A Prospective, Multi-centre, Randomized, Double-blind, Sham-controlled, Parallel-group, Group-sequential Study to Investigate Safety and Effectiveness of the Rehaler Partial Rebreathing Device, in Adults Suffering From Migraine With Aura
Phase: NA
Conditions: Migraine With Aura
Sponsor: Rehaler

PAREMA1 Clinical Investigation Plan version 3.6 
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Clinical Investigation Plan 
 
Study title:  
PArtial REbreathing for Migraine with Aura 1 (PAREMA1): 
A prospective, multi-centre, randomized, double-blind, sham-controlled, 
parallel-group, group-sequential study to investigate safety and effectiveness 
of the Rehaler partial rebreathing device, in adults suffering from migraine 
with aura 
 
Study identifier: RH-001 
EUDAMED Number of clinical investigation: CIV-23-04-042876 
 
Sponsor: 
 
Absalonsgade 26 
8000 Aarhus C 
Denmark 
Contact: Troels Johansen (Chief Technology Officer)  
Email: tj@rehaler.com. Cell phone: +45 40977313 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality statement: 
The following confidential information is the property of Rehaler. As long as the information contained 
in this protocol has not been published it may only be used when permission has been obtained from 
Rehaler in writing. It is not permitted to reproduce all or sections of this protocol. 

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Table of contents:  
1 
Change log ___________________________________________________________ 6 
2 
Sponsor statement ____________________________________________________ 7 
3 
Principal Investigator statement _________________________________________ 9 
4 
Overview of Sponsor representatives _____________________________________ 10 
5 
Study synopsis _______________________________________________________ 11 
6 
Study Flowchart ______________________________________________________ 13 
7 
Abbreviations _______________________________________________________ 14 
8 
Background _________________________________________________________ 17 
8.1 
Disease State and Current Treatments _______________________________________ 17 
8.2 
Investigational Device and Usage ___________________________________________ 17 
8.2.1 
Device materials and contact with user ___________________________________________ 20 
8.3 
Intended Use and Population ______________________________________________ 21 
8.4 
Scientific rationale for the investigational treatment ___________________________ 22 
8.5 
Report of Prior Investigations ______________________________________________ 23 
8.5.1 
Data on CO2 treatment from the scientific literature ________________________________ 23 
8.5.2 
Device performance data relating to the intended physiological effect __________________ 23 
8.5.3 
Device performance data relating to the indication for use (migraine with aura) __________ 25 
8.5.4 
Post-market data _____________________________________________________________ 26 
8.6 
Sham device ____________________________________________________________ 26 
8.7 
Pulse Oximeter __________________________________________________________ 28 
8.8 
Anaemia analyser ________________________________________________________ 28 
8.9 
Study diary smartphone app _______________________________________________ 28 
9 
Justification for the design of the clinical investigation ______________________ 28 
10 
Objective and Hypotheses______________________________________________ 28 
10.1 
Objective _______________________________________________________________ 28 
10.2 
Hypothesis _____________________________________________________________ 28 
10.3 
Study Design Description __________________________________________________ 29 
10.3.1 
Number of subjects and duration of study _________________________________________ 29 
10.3.2 
Measures to minimize bias _____________________________________________________ 30 
10.3.3 
Blinding _____________________________________________________________________ 30 
11 
Endpoints ___________________________________________________________ 30 

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11.1 
Primary effectiveness endpoint _____________________________________________ 31 
11.2 
Primary safety endpoint __________________________________________________ 31 
11.3 
Secondary effectiveness endpoints __________________________________________ 31 
11.4 
Explorative endpoints ____________________________________________________ 32 
11.4.1 
Stage 1 exploratory endpoints ___________________________________________________ 32 
11.4.2 
Stage 2 exploratory endpoints ___________________________________________________ 32 
12 
Study population _____________________________________________________ 33 
12.1 
Eligibility _______________________________________________________________ 33 
12.1.1 
Inclusion criteria ______________________________________________________________ 33 
12.1.2 
Exclusion criteria _____________________________________________________________ 34 
13 
Study procedures _____________________________________________________ 34 
13.1 
Identification of potential study participants __________________________________ 37 
13.1.1 
Identification by trial sites ______________________________________________________ 37 
13.1.2 
Online automatic pre-screening _________________________________________________ 37 
13.2 
Site Visit 1 ______________________________________________________________ 37 
13.2.1 
Informed Consent _____________________________________________________________ 37 
13.2.2 
Information to be recorded: ____________________________________________________ 38 
13.2.3 
Pulse oximeter test ____________________________________________________________ 38 
13.2.4 
Point of enrolment ____________________________________________________________ 39 
13.2.5 
General data capture __________________________________________________________ 39 
13.2.6 
Finalization of Site Visit 1 _______________________________________________________ 39 
13.2.7 
Summary of tasks during Site Visit 1: _____________________________________________ 40 
13.3 
Instruction Session _______________________________________________________ 40 
13.4 
Stage 1 ________________________________________________________________ 41 
13.4.1 
Stage 1 At-Home Activities______________________________________________________ 41 
13.4.2 
Stage 1 Telephone/Teleconference Follow-up Contacts ______________________________ 42 
13.5 
Site Visit 2 ______________________________________________________________ 42 
13.6 
Stage 2 ________________________________________________________________ 43 
13.6.1 
End-of-Stage-2 Follow-up_______________________________________________________ 43 
13.7 
Randomization __________________________________________________________ 43 
13.8 
Treatment Unblinding ____________________________________________________ 44 
13.9 
Concomitant Medications _________________________________________________ 44 
13.10 Patient reported outcomes ________________________________________________ 44 
13.10.1 
Adverse events and device deficiencies ___________________________________________ 44 
13.10.2 
Migraine Headache Pain Scale ___________________________________________________ 45 
13.10.3 
Other Migraine Symptoms ______________________________________________________ 45 
13.10.4 
Delay until treatment initiation __________________________________________________ 45 
13.10.5 
Aura duration and symptoms ___________________________________________________ 45 
13.10.6 
Use of rescue medication _______________________________________________________ 45 
13.10.7 
Impact on life and work ________________________________________________________ 45 
13.10.8 
Patient satisfaction (Stage 1) ____________________________________________________ 45 

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13.10.9 
Assessment of blinding ________________________________________________________ 45 
13.10.10 Long term patient satisfaction (Stage 2) ___________________________________________ 46 
13.10.11 Long term migraine drug and neurostimulator use __________________________________ 46 
13.10.12 Migraine-related hospitalizations ________________________________________________ 46 
14 
Risks and Benefits ____________________________________________________ 46 
14.1 
Known Potential Risks ____________________________________________________ 46 
14.1.1 
Risks related to the active device ________________________________________________ 46 
14.1.2 
Risks related to the sham device _________________________________________________ 48 
14.2 
Known Potential Benefits _________________________________________________ 48 
14.3 
Benefit-Risk Analysis _____________________________________________________ 48 
15 
Adverse events and device deficiencies ___________________________________ 49 
15.1 
Definitions _____________________________________________________________ 49 
15.2 
Classification of an Adverse Event ___________________________________________ 50 
15.2.1 
Severity of Event ______________________________________________________________ 50 
15.2.2 
Causality assessment __________________________________________________________ 50 
15.2.3 
Expectedness ________________________________________________________________ 51 
15.3 
Adverse event recording __________________________________________________ 51 
15.4 
Adverse Event Reporting by Investigators ____________________________________ 52 
15.5 
Adverse Event Reporting by Sponsor ________________________________________ 52 
15.6 
Monitoring and Follow up _________________________________________________ 52 
16 
Methods for analyzing data ____________________________________________ 53 
16.1 
Primary Effectiveness Analysis _____________________________________________ 53 
16.2 
Sample Size and Statistical Power ___________________________________________ 54 
16.3 
Interim analysis _________________________________________________________ 54 
16.4 
Analysis of Secondary Effectiveness Endpoints ________________________________ 54 
16.5 
Analysis of Explorative Endpoints ___________________________________________ 55 
16.6 
Analysis of Safety Endpoints _______________________________________________ 55 
16.7 
Pass/fail criterion to be applied to the results of the clinical investigation __________ 55 
16.8 
Analysis sets ____________________________________________________________ 55 
16.8.1 
Intention-to-treat (ITT) analysis set _______________________________________________ 55 
16.8.2 
As-treated analysis set _________________________________________________________ 55 
16.8.3 
Per-protocol analysis set _______________________________________________________ 55 
16.9 
Handling of Missing Data __________________________________________________ 56 
17 
Data capture and management _________________________________________ 56 
17.1 
EDC system _____________________________________________________________ 56 
17.2 
Source data _____________________________________________________________ 57 

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17.3 
Database lock and Record retention _________________________________________ 57 
18 
Device accountability _________________________________________________ 57 
19 
Supporting Documentation and Operational Considerations __________________ 58 
19.1 
Study Oversight _________________________________________________________ 58 
19.2 
Quality Management _____________________________________________________ 58 
19.2.1 
Site Selection ________________________________________________________________ 58 
19.2.2 
Training _____________________________________________________________________ 58 
19.2.3 
Monitoring __________________________________________________________________ 59 
19.3 
Protocol deviations ______________________________________________________ 60 
19.4 
Confidentiality and Privacy ________________________________________________ 60 
19.5 
Participant Discontinuation or Withdrawal from the Study_______________________ 61 
19.6 
Study Discontinuation or Suspension ________________________________________ 61 
19.7 
Lost to Follow-up ________________________________________________________ 62 
19.8 
End of Study Definition ___________________________________________________ 62 
20 
Ethical Considerations _________________________________________________ 62 
20.1 
Compliance statement ____________________________________________________ 62 
20.2 
Modifications to the Clinical Investigation Plan ________________________________ 63 
20.3 
Responsibility of the Principal Investigator(s) _________________________________ 63 
20.4 
Informed Consent Process _________________________________________________ 63 
20.5 
Insurance and compensation _______________________________________________ 64 
20.6 
Financial Disclosure and Conflict of Interest ___________________________________ 64 
21 
Publication policy ____________________________________________________ 64 
22 
Bibliography ________________________________________________________ 65 
 
 
 

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1 Change log 
Version 
Issue Date 
Changes 
1.0 
17 Aug 2022 
Initial version 
1.1 
19 Sep 2022 
• 
Addition of Figure 8 showing that the sham device does not 
impact CO2 and oxygen levels 
• 
Addition of the DASS-21 questionnaire to the protocol, 
administered at Site Visit 1 and 2 
• 
Addition of an exploratory endpoint comparing DASS-21 score 
at Site Visit 1 and 2 
• 
More detailed description of procedures during Site Visit 1 and 
the Instruction Session  
• 
Clarification of the study flow chart that patient instruction 
mainly takes place during Instruction Session 
• 
Minor edit in the Attack Checklist 
2.0 
07 Oct 2022 
• 
Addition of global coordinating investigator to study 
• 
Inclusion of DASS-21 questionnarie 
• 
Minor clarification of unblinding procedures 
• 
Safety evaluation by Medical advisor 
• 
Update of risk section including salivation as a known side effect. 
3.0 
28 Nov 2022 
• 
Change of method for measuring the anaemia exclusion 
criterion (cf. section 8.8), specifically using the more accurate 
parameter of total hemoglobin instead of ferritin concentration. 
• 
Clarification that trial sites are allowed to identify and contact 
potential study participants from among their relevant patients  
• 
Administrative updates  
3.1 
13 Feb 2023 
• 
Clarification of methods for calculating statistical significance 
and confidence interval for primary endpoint (section 16.1) 
• 
Info on Intention-to-Treat analysis set to be used as population 
analysis set included (section 16.1)  
• 
Info on Multiple imputation for handling missing data included 
(section 16.9) 
3.2 
14 Feb 2023 
• 
Added exclusion criterion: Sickle Cell Disease 
3.3 
14 Feb 2023 
• 
Corrected maximum duration of treatment in consistency with 
IB and IFU (section 13.4) 
• 
Added clarifying sentences 
• 
Administrative updates 
3.4 
15 Jun 2023 
• 
Clarified that the indication for use of the marketed device from 
2018 to 2020 was also migraine with aura 
• 
Clarification that the minimum number of participants in the 
study will be 174 

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3.5 
20 Sep 2023 
Added section on the device materials and their contact with the 
user9s body 
Added the clinical investigation9s EUDAMED number  
3.6 
05 Feb 2024 
Removal of mentions of electronic signature of the informed 
consent form that were left by mistake. 
Minor changes in study procedures and eligibility criteria to clarify 
the text interpretation. 
Updates in the number of participating sites and study timeline. 
 
2 Sponsor statement 
The sponsor of this study, Rehaler A/S, manufacturer of the Rehaler migraine treatment device, 
states the following:  
 
a) This study will be conducted in compliance with the protocol (after being approved by the 
local Institutional Review Board (IRB)/Research Ethics Committee (REC) and, if required, 
by the relevant competent authorities), US 21 CFR Parts 50, 54, 56 and 812, 45 CFR Part 
46, national laws and regulation concerning clinical trials, the Good Clinical Practices (GCP) 
set forth in ISO 14155 (2020) standard and the ethical principles that have their origin in 
the Declaration of Helsinki. The most stringent requirements, guidelines or regulations 
will also be followed. 
b) The Clinical Investigation Plan, Informed Consent Form (ICF), patient9s information 
material, and advertising material will be submitted and approved by the local IRB/REC 
and, if required, by the relevant competent authorities, and any request by the IRB/REC 
or regulatory agencies will be complied with. Approval will be obtained prior to enrolment 
of any patients.  
c) Adequate insurance policy will be held valid for the entire study duration as well as for 
the discovery period required per local regulation.  
 
Prepared by: 
Date:  
 
 
__________________________________ 
 
30-Apr-2024 
Troels Johansen 
 
CEO 
 
Rehaler 
 
 
 
 

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Approved by: 
Date: 
Signature: 
Global Coordinating Investigator Charly 
Gaul, PhD Dr. Med 
 
 
Miranda Kunz, Biostatistician, 
Technomics Research 
 
 
 
 
 

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3 Principal Investigator statement 
As Principal Investigator I hereby confirm that:   
• 
I will ensure that the study is conducted in accordance with the Clinical Investigation Plan 
(CIP) documents, its amendments, the clinical trial agreement and the applicable regulatory 
requirements, including the Declaration of Helsinki, International Conference on 
Harmonisation Good Clinical Practice (ICH E6(R2) GCP) and the International Organization for 
Standardization (ISO) 14155:2020 Clinical investigation of medical devices for human subjects 
– Good Clinical Practice. 
• 
Written Institutional Review Board (IRB) or Research Ethics Committee (REC) and (if 
applicable) Competent Authority approval will be obtained prior to commencing with 
participant enrolment.  
• 
I have read the entire CIP and I understand what my tasks are as a study investigator. 
• 
I will conduct this study following this protocol and will make a reasonable effort to complete 
the study in the time frame agreed with Sponsor. 
• 
I will provide copies of this CIP and all pertinent information to the study personnel under my 
supervision and ensure they are fully informed regarding the conduct of the Study. 
• 
I understand that the study may be terminated or enrolment suspended at any time by the 
Sponsor, with or without cause, or by me if it becomes necessary to protect the interests of 
the study participants. 
• 
I understand that the CIP documents contain information that is confidential and proprietary 
to the Sponsor, and I will ensure that my study staff keep the CIP documents confidential. 
 
 
__________________________________ 
 
 
____________________ 
Principal Investigator9s signature 
Date 
 
 
 
__________________________________ 
 
 
 
Principal Investigator9s printed name 
 
 
 
 
___________________________________ 
 
 
 
___________________________________ 
Site name 
Site number 
 
 
 
 
 

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4 Overview of Sponsor representatives 
Clinical Project 
Manager 
Lene Lyngsie, 
Qmed Consulting A/S 
Koebmagergade 53, 1. 
DK-1150 Copenhagen K. 
Denmark 
Biostatistician 
Miranda Kunz 
Technomics Research, LLC 
1815 Medina Rd Suite 101 
Long Lake, MN 55356, USA 
Contract Research 
Organisation (CRO) 
Qmed Consulting A/S 
Koebmagergade 53, 1. 
DK-1150 Copenhagen K. 
Denmark 
EDC System 
Crucial Data Solutions 
18124 Wedge Parkway, Suite 139, Reno, NV 89511, USA 
 
 

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5 Study synopsis 
STUDY TITLE 
PArtial REbreathing for Migraine with Aura 1 (PAREMA1): 
A randomized, controlled, double-blind, parallel-group, group-
sequential clinical trial to investigate safety and effectiveness of the 
Rehaler partial rebreathing device, in adults suffering from migraine 
with aura.  
Sponsor 
Rehaler A/S 
Absalonsgade 26  
8000 Aarhus C 
Denmark 
INVESTIGATION PLAN ACRONYM 
PAREMA1 
STUDY DESIGN 
PAREMA1 is a randomized, controlled, double-blind, parallel-group, 
group-sequential clinical trial and will randomize minimum 174 and 
maximum 220 participants with migraine with aura (MA), ages 18 to 
65.  
In Stage 1 of the trial the participants will treat up to four attacks each, 
with one of two devices: either an active device which delivers a 
moderate inspired CO2 content (1.5 to 2.5%) or a sham device which 
delivers a very low inspired CO2 content.  
After four treated attacks, participants will end study Stage 1 and 
start Stage 2 which is an open-label extension in which the 
participants are provided with active devices and each month are 
automatically prompted to report data about their migraine attacks 
and treatment effectiveness.  
After 60 participants have provided per-protocol data from two 
attacks in Stage 1, an interim analysis will be conducted by 
Technomics Research. At that point there will be an a priori 
determined decision point about how many additional participants to 
recruit, based on the interim data.  
NUMBER OF SITES (Estimate) 
Europe: 6 
USA: 7 
INVESTIGATIONAL DEVICE  
The active device (Rehaler) is a single-use medical device for home 
use for the treatment of acute migraine attacks with aura in 
participants of ages 18+. 
The mechanism of the Rehaler device is partial rebreathing. 
Intended Use 
The intended use application of the Rehaler is early treatment of 
acute attacks of migraine with aura in patients of ages 18+ to stop or 
alleviate migraine with aura attacks.  The user breathes through the 
mouthpiece from the beginning of the aura symptoms until they 
disappear. 

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EXPECTED STUDY DURATION  
Randomized controlled Stage (Stage 1): Estimated 15 months from 
Study Initiation to end of Stage 1. 
Open-label extension (Stage 2): 12 months. 
OBJECTIVES 
Collect clinical data on Rehaler9s effectiveness and safety for the early 
treatment of migraine with aura, in adults.  
PRIMARY EFFECTIVENESS 
ENDPOINT 
Absence of Moderate or Severe pain at 2 hours (AMSP2)  
MOST IMPORTANT SECONDARY 
ENDPOINT 
Pain Freedom at 2 hours (PF2) 
SAFETY PARAMETERS 
1. Incidence of device- or treatment-related adverse events. 
2. Incidence of device- or treatment-related serious adverse 
events (SAEs) and/or serious adverse device effects (SADE). 
SAMPLE SIZE 
Minimum 174, maximum 220 (randomized participants) 
STUDY POPULATION 
Adult migraine with aura patients, ages 18-65 
KEY INCLUSION CRITERIA 
• 
Participant has migraine with typical aura (ICHD3 classification 
1.2.1) with the additional criterion that a moderate or severe 
headache historically follows the aura in more than 75% of cases 
of aura, beginning between 10 and 60 minutes after aura onset.  
• 
3 or more migraine-with-aura attacks over the last six months. 
KEY EXCLUSION CRITERIA 
• 
15 or more headache days per month 
• 
History of chronic pulmonary disease or severe cardiovascular 
disease 
• 
Anaemia 
TREATMENT 
Treatment with the study device starting as early as possible after 
onset of aura, and continuing until the aura symptoms have 
disappeared 
STUDY PROCEDURES  
 
1. Site Visit 1 (screening/inclusion visit at trial site):  
- 
General and headache-specific anamnesis 
- 
Pulse oximeter spot check and anaemia test 
- 
Randomization 
2. Teleconference instruction in use of study device and study 
diary app 
3. Home treatment (by participant) of up to four migraine-with-
aura attacks. Symptom intensities are reported at the time 
points 0 (treatment start), 60 minutes, 120 minutes, 24 hours 
and 
48 
hours. 
Symptoms 
are: 
Headache 
Pain, 
Nausea/Vomiting, Photophobia, Phonophobia and Functional 
Disability, all rated on a 4-point scale (0 = none, 1 = mild, 2 = 
moderate, 3 = severe)  
4. Follow-up calls via telephone 

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6 Study Flowchart 
 
 
 
 
Figure 1: Participant contact flow chart, PAREMA1 clinical study 
 
 
5. Site Visit 2 (End-of-Stage 1 visit + Stage 2 instruction): 
6. End-of-study follow-up via telephone 

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7 Abbreviations 
ACT 
Assessment of Current 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
AMSP2 
Absence of moderate or severe pain at 2 hours (AMSP2) evaluated at the time point 
two hours after start of treatment, i.e. the percentage of participants who did not report 
a moderate (grade 2) or strong (grade 3) headache within two hours of starting the 
treatment.  
CaO2 
Arterial oxygen content 
CBF 
Cerebral Blood Flow 
CFR 
Code of Federal Regulations 
CGRP 
Calcitonin Gene-Related Peptide 
CHF 
Congestive heart failure 
CIP 
Clinical Investigation Plan 
CNS 
Central Nervous System 
COPD 
Chronic Obstructive Pulmonary Disease 
CRO 
Contract Research Organization 
CSD 
Cortical Spreading Depression 
DD 
Device Deficiency, i.e. inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance 
EDC 
Electronic Data Capture 
ECF 
Extracellular Fluid 
eCRF 
Electronic Case Report Form 
ePRO 
electronic Patient Reported Outcome 
ETCO2 
End Tidal CO2 tension, a widely used non-invasive proxy for arterial CO2 tension (PaCO2), 
having high accuracy and precision in the patient group in question (individuals without 
pulmonary disease). 
EU 
European Union 
FDS2 
Functional Disability Score two hours after treatment initiation 
FICO2 
Fraction of CO2 in inspired air (%) 
FR48 
Freedom from Relapse at 48 hours 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation (EU) 
HS2 
Headache Score two hours after treatment initiation 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICHD-3 
International Classification of Headache Disorders 3, classification system of the 
International Headache Society, available online at https://ichd-3.org/ 

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IDA 
Iron Deficiency Anaemia 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IHS 
International Headache Society 
IMD 
Investigational Medical Device 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
kPa 
Kilo Pascal 
KRI 
Key Risk Indicator 
LPIS1 
Last patient In Stage 1 
LPOS1 
Last Patient Out Stage 1 
LPOS2 
Last Patient Out Stage 2 
LSS2 
Light Sensitivity score two hours after treatment initiation 
MA 
Migraine with aura 
MBS 
Most Bothersome Symptom other than pain, chosen among nausea, phonophobia and 
photophobia. 
mmHg 
Millimetres of mercury 
MDCG 
Medical Device Coordination Group 
NH 
Normoxic Hypercapnia, i.e. an arterial CO2 tension above the normal range (35 - 
45mmHg), combined with an arterial oxygen saturation within the normal range (90-
100%) 
NMDA 
N-methyl-D-aspartate 
NS2 
Nausea Score two hours after treatment initiation 
PaCO2 
Arterial partial pressure of CO2 
PAREMA1 PArtial REbreathing for Migraine with Aura 1 
PF2 
Pain Freedom, 2 hours after starting treatment, i.e. the percentage of participants with 
grade 0 on the 4-point headache scale, two hours after treatment start.   
PI 
Principal Investigator 
PS48 
Participant Satisfaction evaluated at 48 hours after treatment initiation 
RBM 
Risk-based Monitoring 
RCT 
Randomized Controlled Trial 
REC 
Research Ethics Committee 
RES24 
Percentage of attacks with use of rescue medication from the 2 hours9 time point until 
24 hours 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SC 
Study Coordinator 
SKIC 
Study Kit Identifying Code 
SOP 
Standard Operating Procedure 
SPF24 
Sustained Pain freedom at 24 hours 

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SpO2 
Arterial oxygen saturation percentage measured with pulse oximeter 
SSS2 
Sound Sensitivity score two hours after treatment initiation 
USADE 
Unanticipated Serious Device Effect 
VARS 
Visual Aura Rating Scale 
 
 
 

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8 Background 
8.1 Disease State and Current Treatments 
Migraine affects 14.7% of the world9s population and is the most common neurological disease, 
characterized by recurrent debilitating attacks that can last from a few hours to several days. The 
primary symptoms are severe headache, nausea, vomiting and light/sound sensitivity. In some cases, 
attacks are triggered by hunger, stress, sleep disturbances, exercise, or by certain foods, drinks or 
drugs. For women, migraine attacks often occur in conjunction with their menstrual cycles.  
Migraine with aura (MA) is a subset of migraine also known as classical migraine, comprising about a 
third of migraine patients (Launer et al., 1999; Russell et al., 1996). MA attacks are preceded or 
accompanied by so-called aura symptoms, most commonly visual disturbances, somatosensory 
disturbances and/or speech-related problems. Manifestations of visual auras can be numerous, e.g. 
zigzag lines. Somatosensory symptoms can be manifested as tingling or numbness.  
Aura symptoms are thought to be caused by the phenomenon Cortical Spreading Depression (CSD).  
Current acute treatments for MA include the so-called triptans (serotonin receptor agonists), over-
the-counter pain-killers, opioids, anti-nausea medications, the recently approved so-called gepants 
(calcitonin gene related peptide (CGRP) receptor antagonists) and others. However, these 
medications are only moderately effective and often poorly tolerated, causing significant side effects 
and restricting use in many sub-groups (adolescents and children, pregnant and breast-feeding 
women, heart disease patients and more). Furthermore, too frequent use of migraine medications is 
a significant problem which often leads to a vicious cycle of medication overuse headache with 
headaches most days.  
In a survey of more than 15,000 US migraine patients, 74% reported that they were not fully 
satisfied with their current acute treatment (Lipton et al., 2019).  
A number of neurostimulation devices have been marketed for migraine but are not widely adopted 
or reimbursed, due to high prices, and (for many patients) side effects and limited effectiveness.  
Consequently, there is a need for new, effective and affordable non-pharmaceutical migraine 
treatments.   
8.2 Investigational Device and Usage 
The active device in the PAREMA study is the Rehaler device, a single-use Class I medical device 
produced by the medical technology company Rehaler A/S (Denmark).  
The intended use of the device is early treatment of acute attacks of migraine with aura in patients of 
ages 18+, in order to stop or alleviate attacks of migraine with aura.   
The device was previously CE-marked under the Medical Device Directive (European Union Directive 
93/42/EEC), after a randomized, controlled clinical study at Aarhus University Hospital (Denmark) had 
shown a favorable risk/benefit ratio. The device was marketed on a limited scale from October 2018 
to April 2020 in Germany, Denmark and Sweden, a total of 1450 patients having bought and used the 
device in this time period. The indication for use of the device was migraine with aura. The post-market 
surveillance data collected in this period confirmed the low risk profile and beneficial treatment effect 
of the device.  

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The device has not yet been re-certified under the Medical Device Regulation (Regulation 2017/745 
of the European parliament) which went into effect in 2021, and the device is therefore not currently 
being marketed.  
The Rehaler device works through accurately balanced partial rebreathing, meaning that part of the 
expired air is captured and subsequently rebreathed together with a controlled amount of 
atmospheric air. The physiological effect of the Rehaler device is to induce steady state moderate 
hypercapnia with normoxia (NH), i.e. a moderate increase in arterial CO2 tension combined with an 
arterial oxygen saturation within the normal range, no matter how long the device is used. Moderate 
hypercapnia is here defined as an increase in the CO2 content of the user9s body which is low enough 
to not cause discomfort and which is not detrimental to the health of the user. Though CO2 comfort 
levels vary, this will generally mean that the increase in the arterial partial pressure of CO2 (PaCO2) 
should be less than 30%. 
The user breathes through the mouthpiece from the beginning of the aura symptoms until they 
disappear. 
The Rehaler device is shown in Figure 2 to Figure 5. Figure 3 shows the device in use.  
 
 
Figure 2: The Rehaler device, showing the mouthpiece (A), rebreathing chamber (B) and valve unit (C) with regulator (D). 
When using the device, the user breathes through the mouthpiece (A) while wearing a nose clip. Part 
of his/her expired air is captured in the rebreathing chamber (B), while the rest of the expired air exits 
the rebreathing chamber through the slits in the valve unit (C). When the user subsequently inspires, 
the air collected in the chamber is re-inspired along with an amount of fresh air entering from the 
atmosphere through the slits in the valve unit.  

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Figure 3: The Rehaler device in use 
The concentration of CO2 in the inspired air can be regulated by means of the green regulator (D) 
mounted on the valve unit, from a minimum of 1.5% to a maximum of 2.5%. This will in turn increase 
the user9s End Tidal CO2 tension1 (ETCO2) by between 10 and 30% above the normal level. 
The inflow of fresh air through the slits in the valve unit can by design never be completely blocked, 
meaning that there is an absolute upper limit to the induced CO2 concentration in the inspired air, and 
that the user at all times retains normal oxygen saturation no matter the duration of the treatment. 
As shown in Figure 5, this is primarily accomplished by the regulator9s design preventing it from 
moving into a position in which it would cover the always-open slits.  
 
Figure 4: The maximum CO2 level is attained by setting the regulator at level 7, in which case all the adjustable slits (F) are 
closed but air can still flow through the always-open slits (E) at the top. 
If using excessive force it is theoretically possible that a user could push the regulator above the 
protrusion G (see Figure 5). In that case between one and three of the always-open slits (E) would 
become blocked, but moving the regulator in this way would simultaneously un-block the same 
number of adjustable slits (F). As a consequence, at least three slits will always remain open, even in 
cases of user error.  
 
1 End Tidal CO2 (ETCO2) is a widely used non-invasive proxy for arterial CO2 tension (PaCO2), having high 
accuracy and precision in the patient group in question (individuals without pulmonary disease). 

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Figure 5: Valve unit seen from the rebreathing chamber side (i.e. the side facing away from the user), showing how the 
regulator’s top corner (H) is prevented from moving above level 7 by a protrusion (G) on the edge of the valve unit. 
By these design measures, the Rehaler has been provided with an in-built safety measure which 
prevents it from erroneously being used at a setting leading to oxygen desaturation or excessive CO2 
increases.   
There are some specific cases of incorrect device use in which the user9s oxygen saturation could 
conceivably drop below the normal level while using the device. These are specifically cases where a 
user doesn9t follow the instructions for use as it pertains to A) that he/she should not suffer from the 
contraindication pulmonary disease, and B) that the device should not be used at atmospheric 
pressures below 80 kPa (reached at altitudes above 2000 meters and in most pressurized aircraft flying 
above that altitude). To ensure user safety the following precautions are taken: 
1. Study participants9 oxygen saturation at baseline is measured at Site Visit 1, with a high quality 
pulse oximeter (cf. section 8.7). Participants who have a baseline oxygen saturation level 
below 95% will not be included in the study. 
2. Participant instructions (verbal and written), Instructions for Use and study kit label clearly 
state the conditions for use, and instruct the user to decrease the regulator setting if they 
experience any problematic discomfort or side effects (see the document PAREMA1 
Instructions for Use).  
 
8.2.1 Device materials and contact with user 
Table 1 lists the device components in contact with the patient, the material they are constructed 
from, and the degree of patient contact.  
Parts  
Material  
Patient contact and 
duration 
Mouth piece and valve 
unit 
Polypropylene granulate 
(PP mb 4% white 0A900355MA) 
Direct mucosal contact 
(up to two hours) 
Rebreathing chamber 
Transparent cast polypropylene (CPP) film 
Indirect contact 
Regulator 
Thermoplastic polymer Acrylonitrile Butadiene 
Styrene (ABS) 
Direct contact with intact 
skin (few seconds) 

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Nose clip component 1: 
Inner aluminium core 
Aluminium 
Indirect contact 
Nose clip component 2: 
Thermoplastic casing 
Mediprene type 500200M-02 
Direct contact with  intact 
skin (up to two hours) 
Table 1 
The device materials have been chosen specifically for their well-documented biocompatibility, and 
full biocompatibility evaluation has been carried out according to ISO 10993 and ISO 18562 (results 
available in Investigator9s Brochure) 
The device is indicated for use up to two hours continuously. Reapplication of the device is allowed, 
though limited in the PAREMA1 study (cf. the study IfU) to 12 hours in total, and a break of 30 
minutes is indicated if the device has been used for two hours continuously. 
The device components and the finished device are non-sterile, but produced in a controlled 
environment. 
8.3 Intended Use and Population 
The intended use application of the Rehaler is early treatment of acute attacks of migraine with aura 
in patients of ages 18+ to stop or alleviate migraine with aura attacks.  The user breathes through the 
mouthpiece from the beginning of the aura symptoms until they disappear. 
Migraine with aura is defined by the International Classification of Headache Disorders 3 (ICHD-3), 
category 1.2, according to the diagnostic criteria A to D below: 
A. At least two attacks fulfilling criteria B and C 
B.  One or more of the following fully reversible aura symptoms: 
• 
visual 
• 
sensory 
• 
speech and/or language 
• 
motor 
• 
brainstem 
• 
retinal 
C. At least three of the following six characteristics: 
• 
at least one aura symptom spreads gradually over ≥5 minutes 
• 
two or more aura symptoms occur in succession 
• 
each individual aura symptom lasts 5-60 minutes 
• 
at least one aura symptom is unilateral 
• 
at least one aura symptom is positive 
• 
the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis. 
The study will include individuals aged 18 to 65, and exclude individuals with chronic pulmonary 
disease (e.g. COPD or pulmonary fibrosis), severe cardiovascular disease, cerebrovascular disease, 
anaemia, brain abnormalities, as well as pregnant women (see section 12). 
 

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8.4 Scientific rationale for the investigational treatment 
CO2 inhalation has been known to be an effective abortive migraine treatment since a seminal 1950 
paper by Wolff, and this has been confirmed since (Dexter, 1982; Marcussen and Wolff, 1950; 
Spierings, 2005), but until the Rehaler no CO2-delivering device has existed that was at the same 
time safe (i.e. no risk of hypoxia or severe acidosis), compact (i.e. small enough to fit in a pocket) and 
practical (i.e. needing no power supply or gas refilling, and not requiring the user to breathe in any 
particular way).   
Clinical, animal, brain slice and cell studies point to a number of interlinked physiological 
mechanisms that likely play a role for the observed migraine treatment effectiveness of normoxic 
hypercapnia (NH), as induced by the Rehaler: 
1. Introducing moderate NH allows the cerebral oxygen/glucose delivery to be increased by up to 
50% over baseline by increasing cerebral blood flow (Ashkanian et al., 2008; Fuglsang et al., 
2018; Johansen, 2017); this has particular relevance in migraine with aura (MA) because imaging 
studies show that cerebral hypoperfusion is the norm before and long into MA attacks (Olesen 
et al., 1990), implicating hypoperfusion and resulting local hypoxia as a migraine trigger. This 
hypothesis is supported by the facts that A) hypoxemia reliably triggers attacks with and without 
aura in migraine patients (Arngrim et al., 2016), B) imaging studies show impaired regulation of 
cerebral oxygen/energy homeostasis in migraine patients (Lisicki et al., 2018) and C) local tissue 
hypoxia is known to induce and perpetuate Cortical Spreading Depression (CSD) (Ayata and 
Lauritzen, 2015; von Bornstädt et al., 2015) – the migraine trigger phenomenon implicated in 
MA. As one of the most effective cerebral vasodilators, and by far the fastest-acting, CO2 elicits a 
marked increase in cerebral blood flow (CBF) within ten seconds (Claassen et al., 2007; Madden, 
1993), counteracting local brain tissue hypoperfusion and increasing global cerebral 
oxygen/energy supply markedly (Ashkanian et al., 2009, 2008; Fuglsang et al., 2018; Johansen, 
2017). 
2. Whether or not CSD is, in a given case, elicited by local hypoxia/ischemia, NH has been shown to 
markedly inhibit CSD triggering and propagation (Tombaugh, 1994; Tong and Chesler, 2000). This 
inhibition likely stems partly from the capacity of NH to protect against spikes in the extracellular 
potassium level (a main factor in generation and propagation of the CSD wave (Pietrobon and 
Moskowitz, 2013)), by increasing the highly oxygen/glucose-reliant activity of Na+/K+-ATPase 
(Balestrino et al., 1999; Chang et al., 2013) as well as by raising the CBF-mediated clearance rate 
of potassium from the extracellular fluid (ECF) (Ayata and Lauritzen, 2015). Such NH-mediated 
increases in advective clearance from the ECF also accelerate the removal of other mediators 
released during CSD (ibid.) and implicated in down-stream activation of meningeal nociceptors, 
e.g. glutamate, nitric oxide and serotonin (Pietrobon and Moskowitz, 2013). 
3. In addition, hypercapnia and the resulting acidemia have been shown to reduce the excitability 
of neurons, by a number of mechanisms (Ruusuvuori E. and Kaila K., 2014; Somjen and 
Tombaugh, 1998; Vause et al., 2007) including  increase of resting membrane potential, increase 
of firing threshold, decrease of impulse conduction velocity, inhibition of GABAA and NMDA 
receptors, voltage-gated and acid-sensitive ion channels, and inhibition of Calcitonin Gene-
Related Peptide (CGRP) release (Vause et al., 2007). 
 
Figure 6 is a schematic overview of the proposed mechanisms of action responsible for NH9s effects 
on migraine-with-aura attacks: 

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Figure 6 Physiological mechanisms of action proposed to be involved in the effect of normoxic hypercapnia (NH) on migraine-with-aura 
attacks 
8.5 Report of Prior Investigations 
8.5.1 Data on CO2 treatment from the scientific literature 
A large number of clinical studies have in the past investigated the safety and physiological effects of 
increasing CO2 in the inspired air, including the following categories of studies: 
• 
Investigating the increase in breathing depth and frequency elicited by increasing inspired 
CO2, e.g. (Schaefer, 1958). 
• 
Investigating cerebrovascular reactivity, i.e. the increase of cerebral blood flow elicited by 
increasing CO2 in the inspired air, e.g. (Madden, 1993). CO2 inhalation is often used for this 
purpose (Liu et al., 2019). 
• 
Use in combination with radiotherapy, to increase the effect of the latter, e.g. (Kaanders et 
al., 1998). 
• 
Investigating physiological effects of an increased inspired CO2 administered over hours or 
days, e.g. (Elliott et al., 1998) 
The effects of increasing inspired CO2 are thus well-studied and has been shown to be highly safe in 
the concentration range elicited by the Rehaler device (1.5 to 2.5%), as shown in e.g. (Guillerm and 
Radziszewski, 1979; Schaefer, 1958).  
8.5.2 Device performance data relating to the intended physiological effect 
As mentioned, the intended physiological effect is partial rebreathing inducing steady-state moderate 
hypercapnia without incurring hypoxemia.  
The device has in previous, functionally equivalent, designs been tested on patients as part of the pilot 
studies CapnoMigra (migraine patients, (Fuglsang et al., 2018)) HVMASKE (patients with chronic 
hyperventilation, (Johansen et al., 2013)) and EpiCapno (patients with a history of petit mal epilepsy), 

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in which it was confirmed that the bodily CO2 level increases into the desired therapeutic range, with 
negligible effects on arterial oxygen saturation and no SADE9s (Fuglsang et al., 2018; Johansen, 2017; 
Johansen et al., 2013).  
In the study HVMASKE, six participants used a functionally equivalent device continuously for two 
hours at home, each day for four weeks. No SADE9s occurred.  
In the study EpiCapno a functionally equivalent earlier device version was used in ten participants who 
were monitored during 1) a baseline period of 45 minutes without the device, 2) a period of 45 
minutes using the device, and 3) a control period of 15 minutes without the device. No SADE9s 
occurred. 
Figure 7 shows average traces of ETCO2 and pulse oximeter saturation (SpO2) for all ten participants in 
the EpiCapno study, demonstrating that ETCO2 increased to a new stable level after the participants 
started using the device, and fell back to the baseline level after it was discontinued.  
The lowest oxygen saturation measured while using the device was 96%, and the highest increase in 
ETCO2 was 8.5 mmHg (1.13 kPa), corresponding to a 22% increase from baseline. 
 
 
 
Figure 7: Average traces for ten participants of End Tidal CO2 and oxygen saturation, before, during and after use of a 
functionally equivalent PRD 
In a study on one 34 year old male test subject, an indwelling arterial cannula was inserted, and arterial 
blood gases obtained before and during use of a functionally equivalent device. The arterial blood gas 
samples showed an increase in PaCO2 from 5.4 to 6.7 kPa (an increase of 24%), with only a very small 
drop in arterial oxygen content (CaO2) from 20.6 ml/dl to 20.3 ml/dl, confirming that hypoxemia is 
unlikely to occur in use, provided that the user does not suffer from serious pulmonary disease or 
anaemia. 
In the pilot study CapnoMigra (Fuglsang et al., 2018), 18 patients used the device at the hospital for 
between 15 and 25 minutes while being monitored with capnography and pulse oximeter. 11 patients 
subsequently used the device at home in two treatments, each with a duration of 20 minutes. In the 
hospital tests, the mean baseline ETCO2 was 36.8mmHg (range 26–41 mmHg). Using the device, 

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ETCO2 increased to a mean of 45.8mmHg (range 39 to 51); that is, a mean increase of 9.0mmHg (equal 
to a 24% increase compared to baseline). 
The average oxygen saturation at baseline was 98.7% (range from 95% to 100%), compared to 97.3% 
during use of the device (likewise range 95 to 100%). There was thus no indication that the device 
leads to clinically relevant desaturation.  
After the completion of the Capnomigra study, the device design was modified in the following ways: 
- 
Reduction of weight from 60 to 10 grams, allowing hands-free use 
- 
Device constructed in one piece, thereby removing the need to assemble the device 
before use – in turn reducing the likelihood of user error 
- 
Reduction of the maximum rebreathing level which the device can be set at 
Technical and clinical tests of the Rehaler device have shown that the final Rehaler device is 
functionally equivalent to the earlier version tested in the Capnomigra study, apart from a reduction 
in the maximum attainable concentration of inspired CO2 from 2.9% to 2.5% (see Investigator9s 
Brochure, section 11).  
Overall, these clinical and technical data confirm that the Rehaler9s physiological effect matches the 
intended effect, and that the device is safe for use by the patient population in the study.   
8.5.3 Device performance data relating to the indication for use (migraine with aura) 
Past clinical studies have shown that increasing inspired CO2 (in turn inducing moderate hypercapnia) 
is effective in aborting a high proportion of migraine attacks (Dexter, 1982; Marcussen and Wolff, 
1950; Spierings, 2005) and post-spinal headaches (Sikh and Agarwal, 1974). The studies by Marcussen 
and Dexter found that the effect was particularly effective in migraine with aura, and particularly when 
starting treatment already in the aura phase.  
In contrast to the CO2-delivering devices used to treat migraine in the studies cited above, the Rehaler 
instead operates by means of the partial rebreathing principle, yielding a number of advantages: 
• 
Safe, since it does not incur hypoxia – no matter how long the device is used. In addition, the 
CO2 level achieved is moderate, adjustable and stable, allowing the user to be in the correct 
treatment window for as long as needed. 
• 
Practical: because it does not use gas bottles, the Rehaler is very lightweight (10 grams) and 
compact (can easily fit in a pocket), and does not require refilling. 
• 
Ease of use: the user does not need to control his/her breathing in any particular way while 
using the device, but can relax and breathe normally. 
The Rehaler treatment for migraine was from 2016-2017 tested in the aforementioned randomized, 
controlled, double-blind cross-over pilot study that included 11 participants with migraine with aura, 
treating at home for 20 minutes at the onset of aura. The study was conducted with a prototype of 
the Rehaler with the same effect on inspired CO2 and oxygen as the current mass-produced device, 
compared against a non-rebreathing sham comparator device. The study was conducted at the 
Headache Clinic at Aarhus University Hospital (Denmark), and the results were in August 2018 
published in the peer-reviewed headache journal Cephalalgia (Fuglsang et al., 2018). 
The study found the following results:  
• 
Absence of moderate or severe pain at two hours was statistically and clinically superior to 
sham (p < 0.05), and notably increased with each use of the active device (first attack: 45%, 
second attack: 78%). 

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• 
User satisfaction was superior to sham at the 5% significance level. 
• 
The partial rebreathing device increased the mean body CO2 level by 24%, while retaining 
mean oxygen saturation above 97% (no SpO2 level lower than 95% was recorded). 
• 
No serious adverse events or oxygen desaturations were seen. 
 
In addition, the study identified a number of potential improvements that were subsequently 
implemented in the device used in this clinical study, including: 
• 
Reduction in size and weight of the device, making it possible to use the device hands-free. 
• 
Integrating all device parts in one device, removing the need to assemble the device before 
use. 
• 
A better effectiveness is achieved by using the device throughout the aura phase, and not (as 
in the pilot study) stopping after 20 minutes even if the aura is still present. 
8.5.4 Post-market data 
The Rehaler device was CE approved (Class I) in 2018 and put on the market on a limited scale from 
October 2018 until April 2020, in Denmark, Sweden and Germany. During this period, data and 
feedback was collected from users in order to ensure safety as well as improve the device, instructions 
for use and other aspects of the treatment.    
If the present clinical study is successful, we intend to CE certify the device according to the new EU 
regulations (MDR), followed by resuming marketing of the device. 
As detailed in the Investigator9s Brochure, out of a total of 1450 patients that bought a Rehaler Starter 
Kit from 2018 to 2020, only two serious incidents occurred, the first with a patient who had the 
indication for use but also had intracranial hypertension, and the second with a patient who did not 
have the indication for use and who had previously undergone stenting of an unruptured brain 
aneurysm. In both incidents, the adverse event reported was headache.  
Subsequently, the list of contraindications was expanded in order to prevent the occurrence of such 
incidents again in the future. Specifically, the following contraindications were added to the labelling 
and IfU: 
- 
Previous aneurysm and/or brain surgery, including stenting 
- 
Intracranial hypertension  
Neither of the incidents qualified as Serious Adverse Events as defined in the MDR regulation (article 
2, paragraph 58), since they did not incur a risk of death or permanent impairment, or led to 
hospitalization or a need for an acute medical or surgical intervention.  
8.6 Sham device  
NB: The details below concerning the sham device must not be communicated to the study 
participants. 
The sham device (device to the left in Figure 9 and Figure 10) only has a minimal effect on PaCO2 because 
the air flow is redirected by means of a one-way check valve. During exhalation, the expired breath is 
allowed by the check valve to enter the rebreathing chamber, wherefrom it is expelled to the 
atmosphere over approximately two seconds, through the valve unit9s slits. During inhalation, the 
inspired air is drawn in through three holes in the underside of the mouthpiece (see Figure 10). In this 
way the design of the sham device ensures that it looks very similar to the active device (also when in 

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use), but that minimal rebreathing occurs. A series of technical tests with the sham device found that 
the inspired CO2 percentage (FICO2) with the sham device was less than 0.1% (cf. Figure 8) and no 
clinically or statistically significant changes in ETCO2 occur during use. 
 
Figure 8: ETCO2 at baseline (10 minutes) followed by the sham device (10 minute). Average ETCO2 levels: 4.44% (baseline) 
vs. 4.55% (sham), Average FICO2 levels: 0.00% (baseline) vs 0.07% (sham). 
  
 
Figure 9: Active device (right side) and sham (left side) 
 
Figure 10: Active device (right side) and sham (left side), devices facing upside-down. 
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
3.00%
3.50%
4.00%
4.50%
5.00%
5.50%
0.00
200.00
400.00
600.00
800.00
1000.00
1200.00
End tidal CO2 (%)
Seconds elapsed
ETCO2
baseline
ETCO2
sham

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8.7 Pulse Oximeter 
The pulse oximeter used at Site Visit 1 is the CE and FDA approved Nonin PalmSAT® 2500. This has 
been proven in clinical studies to have superior accuracy to other models and provide accurate 
measurement irrespective of skin color or pulse strength (Feiner et al., 2007).   
This pulse oximeter is not susceptible to calibration drift and so does not require continual calibration 
during the study. 
8.8 Anaemia analyser 
The anemia test device is the CE certified and FDA cleared DiaSpect Tm hemoglobin analyzer 
(Diaspect Medical GmbH, Barleben, Germany) which measures the total hemoglobin level 
(grams/deciliter) in capillary blood. 
The cut-off point for exclusion is a hemoglobin level below 11.0 g/dL, in accordance with WHO 
guidelines (WHO, 2011). 
8.9 Study diary smartphone app 
In the study, the electronic Patient Reported Outcome (ePRO) smartphone app software TrialKit will 
be used for capturing patient symptom data (cf. section 17 and the Data Management Plan for the 
study). The ePRO app is linked directly to the study9s Electronic Data Capture (EDC) system. 
9  Justification for the design of the clinical investigation 
Bench tests, pre-clinical data, clinical data and post market data are available for previous versions 
of the Rehaler device and support the design concept, performance claim and safety claim. The 
purpose of the proposed clinical pivotal study is to collect further safety and performance data using 
the current design of the device (Rehaler device) in patients undergoing migraine attacks with aura. 
10 Objective and Hypotheses  
10.1 Objective 
The primary objective of the study is to assess the effectiveness and safety of the Rehaler device as 
treatment of migraine with aura when used during the migraine aura phase, compared to a sham 
device. 
Effectiveness will be assessed by measuring the percentage of attacks in which moderate or severe 
headache was not present two hours after treatment initiation, with respectively the active and 
sham device. 
10.2 Hypothesis 
It is the primary hypothesis of the study that early treatment with the Rehaler device increases the 
likelihood of having no or only mild headache two hours after starting the treatment, compared with 
a sham device. <Early treatment= is here defined as treatment that is initiated during the aura phase, 
within ten minutes of aura symptoms onset, and before the start of moderate or severe migraine 

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headache. The primary endpoint is the absence of moderate or severe pain at 2 hours (AMSP2) after 
early treatment. 
The primary effectiveness hypotheses are: 
H0: pRehaler = psham (null hypothesis) 
Ha: pRehaler b psham (alternative hypothesis) 
Where:  
pRehaler = proportion of attacks in the Rehaler group with AMSP2 
psham = proportion of attacks in the sham group with AMSP2 
The primary effectiveness hypothesis will be tested using a two-sided adjusted χ2 test for clustered 
binary data developed by Donner and Banting (Donner and Banting, 1988), with a 5% level of 
significance. 
10.3 Study Design Description 
The study has two consecutive stages: 
Stage 1 is a prospective, multi-centre, randomized, double-blind, sham-controlled, parallel-group, 
group-sequential study. The RCT design has been chosen to obtain high quality clinical data. 
Stage 2 is an open-label extension with the active device (i.e. irrespective of the type of device 
(active/sham) used in Stage 1). At the start of Stage 2 the participant receives five devices for home 
use. This stage is included to provide more data on the consistency of the treatment response.  
Each study participant will have two site visits:  
• 
Site Visit 1 which is the screening/inclusion visit at which the participant starts their 
participation in Stage 1 (the randomized, controlled part of the study)   
• 
Site Visit 2 which is the end of Stage 1 and start of Stage 2 (open-label extension)  
10.3.1 Number of subjects and duration of study 
A minimum of 174 participants and a maximum of 220 participants will be randomized in this clinical 
study at up to 15 sites in the EU and the United States. The enrolment of participants is intended to 
start in Q1 of 2023 and continue until the target number has been enrolled (<Last Patient In Stage 1= 
(LPIS1)), which is estimated to occur in Q2 of 2025. From the point of LPIS1, there will be a period of 
six months until conclusion of Stage 1 for all participants (<Last Patient Out Stage 1= (LPOS1)), 
estimated to occur in Q4 of 2025. 
Individual participants will participate in Stage 1 until either of the following conditions are met: 
1. The participant has treated and reported four attacks 
2. The overall conclusion of Stage 1 (six months after LPIS1)  
3. The participant no longer wishes to participate or is lost to follow up.  
Participants meeting condition 1 or 2 will after concluding Stage 1 have the option of continuing in 
Stage 2 (open-label extension) which has a maximum duration of 12 months. Individual participants 
will participate in Stage 2 until either of the following conditions are met:  
1. The participant has used all five devices received when starting Stage 2 
2. 12 months have passed since the participant9s inclusion in Stage 2. 
3. The participant no longer wishes to participate or is lost to follow up.  

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The study is concluded when all participants have concluded Stage 2 (<Last Patient Out Stage 2= 
(LPOS2)).  
The maximum estimated duration of total participation for an individual participant (Stage 1 + Stage 
2) is 27 months.   
10.3.2 Measures to minimize bias 
Design Attribute 
Justification 
Prospective 
A prospective study design will eliminate the bias associated with case 
selection in a retrospective review and will ensure that identical procedures 
are followed for data capture and review. 
Multi-centre 
Inclusion of multiple study centres will reduce the impact of bias associated 
with any one investigator, clinic population, or geography. 
Randomized 
Randomization will minimize selection bias and minimize differences in 
demographic variables. 
Double-blinded 
The participants will not be informed about whether they have received the 
active or sham device, until the conclusion of Stage 1.  
The blinding of the investigators is preserved by having the training of the 
patient be carried out by an instructor who is not a study investigator (the 
training process may unblind the instructor because he/she may be able to 
discern which type of device the participant is using).  
Blinding the participants and investigators in this way will minimize bias that 
might impact participant selection and participant outcome measures.  
In order to minimize bias during data analysis, the data analysis will be 
conducted by a biostatistician who is blinded with respect to which of the 
two treatment groups received respectively the active or sham device.  
Sham-controlled 
Use of a sham device will allow to control for the placebo effect, thereby 
increasing the accuracy of the evaluation of the treatment9s effectiveness. 
 
10.3.3 Blinding 
To ensure optimal blinding of participants, the active and sham devices have been designed to look 
and feel as similar as possible (see section 8.6). 
11 Endpoints 
For this study to be considered successful, all primary performance and safety endpoints must be 
achieved. Data for all endpoints will be collected through electronic Patient Reported Outcome 
(ePRO). All end points have been selected with the aim of measuring effects and factors that are 
relevant and valuable for migraine patients. 
All primary and secondary effectiveness endpoints are calculated based on data from Stage 1 of the 
study. 

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11.1 Primary effectiveness endpoint 
Absence of moderate or severe pain at 2 hours (AMSP2), i.e. the proportion of attacks in which the 
participant reported absence of headache of moderate or severe intensity at 2 hours post-treatment 
initiation. 
Headache is measured on a 4-point Scale (0 = None, 1 = Mild, 2 = Moderate, 3 = Severe).  
The choice of ASMP2 as primary endpoint is in line with earlier studies on migraine treatment starting 
at the onset of aura (Bates D. et al., 1994; Olesen J. et al., 2004).  
In studies treating before the onset of pain, AMSP2 is the equivalent to the endpoint Pain Relief at 2 
hours (PR2) in studies treating after pain onset. PR2 has been used as the primary end point in other 
recent acute migraine treatment device studies (see (Yarnitsky et al., 2019) and ClinicalTrials.gov study 
NCT03631550). 
11.2 Primary safety endpoint 
• 
Incidence of device- or treatment-related adverse events 
• 
Incidence of device- or treatment-related serious adverse events (SAEs) and/or serious 
adverse device effects (SADE)  
11.3 Secondary effectiveness endpoints 
1. Pain Freedom at 2 hours (PF2), i.e. the proportion of attacks with absence of headache pain 
two hours after treatment initiation (pain score 0 on the 4-point scale) 
2. Freedom from Most Bothersome Symptom at 2 hours (MBSF2), i.e. the proportion of 
attacks with absence of MBS two hours after treatment initiation (symptom score 0 on the 
4-point scale) 
3. Sustained Pain Freedom at 24 hours (SPF24), i.e. the proportion of attacks having no 
headache pain at 2 hours after dose, with no use of rescue medication and no relapse of 
headache pain within 24 hours (pain score 0 on the 4-point scale) 
4. Headache Score at 2 hours (HS2), i.e. headache score two hours after treatment initiation 
(headache measured on 4-point scale) 
5. Most Bothersome Symptom Score at 2 hours (MBS2), i.e. MBS score two hours after 
treatment initiation (symptom score measured on 4-point scale) 
6. Functional Disability Score at 2 hours (FDS2), i.e. Functional Disability Score two hours after 
treatment initiation (disability measured on 4-point scale) 
7. Proportion of attacks with use of rescue medication from the 2 hours’ time point until 24 
hours (Res24) 
8. Participant Satisfaction at 48 hours (PS48), i.e. participant9s global impression of acute 
treatment effect on attack, evaluated at 48 hours after treatment initiation (5 point scale: 5 = 
Satisfied, 4 = Partially Satisfied, 3 = Neutral, 2 = Partially Unsatisfied, 1 = Unsatisfied) 
9. Light Sensitivity Score at 2 hours (LSS2), i.e. photophobia score two hours after treatment 
initiation (photophobia measured on 4-point scale) 
10. Nausea Score at 2 hours (NS2), i.e. Nausea Score two hours after treatment initiation (nausea 
measured on 4-point scale) 
11. Sound Sensitivity Score at 2 hours (SSS2), i.e. phonophobia score two hours after treatment 
initiation (phonophobia measured on 4-point scale) 

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12. Freedom from Relapse at 48 hours (FR48), i.e. the proportion of attacks having no headache 
pain at 2 hours after dose, with no use of rescue medication and no relapse of headache 
pain within 48 hours (pain score 0 on the 4-point scale) 
 
11.4 Explorative endpoints 
11.4.1 Stage 1 exploratory endpoints 
1. Impact of the migraine attack on participant9s work/school attendance and ability to do 
household chores, during the first 48 hours since the beginning of the attack (impact 
measured on 4-point scale)  
2. Impact of the migraine attack on participant9s social life and leisure time, during the first 48 
hours since the beginning of the attack (impact measured on 4-point scale)  
3. Absence of moderate or severe pain at 1, 24 and 48 hours (% of reported attacks) 
4. Pain Freedom at 1, 24 and 48 hours (% of reported attacks)  
5. Freedom from MBS at 1, 24 and 48 hours (% of reported attacks) 
6. MBS Score at 1, 24 and 48 Hours (4-point scale) 
7. Functional Disability Score at 1, 24 and 48 Hours (4-point scale) 
8. Nausea Score at 1, 24 and 48 Hours (4-point scale) 
9. Light Sensitivity Score at 1, 24 and 48 Hours (4-point scale) 
10. Sound Sensitivity Score at 1, 24 and 48 Hours (4-point scale)  
11. Patient-estimated aura duration (minutes)  
12. Overall participant satisfaction at end of stage 1, i.e. participant9s global impression of study 
device9s treatment effect averaged over all study attacks (5 point scale: 5 = Satisfied, 4 = 
Partially Satisfied, 3 = Neutral, 2 = Partially Unsatisfied, 1 = Unsatisfied) 
13. Difference in DASS-21 score from Site Visit 1 to Site Visit 2 
14. Correlation between AMSP2 and the following parameters: Gender, age, body weight, 
ethnicity, nationality, pain level at treatment start, treatment delay at attack (i.e. from first 
aura symptoms to treatment start), regulator setting during attack, Visual Aura Rating Scale 
(VARS) score, baseline MA attack frequency, baseline headache days per month, baseline 
Migraine-ACT score, baseline DASS-21 score, in prophylactic migraine treatment or not  
15. Correlation between PF2 and the following parameters: Gender, age, body weight, ethnicity, 
nationality, pain level at treatment start, treatment delay at attack (i.e. from first aura 
symptoms to treatment start), regulator setting during attack, Visual Aura Rating Scale (VARS) 
score, baseline MA attack frequency, baseline headache days per month, baseline Migraine-
ACT score, baseline DASS-21 score, in prophylactic migraine treatment or not  
16. Consistency of response among participants who treated three attacks during Stage 1 
17. Use of rescue medication from time 0 until the 2 hours9 time point 
18. Bang Blinding Index 
11.4.2 Stage 2 exploratory endpoints 
1. Number of MA attacks during past month of Stage 2 and how many of these attacks were 
treated with the study device. 

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2. Overall satisfaction with study device treatment effect in attacks treated in past month of 
Stage 2 (satisfaction measured on 5 point scale: 5 = Satisfied, 4 = Partially Satisfied, 3 = Neutral, 
2 = Partially Unsatisfied, 1 = Unsatisfied) 
3. How many times in the past month of Stage 2 has the participant taken respectively a 
prescription acute migraine drug, an over-the-counter acute analgesic or treated with a 
neurostimulator device, with the intention to treat migraine. Follow-up question: What was 
the type and dose of drug taken?  
4. Proportion of participants who used an opioid drug to treat migraine during past month of 
Stage 2.  
5. Proportion of participants who have been hospitalized for migraine during past month of 
Stage 2.  
6. Consistency of response among participants who treated three attacks or more during Stage 
2. 
12 Study population 
Participants who meet all the inclusion criteria and none of the exclusion criteria and who are willing 
and able to provide written informed consent, may be enrolled in the study. Participants may be 
recruited from patients followed at the study sites for their migraine, or from the general population 
by advertisements online and in newspapers, as well as informational brochures and posters.  
12.1 Eligibility 
12.1.1 Inclusion criteria 
Participants must meet all of the following inclusion criteria: 
1. Participant has migraine with typical aura (ICHD3 classification 1.2.1)2 with the additional 
criterion that historically in more than 75% of cases of aura a moderate or severe headache 
begins between 10 and 60 minutes after aura onset.  
2. Participant has had 3 or more migraine-with-aura attacks over the last six months. 
3. Participant is 18 to 65 years of age. 
4. Participant9s age at onset of migraine with aura was less than 50 years. 
5. If participant is taking migraine prophylactic drugs, the dose must have been stable for three 
months or more.  
6. Participant agrees to withhold usual acute migraine medications until at least two hours after 
treatment with the study device. 
7. Participant does not plan to initiate new (and/or change existing) migraine prophylaxis 
medication for the duration of Stage 1 of the study. 
8. For female participants: is willing to use adequate contraception during study participation 
9. Participant owns a smartphone compatible with the ePRO study diary app. 
10. Participant agrees to use the study device as intended, comply with all study requirements 
including treatment, follow-up visits, and recording required study data in the ePRO app. 
11. Participant is willing and able to provide written informed consent. 
 
2Migraine without Aura (MO) is NOT an exclusion criterion. Patients with Aura (MA) very often also have MO. 

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12.1.2 Exclusion criteria  
Participants must meet none of the following criteria: 
1. Participant has a history of chronic pulmonary disease (e.g. Chronic Obstructive Pulmonary 
Disease (COPD) or pulmonary fibrosis). 
2. Participant has a history of severe cardiovascular disease (e.g. symptomatic coronary artery 
disease, prior myocardial infarction, congestive heart failure) or cerebrovascular disease 
(e.g. prior stroke or transient ischemic attack, symptomatic carotid artery disease, prior 
carotid endarterectomy or other vascular neck surgery).  
3. Participant has a history of intracranial hyper/hypo-tension. 
4. Participant has a history of cerebral aneurysm. 
5. Participant has had previous brain surgery, including stenting.  
6. Anaemia, defined as a hemoglobin concentration in capillary blood lower than 11 g/dL 
7. Participant has a baseline SPO2 level which is lower than 95% 
8. Participant has 15 or more headache days per month 
9. Participant has medication-overuse headache (ICHD3 classification 8.2). 
10. Participant has a known history or suspicion of recurring secondary headache which in the 
opinion of the investigator may interfere with the study. 
11. Hemiplegic migraine 
12. Participant has other significant and relevant pain problem (e.g. cancer pain, fibromyalgia or 
other head or facial pain disorders) 
13. Participant has a known history or suspicion of substance abuse or addiction (within the last 
5 years) that in the opinion of the investigator may confound the study assessments.  
14. Participant has a history of psychiatric or cognitive disorder and/or behavioural problems 
which in the opinion of the investigator may interfere with the study. 
15. Participant belongs to a vulnerable population or has any condition such that his or her ability 
to provide informed consent, comply with the follow-up requirements, or provide self-
assessments is compromised (e.g. homeless, developmentally disabled, prisoner). 
16. For female participants: is pregnant or actively trying to become pregnant.  
17. Participant is participating in any other clinical investigation or has participated in an 
interventional clinical trial in the preceding 30 days. 
18. Participant has any condition that according to the investigator may pose the participant at 
risk or provide confounding data.  
19. Participant is unable, as perceived by study personnel, to correctly understand and follow the 
instructions for use of the device and ePRO app. 
20. Sickle Cell Disease 
21. Participant is being treated with nerve blocks or injections for migraine prophylaxis on a 
regularly scheduled basis (including Botox, Aimovig/Erenumab, Ajovy/Fremanezumab, 
Emgality/Galcanezumab or Vyepti/Eptinezumab). 
13 Study procedures 
Figure 11 below shows the flow chart for the study and Table 2 lists the schedule of events.  

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Figure 11 
 
 
 
 
 
 
 
 

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Site Visit 1 
(screening / 
inclusion) 
At-home 
training 
session 
Follow-up A 
Follow-up B 
Follow-up C 
Site Visit 2 
End-of-Stage-
2 follow-up 
Type of 
participant 
contact 
Site visit 
Tele-
conference 
with 
instructor 
Phone or 
tele-
conference 
Phone or 
tele-
conference 
Phone or 
tele-
conference 
Site visit 
Phone or 
tele-
conference 
Time point 
As soon as 
possible after 
successful 
online pre-
screening or 
site 
identification 
Maximally 
one week 
after 
randomizatio
n 
 
Maximally 
one week 
after first 
reported 
attack 
Within one 
week if the 
participant 
has not 
registered an 
attack in the 
past eight 
weeks 
Maximally 
one week 
after 4 
reported 
attacks 
Maximally 
two weeks 
after Follow-
up C 
Maximally 
two weeks 
after 
participant 
has used all 
Stage 2 
devices or 12 
months after  
Site Visit 2 
Procedures: 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Pulse oximeter 
test 
X 
 
 
 
 
 
 
Anaemia test 
X 
 
 
 
 
 
 
Pregnancy test (if 
applicable) 
X 
 
 
 
 
 
 
Migraine ACT 
questionnaire 
(part of CRF) 
X 
 
 
 
 
 
 
DASS-21 
questionnaire 
(part of CRF) 
X 
 
 
 
 
X 
 
Medical history 
and migraine 
characteristics 
X 
 
 
 
 
 
 
Eligibility 
evaluation 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
ePRO/safety and 
DD training 
X 
 
X 
X 
X 
X 
 
Device and ePRO 
training 
 
X 
 
 
 
 
 
Device dispensing 
X 
 
 
 
 
X 
 
Device return 
 
 
 
 
 
X 
X (by mail) 
Reimbursement of 
participant9s costs 
 
 
 
 
 
X 
 
AE/SAE/DD 
reporting 
 
 
X 
X 
X 
X 
X 
Deviation 
reporting 
X 
 
X 
X 
X 
X 
X 
Table 2: Schedule of events and procedures during each contact 
 
 
 

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13.1 Identification of potential study participants 
Study participants can be identified by either of two methods: 
• 
Identification by the trial site personnel, from among the site9s MA patients  
• 
Online pre-screening 
13.1.1 Identification by trial sites 
Trial sites will be allowed to contact its MA patients, informing them about the study and inquiring 
about their interest in participating. The trial site personnel are allowed to contact such individuals 
via letter, telephone or in the clinic. 
The sponsor will supply trial sites with informational brochures and/or posters about the study, for 
placing in relevant locations at the site (e.g. in waiting rooms), cf. the documents PAREMA1 
information flyer and PAREMA1 advertisement. 
13.1.2 Online automatic pre-screening 
This recruitment will be organized by the sponsor and will focus on areas near study sites.  
Online and physical advertisements of the study will include a link to a pre-screening website with an 
online eligibility questionnaire to be completed by the potential participant before being invited to 
the study site for the screening/inclusion visit (Site Visit 1), cf. the document PAREMA1 Case Report 
Form content. This pre-screening step aims to reduce the screen failure rate of the on-site visits. 
Before completing the pre-screening survey, the potential participant will be provided with a privacy 
statement and required to provide consent to being contacted by trial site personnel. 
If the individual9s answers in the online pre-screening conform to the in/exclusion criteria, they will 
receive the Informed Consent Form for their perusal, as well as the telephone number to the study 
site, and they will be asked to call in order to book a time for the Site Visit 1. The potential participant 
will in this process be required to provide their telephone number and email so that the study site has 
the option of contacting the patient.  
The pre-screening website will be hosted by the sponsor on a secure server, and the telephone 
numbers and emails will be handled confidentially and in accordance with local and national data 
protection rules. 
When the visit has been booked and entered in the study site9s calendar, the potential participant will 
receive an email with information about the study and Site Visit 1. A text message and email reminder 
will also be sent to the patient 24 hours prior to the site visit. 
13.2 Site Visit 1 
13.2.1 Informed Consent 
The potential participant is briefed by the PI or delegated study personnel (hereafter designated PI) 
about the study, including the study rationale, study plan, randomization to either study device or 
sham device, study design and possible side effects of the treatment.  It is clearly explained to the 
patient that they may be assigned to either a functional (active) or non-functional (sham) device in 
Stage 1, that it is believed that the active device has the best treatment effect and that the participant 
is guaranteed to be assigned to this in Stage 2.   

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If the participant wishes, he/she can have up to a week to consider before deciding whether or not to 
participate (in that case, the visit will be stopped after Step 1 and resumed when the participant has 
decided). 
A potential study participant considered for this study must be listed on a screening log to be 
maintained at the site. The PI must also enter in the participant9s medical records that he/she is 
participating in the study. If the participant does not have a medical record at the study site, a new 
record must be started for him/her.  
PI will instruct female participants of childbearing potential to practice effective contraception during 
their participation in the study.  
13.2.2 Information to be recorded: 
The following information is obtained and documented in the eCRF during Site Visit 1 (cf. document 
PAREMA1 Case Report Form content): 
• 
General eligibility questions (e.g. age, headache frequency, current participation in other 
clinical investigations) 
• 
Eligibility questions related to migraine with aura diagnosis (presence of aura symptoms, 
frequency of MA attacks, age at MA onset) 
• 
Eligibility questions related to headache drug use and overuse 
• 
Eligibility questions related to comorbidities (e.g. pulmonary, cardiovascular and 
cerebrovascular disease)  
• 
Eligibility questions related to secondary headaches (e.g. caused by head/neck trauma or 
infection)  
• 
Pulse oximeter test result (see section 13.2.3) 
• 
Capillary blood test for anaemia 
• 
For female patients: 
o Whether the patient has gone through menopause 
o If patient has not gone through menopause: urine pregnancy test 
• 
Other eligibility questions, including participant9s willingness to abide by study instructions, 
and ability and willingness to provide informed consent. 
• 
Migraine without aura (MO) diagnosis and frequency 
• 
Miscellaneous baseline information (e.g. self reported height and weight, ethnicity, Most 
Bothersome Symptom during MA attacks, currently and previously used migraine drugs, 
questions regarding efficacy of current acute treatment, evaluation of depression, anxiety and 
stress via the DASS-21 (Depression Anxiety Stress Scales 21 item questionnaire)) 
13.2.3 Pulse oximeter test 
The oxygen saturation (SpO2) of the participant is measured with the pulse oximeter (see section 8.7).  
Initially, the study personnel should check whether the participant is wearing nail polish and/or false 
nails. In that case, the pulse oximeter finger probe must be placed on the finger at a 90 degree angle 
to avoid measurement inaccuracies. 
The SpO2 measurement should be performed at baseline, after the participant has relaxed in a chair for 
one minute. The study personnel must enter the SpO2 reading at the one minute time point into the 
eCRF. The study personnel should during the one minute conduct small talk with the participant in 
order to make them relax and breathe normally, in order to avoid as much as possible that white coat 

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syndrome biases the reading. If the baseline SpO2 reading is lower than 95%, the patient is ineligible 
for the study. 
13.2.4 Point of enrolment 
A participant is considered finally enrolled at the time the informed consent form (ICF) is signed and 
all eligibility criteria are met. The PI is responsible for the selection and screening process at the site 
and will document eligibility in electronic CRF (eCRF). No study related tests or procedures will take 
place before informed consent is obtained. All participants that are successfully enrolled will be 
documented on the enrolment log. Participants not meeting eligibility criteria after having signed the 
ICF are considered screen failures and documented on the screening log. The reason for screen failure 
must also be documented. Excluded participants will at this point be informed about other treatment 
options. Screen failures are not included in the intended sample size. Screen failures may be enrolled 
at a later stage, if by then eligibility can be met. Participants can only be enrolled and participate in 
the study once. 
13.2.5 General data capture 
The participant will receive an email via the EDC system, with a link to download the ePRO app (iOS or 
Android), and with their unique Participant Identification Number (PIN) which is generated by the EDC 
system and is used as access code when entering data in the ePRO app.  
At this point the PI must help the participant install the ePRO app on their smartphone. This includes: 
- 
Setting up automatic login to the ePRO app via either thumb or face recognition (according 
to the participant9s preference) – provided that this type of login is possible on the user9s 
specific smartphone 
- 
Turning on notifications for the Trialkit app, with all available types of notifications turned on 
(sounds, banners, popup messages and others). 
13.2.6 Finalization of Site Visit 1 
The participant receives their study device kit, which contains: 
- 
Five study/sham devices. The Attack Checklist (cf. section 13.4.1) is printed on each device9s 
packaging.  
- 
PAREMA1 Instructions for Use (active or sham type as appropriate)  
- 
Label on the study device kit9s lid including the Study Kit Identifying Code (cf. Investigator9s 
Brochure)  
 
The participant9s PIN is at this point written on the designated space on the packaging of all study 
devices, as well as on the study device kit9s label. 
 
The PI and participant then schedule the participant9s at-home Instruction Session that takes place 
at home via teleconference between an instructor from the CRO and the participant (see section 
13.3 below). The Instruction Session must be scheduled as soon as possible after Site Visit 1 
(maximum one week later). 
 
 

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13.2.7 Summary of tasks during Site Visit 1: 
Table 3: Tasks during Site Visit 1 
TASKS, Site Visit 1: 
1. Inform the participant about the study, including the study rationale, study plan and possible side 
effects of the treatment.  
2. Participant signs informed consent form  
3. General eligibility questions 
4. Pulse oximeter test 
5. Anaemia test 
6. For female participants: Pregnancy test 
7. Decision on eligibility for study according to checklist and investigator9s evaluation 
8. Randomization 
9. Install ePRO study app on subject9s smartphone 
10. Patient receives study device kit and Instruction Session is scheduled 
 
13.3 Instruction Session 
In order to preserve the blinding of the investigator, the participant training and device configuration 
are performed via teleconference by a Contract Research Organization instructor. This Instruction 
Session takes place via teleconference and covers configuring and using the study device, reporting 
data via the ePRO app, and safety reporting.  
The instruction session has five parts (for details refer to the document PAREMA1 Case Report Form 
Content) 
1. Initial briefing of the participant. This entails explaining the aims of the instruction session 
and what will happen during it. The participant is encouraged to ask any questions they have. 
2. Briefing on essential steps when an aura begins. The instructor explains the steps the 
participant must follow when an aura begins, as described in Part 3 of the Instructions for 
Use and summarized in the Attack Checklist printed on the device packaging. 
3. Using the study device for the first time. The participant follows the steps described in Part 
1 of the IfU, in order to learn how to use the device and to find the optimal regulator setting. 
The instructor corrects any errors. Afterwards, the participant is instructed to write their 
optimal regulator setting on each of the attack checklists on the device packages. 
4. Learning how to report symptoms in the Trialkit app. The participant follows the steps 
described in Part 2 of the IfU, in order to learn how to correctly report symptoms in the app. 
The instructor checks that the attack is correctly reported and registered in the EDC, and 
corrects any errors. 
5. Final instructions and reminders. The participant describes the essential attack instructions 
in their own words to the instructor, and any errors are corrected. In addition, a number of 
general instructions and reminders are given to the participant (cf. PAREMA1 Case Report 
Form Content)   

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13.4 Stage 1 
In Stage 1 of the study, the participants will treat up to four attacks each, all of which with either the 
active or sham device. The treatment is started at the onset of aura symptoms and continues until the 
aura symptoms have disappeared, or until 120 minutes have passed, whichever occurs first. At that 
point, the participant turns the slider to position 1 and breathes through the device for five more 
minutes3. Due to the nature and normal duration of aura, and the in/exclusion criteria related to aura, 
the great majority of participants will use the device for less than an hour. As an added control 
mechanism, the eCRF study app asks participants if they are still using the device at the 2-hour time 
point; if this is confirmed the participant is directed to stop using the device at that point. 
The first treated attack is designated a training attack and will not be used in the statistical analysis. 
The subsequent treated attacks are designated study attacks and will be used in the statistical analysis. 
After four treated attacks or overall conclusion of Stage 1 (whichever comes first), participants will 
end study Stage 1 and have the option to start Stage 2 which is a follow-up open-label period during 
which the participant will treat up to five attacks with the active device type. 
13.4.1 Stage 1 At-Home Activities 
Participants are instructed to have a study device and the ePRO app at hand at all times, and at the 
onset of aura symptoms follow the Attack Checklist (see section 13.4.1.1) to start the treatment and 
the logging of the attack in the ePRO app.  
In the following cases, the participant should NOT treat the attack with the study device or record it 
in the study diary app: 
1) If there are no aura symptoms (these are pre-specified in the Instructions for Use and ICF) 
2) If there is moderate or severe headache at the time the aura symptoms start  
3) If they are not able to start treatment within 10 minutes of beginning of the aura symptoms  
The start of treatment is counted as time point 0.  
Data are collected via the ePRO app at specified time points (0, 1, 2, 24 and 48 hours). If the app is not 
available (e.g. internet connection issues), the patient should report the data in paper forms provided 
during Site Visit 1. 
13.4.1.1 Attack Checklist 
The following is the Attack Checklist: 
Do this as soon as the aura symptoms start: 
1. 
Unpack a study device 
2. 
Move green slider to this setting: □ 
3. 
Unfold the device’s bag and pull the black plastic strip 
4. 
Click the top of the device into place at an angle 
5. 
Put on the nose clip (not tight) 
6. 
Inflate the bag with 2 to 3 breaths  
 
3This prevents post-treatment hyperventilation symptoms (mainly paresthesias and lightheadedness) which 
otherwise may occur in approx. 10-15% of users. 

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7. 
Start breathing through the device while sitting comfortably 
8. 
IMPORTANT: Open the study app with Touch ID or PIN: □ , then go to My Forms and 
press <Attack Start=.  
9. 
Answer all questions in the app (scroll all the way down), then press <Save= 
10. 
Breathe through the device until the aura symptoms are gone (minimum 10 min.) 
11. 
Turn the slider to setting 1 and breathe through it for five minutes 
12. 
Set a timer to remember to report symptoms in app 1, 2, 24 & 48h after <Attack Start= 
 
NB: The □ symbol in step 2 and 8 is an empty text box. This is filled out during the Instruction 
Session.  
13.4.2 Stage 1 Telephone/Teleconference Follow-up Contacts 
13.4.2.1 Follow-up A (obligatory) 
When the participant has reported his/her training attack in the ePRO app, the PI must within one 
week check whether the data was entered correctly, and then contact the participant via phone or 
teleconference in order to correct any data entry method errors observed, verify that the participant 
understands the use of the device and ePRO app, and answer any questions the participant may have. 
13.4.2.2 Follow-up B (conditional) 
If the participant has not registered an attack in the pasteight weeks, the PI must within one week 
contact the participant via phone or teleconference, in order to verify that the participant understands 
the use of the device and ePRO app and answer any questions the participant may have. 
13.4.2.3 Follow-up C (obligatory) 
When participants have treated and reported four attacks, the PI must within one week contact the 
participant in order to schedule his/her Site Visit 2. 
Participants who at the overall conclusion of Stage 1 have not reported at least one study attack will 
be concluded from Stage 1 and invited to participate in Stage 2.  
13.5 Site Visit 2 
At Site Visit 2, the participant answers additional general questions about Stage 1, and it is disclosed 
to the participant whether they have received the active or sham device in Stage 1. Participant is asked 
to re-consent to further participation in Stage 2.  This will be documented in the eCRF form for Stage 
2. 
If the participant does not wish to continue, they at this point give back all study materials and their 
participation in the study is concluded. Devices are accounted for in accountability logs and filed in 
Investigational Site File and Trial Master File. 
If the participant wishes, they at this point continue into Stage 2 in which case they receive a Stage 2 
study kit including with five active devices and the Instructions for Use for the active device. PI trains 
the participant in study procedures for this stage, including use of the study device, as well as data 
and safety reporting. 
 

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Table 4: Tasks during Site Visit 2 
TASKS, Site Visit 2: 
- 
End-of-Stage-1 interview (subjective satisfaction, side effects, non-reported adverse events, 
DASS-21 questions, participant9s belief about which device type they were assigned in Stage 1 
(active/sham)) 
- 
Disclosure to patient of study device type used in Stage 1 
- 
Return of unused devices from Stage 1 
- 
Information and training about Stage 2 (open-label extension). Participant receives Stage 2 study 
kit if he/she re-consents to participating in Stage 2.   
 
13.6 Stage 2 
During Stage 2, participants can use the study devices to treat migraine-with-aura attacks. 
Once each month during Stage 2, the participant is prompted (by notification via the study diary app) 
to answer the Stage 2 questions regarding use of the study device as well as use of prescription acute 
migraine drug or an over-the-counter acute analgesic, with the intention to treat migraine (cf. 
PAREMA1 Case Report Form content). The study diary questionnaire includes an option for reporting 
problems and/or adverse events. 
13.6.1 End-of-Stage-2 Follow-up 
The End-of-Stage-2 Follow-up marks the end of the study participation and is a 
telephone/teleconference follow-up which must be performed by the PI at the latest two weeks after 
occurrence of one of the following: 
1. The participant has reported a total of five treated attacks in Stage 2, implying that all the 
devices received at Site Visit 2 have been used. 
2. 12 months have passed since the participant9s inclusion in Stage 2. 
3. The participant no longer wishes to participate or is lost to follow up.  
The PI must during the telephone/teleconference follow-up interview collect and record in the eCRF 
the following information: subjective satisfaction, side effects, non-reported adverse events, any 
other comments the participant has about the treatment and study participation, as well as the DASS-
21 questions (cf. document PAREMA1 Case Report Form content).  The patient should return unused 
Stage 2 devices by mail or at the site. 
 
13.7 Randomization 
The participants will be randomized in a 1:1 ratio to use either the active or sham device in Stage 1.  
Participants and investigators will be blinded with respect to which device (active or sham) each 
participant will use or has used. The randomization scheme will be generated by study biostatisticians 
using permuted block randomization prior to the start of the clinical trial and implemented through 
the randomization module in the EDC. Randomization will be stratified by site, and each site will have 
a separate randomization scheme using random predetermined block sizes.  

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13.8 Treatment Unblinding 
Blinding of individual study participants can be broken in circumstances of medical emergency where 
knowledge of blinded treatment is necessary. In such cases, the randomization codes will be broken 
and the PI must be unblinded with regards to the participant in question. Upon unblinding of a study 
participant, Stage 1 will be prematurely ended for this participant and site will call in for Site Visit 2 
and participant will be transferred to Stage 2, if agreed to by the participant. If necessary to break the 
blind, the involved competent authority (if applicable) and EC/IRB will be informed. The procedure of 
unblinding is further described in Safety Management Plan for the study. In addition to emergency 
unblinding, the code for the individual participant will also be broken at conclusion of Stage 1 and 
study participant will at site visit 2 be informed of their study allocation during Stage 1. 
13.9 Concomitant Medications 
For this study, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Relevant medications to be reported in the eCRF are 
concomitant prescription medications and over-the-counter medications. 
Medication usage will be documented for medications a participant is currently taking at the time of 
the screening visit, and any medication stopped within the previous thirty (30) days, and for 
medication changes (started, stopped, or change of dose/frequency) through to study exit.   
Participants should, if possible, refrain from using rescue medication for at least the first two hours 
after the initiation of treatment with the study device during Stage 1.  <Rescue medication= is here 
defined as the following: 
• 
Prescription or OTC pharmaceuticals that have migraine as an indication for use 
• 
OTC painkillers/analgesics, including acetaminophen/paracetamol, aspirin, ibuprofen and 
naproxen 
• 
Neurostimulators for pain treatment 
Any use of rescue medications within 48 hours from initiation of treatment will be documented via 
the ePRO app.  
Additionally, any medication that is determined by the investigator to be a potential safety issue or 
concern, and/or any medication taken in connection with treatment for an adverse event (AE) will be 
documented. 
13.10 
Patient reported outcomes 
Below is given short description of patient reported outcomes. Please refer to the document 
PAREMA1 Case Report Form content for full details of collected information. 
13.10.1 
Adverse events and device deficiencies 
Participants are instructed to report adverse events experienced during the course of the study. The 
events can be encountered in relation to a treatment session or any time thereafter. Safety 
reporting will create an alert and site will call the participant without undue delay (within 1 business 
day) to follow up on the report.  

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13.10.2 
Migraine Headache Pain Scale 
Participants will be asked to report their migraine-associated headache pain via electronic Patient 
Reported Outcome (ePRO) app using a four-point Likert Scale.  Participants will be prompted for this 
symptom rating at the initial report of aura symptoms and at the time points one, two, twenty-four 
and forty-eight hours after the initiation of treatment. 
13.10.3 
Other Migraine Symptoms 
Participants will be asked to report their migraine symptoms via ePRO using a four-point Likert Scale, 
including the nausea, phonophobia, photophobia and functional disability. Participants will be 
prompted for this symptom rating at the initial report of aura symptoms and at the time points one, 
two, twenty-four and forty-eight hours after the initiation of treatment 
13.10.4 
Delay until treatment initiation 
At the 0 time point, the participant is prompted to estimate how long time went by from the beginning 
of aura symptoms until the beginning of treatment.  
13.10.5 
Aura duration and symptoms 
At the time point when the participant reports that the aura has stopped, he/she is prompted to 
estimate the duration of the aura phase (minutes), as well as indicate the type of aura symptoms 
experienced.   
13.10.6 
Use of rescue medication  
The participants will via ePRO be prompted to answer whether they have used rescue medication, at 
the time points two, twenty-four and forty-eight hours after the initiation of treatment. 
13.10.7 
Impact on life and work  
At the 48-hour time point, participants will via ePRO be prompted to rate: 
- 
Impact of the migraine attack on participant9s work/school attendance and ability to do 
household chores, during the first 48 hours since the beginning of the attack (4-point 
Likert scale)  
- 
Impact of the migraine attack on participant9s social life and leisure time, during the first 
48 hours since the beginning of the attack (4-point Likert scale)  
13.10.8 
Patient satisfaction (Stage 1) 
48 hours after each attack start, participants will be asked to rate their subjective satisfaction with the 
device treatment9s effect (satisfaction measured on 5 point scale: 5 = Satisfied, 4 = Partially Satisfied, 
3 = Neutral, 2 = Partially Unsatisfied, 1 = Unsatisfied) 
13.10.9 
Assessment of blinding  
At Site Visit 2, patients will be asked whether they believed they received the active or placebo device 
during Stage 1. This data will be used to compute the Bang Blinding Index (Bang et al., 2004)    

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13.10.10 
Long term patient satisfaction (Stage 2)  
Once each month during Stage 2, participants will be prompted to report how many MA attacks they 
have had during the past month, how many of these they treated with the study device, as well as 
their overall subjective satisfaction with study device treatment overall during the last month 
(satisfaction measured on 5 point scale: 5 = Satisfied, 4 = Partially Satisfied, 3 = Neutral, 2 = Partially 
Unsatisfied, 1 = Unsatisfied). The question also has the option of answering that the participant did 
not have any attacks during the past month.  
13.10.11 
Long term migraine drug and neurostimulator use 
Each month during Stage 2, participants will be asked how many times in the past month they have 
taken respectively a prescription acute migraine drug, an over-the-counter acute analgesic or a 
neurostimulation device, with the intention to treat migraine. They will also be asked about the type 
and dose.  
13.10.12 
Migraine-related hospitalizations  
Each month during Stage 2, participants will be asked whether they have been hospitalized for 
migraine over the last month, and if yes, how many days in total.  
14 Risks and Benefits 
This section gives an overview of the risks and benefits of the study. For a more detailed risk analysis 
please refer to the Investigator9s Brochure. 
14.1 Known Potential Risks 
14.1.1 Risks related to the active device 
By increasing CO2 in the inspired air, the device induces an increase in bodily CO2 as well as a fall in 
pH, which are the intended physiological effects. With the device, the inspired CO2 fraction is between 
1.5% and 2.5% leading to an increase in PaCO2 of approximately 4 - 12 mmHg. This range has been in 
the previous experimental tests been found to be well-tolerated, safe and effective (Fuglsang et al., 
2018; Johansen, 2017; Johansen et al., 2013); in the clinical studies undertaken using the device (in 
different but functionally equivalent forms), no serious adverse events occurred.  
After having used the active device for five minutes, participants may start to experience harmless 
side effects which according to a benefit-risk ratio are judged as acceptable, and which for the purpose 
of the clinical investigation are categorized as 8expected side effects’.  
The expected side effects are (cf. (Fuglsang et al., 2018)):  
- 
Deeper and/or faster breathing (hyperpnea due to the increase in PaCO2) 
- 
Feeling slightly warmer or colder than normal 
- 
Increase in salivation  
- 
Increase in perspiration  
Additional device effects have in the clinical pre-market data and in the post market surveillance been 
reported in a small percentage of patients using the device, including: 
- 
Dyspnea (probability less than 10%) 

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- 
Mild nausea (probability less than 10%) 
- 
Dizziness (probability less than 10%) 
- 
Mild claustrophobia (probability less than 5%) 
- 
Anxiety (probability less than 5%) 
- 
Headache (probability less than 0.1%) 
- 
Any other symptoms causing moderate to severe discomfort 
The side effects listed above should be counteracted by decreasing the CO2 setting of the Rehaler, in 
practice by moving the regulator (see Figure 2) to a lower setting. Study participants will receive very 
clear instructions about how to recognize and counteract such effects should they occur: respectively 
during the Training Session and in the Informed Consent Form and Instructions for Use (see these 
documents).   
Apart from CO2 effects, the risk assessment must also address the issue of possible hypoxemia. Any 
partial rebreathing device without an external source of compressed oxygen gas will inevitably lead 
to a decrease in the inspired oxygen level.  However, individuals conforming to the in/exclusion criteria 
(i.e. without pulmonary or cardiovascular disease or anaemia) have a significant extra-capacity for 
oxygen uptake, meaning that decreases in the inspired oxygen pressure from the normal sea level 
value of 21 kPa (dry basis) down to 16 kPa are unproblematic and do not lead to hypoxemia (West, 
2008). This corresponds to the situation which arises when a person travels from sea level to a high 
altitude. Signs of oxygen inadequacies upon exertion typically do not manifest themselves below 
altitudes of approx. 2200 meters, where the oxygen partial pressure is 16 kPa. In the present case, 
where the device users will be sitting at rest while using the device, the potential for hypoxemia is 
even smaller. This is supported by the arterial blood data which showed a drop of CaO2 of less than 2%, 
as well as the pulse oximetry data showing that the SpO2% range was the same (95%-100%) with the 
study device as at baseline (see section 8.5.1). 
Use of the Rehaler is contraindicated for the following: 
• 
Chronic pulmonary disease (e.g. Chronic Obstructive Pulmonary Disease (COPD) or pulmonary 
fibrosis) 
• 
Severe cardiovascular disease (e.g. symptomatic coronary artery disease, prior myocardial 
infarction, congestive heart failure (CHF) 
• 
Cerebrovascular disease (e.g. prior stroke or transient ischemic attack, symptomatic carotid 
artery disease, prior carotid endarterectomy or other vascular neck surgery) 
• 
Anaemia 
• 
Sickle Cell Disease 
• 
Uncontrolled intracranial hyper/hypo-tension 
• 
Past or present cerebral aneurysm 
• 
Individuals with previous brain surgery, including stenting 
• 
Use in airplanes or at altitude over 2000 meters (6600 feet) above sea level 
• 
Pregnant or breastfeeding women 
• 
Children under the age of 18  
 
Rehaler has potential interactions when used in conjunction with the following pharmaceutical 
agents: 
1. Anesthetic agents: interaction can give rise to cardiac dysrhythmias. 

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2. Neuromuscular blocking agents and hypotensive agents: the change in pH induced by Rehaler 
can influence uptake, distribution and action of drugs (including neuromuscular blocking 
agents, and hypotensive anesthetic agents). 
3. Adrenaline: carbon dioxide increases the uptake rate of adrenergic substances such as 
adrenaline. 
14.1.2 Risks related to the sham device 
The sham device has been altered so that participants breathe very low CO2 concentrations when 
using it (cf. section 8.6 and Investigator9s Brochure).  
A series of technical tests with the sham device found that the inspired CO2 percentage with the sham 
device was less than 0.1% and no clinically or statistically significant changes in ETCO2 occur during 
use. 
There are therefore no known or suspected risks with the sham device. 
14.2 Known Potential Benefits 
Based on the migraine treatment results presented in section 8.5.3, we anticipate that the 
investigational (active) device will increase the likelihood of avoiding moderate or severe pain during 
migraine with aura attacks.  
14.3 Benefit-Risk Analysis 
Section 14.1 describes possible adverse device effects and risks pertaining to the clinical investigation. 
Based on that analysis, we believe that it is unlikely that the use of the investigational device or sham 
device will lead to serious adverse device effects.  
As detailed in the Risk Management file and summarized in the Investigator9s Brochure, relevant 
measures have been taken to mitigate residual risks. 
Based on the data from the scientific literature, prior clinical studies of functionally equivalent versions 
of the device (the studies CapnoMigra, HVMASKE and EpiCapno), the extensive post-market safety 
data, and the mitigations applied to residual risks, we believe it will be safe to use the investigational 
device and the sham device in the clinical investigation, in the population defined by the in/exclusion 
criteria.  
The study is intended to examine in a large-scale, randomized, controlled study whether it is possible 
to treat and prevent migraine with aura by using partial rebreathing. Such a study has not previously 
been reported in the literature and will provide valuable new knowledge about migraine and its 
treatment. In the light of the risk evaluation performed, it is our assessment that those potential 
benefits of the study outweigh the risks and possible discomforts that participants may experience 
during the study, and that the benefit-risk ratio of the clinical investigation is therefore acceptable. 
Our group (sponsor and investigators) possesses the required expertise, experience, equipment and 
facilities to carry out the proposed study, as well as subsequently analyze and communicate the results 
in a peer-reviewed journal. 

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15 Adverse events and device deficiencies 
15.1 Definitions  
Device Deficiency  
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, usability, 
safety or performance. Device deficiencies include malfunctions, use errors and inadequacy in the 
information supplied by the manufacturer, including labelling. 
This definition includes device deficiencies related to the investigational medical device or the 
comparator. 
 
Adverse Event (AE) 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not related to 
the investigational medical device and whether anticipated or unanticipated.  
Adverse Device Effect (ADE) 
Any AE related to the use of the investigational medical device. 
This definition includes adverse events resulting from insufficient or inadequate instructions  
for use, deployment, implantation, installation, or operation, or any malfunction of the  
investigational medical device. 
This definition includes any event resulting from use error or from intentional misuse of the  
investigational medical device. 
This includes <comparator= if the comparator is a medical device. 
Serious Adverse Event (SAE) 
An AE that led to any of the following: 
a) Death,  
b) Serious deterioration in the health of the subject, users or other persons as defined by one or 
more of the following: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function including chronic 
diseases, or  
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or a body function, 
c) Foetal distress, foetal death, a congenital abnormality, or birth defect including physical or 
mental impairment 
Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a serious adverse event.  
Serious adverse device effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event. 
Unanticipated Serious Device Effect (USADE) 

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Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current risk assessment. 
Anticipated serious adverse device effects (ASADE) is an effect which by its nature, incidence, severity 
or outcome has been identified in the risk assessment. 
15.2 Classification of an Adverse Event 
15.2.1 Severity of Event 
For all AEs, the following guidelines will be used to describe severity: 
• 
Mild – Events require minimal or no treatment and do not interfere with the 
participant9s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• 
Severe – Events interrupt a participant9s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating.  Of note, the term <severe= does not necessarily equate 
to <serious=. 
15.2.2 Causality assessment  
All AEs must have their relationship to both the study device and study procedure assessed and 
categorized by the Principal Investigator who examines and evaluates the participant based on the 
temporal and/or biological relationship and his/her clinical judgment. During assessment, relevant 
core documents (e.g. CIP, IB and RM report) must be consulted. The Sponsor and the investigators will 
use the following definitions to assess the relationship of the serious adverse event to the 
investigational device, sham or the investigation procedure.  
Not related: 
Relationship to the device, sham or procedures can be excluded when: 
• 
the event has no temporal relationship with the use of the investigational 
device, or the procedures related to application of the investigational 
device;  
• 
the serious adverse event does not follow a known response pattern to the 
medical device (if the response pattern is previously known) and is 
biologically implausible; 
• 
the discontinuation of medical device application or the reduction of the 
level of activation/exposure - when clinically feasible - and reintroduction 
of its use (or increase of the level of activation/exposure), do not impact on 
the serious adverse event; 
• 
the event involves a body-site or an organ that cannot be affected by the 
device or procedure; 
• 
the serious adverse event can be attributed to another cause (e.g. an 
underlying or concurrent illness/ clinical condition, an effect of another 
device, drug, treatment or other risk factors); 
• 
the event does not depend on a false result given by the investigational 
device used for diagnosis, when applicable; 
Possible: 
The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, is weak but cannot be ruled out completely. 

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Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical 
condition or/and an effect of another device, drug or treatment). Cases where 
relatedness cannot be assessed, or no information has been obtained should also 
be classified as possible. 
Probable: 
The relationship with the use of the investigational device or comparator, or the 
relationship with procedures, seems relevant and/or the event cannot be 
reasonably explained by another cause. 
Causal 
relationship: 
The serious adverse event is associated with the investigational device, comparator 
or with procedures beyond reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs 
to or of similar devices and procedures; 
• 
the event has a temporal relationship with investigational device 
use/application or procedures; 
• 
the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
• 
the serious adverse event follows a known response pattern to the medical 
device (if the response pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level 
of activation/exposure) and reintroduction of its use (or increase of the 
level of activation/exposure), impact on the serious adverse event (when 
clinically feasible); 
• 
other possible causes (e.g. an underlying or concurrent illness/ clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out; 
• 
harm to the subject is due to error in use; 
• 
the event depends on a false result given by the investigational device used 
for diagnosis, when applicable; 
 
15.2.3 Expectedness 
Expected events have been identified from vigilance data, available clinical data and literature 
searches. Investigator will use available technical documentation to determine if the event is 
anticipated or not. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention. 
15.3 Adverse event recording 
The Investigator will monitor the occurrence of adverse events for each subject during the course of 
the clinical study. Adverse events (AEs) may be reported by the participant, identified by the PI or 
documented in the medical record. All AEs regardless of source, must be recorded in the EDC system. 
Throughout the study, participants must immediately report any adverse events and device 
deficiencies experienced through the ePRO, which will be recorded by investigators in the electronic 
Case Report Form (eCRF). The Investigator must provide information on symptoms, date and time of 
onset, duration, severity, seriousness rating, causality, actions taken, outcome and any other 
pertinent information. All AEs occurring while in study must be documented appropriately regardless 
of relationship. All AEs will be followed to adequate resolution. Any medical condition that is present 

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at the time of screening will be considered as baseline and not reported as an AE. However, if the 
study participant9s condition deteriorates at any time during the study, it may be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed.  
A hard copy of the electronic AE section will be available to allow the Investigator to report SAEs and 
device deficiencies in the event the EDC is not available. The AE report must then be sent to: 
safety@qmed-consulting.com   
Detailed instruction on reporting and completion of the AE section will be provided to the sites as part 
of the Site Initiation Visit (SIV).  
15.4 Adverse Event Reporting by Investigators 
If any event is considered (possibly) related to the device, event is considered serious or event is device 
deficiency with SAE potential, it is the responsibility of the Investigator to report this event within 24 
hours of awareness. If event is not serious or not related to the device, the Investigator must complete 
recording in EDC within 7 days of having become aware of the adverse event.  
Overview of all (S)AEs will be provided to involved ECs in annual reports. 
15.5 Adverse Event Reporting by Sponsor 
The safety monitoring and documentation by Sponsor as well as reporting of events and device 
deficiencies to involved regulatory authorities is described in the Safety Management Plan for the 
study. Sponsor9s Medical Advisor for study will review clinical events that occur during the study to 
adjudicate the relationship to the study device and safety, seriousness, severity and expectedness. 
Sponsor will together with Medical Advisor be responsible for monitoring the safety of study 
participants throughout the study on an on-going basis. Based on safety data, the Medical Advisor 
may recommend the Sponsor to modify or stop the clinical investigation. All relevant documentation 
for safety review will be filed in the TMF.  
The Medical Advisor for study has no involvement in the design of the clinical study and no financial 
interest in the investigational study product and is not involved in the conduct of the study except for 
his/her role as Medical Advisor and for being part of Sponsor9s advisory board.  
No Data Monitoring Committee will be established for this study.  
This plan will be updated throughout the duration of the study if new information and/or guidance 
become available. Adverse events and device deficiencies will be collected and documented and 
reported according to applicable regulation (EU, MDCG 2020-10; US: §812.150(b)(1).  In addition to 
the reporting requirements outlined above, national requirements, will be followed. Once Eudamed 
becomes available and fully functional, the Safety plan will be updated to reflect the new web-based 
reporting structure. 
15.6 Monitoring and Follow up 
Study site will record all events and will monitor those throughout the study until 7 (for non-serious 
AEs) or 30 days (for SAEs) after the last day of study participation.  

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16 Methods for analyzing data 
The PAREMA1 Statistical Analysis Plan (SAP) describes the statistical method and analysis in detail.  
Following is a summary of the intended analyses and sample size justification. 
16.1 Primary Effectiveness Analysis 
The primary endpoint is Absence of Moderate or Severe pain at 2 hours (AMSP2), i.e. the percentage 
of study attacks in which the participant reported absence of headache of moderate/severe intensity 
at 2 hours post-treatment initiation. <Study attacks= are all attacks treated and reported during 
Stage 1, apart from the first attack which is a training attack and is not included in the analysis. The 
intention-to-treat (ITT) analysis set will be used for the primary effectiveness hypothesis test. The 
primary effectiveness hypothesis is: 
H0: pRehaler = psham 
Ha: pRehaler b psham 
Where:  
pRehaler = proportion of attacks in the Rehaler group with AMSP2 
psham = proportion of attacks in the sham group with AMSP2 
The primary effectiveness hypothesis will be tested using a two-sided adjusted χ2 test for clustered 
binary data (Donner and Banting, 1988), at a 5% level of significance. If Pearson9s chi-squared test 
statistic is written as �㔒2 = ∑
�㔒ÿ
2
�㔺
ÿ=1
 with G = the number of treatment groups, then the adjusted χ2 
approximately follows a chi-squared distribution with G-1 degrees of freedom and is calculated as 
follows (Donner and Banting, 1988):  
�㔒�㔴
2 = ∑�㔒ÿ
2
�㔶�㕖ഥ
�㔺
ÿ=1
 
Where: 
�㔶�㕖ഥ= ∑�㕚ÿĀ�㔶ÿĀ
∑�㕚ÿĀ
ÿÿ
Ā=1
 
�㔶ÿĀ = 1 + (�㕚ÿĀ 2 1)�㔌 
G is the number of treatment groups 
ni is the number of individuals in group j 
ρ is the correlation coefficient between any two responses in the same individual  
mij denotes the number of observations for individual j in group i 
 
The corresponding 95% confidence interval for the difference in proportion of attacks with AMSP2 
between the Rehaler and sham groups will be calculated as follows (Donner and Klar, 1993): 
95% Confidence Interval: (�㕝̂�㕅�㕒/�㕎ý�㕒ÿ 2 �㕝̂Ā/�㕎þ) ± 1.96 ∗�㕆�㔸
̂(�㕝̂�㕅�㕒/�㕎ý�㕒ÿ 2 �㕝̂Ā/�㕎þ) 
Where: 
�㕝̂�㕅�㕒/�㕎ý�㕒ÿ = observed proportion of attacks in the Rehaler group with AMSP2 
�㕝̂Ā/�㕎þ = observed proportion of attacks in the sham group with AMSP2 

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�㕆�㔸
̂(�㕝̂�㕅�㕒/�㕎ý�㕒ÿ 2 �㕝̂Ā/�㕎þ) = (
�㔶1
തതത�㕝̂�㕅�㕒/�㕎ý�㕒ÿ(12�㕝̂�㕅�㕒/�㕎ý�㕒ÿ)
ÿ1
+ 
�㔶2
തതത�㕝̂Ā/�㕎þ(12�㕝̂Ā/�㕎þ)
ÿ2
)
1/2
  
�㔶�㕖ഥ= ∑�㕚ÿĀ�㔶ÿĀ
∑�㕚ÿĀ
ÿÿ
Ā=1
 
�㔶ÿĀ = 1 + (�㕚ÿĀ 2 1)�㔌 
ni is the number of individuals in group i 
ρ is the correlation coefficient between any two responses in the same individual  
mij denotes the number of observations for individual j in group i 
 
16.2 Sample Size and Statistical Power 
The study9s key secondary endpoint is Pain Freedom at 2 hours (PF2). Recognizing that this is the ideal 
outcome for migraine patients, the study has been designed with a moderately high statistical power 
(80%) for PF2. The estimated study size of 174 included participants has been determined on the basis 
of data from the pilot study and post-market data collected in Denmark, Sweden and Germany from 
2018 to 2020, indicating that the PF2 rate will be 30% in the active device group and 12% in the sham 
group, that each patient will contribute data from two attacks while in Stage 1, and that the total 
percentage of included patients not yielding analyzable data will be 30%. These data were utilized in 
a sample size analysis, conducted by simulation and using the χ2 significance test adjusted for clustered 
data. Under the given assumptions and including 174 patients, the estimated power for PF2 is 80%. 
Pilot study and post-market data indicated an AMSP2 rate of 61% in the active device group and 26% 
in the sham group. Under the given assumptions, including 174 patients in the study will result in 95% 
power for AMSP2. Therefore, the clinical investigation will randomize at minimum 174 participants.  
16.3 Interim analysis 
After 60 subjects have provided data from at least one study attack in Stage 1, an interim analysis 
(IA) will be conducted to re-estimate the study sample size. Based on the data from the IA it will be 
decided how many additional patients to recruit into the study. The IA will include two hypothesis 
tests on the interim data set, respectively of PF2 and AMSP2. These analyses will use the O9Brien 
Fleming Spending function in which the significance thresholds of the p-value are respectively 
0.0052 at the IA and 0.048 in the full analysis. The IA will estimate the power for PF2 in the final 
analysis based on the observed PF2 rates in the trial thus far and re-estimate the study sample size 
accordingly. Regardless of the results of the IA, enrolment will continue to the originally estimated 
174 subjects, and the total number of included participants will be capped at 220 since this is the 
largest study that will be feasible to conduct. The minimum number of participants in the study will 
be 174. 
16.4 Analysis of Secondary Effectiveness Endpoints 
To support potential device labelling claims, key secondary end points will be analyzed according to a 
fixed-sequence step-down procedure. The ITT analysis set will be used for hypothesis tests for the 
secondary endpoints. 

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The end point analysis will be performed by an independent evaluator who is blinded to the type of 
intervention (active/sham) assigned to each of the two Stage 1 treatment groups. 
16.5 Analysis of Explorative Endpoints 
Explorative endpoints in Stage 1 and Stage 2 will be analyzed to gather additional effectiveness 
information. 
16.6 Analysis of Safety Endpoints 
The incidence of device- or treatment-related adverse events (AEs) and device- or treatment-related 
serious adverse events (SAEs) and/or serious adverse device effects (SADE) will be tabulated. The as-
treated analysis set will be used for the assessment of safety. 
16.7 Pass/fail criterion to be applied to the results of the clinical 
investigation 
The pass/fail criterion for the clinical investigation is whether using the active device per protocol 
results in a higher percentage of absence of moderate or severe pain at two hours compared to the 
sham device. 
 
16.8 Analysis sets 
16.8.1 Intention-to-treat (ITT) analysis set 
The ITT includes all study attacks from all participants who underwent randomization and who 
reported headache score at the two-hour time point in at least one study attack. The ITT analysis set 
will not exclude attacks with protocol deviations or use of rescue medication before the two-hour 
time point. The ITT data set will be used for analysis of the primary and secondary effectiveness end 
points.  
If any subjects in the ITT population have a missing headache score at the two-hour time point, 
multiple imputation will be used to impute their headache score for the analysis of primary and 
secondary endpoints, as described in the Statistical Analysis Plan. 
16.8.2 As-treated analysis set 
The as-treated analysis set includes all participants who received a study device, whether or not it 
was the actual randomized device.  Subjects will be grouped by the device they actually used. This 
analysis set will be used for assessment of safety. 
16.8.3 Per-protocol analysis set 
The per-protocol analysis set includes all study attacks with a reported headache score at the two-
hour time point, in which: 
• 
The participant started using the study device within five minutes of the beginning of aura 
and before development of moderate or severe pain 
• 
The participant did not use rescue drugs before the two-hour assessment point 
• 
There were no changes in concomitant preventive treatment during the study that might 
potentially affect response. 

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• 
There were no other major protocol deviations 
When comparing the ITT and Per Protocol analysis sets, the impact of protocol deviations and user 
errors can be investigated with the aim of identifying potential improvements to the investigational 
device and instructions for use. The ITT analysis set will also be used to analyse the impact of 
protocol deviations on the outcome parameters (e.g. use of rescue medication during the first two 
hours and starting the use of the device after the onset of headache). 
 
16.9 Handling of Missing Data 
All attempts will be made to minimize missing data. However, if any subjects in the ITT population 
have missing primary endpoints, five (5) multiple imputations will be used for the analyses. This 
consists of imputing values for each missing value as a set, analyzing the results for each set, and 
then pooling the results. The primary effectiveness endpoint is binary, so the imputation method will 
be a multiple logistic regression. 
17 Data capture and management 
17.1 EDC system 
The study will utilize the TrialKit electronic data capture (EDC) and ePRO platform (Crucial Data 
Solutions, 18124 Wedge Parkway, Suite 139, Reno, NV 89511, USA) for data collection, an EU GDPR 
compliant system.  The TrialKit EDC may be accessed securely via either the web or the mobile app 
(smartphone or tablet).  The data are hosted on a secure server located in the EU (for European study 
sites) or USA (for US trial sites).   
At Site Visit 1, the TrialKit app will be downloaded to the participant9s smartphone (the TrialKit ePRO 
app is compatible with all major smartphone types). 
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 may be 
entered directly into the database or from the source documents. 
Study personnel will be able to access the EDC system via either web browser or mobile app.   
The EDC database system will be designed based on the protocol requirements, the approved eCRF 
layouts and specifications (cf. document PAREMA1 Case Report Form content), and in accordance 
with all local data protection regulations. The eCRF layouts and specifications define and identify the 
applicable source data that will be collected and captured into the EDC database system. The 
applicable source data will be electronically transcribed by the site designee onto the eCRF (data entry 
screens) in the EDC database system or entered directly into the eCRF without further written 
documentation available. The relevant sections of the eCRF must be completed without undue delay. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. The investigator shall provide justification for any missing data and must document 
this as deviation. The Investigator can delegate EDC entries to a study team member, this delegation 
must be documented in Site Delegation Log. The Investigator is ultimately responsible for the accuracy 
of the data collected in the eCRF.  

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All study data will be entered into the eCRF. The information in the eCRF will not identify the 
participant by name, only by his/her study Participant Identification Number and initials. The  Principal 
Investigator maintains (and has continual access to) the site9s Participant List in the secure EDC system. 
This list includes the site9s participants9 name, Participant Identification Number, device kit number, 
cell phone and landline phone number(s), if applicable, email address, and physical address. This 
section of the EDC will be blinded to Sponsor and CRO. 
Participants will only be identified by their study Participant Identification Number (not name), in the 
data analysis as well as in all communications and publications of results. 
The CRO will be responsible for the data management for the study. Full details about the data 
management are described in the Data Management Plan for the study. This plan will include 
specifications for consistency and plausibility checks on data and also include data handling rules. 
Queries resulting from automated checks will be available for sites during data entry. Obvious data 
errors will be treated according to the established rules for the study and queries for unresolved issues 
will be created in the EDC system. All missing or spurious will be subjected to review. All data will be 
considered for analysis as specified in the Statistical Analysis Plan.  
17.2 Source data 
Source data includes all information in original records and certified copies or original records of 
clinical findings, observations, or other activities in a clinical investigation used to reconstruct and 
evaluate the study. Source documents include hospital records, laboratory findings, completed scales, 
images and reports etc. The source documents will be retained at the site but the 
Investigator/Institution will permit direct access to source data/documents for study related 
monitoring, Sponsor audits, representatives from the Ethics Committee and regulatory inspections. 
Site will ensure copies of patient data for distribution is redacted of patient identifiers. 
The legal basis for accessing the medical records, including monitoring, audits and inspections will be 
the consent for participation provided by study participants.  
17.3 Database lock and Record retention 
At the conclusion of the study, the database will be locked once all subjects have a final status, queries 
have been resolved and any protocol deviations have been addressed. All edit/write access to the 
database will be removed and changed to view-only. Each participating site will receive a file of their 
site9s data, including raw and final eCRF data and audit trail. Study documents and data should be 
retained for a minimum of 15 years after the close-out of the study and until there are no pending or 
contemplated marketing applications. These documents should be retained for a longer period, 
however, if required by local regulations. No records will be destroyed without the written consent of 
the sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
18 Device accountability 
When individual sites are activated within the EDC system, the Sponsor and site are alerted which 
device study kits they should expect to receive along with pertinent information of devices, based on 
a predefined site level ceiling. The Sponsor ships device study kits to site and site will then log the 

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receival in the system, thereby making the device study kits available to the study participants.  When 
the number of device study kits at a site reaches a predefined minimum quantity of inventory, the EDC 
system will generate a re-order and new stock will be shipped from the Sponsor. Automated status 
reports can be generated from the system at all times. Such status reports may include inventory at a 
given site, audit history on a per item basis or an audit history of e-mail notifications sent out by the 
system. 
 
19 Supporting Documentation and Operational Considerations 
19.1 Study Oversight 
The sponsor will be responsible for the following tasks and activities, performed either by the sponsor 
or a Contract Research Organization (CRO) employed by the sponsor:  
- 
Overall project management to ensure adherence to the clinical investigation plan, and timely 
conclusion of the study.  
- 
Training investigators in study procedures, study devices and the EDC system. 
- 
Ensuring that all sites receive all test devices, study equipment and documents.  
- 
Performing study site activations and monitoring. 
- 
Supporting the study sites with patient recruitment (including producing and publishing 
advertisements of the study). 
- 
Collaborating with the investigators on handling, reporting and following up on SAE9s. 
19.2 Quality Management 
19.2.1 Site Selection 
Principal Investigators and investigational sites will be selected by Sponsor based on their experience, 
training, qualifications and availability of resources for study conduct. PIs must be legally entitled to 
perform clinical research and to participate in clinical investigations of medical devices. Sites will be 
selected after screening procedures and upon review of a site assessment and PI qualification. A site 
qualification visit (onsite or remote) will be performed to ensure site facilities are adequate and site 
staff and other resources are available for study conduct.  
19.2.2 Training 
All Principal Investigators and site staff are required to attend training on the investigational medical 
device (IMD) and study procedures. Training will include, but is not limited to, the protocol, IMD usage, 
EDC completion, applicable legislation and PI responsibilities. All training will be documented in a 
Training Log. 
The Principal Investigators acknowledge that the medical devices are investigational and must be 
treated accordingly. The Principal Investigators have the overall responsibility for the administration 
and accountability of the IMDs and the Sham Devices at their respective sites. This responsibility can 
be delegated to another study staff member. Delegation must be documented in a Delegation Log. 

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19.2.3 Monitoring 
The study will be monitored throughout study duration according to the Monitoring Plan.  
Study monitors are designated to oversee the progress of the study. The monitors are appropriately 
trained and qualified and monitoring will be carried out according to ISO 14155:2020 and applicable 
SOPs and Working Instructions. 
Data monitoring and management will be performed in the EDC database system by the study clinical 
monitor. 
The study monitor will conduct remote monitoring at a minimum of the following time points: 
1. As part of the site9s activation 
2. At a time point maximum two business days after the first participant has been included at 
the site  
3. At the close out of the site  
The study monitor must confirm that the procedures described in the clinical investigation plan are 
adhered to, including: 
1. Electronic Case Report Forms will be reviewed to ensure accurate and complete collection of 
data 
2. Confirmation of timeliness and quality of data entry 
3. Review of query resolution 
4. Review of EDC to check for protocol compliance 
5. Review of site9s completion of outstanding action items 
6. Assessment of site9s subject recruitment end enrolment 
7. Training of site staff 
8. Confirmation that a medical record exists for each participant 
The study monitor is also responsible for verifying that the appropriate measures are adhered to 
regarding any adverse events. The study monitor must perform full verification of the presence of 
signed informed consent forms.  
This study will incorporate risk-based monitoring (RBM) practices to ensure data integrity for the 
study.  Risk based monitoring allows for targeted review of critical data by assessing Site and Study 
level Key Risk Indicators (KRIs) throughout the study and determining where monitoring efforts are 
best employed.  Data metrics from the EDC system, organized by site, will be reviewed during regular 
RBM meetings.  This process will be detailed in the Monitoring Plan.  Key Risk Indicators include: 
informed consent form (ICF) signed, inclusion/exclusion criteria, enrolment rate per month, number 
of protocol deviations, visits performed with protocol windows, adverse event reporting and query 
management.  During the RBM meetings, the sites will be categorized into High, Medium or Low Risk, 
based on the site evaluations performed.  The frequency of data review and percentage of participants 
checked will be adjusted based on the incidence rate of deviations and the enrolment rate. 
The site investigators and sponsor will allow direct access to source data and other study documents 
at auditing and/or inspection from Sponsor and its representatives, Ethical Committees/Institutional 
Review Board and Competent Authorities. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
study is conducted and data are generated, documented (recorded), and reported in compliance with 
the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), the 

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International Organization for Standardization (ISO) 14155:2020 Clinical investigation of medical 
devices for human subjects – Good Clinical Practice and applicable regulatory requirements.  
19.3 Protocol deviations 
A protocol deviation is any noncompliance with the Clinical Investigation Plan. The non-compliance 
may be either on the part of the participant, the investigator, or the study site staff.  
The Principal Investigator is not allowed to deviate from the CIP, except to protect the patient9s rights, 
safety and well-being. Such deviations will be documented and reported to the Sponsor and REC/IRBs 
as per national/local requirements. 
A deviation may be identified by the site itself, the monitor, data manager, or Clinical Project Manager. 
Deviations must be reported to Principal Investigator and/or Sponsor within five (5) working days. 
Sponsor is responsible for the assessment of the deviation and its impact on the participant(s) or the 
scientific validity of the study. Reportable deviations will be reported to involved authorities according 
to local requirements. Sponsor will determine the need for corrective and preventive actions. The 
Principal Investigator shall be informed in writing of the violation and the actions to be taken. Sponsor 
will assess all CIP deviations periodically for trends, this will be performed for both systematically 
reoccurring deviations across sites and for site(s) that are consistently associated with the CIP 
deviations. 
Investigators will be evaluated based on any CIP deviations affecting the integrity of the data and/or 
participant safety. Such evaluation may result in suspension of further enrolment at their site(s) or 
disqualification. Criteria for suspension are: 
- 
CIP deviations specifically related to eligibility criteria, device accountability or participant 
safety 
- 
Corrective actions pertaining to CIP deviations not implemented by site 
 
19.4 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, the Contract Research Organization, and the sponsor, to the extent provided by applicable laws 
and regulations. This confidentiality is extended to cover the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB/REC 
and/or regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. The clinical study site will permit access to such records. 
Study participant research data intended for statistical analysis and scientific reporting will be 
captured in the EDC system. After the conclusion of the study, the data will be transferred to a secure 
database maintained by the sponsor.  The transferred data will not include the participants9 contact 
details or identifying information. Rather, individual participants and their research data will be 
identified by their unique Participation Identification Number. The study data entry and study 

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management systems used by clinical sites and by sponsor research staff will be secured and password 
protected. 
19.5 Participant Discontinuation or Withdrawal from the Study 
Participants leaving the study will not be replaced by new participants. 
All participants have the right to withdraw consent and discontinue participation without prejudice at 
any time during the study. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
- 
Significant study non-compliance. 
- 
If any clinical AE, laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study is judged not to be in the best interest of the 
participant 
- 
Lost to follow up 
- 
Serious or repeated deviation detected by Sponsor at site audits 
For participants wishing to leave the study, the study personnel must ask their permission to contact 
them regarding any side effects or possible adverse events that may have contributed to their 
decision.   
The PI must inform the Sponsor of the discontinuation of a participant by completing the relevant 
section of the eCRF. No new data is collected from the participant after withdrawal from the study. In 
order to preserve the scientific integrity of the study, the study data collected up until the point when 
the participant leaves the study will not be deleted.   
In case of a serious adverse event occurring, the participant is asked to consider not exiting the study 
before resolution of the event.  However, participants are made fully aware that participation is 
voluntary at all times throughout the study. 
19.6 Study Discontinuation or Suspension 
The sponsor may choose to temporarily suspend or prematurely terminate the study or a study site 
with or without cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the sponsor, as applicable, to the investigator, regulatory authorities 
and REC/IRB. If the study is prematurely terminated or suspended, the Principal Investigator (PI) at 
each clinical site will promptly inform, as applicable, study participants, the REC/IRB, and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of any changes to the study. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
- 
Determination of unexpected, significant, or unacceptable risk to participants 
- 
Demonstration of effectiveness that would warrant stopping    
- 
Insufficient compliance to protocol requirements 
- 
Data that are not sufficiently complete and/or evaluable 
- 
Determination that the primary endpoint has been met 
- 
Determination of futility 
Study and/or study site may resume once concerns about safety, protocol compliance, and data 
quality are addressed, and satisfy the sponsor, IEC and/or relevant regulatory body. 

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19.7 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for at least one scheduled 
visit and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
- 
The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain if 
the participant wishes to and/or should continue in the study. 
- 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, three telephone calls and, if 
necessary, a certified letter to the participant9s last known mailing address, or local equivalent 
methods). These contact attempts should be documented in the participant9s medical record 
or study file.  
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with the primary reason of lost to follow-up.  
19.8 End of Study Definition 
A participant is considered to have completed Stage 1 of the study if the participant has completed 
Site Visit 2. A participant is considered to have completed Stage 2 of the study if the participant has 
completed the End-of-Stage-2 follow-up. The end of the study is defined as the completion of the last 
participant9s End-of-Stage-2 follow-up, or withdrawal from the study of the last participant. The End 
of Study Form in the eCRF must be completed by the PI. 
After completion of the study, an integrated comprehensive Clinical Study Report will be prepared by 
Sponsor. 
20 Ethical Considerations 
20.1 Compliance statement 
This study will be conducted in accordance with the Declaration of Helsinki, this Clinical Investigation 
Plan and applicable national and local laws and regulations. In writing the clinical investigation plan, 
we have adhered to the standard ISO-14155 and US regulation 21 CFR regarding clinical studies of 
medical devices according to Good Clinical Practice. This compliance includes the protection of the 
rights, safety and well-being of human subjects, controls to ensure the scientific conduct, credibility 
and data integrity of the clinical investigation as well as the clear definitions of responsibilities of the 
Sponsor and Principal Investigators. 
The Sponsor will avoid improper influence on or inducement of the subject, monitor, any investigators, 
or other parties participating in, or contributing to the clinical investigation. 
The Principal Investigators are not allowed to deviate from the CIP, unless there is a need to maintain 
the participant9s rights, safety and well-being or the scientific integrity of the investigation. The 
principles of the Declaration of Helsinki are implemented in this study by the use of the informed 
consent process, ethical review, study training, registration of study in publicity available database, 
publication policy and risk benefit assessment. 

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The investigation will not begin until the required regulatory and ethical approvals are obtained. In 
addition, any additional requirements of the individual study site, local REC/IRB and any regulatory 
body will also be followed.  
The study will be registered prior to first enrolment, in the database https://clinicaltrials.gov/ 
The study will adhere to all regional and local legislation concerning the collection and processing and 
safekeeping of personal data. Information about the participants is handled according to the 
appropriate regional and local data protection laws. All participants enrolled or screened in the study 
will be anonymous vis-a-vis the public and will not be identifiable from any published report or article 
on the study9s findings. 
The study data analysis only uses data collected as part of the study and does not use information 
obtained from patient files.   
20.2 Modifications to the Clinical Investigation Plan 
Sponsor or an individual Investigator can take initiative to modify the clinical investigation. 
Investigators/sites shall not make modifications to this protocol or any other study documentation 
without prior written approval from the Sponsor. All approved modifications must be described and 
duly justified. The modifications must be classified as either substantial or non-substantial. Substantial 
amendments will be submitted to the relevant authorities for approval. Substantial amendments with 
a substantial impact on the safety, health or rights of the participants or the robustness or reliability 
of the clinical data will not be implemented until approval by authorities. Non-substantial 
amendments are submitted for notification. The use of CIP waivers is strictly prohibited. 
20.3 Responsibility of the Principal Investigator(s) 
The individual Principal Investigator is responsible that the conduct of study at the study site is in 
compliance with the CIP, the Declaration of Helsinki and Good Clinical Practice. In addition, the PI is 
responsible for complying with any relevant local requirements at their study site. The Principal 
Investigator will ensure that all staff delegated to the study have the appropriate qualifications and 
that they have completed relevant study trainings and are GCP certified. 
20.4 Informed Consent Process 
Study activities for a given patient will not be initiated until informed consent has been obtained from 
them. 
Before signing the informed consent, each patient will receive verbal and written information about 
the study and investigational device, study procedures, and risks. The study will be explained in lay 
language. The participant will also have the opportunity to ask questions they have about the study.   
The Principal Investigator or delegated staff must obtain written consent from the eligible participants 
prior to any study procedures, using the most recent approved informed consent form. A verbal 
explanation of the informed consent form will be provided in terms suited to the participant9s 
comprehension of the purposes, procedures, alternative treatments, and potential risks and benefits 
of the study and of their rights as research participants. Each participant will be provided the time 
necessary for them to read and understand the informed consent form and get the opportunity to ask 
questions they have about the study before signing.  

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The participants will have the opportunity to discuss the study with their family and/or think about it 
prior to agreeing to participate.  
Participants will be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice and that they will in case of withdrawal not lose the right to any 
treatment which they were otherwise entitled to. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected 
if they decline to participate in this study or drop out at a later date. If any new information becomes 
available that may affect the participant9s willingness to continue in the study, the Principal 
Investigator will inform the participant and ask if he/she wishes to continue in the study. 
20.5 Insurance and compensation 
The Sponsor has an insurance coverage for the treatment of participants in the event of injuries 
related to the clinical investigation, according to national regulations. 
Participants will not receive payments for participation in the investigation. However, documented 
expenses such as travel and parking will be covered. 
20.6 Financial Disclosure and Conflict of Interest 
This study is initiated by and financed by Sponsor. Sites are reimbursed for all their expenses related 
to the study, including time and resources spent. Sponsor will provide all study devices and pay for all 
expenses related to the conduct of this study.  Investigational sites and investigators with a financial 
interest in the outcome of the study will not be allowed to participate in the study as sites or 
investigators respectively.  
21 Publication policy 
Sponsor and Principal Investigators are committed to dissemination of study results. Results will not 
be withheld regardless of the findings.  
The data and statistical analyses from Stage 1 and Stage 2 will be presented in scientific articles (one 
or more for each Stage) which will be submitted to a peer-reviewed journal in the field of headache, 
pain medicine or general neurology.  Data and manuscripts will not be released before approval by 
Principal Investigators. All Principal Investigators will be listed as authors on abstracts and 
publications.  All proposed publications and presentations resulting from or relating to the study 
(either from single sites or multiple sites) must be reviewed and approved by Sponsor before release.  
The clinical investigation will be pre-registered in the database clinicaltrials.org.  
 
 

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