant has received Botox treatment, barbiturates, SPG 
block, nerve blocks or trigger point injections in the head or 
neck within the last 4 weeks of screening. 
5. Participant lives at an altitude of 2000 meters or more above sea 
level. 
6. Self-reported intolerance to intranasal therapy.  
7. Self-reported recurrent epistaxis or chronic rhinosinusitis. 
8. Self-reported sinus or intranasal surgery within the last 4 months 
of screening. 
9. Self-reported history of ‘complicated migraine or headaches’ 
(i.e., hemiplegic migraine, ophthalmoplegic migraine, 
migrainous infarction, basilar migraine, post-traumatic 
headaches, post-concussion syndrome). 
10. Known or suspected pregnancy as self-reported by the 
prospective participant at the time of screening. 
11. Prospective participant unable to fully understand the consent 
process and provide informed consent due to either language 
barriers or mental capacity. 
12. Self-reported diagnosis of alcohol or substance abuse disorder 
at the time of screening. 

 
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13. Participant with active chronic pain syndromes, such as 
fibromyalgia, chronic pelvic pain, or Complex Regional Pain 
Syndrome (CRPS); or other pain syndrome like trigeminal 
neuralgia. 
14. Participant with uncontrolled or severe psychiatric conditions or 
significant neurological disorders (other than migraine) that, in 
the Investigator’s opinion, might interfere with study 
assessments. 
15. Failure to adhere to or inability to complete Study App inputs 
and onboarding activities during the screening period. 
Participants who are not adherent during the screening period 
are not eligible for study entry. 
16. Participation in a previous clinical study with the Mi-Helper 
device. 
17. Participation in a migraine study or any other interventional 
clinical study within the 3 months prior to screening.  
18. Participant has an uncontrolled medical issue at the time of 
screening. 
19. Any condition for which transnasal air flow would be 
contraindicated, as determined by the Principal Investigator (PI).  

 
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2.1 
Table 1: Schedule of Events 
Study Phase 
PRE-SCREENING 
INFORMED 
CONSENT 
PROCEDURES 
SCREENING 
PROCEDURES 
RUN-IN 
PROCEDURES 
RANDOMIZATION 
PROCEDURES 
BASELINE 
PROCEDURES 
TREATMENT PROCEDURES 
END OF STUDY 
ADMINISTER TREATMENT (Day 0) 
Post-treatment  
(0 hours)  
+ 30 minutes 
Post-treatment 
(2 hours) 
± 30 minutes 
Post-
treatment 
(24 hours) 
± 1 hour 
 
 
Post-
treatment 
(48 hours) 
± 2 hours 
Event/Timeline 
 
~3 
weeks 
~1 
week 
~6 
weeks 
~1 
week 
Day 0 
Day 0 
Day 0 
Day 1 
Day 2 
 
Pre-screening 
questionnaire  
X 
 
 
 
 
 
 
 
 
 
 
Electronic Informed 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
Screening 
questionnaire  
 
 
X 
 
 
 
 
 
 
 
 
Medical History & 
Demographics 
 
 
X 
 
 
 
 
 
 
 
 
Concomitant 
medications review1 
 
 
X 
X 
 
Eligibility assessment 
 
 
X 
X1 
 
 
 
 
 
 
 
Training 
 
 
 
X2 
X3 
 
 
 
 
 
 
Migraine run-in eDiary 
(28 days) 
 
 
 
X 
 
 
 
 
 
 
 
Participant check-in  
 
 
 
X 
 
 
 
 
 
 
 
Eligibility confirmation 
 
 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
Device shipment 
 
 
 
 
X 
 
 
 
 
 
 
Head pain severity 
score3,4 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Most Bothersome 
Symptom3,4 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Nausea severity 
score3,4 
 
 
 
 
 
X 
X 
X 
X 
X 
 

 
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Photosensitivity 
severity score3,4 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Phonosensitivity 
severity score3,4 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Rescue medication 
use4,5 
 
 
 
 
 
 
X 
X 
X 
X 
 
Adverse Event review 
and evaluation 
 
 
 
 
 
X 
X 
 
Device tolerability and 
user experience 
questionnaire  
 
 
 
 
 
 
 
X 
X6 
 
 
Return of test article 
 
 
 
 
 
 
 
 
 
 
X 
1Eligibility Confirmation will include review of relevant medical records to confirm diagnosis of migraine in participants who pass the E-Diary. 
2Training will cover how to complete the migraine eDiary. 
3Training will cover set-up and use of the Mi-Helper Device. 
4Based on a 4-point Verbal Rating Scale (VRS). 
5Participants will be advised against using rescue medication until collection of the Migraine Symptom Questionnaire at 2 hours post-treatment, however, the 
use of rescue medication prior to 2 hours post-treatment will be captured as a treatment failure, and will be assigned a status of no reduction 
6Select user experience questions will be repeated as a part of 24-hour post-treatment assessment. 

 
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3. Introduction and Background 
3.1 
Study Rationale 
Migraine is a severely disabling neurologic condition and is the sixth most disabling disorder 
worldwide, affecting over a billion people. The majority of those with migraines experience 
them episodically, defined as less than 15 migraine days per month. Migraine can cause a 
significant reduction in quality of life as well as loss of productivity. The global economic 
burden of migraine is staggering at approximately $20 billion in the U.S. and $56 billion 
worldwide per year.    
Migraine affects significantly more women than men and is the leading cause of disability in 
people under fifty (Steiner, 2018). First-line treatment options are medications such as triptans 
and NSAIDs, which are associated with adverse effects, are contraindicated in those with 
cardiovascular issues, and put patients at risk for medication-overuse headache. In addition, 
more than 50% of people with chronic migraine discontinue or change their preventive 
treatment at some point due to its lack of efficacy or tolerability (Ford, 2017). Neuromodulation 
therapies that target the autonomic nervous system are gaining traction due to their safety 
profile and relative effectiveness.    
The prevalence of migraine in the U.S. is increasing, with 15% of the population suffering from 
either episodic or chronic migraine. Migraine is one of the most common reasons for 
emergency room visits. Despite treatment recommendations, opioids are still overprescribed 
for migraine patients. This is especially the case in emergency departments (EDs) where one 
study found that opioids are prescribed at over 50% of migraine ED visits (Minen, 2014). It is 
apparent that this phenomenon is contributing significantly to the growing opioid epidemic. 
The use of opioids in this population carries a high risk of ‘medication-overuse-headache’, 
when used more than 10 times/month, and can quickly lead to opioid dependency (Bigal, 
2008). Medication overuse is also the most common reason why episodic migraine transforms 
into chronic migraine. There is a need for non-invasive, drug-free therapies that can be 
administered quickly and in the comfort of one’s home. 
The pathophysiology of migraine is complex, not fully understood, and not within the scope of 
this study. There is evidence that the headache phase of migraine is caused by activation of 
nociceptors in the trigeminal ganglion (Puledda, 2017). The sphenopalatine ganglion (SPG), a 
large ganglion located behind the superior nasal turbinate, is closely associated with the 
trigeminal system (Robbins, 2016). Several studies have shown that intranasal SPG nerve block 
with lidocaine provides relief from acute migraine headaches (Maizels, 1999; Kudrow, 1995; 
Binfallah, 2018). Another possible mechanism is stimulation through the nasal cerebral 
pathway via olfactory epithelium. The Mi-Helper transnasal cooling device has the potential, 
using a simple non-invasive transnasal evaporative cooling process, to activate these (or other) 
mechanisms, providing pain and symptom relief reduction in patients with migraine.    

 
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The Mi-Helper device is a portable, transnasal in-home therapy that uses transnasal low flow 
dry air to cause local cooling of the nasopharynx due to evaporation of nasal mucosal water. 
The device also delivers a continuous mist of saline into the nose to aid in the evaporative 
cooling process, prevent nasal turbinate desiccation, and minimize discomfort to the patient. 
The hypothesis is that optimized transnasal cooling delivered through the Mi-Helper device 
will reduce the intensity of migraine headaches during an acute episode. More detail can be 
found in the Mi-Helper Investigator Brochure.   
This study evaluates the safety and efficacy of the Mi-Helper device for acute treatment of 
migraine in an at home setting. 
3.2 
Background 
Mi-Helper Device 
The Mi-Helper device is a non-invasive, drug-free, novel therapy that uses a patented process 
of dry air flow across the nasal turbinates to induce a phase change (evaporation) that extracts 
energy (thermodynamics) causing local cooling which modulates nerves associated with pain 
and other symptoms of migraine. The device delivers a controlled pressure and flow of dry 
room temperature air along with a nebulized saline mist for added comfort and evaporative 
efficiency. 
The Mi-Helper device works by cooling and inhibiting structures of the pterygopalatine fossa, 
including the sphenopalatine ganglion (SPG) and maxillary division of the trigeminal nerve 
(V2). These nerve pathways have a clinically proven association with migraine pain and other 
symptoms (Arslan et al, 2014; Kesserwani, 2021; Urits et al, 2020).  
Migraine prototype study 
A single-blind, randomized trial was conducted at the Johns Hopkins Bayview Hospital 
headache clinic in Baltimore, MD, to study potential therapies for migraine, centered on 
evaporative cooling (Shah, 2021). This study evaluated the safety and efficacy of four potential 
therapies consisting of different air mixtures flowing in the nose and out the mouth: (1) a flow 
of dry oxygen, (2) a flow of dry air, (3) a flow of humidified oxygen, and (4) a flow of humidified 
air (control). All four gases were warmed to 37°C and delivered through a face mask (not the 
Mi-helper device) with the study gases flowing in the nose and freely out of the mouth. The 
participants were awake and otherwise healthy, excluding their migraine symptoms. The 
objective of the study was to assess safety and the ability to reduce symptoms from migraine.  
Fifty-one (51) patients were enrolled in the study, of which 13 patients (mean age 49 years, 81% 
female) received humidified oxygen therapy and 9 patients (mean age 42 years, 82% female) 
received dry air therapy. Patients were randomized and blinded to their treatment group. 
There was significant pain relief at 2 hours post-treatment compared to baseline reported by 
patients who received dry air, dry oxygen, and humidified oxygen. Patients in the control group 
did not show significant pain relief from baseline to 2 hours post-treatment.    

 
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A two-way ANOVA was conducted to examine the effect of gas type and moisture content in 
reducing headache symptoms in migraine (pain score reduction). There was a statistically 
significant interaction between the effects of gas type and moisture content on the headache 
score reduction, F (1,47) = 10.471, p = 0.002. Simple main effects analysis showed that there 
were no significant differences between dry oxygen and dry air (p = 0.906), but there were 
statistically significant differences between these gases when they were humidified (p < 0.001).  
No adverse events were reported in this study. It was concluded that high flow dry air is safe 
and appears to be effective in treating acute migraine pain and associated symptoms.    
Migraine dose escalation study 
A dose escalation and tolerability study was completed using the CoolStat device, a 
predecessor to the Mi-Helper that was designed for in-clinic use, at the Johns Hopkins Bayview 
Hospital headache clinic in Baltimore, MD. Fifteen (15) participants experiencing migraine on 
the day of treatment were enrolled. Three air flow rates were tested, and tolerability and 
efficacy were assessed for increasing air flow rates: 24 LPM, 36 LPM and 48 LPM. Five (5) 
participants were tested at each flow rate, starting at the lowest flow rate (24 LPM). If the 
majority (3/5) of the participants in the lowest flow rate group tolerated the full 10-minute 
treatment, the next group would receive an incrementally higher flow rate. Air flow was 
delivered using a double nostril, nasal mask configuration.  
All the flow rates were found to be tolerable by study participants, with 13 of the 15 participants 
tolerating the full 10-minute treatment session. Although anecdotal (due to the small size of 
the study), participants also reported reductions in migraine symptoms, which appear to be 
related to flow, i.e., migraine symptoms reduced more with increased flow rates. 73% of the 15 
participants experienced pain relief immediately after treatment compared to baseline and 
53% of participants reported sustained pain relief at 2 hours post-treatment. 67% of 
participants reported that the benefit of the CoolStat treatment outweighed any discomfort 
they experienced during the treatment session and 73% said they would use the device again. 
60% of participants said that CoolStat works as well or better than their current rescue 
medication. The adverse events that occurred were all graded as mild and anticipated (stuffy 
nose, burning sensation during treatment session) and resolved on their own. There were no 
serious adverse events or unanticipated device effects. This study demonstrated that the 
CoolStat is safe and tolerable for use in patients with acute migraine attacks.   
Migraine in-clinic, double-blind, RCT 
A multi-center, double-blind, randomized study was conducted using the CoolStat device, a 
predecessor of the Mi-Helper designed for in-clinic use. The objectives of this study were to 
assess safety, tolerability, and determine the optimal dose of dehumidified, room temperature 
air for the acute treatment of migraine with or without aura. The primary endpoint was pain 
relief at 2 hours post-treatment. Secondary endpoints included tolerability, Most Bothersome 
Symptom (MBS) relief and pain freedom at 2 hours post-treatment. Participants were treated 

 
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at Atrium Health in Charlotte, NC, Mayo Clinic in Scottsdale, AZ, and Michigan State University 
in East Lansing, MI.  
Eighty-seven (87) participants were enrolled in this study and were instructed to return to the 
clinic when experiencing a migraine attack. Twenty-four (24) participants returned to the clinic 
and were randomized to flow rates of either 6 liters per minute (LPM), 18 LPM or 24 LPM. 
Participants were randomized in a 1:1:1 fashion. The length of treatment was 15 minutes. Air 
flow was delivered through a single nostril tube set configuration with a nebulizer that 
administered saline mist into the nasal turbinates.  
Eighty-eight percent of the 6 LPM group reported pain relief at 2 hours without rescue 
medication (woRM). 44% of the 6 LPM group reported pain freedom at 2 hours woRM. PR at 2 
hours woRM was reported by 44% and 50% in the 18 LPM and 24 LPM group, respectively. 
MBS relief was reported at 2 hours by 77% in the 6 LPM group. MBS relief at 2 hours was 
reported by 66% and 50% of the 18 LPM and 24 LPM groups, respectively. There were no 
adverse events in the 6 LPM group. No adverse events reported in the 18 LPM or 24 LPM 
groups were serious or severe. 11% of the 6 LPM group reported moderate intra-nasal 
discomfort during treatment. 33% percent and 83% of participants in the 18 LPM and 24 LPM 
groups, respectively, reported moderate or severe discomfort during treatment. There were 
no serious adverse events or unanticipated device adverse events. All adverse events reported 
in the study were anticipated and were graded as mild or moderate. No adverse events 
occurred in the 6 LPM group. The study was terminated due to insufficient participant accrual 
rate. This study demonstrated that transnasal cooling at lower flow rates is effective and 
tolerable for treating acute migraine attacks. 
Decentralized randomized, double-blind, sham-controlled dosing study with Mi-Helper 
A prospective, double-blind, sham-controlled, decentralized, randomized dosing study was 
conducted to evaluate the efficacy and safety of the Mi-Helper device in adult patients 18 to 65 
years of age with episodic migraine with or without aura. The study, deemed Non-significant 
Risk (NSR) by the Sterling Institutional Review Board, aimed to determine the most effective 
dose of Mi-Helper compared to sham treatment. The study included a 4-week e-diary run-in 
period for participant eligibility confirmation and compliance with protocol before 
randomization.  
A total of 172 participants were randomized to one of four treatment arms: three active arms 
with flow rates of 4, 6, and 10 LPM, and a sham arm. The primary endpoints were pain relief at 
2 hours post-treatment, safety (incidence of adverse events), and tolerability (completion of the 
full treatment session). The safety population included 137 participants, the modified intent-
to-treat (mITT) population included 128, and the per protocol (PP) population, which required 
full treatment compliance, included 74 participants.   
The study found that the 10 LPM dose was the most effective, with 71% of participants 
reporting pain relief at 2 hours post-treatment without the use of rescue medication, and 47% 
achieving complete pain freedom, compared to only 16% achieving pain freedom in the sham 

 
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group (p=0.0407). This statistically significant difference in pain freedom between the 10 LPM 
and sham groups supports further study of the winning Mi-Helper dose. A blinding index 
confirmed successful blinding across all study arms, including the sham group.  
At 24 hours post-treatment, 88% of participants in the 10 LPM group remained pain-free, with 
all but one subject maintaining pain freedom without rescue medication. No serious or 
unanticipated adverse device events were reported, and no participants discontinued 
treatment due to discomfort.  
Overall, 82% of participants indicated they would use the Mi-Helper device again outside the 
study, 53% felt the device worked as well or better than their current rescue medications, and 
100% rated the setup and use of the device as "very easy" or "easy."  
The study demonstrated that, of those who received a study intervention, the 10 LPM dose of 
Mi-Helper is the most effective for acute migraine treatment and is safe, well-tolerated, and 
easy to use, providing strong support for further clinical trials.  
This study aims to evaluate the safety and efficacy of the Mi-Helper device for acute treatment 
of a single migraine attack in an at home setting. 
 
3.3 
Risk/Benefit Assessment 
3.3.1 
Known Potential Risks 
Anticipated risks associated with the Mi-Helper device are temporary nasal discomfort, dry 
nose or mouth, and runny nose during device use. These risks are considered minimal, 
transient, and likely to resolve on their own.  
Participants will be trained in how to use the device.  Any potential risks from incorrect use have 
been mitigated as per the User Failure Modes Analysis in accordance with the ISO 14971 risk 
management process implemented by the Sponsor. 
Monitoring of study participants will provide scrutiny for unexpected outcomes and adverse 
effects.   
3.3.2 
Known Potential Benefits 
Transnasal neuromodulation therapy may reduce migraine pain and associated symptoms in 
people with acute migraine. The set-up and use of the Mi-Helper device is relatively simple, 
and the treatment provided is drug-free. Using the device for 15 minutes is expected to 
provide targeted relief from migraine symptoms. 

 
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3.3.3 
Assessment of Potential Risks and Benefits  
The risks to participants in this study are considered minimal. Participants will be awake and 
healthy and may stop the treatment session at any time simply by moving the handheld 
nebulizer away from their nose. The duration of the treatment is only 15 minutes. 
 
This is an investigational study which does not guarantee any direct benefit to the 
participants, but the proposed treatment may provide some relief of pain and symptoms of 
acute migraine. In the near term, this study may show the benefit of using a new device, the 
Mi-Helper, in an at-home setting, for treating migraine pain and associated symptoms using 
only a flow of dry, ambient air. These potential benefits are considered to outweigh the 
minimal risk associated with participation in this study. 
 
Participants will be advised of the potential risks and benefits associated with this study in the 
IRB approved ICF. 
 
4. Study Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To determine the safety and 
efficacy of one dose of Mi-Helper 
therapy compared to sham for the 
acute treatment of a single 
migraine attack. 
 
Primary Efficacy Endpoint 
Pain freedom (PF) at 2 hours post-treatment completion (defined as 
reduction in headache severity from mild/moderate/severe pain at 
baseline to no pain at 2 hours after treatment completion). Use of 
rescue medication prior to 2 hours post treatment completion will 
be considered a failure for this endpoint (i.e. patient will be assigned 
the status of no reduction). 
Safety Endpoint 
Safety of the Mi-Helper device following study treatment, measured 
by the incidence of adverse events related to the study device for 48 
hours post treatment completion 
 
 

 
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Secondary 
 
• 
To determine the effect of Mi-
Helper therapy on the most 
bothersome symptom (MBS) 
other than headache post 
treatment completion. 
• 
To assess sustained pain 
freedom and sustained pain 
relief from 2 to 24 hours post 
treatment completion without 
the use of rescue medication 
• 
To determine the proportion of 
participants reporting pain 
relief after Mi-Helper therapy 
without the use of rescue 
medication. 
• 
Freedom from MBS at 2 hours post treatment completion 
• 
Sustained Pain Freedom (SPF) from 2 to 24 hours after treatment 
completion (defined as pain freedom with no administration of 
rescue medication and with no recurrence of a 
mild/moderate/severe headache). 
• 
Pain relief (PR) at 2 hours post-treatment completion (defined as 
the reduction of severe or moderate pain at baseline to mild or 
no pain, or from mild pain at baseline to no pain at 2 hours post 
treatment completion). 
• 
Participants’ global impression of acute treatment effect, as 
measured by the Patient Global Impression of Change(PGIC), on 
which participants use a 7 point scale, where 1=very much 
improved to 7=very much worse. Scores of 1 or 2 will be 
considered successes. 
Exploratory  
 
• 
To explore the use of rescue 
medication following a single 
therapeutic treatment 
• 
To assess sustained pain 
freedom and sustained pain 
relief from 2 to 48 hours post 
treatment completion without 
the use of rescue medication 
 
• 
Use of rescue medication before 2 hours post treatment 
completion. 
• 
Pain relief immediately post treatment completion (defined as 
the reduction of severe or moderate pain at baseline to mild or 
no pain, or from mild pain at baseline to no pain immediately 
post treatment completion). 
• 
Sustained pain freedom (SPF) from 2 to 48 hours after the initial 
dose (defined as pain freedom with no administration of either 
rescue medication and with no recurrence of a 
mild/moderate/severe headache). 
• 
Use of rescue medication 2–48 post-treatment completion. 
• 
Relief from MBS immediately following treatment completion 
and at 2 hours post-treatment completion (from severe or 
moderate to mild or none, or from mild to none). MBS may be 
nausea, photophobia, or phonophobia as defined by each 
participant at baseline. 
• 
Freedom from migraine associated symptoms (nausea, 
photophobia, and phonophobia) immediately following 
treatment completion and at 2 hours post-treatment completion. 
 
 
 
 

 
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5. Study Design 
Overview 
 
This is a prospective, double-blind, sham-controlled, randomized clinical trial. This study aims 
to assess the efficacy and safety of the Mi-Helper transnasal neuromodulation device for acute 
treatment of migraine in an at home setting.  
 
Treatment Assignment Blinding for this study will be applied to the PI and the study team. The 
team members who are directly involved in the analysis of the study results, including the 
biostatistician, will also be blinded. Only the designated group of team members directly 
involved in overseeing the logistical and distribution aspects of the study products will be 
unblinded. As needed, the PI may be unblinded in case of an AE/SAE that may impact 
participant safety. If the unblinding occurs inadvertently or through PI’s need due to an AE/SAE 
impacting participant safety, that event will be noted as a protocol deviation. 
 
Adults aged 18 years to 70 years old ,inclusive, with a diagnosis of migraine (with or without 
aura) for at least one year will be recruited for this study. 
 
Recruitment & Pre-screening 
Digital and social media advertisements approved by the IRB will be used to recruit eligible 
participants. Participants that respond to the ad, complete the pre-screening questionnaire, 
and meet the study’s eligibility criteria will be sent a link via email to download the Study App 
and complete the registration process.  
Informed Consent Procedures (~3 weeks) 
Adult participants that download the Study App to their personal mobile smartphone devices, 
complete the registration process, and provide eIC will be enrolled, if eligible. The informed 
consent process will include a Health Insurance Portability and Accountability Act (HIPAA) 
Authorization form to allow the Study Team to obtain medical records documenting the 
subject’s diagnosis of migraine. If the subject does not agree to provide HIPAA authorization, 
they will be exited from the study. 
Screening Procedures (~1 week) 
After signing the informed consent, participants will be required to complete a screening 
questionnaire, medical history form, concomitant medications form, and demographic 
information. Participants that meet the eligibility criteria will then enter the run-in period. 
Run-in Procedures (~6 weeks) 
During run-in, each participant will need to complete a training on how to complete the eDiary. 
Training will also include a comprehension quiz to ensure participants understanding. Once 
participants complete the training and the comprehension quiz, they will be required to 
complete the migraine eDiary over a period of 28 days to assess eligibility. 
 

 
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During the run in period, the Study Team  use the Milliman IRIX platform to confirm a diagnosis 
of migraine and review additional eligibility criteria.  If diagnosis history cannot be retrieved 
through IRIX, the participant will have the opportunity to supply evidence of their migraine 
diagnosis themselves. If the subject is unable to provide evidence of diagnosis, they will be 
unable to continue in the study. 
 
After 
Randomization Procedures (~1 week) 
 
If the participant’s migraine e-diary and diagnosis confirmation are sufficient for enrollment, 
the virtual study team will conduct the end of run in call to review information submitted during 
screening and run-in period. The participant record will then be reviewed by an Investigator 
and, if eligible, will be randomized; the device shipment will occur thereafter.  
When the device kit is received, the participant will need to watch a series of videos on how to 
set-up and use the Mi-Helper device. Once the training is completed, they will complete a 
comprehension quiz.  The participant will be able to review the study training video at any time 
within the Study App.   
A total of 156 participants will be randomized equally to one of two groups: 
• 
Group I (active treatment): 10 LPM, dehumidified air, 15 minutes total 
• 
Group II (sham [control] treatment): 2 LPM, ambient air administered intermittently via 
Mi-Helper, 15 minutes total 
Upon receipt of the Mi-Helper device, the participant will be instructed to store the shipment 
at room temperature and to not open the desiccant cartridge and tube set prior to use. The 
training will also instruct the participants that the device may only be used ‘once’, during a 
qualifying migraine attack. A qualifying migraine attack must meet the following criteria based 
on responses to the Baseline Questionnaire: 
• 
Migraine head pain is at least mild intensity (score of 1=mild, 2=moderate, or 3=severe on 
the 4-point VRS). 
• 
Onset of migraine head pain was no more than one hour prior to treatment. 
• 
Participant did not wake up with the migraine attack. 
• 
Participant is not experiencing severe sinus congestion. 
• 
Participant did not have migraine related pain in the 48 hours prior to the migraine attack. 
• 
Participant did not take any migraine rescue medications in the 48 hours prior to the 
migraine attack, such as triptans, NSAIDs, or gepants used for acute treatment.  
The participant may reach out to the study team via the Study App, email, or phone to address 
any questions they have about any study-related procedures. 

 
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Participants will have up to 35 days to complete the treatment session after receiving the 
device. 
Baseline Procedures (pre-treatment) 
Baseline assessments will be initiated at the onset of a migraine attack. Baseline assessments 
will include questions about the participant’s head pain, nausea, photosensitivity, 
phonosensitivity, and the most bothersome symptom (MBS) which will be recorded within the 
Study App prior to treatment initiation.  
Treatment Procedures (48 hours) 
Participants will be instructed to use the Mi-Helper device once their migraine head pain has 
reached at least mild intensity. This will be determined by their response to the question about 
their head pain within the Study App. Participants will be instructed to use the Mi-Helper within 
1 hour from the time of migraine head pain onset.    
Once the migraine headache score is recorded as being mild to severe (score of 1 to 3 
recorded on the 4-point VRS scale) and the participant has confirmed that they have not used 
any acute migraine medications in the last 48 hours, the Study App will instruct the participant 
to initiate treatment with the Mi-Helper device and dose treatment (active or sham) for a total 
of 15 minutes based on their group allocation. Participants will be advised against using any 
rescue medication until collection of the Migraine Symptom Questionnaire at 2 hours post-
treatment with the Mi-Helper device. However, if participants do need to administer rescue 
treatment after administering treatment with Mi-Helper, they will need to report this using the 
‘Rescue Medication Form’ within the Study App. Use of rescue medication within 2 hours of 
treatment will be considered a treatment failure. In the instance that abortive treatments have 
been used 48-hours prior to the start of treatment or the time of onset of migraine head pain 
exceeds 1 hour, the participant will need to wait until their next migraine episode of at least 
mild intensity, to use the device. 
Participants will be instructed that they may stop treatment if they are unable to tolerate it by 
moving the nebulizer away from their nose, and report this within the Study App. 
Participants will be required to respond to questions about their head pain, nausea, 
photosensitivity, phonosensitivity, and the most bothersome symptom (MBS) within the Study 
App immediately post-treatment and then at 2 hours, 24 hours and 48 hours post-treatment.  
At 2 hours post-treatment, participants will also be required to respond to questions about the 
device tolerability and user experience questionnaire. Select user experience questions will be 
repeated in the 24-hour assessment. 
Participants can report any changes in their health through the Study App while participating 
in this study.  
If migraine symptoms have not resolved, participants will be able to use rescue medication 
between the 2-to-48-hour period after using the device. Participants will be instructed to report 
rescue medication use in the ‘Rescue Medication Form’ within the Study App. This form will be 

 
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available for participant use during the entire post-treatment period through the Study App 
and will not be timepoint bound. 
End of Study Procedures 
All participants will receive a single treatment with the Mi-Helper device. After completing the 
24-hour assessment, they will be prompted to return the device body utilizing the packaging 
and prepaid shipping labels provided within the original device shipment. 
Participation in the study will be complete once the participant completes the 48-hour 
questionnaire and returns their device. 
 
6. Study Population 
Participants need to meet the following eligibility criteria to be considered for enrollment in 
this study. 
 
6.1 
Inclusion Criteria 
To be eligible for participation in this study, a participant must meet all the following criteria: 
1. Age of 18 to 70 years, inclusive, of either sex at birth. 
2. Lives in the contiguous United States. 
3. Self-reported to be able to read and understand English sufficiently to provide 
informed consent. 
4. Individual has had a diagnosis of  migraine with or without aura for at least 1 year. 
5. Experiences 2 to 8 migraine attacks per month documented via migraine eDiary 
during screening. 
6. Migraine onset before 50 years of age, self-reported during screening. 
7. Migraine preventive medication unchanged for 4 weeks prior to study enrollment. 
8. Stated willingness to comply with all study procedures and availability for the duration 
of the study. 
9. Individual owns a functioning smartphone device, internet connection (Wi-Fi or data 
plan) and are willing to download the Study App 
6.2 
Exclusion Criteria 
A participant who meets any of the following criteria will be excluded from participation in 
the study: 
1. Participant has difficulty distinguishing his or her migraine attacks from other types of 
headaches such as tension, exertion, cluster, hormonal or sinus headaches. 
2. Participant has 15 or more headache days per month reported via migraine eDiary 
and during screening. 
3. Participant using any opioid medication at the time of screening. 
4. Participant has received Botox treatment, barbiturates, SPG block, nerve blocks or 
trigger point injections in the head or neck within the last 4 weeks of screening. 

 
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5. Participant lives at an altitude of 2000 meters or more above sea level. 
6. Self-reported intolerance to intranasal therapy.  
7. Self-reported recurrent epistaxis or chronic rhinosinusitis. 
8. Self-reported sinus or intranasal surgery within the last 4 months of screening. 
9. Self-reported history of ‘complicated migraine or headaches’ (i.e., hemiplegic 
migraine, ophthalmoplegic migraine, migrainous infarction, basilar migraine, post-
traumatic headaches, post-concussion syndrome). 
10. Known or suspected pregnancy as self-reported by the prospective participant at the 
time of screening. 
11. Prospective participant unable to fully understand the consent process and provide 
informed consent due to either language barriers or mental capacity. 
12. Self-reported diagnosis of alcohol or substance abuse disorder at the time of 
screening. 
13. Participant with active chronic pain syndromes, such as fibromyalgia, chronic pelvic 
pain, or complex regional pain syndrome (CRPS); or other pain syndrome like 
trigeminal neuralgia. 
14. Participant with severe uncontrolled psychiatric conditions or significant neurological 
disorders (other than migraine) that, in the Investigator’s opinion, might interfere with 
study assessments. 
15. Failure to adhere to or inability to complete Study App inputs and onboarding 
activities during the screening period. Participants who are not adherent during the 
screening period are not eligible for study entry. 
16. Participation in a previous clinical study with the Mi-Helper device. 
17. Participated in a migraine study or any interventional clinical study within the 3 months 
prior to screening.  
18. Participant has an uncontrolled medical issue at the time of screening. 
19. Any condition for which transnasal air flow would be contraindicated, as determined 
by the PI. 
6.3 
Screen Failures 
Participants who do not meet study inclusion criteria or meet study exclusion criteria prior to 
randomization will be screen failed. 
6.4 
Recruitment and Retention 
Adult participants will be targeted for recruitment using digital and social media 
advertisements within the contiguous US. A sufficient number of adults will be screened to be 
enrolled after consent is provided and subsequently randomized to obtain approximately 156 
eligible participants, as described in Section 5. An anticipated attrition rate of 25% is expected 
to result in the completion of 116 participants. Participants will have completed the study upon 
completion of all post-treatment study procedures and return of the study device. 

 
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7. Study Intervention 
7.1 
Study Product Description 
7.1.1 
Test and Sham Device Description 
Test Device Description 
Mi-Helper has been designed for use in an at-home setting, whenever patients feel the onset 
of a migraine attack. The device delivers a controlled stream of dry air into the nose. The air is 
mixed with a fine saline mist for added comfort and efficiency. It is a lightweight, low-cost 
device with an integrated nebulizer, disposable tube set and desiccant cartridge. It is software 
controlled.   
The Mi-Helper neuromodulation device is intended for acute treatment of migraine, with or 
without aura, in adult patients.   
The Mi-Helper device is small and lightweight, weighing 7 lbs. It is designed to sit on a tabletop 
next to an afflicted individual. This device produces a low flow of dry, filtered air to induce 
neuromodulation via local evaporative cooling in the nasal turbinates. This air flow is delivered 
through a handheld nebulizer and air hose connected to the device. The nebulizer delivers 
ultrasonic misting to keep the turbinates moist and facilitate continued evaporative cooling. 
The nebulizer sits at the entrance of the nose and does not cannulate into the nostrils. The 
handpiece can be connected to the side of the device via a magnet when not in use. 
The primary functional component inside the device is a blower which generates the flow of 
air. Inlet air is pulled into the device from the local ambient room air; the internal blower is then 
used to pump the air across a desiccant material to extract any moisture from the incoming air 
stream. The desiccant material is in a disposable cartridge that is placed into the Mi-Helper at 
the time of treatment. 
Once treatment is initiated, the flow of air enters the individual’s nostril and exits the other 
nostril, inducing an evaporative cooling energy exchange in the turbinates and upper airway.  
The blower inside the device provides the motive force to move the air supply over the 
desiccant material and across the individual’s turbinates. The Mi-Helper will deliver treatment 
for 15 minutes and will turn off once the treatment is complete.  
The Mi-Helper neuromodulation device is designed for investigational use and does not allow 
users to modify air flow rate or saline. The desiccant cartridge is also electrically erasable 
programmable read-only memory (EEPROM) configured and will only operate for a single use.  
Participant randomization assignments will be programmed within the EEPROM configuration. 
An Operator’s Manual and Quick Start Guide for use during the study have been developed 
and will be available for participant training and will be available to participants upon delivery 
of device. 

 
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Sham Device Description 
The sham treatment will be administered through the Mi-Helper device using cartridges that 
contain inactive material of comparable size and weight as the active desiccant material, which 
will not dehumidify air entering the blower. Additionally, participants will receive less than 2 
LPM of air flow, with the device blower cycling on and off periodically (approximate period of 
active flow will be 70% of the time) during the 15-minute treatment session. 
7.1.2 
Formulation, Appearance, Packaging, & Labeling 
The Mi-Helper device with accompanying AC adapter, one desiccant cartridge, one 
disposable tube set, and two sterile saline packets will be shipped to participants directly from 
the contract manufacturer. Study materials will arrive in one box containing the device and 
disposable materials. It will contain the Mi-Helper device and an internal box that will contain 
the desiccant cartridge, tube set and saline. The Mi-Helper device will be in the inner 
packaging box that will include the return shipping label (See Appendix 1 for Device 
Packaging). The investigational label will be prominently located on the back of the device. 
Investigation device label: 
 
The tube set will be shipped in sealed plastic packaging with a label that will be affixed to the 
front of the packaging. 
 
 
 

 
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The desiccant cartridge will be shipped in a sealed package. 
 
The sterile saline packets will be shipped in zip-sealed plastic packaging. This label will be 
affixed to the front of the packaging. 
 
Saline use only label:
 

 
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The label below indicates temperature, altitude, and humidity ranges that are required for 
device functionality. It will be located on the bottom of the durable device base. 
 
AC adapter label has been shown below.  
 
Do not open packaging label has been shown below. 
 
 
 
 
 

 
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7.2 
Study Product Administration 
Each participant will administer the Mi-Helper device therapy once and will be required to 
report on their migraine-related symptoms at specific timepoints post-treatment. All 
assessments will be recorded within the Study App. 
Instructions on how to use the Mi-Helper device are described in the Quick Start Guide and 
trial user manual. 
7.3 
Study Product Handling, Storage, & Accountability 
Shipping, Handling and Accountability: After enrollment and randomization, the Mi-Helper 
device will be shipped to the participant’s home address. Device shipping will be organized 
by the participant through the Study App. Study devices will be shipped to the subject directly. 
The participant will be required to confirm receipt through the Study App prior to initiating any 
study-related activities and will be required to record the serial number of the material 
received. Once the device is received and the participant confirms receipt, they can use the 
device when they experience a headache that reaches at least mild intensity pain (based on 
the 4-point VRS scale) as recorded in their eDiary. After the single treatment with the device 
and completion of all post-treatment assessments, the participant will need to return the device 
via courier service, which can be organized through the Study App. A log of devices shipped 
out to participants and received back from the participants will be maintained. See the 
Investigational Product Management Plan for more details. 
If a participant experiences a technical difficulty with the Mi-Helper device that cannot be 
resolved with real-time troubleshooting, they may be shipped a replacement tubeset and 
desiccant cartridge to treat their next attack, If this occurs during the last week of their 35 day 
treatment period, a protocol exception may be granted to extend their treatment period at the 
discretion of the sponsor and/or investigator. 
Storage: The Mi-Helper device, disposable desiccant cartridge, sterile saline bottles and tube 
set will be stored at room temperature. External packaging for the disposable components will 
have an additional label stating “do not open before use” to reduce the risk of premature 
damage or use of study materials. All components should stay in original packaging until the 
time of treatment. 
Refer to the Mi-Helper Quick Start Guide and trial user manual for further details. 
7.4 
Concomitant Diets, Treatments, and Medications 
Participants are prohibited from using their acute migraine medications within 48 hours prior 
to using the Mi-Helper device. Acute medication may include over-the-counter medications 
like non-steroidal anti-inflammatory drugs (i.e., aspirin or ibuprofen) and acetaminophen; 
prescription medications like triptans (i.e., sumatriptan, zolmitriptan, etc.), gepants 

 
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(ubrogepant, 
Rimegepant,etc.), 
antiemetics 
(metoclopramide, 
prochlorperazine, 
or 
promethazine); or another medical neuromodulation device like Cefaly®. 
Participants should continue to take any prescribed migraine preventive medications as 
instructed by their physician. 
Participants may use rescue medication(s) after administering treatment with Mi-Helper, 
however, rescue medication used within 2 hours of treatment will be considered a treatment 
failure. Participants will be advised against using their rescue medication until collection of the 
Migraine Symptom Questionnaire at 2 hours post-treatment. An ad hoc rescue medication 
form will be available on the Study App’s dashboard after administration of study treatment 
(control or active) for participants to fill out if they decide to use rescue medication(s) prior to 
collection of the Migraine Symptom Questionnaire at 2-hours post-treatment. They will be 
asked about their migraine symptoms when they fill out the ad hoc rescue medication form. 
No dietary restrictions are required for this protocol. 
8. Safety and Adverse Events Management 
8.1 
Adverse Events 
8.1.1 
Definition of Adverse Events 
An Adverse Event (AE) means any untoward medical occurrence associated with the use of an 
intervention in humans, whether considered intervention-related or not (21 CFR 312.32 (a)). 
8.1.2 
Definition of Serious Adverse Events (SAE) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent 
or significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect. Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition (21 CFR 312.32 
(a)). 
8.1.3 
Adverse Event Reporting 
For the purposes of this study the period of observation for AEs begins after baseline 
procedures and continues through to the participants completion of the study. Any health-
related changes prior to the randomization will be recorded as medical history. 
All AEs occurring during the study will be individually assessed by the PI, reported and 
recorded, regardless of seriousness or relationship to the study device. Participants will be able 

 
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to report possible AEs for consideration by filling out the ad hoc Change in Health form within 
the Study App. There will be delegated unblinded Study Team members for the purposes of 
coordinating shipment logistics in relation to randomization. The participants may also report 
any changes to their health by chat function in the Study App and may choose to contact the 
Study Team via phone or email. Once a change in health is reported by the participant, the PI 
or designee will reach out to the participant in near real-time (within 1 business day) to make 
health assessments and advise on further steps, including referral to their local doctor for 
further assessment and treatment, if applicable. The participants will be directed by the Study 
App or Study Team to go to the nearest emergency room if it’s a medical emergency.   
The following information will be documented in each case: 
• 
Participant ID  
• 
AE Term 
• 
Start Date of event 
• 
End Date of event or Ongoing 
• 
Severity or Intensity 
• 
Seriousness 
• 
Action taken with study device 
• 
Action taken to treat event 
• 
Outcome  
• 
Relationship to study device 
• 
Expectedness  
• 
Participants health status assessed by PI 
8.1.4 
Anticipated Adverse Events 
The following adverse events have been documented in previous studies with the Mi-
Helper Device and/or its prototype: 
 
• 
Nasal discomfort (nasal pain, congestion, nasal irritation, runny nose, rhinorrhea, post-
nasal drip) 
• 
Ear discomfort (ear pressure, ear pain, tinnitus) 
• 
Sore Throat 
• 
Sinusitis 
 
 
8.1.5 
Adverse Event Severity and Causality Assessments 
The severity of AEs will be defined by the following criteria.  
Mild - Symptoms hardly perceived, only slight impairment of general well-being 
Moderate - Clearly noticeable symptoms, but tolerable without immediate relief 

 
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Severe - Overwhelming discomfort 
The investigator will assess the possibility of a link between the study device use and an AE 
based on the following criteria: 
Unrelated   
• 
There is an evident other explanation for the AE 
• 
The AE is in accordance with the effect or adverse effect of the concomitant medication 
being taken by participant  
• 
The AE occurred prior to the administration of the study product 
Unlikely relation 
• 
Reasonable temporal relationship with the intake of the study product, although there 
is another plausible explanation for the occurrence of the AE 
Possible relation 
• 
Reasonable temporal relationship with the intake of the study product, although there 
are a number of other factors that could have caused the AE 
Probable relation  
• 
Reasonable temporal relationship with the intake of the study product although other 
plausible reasons point to a causal relationship with the study product 
Certain relation  
• 
Reasonable temporal relationship with the intake of the study product, and 
• 
There is no other explanation for the AE, and 
• 
Subsidence or disappearance of the AE on withdrawal of the study product 
(discontinuation), and 
• 
Recurrence of the symptoms on reintroduction 
8.1.6 
Unanticipated Problems 
Definition 
Unanticipated problems (UAP) involving risks to participants or others includes, in general, any 
incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 

 
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• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
Notification to Regulatory Authorities and IRBs 
The investigator will report UAPs to the IRB per required timelines (typically within 10 business 
days), and the Sponsor will notify the Food and Drug Administration (FDA) as applicable.   
8.1.7 
Serious Adverse Event Reporting and Follow-Up 
For any SAE the PI must notify the Sponsor’s Medical Monitor, within 24 hours of becoming 
aware of the event and send the completed Serious Adverse Event/Unanticipated Adverse 
Device Effect (SAE/UADE) Report to the Sponsor’s Medical Monitor within 48 hours. In 
addition, all IRB reporting requirements will be followed.  
Any SAE or UADE must be reported to the Sponsor’s Medical Monitor via telephone, fax, or 
email within 24 hours of becoming aware of the event.  
 
In the event of an SAE, the investigator will document the following in addition to information 
outlined in section 8.1.3: 
• 
Seriousness criteria: life threatening, hospitalization, persistent/significant disability, 
congenital anomaly/birth defect, death [if marked, then date of death] 
• 
Event Description: where a narrative would capture the details of the event 
• 
Relevant Medical History: any medical history pertinent to the event 
Within 48 hours after the initial report, the Investigator must provide further information to 
the Sponsor’s Medical Monitor on the SAE or UADE in the form of a written narrative. This 
should include a copy of the completed SAE/UADE Report Form and any other related 
diagnostic information that will assist in the understanding of the event. Significant new 
information on ongoing SAEs should be provided promptly to the Sponsor’s Medical 
Monitor. All identifiable reference to the subject except for the subject screening number will 
be redacted from any report sent to the Sponsor’s Medical Monitor.  
The study investigator shall complete an Unanticipated Adverse Device Effect Form and 
submit to the study sponsor and to the reviewing IRB as soon as possible, but in no event 
later than 10 working days after the investigator first learns of the effect. The study sponsor is 
responsible for conducting an evaluation of an unanticipated adverse device effect and shall 
report the results of such evaluation to the FDA and to all reviewing IRBs and participating 
investigators within 10 working days after the sponsor first receives notice of the effect. 
Thereafter, the sponsor shall submit such additional reports concerning the effect as FDA 
request. 

 
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8.1.8 
Pregnancy Reporting 
Participants who self-report pregnancy will be excluded from the study at screening. If the 
participant reports being pregnant after enrollment, they will be withdrawn from the study and 
a pregnancy form within the study application portal will be filled out by the PI or designee and 
the Sponsor will be alerted of the pregnancy.   
9. Participant Completion and Withdrawal 
9.1 
Participant Completion and Withdrawal 
Participants will have completed the study once the device is used, all post-treatment 
procedures are completed at stipulated timepoints, and the study device is returned.  
The participant may withdraw from the study at any time by notifying the Study Team. 
Participants may be withdrawn from the study by the investigator if study procedures have not 
been followed or if the investigator determines the participant is not able to safely continue 
with the study due to an AE or other health-related issue. 
Participants will have up to 35 days to complete the treatment session after receiving the 
device, after which they will have to return the device and will be withdrawn from the study. 
10. Data Management 
10.1 Data Collection 
Study data will be collected in the ObvioHealth app. ObvioHealth will maintain accurate 
documentation (source data) that supports the information entered in the eCRF.  
Management of clinical data will be performed in accordance with ObvioHealth’s applicable 
standards and data cleaning procedures with oversight by the Sponsor to ensure integrity of 
the data, for example, to remove errors and inconsistencies in the data. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) 
and clinical laboratory data will be entered into ClinicalOne, a 21 CFR Part 11-compliant data 
capture system provided by the study Sponsor. The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be automatically transferred from the 
ObvioGo Platform into ClinicalOne via a continuous API integration. 
In addition to clinical data, device performance data is extracted and reviewed once the Mi-
Helper device body is returned post treatment. These logs include treatment start and stop 
time, confirmation of the flow rate, back pressure, humidity, and any voluntary or involuntary 
treatment interruptions. This data will be accessible by the unblinded sponsor team 

 
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representative. All data points except flow rate will be entered into the ClinicalOne EDC by an 
unblinded study team member. 
To protect the privacy of participants, no personal information (including the participant’s 
name or initials) is to be recorded in the eCRF or as part of the query text. Identifiable data are 
isolated to a special team at ObvioHealth and these data will not be transferred/available to 
the Sponsor. 
The Sponsor will obtain and retain all eCRFs and associated study data as applicable at the 
completion of the study. 
10.2 Data Handling 
Documentation of all data management activities should allow step-by-step retrospective 
assessment of data quality and study performance. 
Any changes or corrections to data will be performed in the Oracle Clinical One Electronic 
Data Capture Platform and will include rationale for changes. The EDC system has an audit 
trail, which will provide a complete record of the changes and corrections endorsed by the 
Investigator. 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
10.3 Computerized Edit Checks 
The database will incorporate the needed programmed edit checks to ensure consistent and 
complete data entry. The data management team will perform edit checks as the data are 
being entered into the system, and queries will be entered on a Data Issues Log for the 
decentralized site staff to address. The data manager will raise queries as needed on safety 
data to code the terms (AEs and Drugs or concomitant medication) appropriately. 
10.4 Audit Trail 
The clinical Data Management System (DMS) complies with Good Clinical Practice (GCP) 
predicated rule requirements, laws and regulations (Personal data protection) for clinical trials 
and allows an audit of actions performed by users. 
All original entries and changes made in the database will be captured by an audit trail which 
will include the date and time of the entry or change, and the individual making the entry or 
change who will be identified via their unique user ID. 
11. Statistical Analysis 
11.1 Determination of Sample Size 
The sample size for this study was calculated to test the null hypothesis with Fisher’s exact test.  

 
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The sample size is calculated to test the null hypothesis with 80% power at a 5% level of 
significance using PASS 2024 software, version 24.0.2. 
If we assume that 41% of the subjects in the active treatment arm will have pain freedom at 2 
hours post treatment versus 16% in the sham arm, then 116 evaluable subjects are required 
(58 per group). Allowing for a 25% dropout rate, a total of 156 (78 active versus 78 sham) 
subjects should be enrolled in the study.  
11.2 Randomization 
For this study, a total of 156 participants will be randomized equally into two groups: 
• 
Group I (active treatment): 10 LPM, dehumidified air, 15 minutes 
• 
Group II (sham [control] treatment): 2 LPM, ambient air administered intermittently via 
Mi-Helper, 15 minutes total 
Following randomization, balance between the two arms will be evaluated and confirmed 
using standardized mean differences (SMD), where absolute SMD values less than 0.2 will be 
considered as indicating good balance on a given variable or confounder. Subjects will be 
randomized in a 1:1 fashion, with stratification for gender. 
11.3 Populations for Analyses 
• 
Intent-to-Treat (ITT) Population – all participants who were randomly assigned to a 
treatment. 
• 
Modified Intention to Treat (mITT) Population – all participants who used the study 
intervention and completed a baseline and 2-hour post-dose pain assessment. 
• 
Per Protocol (PP) Population – all participants in the mITT population who do not 
have a major protocol deviation related to primary endpoint and complete the 
treatment in compliance with the protocol, with group assignment as treated, and 
have no use of rescue medication within 2 hours post treatment. 
 
The ITT analysis set will serve as the main analysis set for all safety evaluations. 
The mITT analysis set will be the primary population used for efficacy analyses in this study.  
The primary and secondary efficacy assessments will also be performed on the PP and the ITT 
analysis sets as a sensitivity analysis. 
11.4 General Considerations 
All statistical analyses will be performed using Stata software (version 19, StataCorp LLC, 
College Station, Texas).   
The Pearson chi-squared test will be used to compare randomized arms with regards to 
primary and secondary endpoints.   Logistic regression modeling will estimate odds ratios and 

 
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95% confidence intervals for pain relief/ freedom endpoints to compare the two groups.   The 
absolute difference in rates of freedom from pain will be estimated with 95% confidence 
intervals.    Binomial exact 95% confidence intervals will be constructed for the incidence of 
primary and secondary endpoints within each group.  
Deviations from the planned analysis will be described, with proper justification, in the clinical 
study report. 
11.5 Significance Level and Handling of Type I Error 
Type I Error: The overall significance level for this study is 5% using two-tailed tests 
Hierarchy Approach for Secondary Endpoint Analysis: A hierarchical testing approach will be 
employed using a fixed-sequence procedure to control type I error due to multiple endpoint 
testing. The primary endpoint will first be tested and only if p<0.05, will the secondary 
endpoints be tested. Testing will proceed sequentially, and each endpoint must achieve 
statistical significance at the 0.05 level to proceed to the next endpoint. If any endpoint in the 
sequence fails to achieve significance, all subsequent endpoints will not be formally tested and 
will be considered exploratory. 
11.6 Efficacy Analysis 
 The Chi-square test will be used to compare randomized arms with regards to primary and 
secondary endpoints.   Logistic regression modeling will estimate odds ratios and 95% 
confidence intervals for pain relief/ freedom endpoints to compare the two groups.   The 
absolute difference in rates of freedom from pain will be estimated with 95% confidence 
interval.    Binomial exact 95% confidence intervals will be constructed for the incidence of 
primary and secondary endpoints within each group 
 
11.6.1 Primary Endpoint(s) 
Pain freedom at 2 hours is defined as the reduction in head pain to “none”, i.e., from severe, 
moderate, or mild head pain to none. Pain will be rated on a scale from 0 to 3, where 0 is no 
pain and 3 is severe pain. The proportion of subjects with pain freedom in the active arm will 
be compared to the sham using a chi-squared test.  
Use of rescue medication prior to 2 hours post treatment completion will be considered a 
failure for this endpoint (i.e., patient will be assigned the status of no reduction). 
A sensitivity analysis of the primary endpoint will be performed to assess the impact of missing 
data on the study outcome. This will be done on the ITT analysis set, where missing 2-hour pain 
assessment is considered not to be pain free. 
Subgroup analyses will be conducted to evaluate whether treatment effects on the primary 
endpoint differ by gender, age group, use of preventive medications, and baseline headache 

 
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severity. These analyses will help assess the generalizability of the treatment effect across 
diverse patient populations. 
11.6.2 Secondary Endpoint(s) 
The secondary efficacy variables will be summarized by a count and percentage and compared 
with a chi-squared test. Analysis of secondary endpoints will follow the hierarchical testing 
approach outlined above to control type I error due to multiple endpoints.  
Patient Global Impression of Change will also be summarized by descriptive statistics per 
treatment group and compared between the groups with a t-test.  
11.7 Safety Analysis 
The primary safety outcome is the incidence of adverse events related to the study device for 
48 hours post treatment completion. 
AEs will be categorized as related, probable, possible, unlikely, or unrelated prior to database 
lock. The number of AEs/SAEs and number of participants with AEs/SAEs will be listed and 
tabulated.  
Adverse event rates will be compared between the study groups with a Fisher’s exact test. 
Treatment tolerability will be compared between the study groups. The number and 
percentage of subjects who fail to complete the study treatment due to discomfort and the 
number and percentage of subjects who fail to complete the study because of Adverse Events 
will be presented as well. 
11.8 Exploratory Analysis 
The exploratory variables will be summarized by a count and percentage and compared with 
a chi-squared test  
Frequency of use of rescue medications will be summarized by descriptive statistics per 
treatment group and compared between the groups with a t-test. 
11.9 Blinding Assessment 
An additional assessment using the Blinding Index will be performed to determine whether 
the study blinding has been maintained. The Blinding index is on a scale of 0 to 1 where 0 
indicates complete lack of blinding and 1 indicates perfect blind. 95% confidence intervals 
will also be presented. 
12. Quality Control and Assurance 

 
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12.1 Acceptability of Case Report Forms (Source Documents) 
A case report form is a printed, optical, or electronic document designed to record the 
protocol required information to be reported to the sponsor on each trial participant. This 
study will utilize electronic Case Report Forms (eCRFs) within the ClinicalOne Electronic Data 
Capture (EDC) platform.  
All study data, including electronic patient reported outcomes, will be collected in the 
ObvioHealth Study App, ObvioGo. Such data will be transferred from the ObvioHealth study 
platform to the oracle ClinicalOne EDC to be stored in eCRFs. ObvioHealth will provide data 
management services for this protocol, with SPRIM PRO providing site-based services.  
The study team will maintain accurate documentation (source data) that supports the 
information entered in eCRF. To protect the privacy of participants, no personal information 
(including the participant’s name or initials) is to be recorded in the eCRF or as part of the query 
text. Personally Identifiable data will not be transferred/available to the Sponsor. 
The study monitor will perform ongoing review the of the eCRFs in accordance with the 
monitoring plan, to confirm that data entered into the eCRF by authorized site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
All source data should be reviewed by the study staff and the study monitor to ensure accurate 
transcription of data and that any potential AEs or concomitant medications reported on these 
documents are discussed with the participant and transcribed accurately to the eCRF and/or 
DMS. ePROs that are classed as source data will be retained by the investigator and 
true/certified copies may be sent to the Sponsor or a designated vendor as required. Any AEs 
or concomitant medications collected as ePRO will be reviewed and transcribed to the eCRF 
by a member of the study team. 
The Sponsor will obtain and retain all eCRFs and associated study data at the completion of 
the study. 
12.2 Modification of Protocol 
The Investigator will not make any changes to this protocol without prior written consent from 
Sponsor and subsequent approval by the IRB. Any permanent change to the protocol, whether 
it is an overall change or a change for a specific study center(s), must be handled as a protocol 
amendment. The written amendment must be submitted to the chairperson of the IRB 
identified with this responsibility. Except for 'administrative amendments', Investigators must 
await IRB approval of protocol amendments before implementing the change(s). 
Administrative amendments are defined to have no effect on the safety of the research 
participants scope of the investigation, or quality of the trial. However, a protocol change 

 
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intended to eliminate an apparent immediate hazard to participants should be implemented 
immediately, and the IRB notified within five days.  
When, in the judgment of the reviewing IRB, the investigators and/or Sponsor, the amendment 
to the protocol substantially alters the study design and/or increases the potential risk to the 
participant, the currently approved written informed consent form will require similar 
modification. In such cases, repeat informed consent will be obtained from participants 
enrolled in the study before expecting continued participation. 
12.3 Reporting Protocol Deviations 
A protocol deviation is any non-compliance with the clinical study protocol or International 
Conference on Harmonization Good Clinical Practice (ICH GCP). The non-compliance may be 
either on the part of the participant, the investigators, or the study staff. It is the responsibility 
of the Investigator to identify and report deviations per IRB requirements.  
Protocol non-compliance will be logged, and a corrective action plan will be implemented. 
The main categories of non-compliance that will be targeted are:  
• 
Informed consent process not adequately performed  
• 
Deviation from Inclusion and/or Exclusion criteria 
• 
Non-compliance with study related assessments 
• 
Any other good clinical practice (GCP) non-compliance 
Protocol non-compliance will be tracked and logged in the Protocol Deviation Log in the 
Oracle ClinicalOne EDC. 
12.4  Monitoring 
The study will be monitored on an ongoing basis beginning with enrollment of the first 
participant until the study exit of the last enrolled participant. 
The monitor will perform ongoing review of the eCRFs in accordance with the monitoring plan 
for completeness, clarity and consistency with the information in participants file (source data 
checking). Monitoring will begin with an initiation visit prior to study commencement to clarify 
all aspects of the protocol and documentation. The purpose of later visits during the 
implementation period will be to evaluate study progress and adherence to protocol. The 
monitor will check that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements; and that the safety and rights of participants are being protected. At the end of 
the trial the monitor will make a study closing visit to ensure that all documentation is complete. 
In all cases, it is the responsibility of the CPM / monitor to maintain participant confidentiality. 

 
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The following measures are in place to ensure consistent and regular participant contact: 
• 
Study Team members will review study compliance daily during business hours  
• 
 Study Team members will maintain electronic or telephone communication with the 
participant as needed 
• 
Under some circumstances, the Investigator or designee may call the participant to 
determine the compliance with study protocol and/or to provide additional compliance 
tracking 
An unblinded Study Team member will be available should participants require support with 
troubleshooting the Mi-Helper device and to maintain the blind. 
13.  Ethics and Regulatory Requirements 
13.1 Institutional Review Board/Independent Ethics Committee 
The study protocol will be submitted by the Investigator for examination by the IRB. 
Commencement of the clinical study is not permitted without written approval of the IRB. 
The study will initiate after approval from the IRB which follows the guidance of USA regulatory 
bodies and general GCP regulations and standards set by the ICH. 
This study will be conducted according to the principles and rules laid down in the Declaration 
of Helsinki and its subsequent amendments. 
13.2 Investigator Responsibilities 
The Investigator or designee is responsible for the following: 
• 
Obtaining the written and dated approval of the applicable IRB and other regulatory 
agency, if any, prior to the conduct of the study. 
• 
Selecting participants in accordance with the inclusion and exclusion criteria after the 
eIC is signed. 
• 
Confirming an existing diagnosis of migraine that satisfies the protocol eligibility 
criteria. 
• 
Maintaining confidentiality and safety of participants in accordance with the Declaration 
of Helsinki. 
• 
Adhering to the study protocol and the spirit of GCP. 
• 
Following procedure if modification becomes necessary. The PI or designee will 
provide a rationale in a protocol amendment, which is signed by the Investigator and 
Sponsor for submission to the IRB. After the protocol amendment approval, participants 
still active in the study must re-sign the eIC to remain in the study. 
• 
Providing accurate, complete and timely data reported to the Sponsor.  
• 
Providing participants with any newly available information that may be relevant to 
them during the study. 

 
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• 
Identifying AEs and notifying the Sponsor, IRB and health authorities, as applicable 
• 
Cooperating in the case of an audit and/or regulatory inspections, providing direct 
access to data and/or documents. 
13.3 Informed Consent Process 
A signed electronic Informed Consent (eIC) is required prior to participation in the study. This 
will be done prior to conducting any study-related activities and will be done in accordance 
with all applicable regulatory requirements. 
The dia before the participant decides they want to participate. The IRB/Ethics Committee (EC) 
will approve the eIC language. Any amendments to these documents must be approved by 
the IRB/EC prior to distribution or use. 
The participant must be informed of the study risks and benefits and provide an electronic 
signature consenting to participate prior to the initiation of any study-related activities.  
The decision of the participant to participate in the study is entirely voluntary. It will be clearly 
stated to the participant within the eIC language that the consent to participate can be 
withdrawn at any time without penalty or loss of benefits to which the participant is otherwise 
entitled. 
14. Study Closure 
Premature Termination of Study 
Should it prove necessary to discontinue the study permanently prior to completion, the 
Sponsor will notify SPRIM PRO and the IRB of the rationale. Participants will be informed by 
SPRIM’s Study Team. All relevant study documents and data will then be returned to the 
Sponsor, and the study devices will be returned to the shipping fulfilment center. 
Termination of Study 
After the completion or termination of the study, all relevant study documents and data will 
then be sent to the Sponsor. Any remaining study devices in the field will be returned to the 
shipping fulfillment center. The Investigator will inform the IRB of the end of the study and a 
certificate of study closure will be issued. 
15. Publication & Data Sharing Policy 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-

 
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reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will 
be made to publish results in peer-reviewed journals. Data from this study may be requested 
from other researchers 5 years after the completion of the primary endpoint by contacting the 
study Sponsor. 
The final publication for this study will be a Clinical Study Report authored by SPRIM PRO and 
the Principal Investigator, Dr. Jessica Ailani. 
 
 

 
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16. References 
Arslan HH, Tokgöz E, Yildizoğlu Ü, et al. Evaluation of the changes in the nasal cavity during 
the migraine attack. J Craniofac Surg. 2014;25(5):e446-e449.  
Bigal ME, Serrano D, Buse D, et al. Acute migraine medications and evolution from episodic 
to chronic migraine: a longitudinal population‐based study. Headache. 
2008;48(8):1157-1168. 
DeSphenopalatine ganglion block for the treatment of acute migraine headache. Pain Res 
Treat. 2018;2018:2516953.  
Ford JH, Jackson J, Milligan G, et al. A real-world analysis of migraine: a cross-sectional study 
of disease burden and treatment patterns. Headache. 2017; 57(10):1532–1544. 
Kesserwani H. Migraine triggers: an overview of the pharmacology, iochemistry, 
atmospherics, and their effects on neural networks. Cureus. 2021;13(4):e14243.  
Kudrow L, Kudrow DB, Sandweiss JH. Rapid and sustained relief of migraine attacks with 
intranasal lidocaine: preliminary findings. Headache. 1995;35(2):79–82. 
Maizels M, Geiger AM. Intranasal lidocaine for migraine: a randomized trial and open-label 
follow-up. [published correction appears in Headache 1999;39(10):764]. Headache. 
1999;39(10):543–551. 
Minen MT, Tanev K, Friedman BW. Evaluation and treatment of migraine in the emergency 
department: a review. Headache. 2014;54(7):1131-1145. 
Olesen J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor antagonist 
BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104-
1110. 
Puledda F, Messina R, Goadsby PJ. An update on migraine: current understanding and future 
directions. J Neurol. 2017;264(9):2031–2039. 
Robbins MS, Robertson CE, Kaplan E, et al. The sphenopalatine ganglion: anatomy, 
pathophysiology, and therapeutic targeting in headache. Headache. 2016;56:240-58. 
Steiner TJ, Stovner LJ, Vos T,et al. Migraine is first cause of disability in under 50s: will health 
politicians now take notice? J Headache Pain. 2018;19(1):17.  
Urits I, Schwartz R, Smoots D, et al. Peripheral neuromodulation for the management of 
headache. Anesth Pain Med. 2020;10(6):e110515.  
 

 
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17. Appendices 
17.1 Appendix 1: Device Packaging