A Randomized, Placebo-controlled, Double-blind, Multicenter Study to Evaluate the Efficacy of Intranasal Kinetic Oscillation Stimulation in the Preventive Treatment of Chronic Migraine
Phase: NA
Conditions: Chronic Migraine
Sponsor: Chordate Medical

 
CLINICAL INVESTIGATION PLAN 
 
A randomized, placebo-controlled, double-blind, multicenter 
study to evaluate the efficacy of intranasal kinetic oscillation 
stimulation in the preventive treatment of chronic migraine 
 
Study code: 
PM007 
Document code: 
1002670E 
Sponsor: 
Chordate Medical AB 
Norgegatan 2 
164 32 Kista, Sweden 
 
Visiting and delivery address from  
01-Apr-2018: 
Chordate Medical AB 
c/o Regus 
Kistagången 20B 
164 40 Kista, Sweden 
Coordinating investigator: 
 
Department of Systems Neuroscience 
University Clinic Hamburg-Eppendorf 
(UKE) 
Martinistrasse 52 
20246 Hamburg, Germany 
Clinical investigation plan version and date: 
Final 7.0, 14-Jun-2021 
Previous clinical investigation plan versions 
and date: 
Final 1.0, 02-Nov-2017 
Final 2.0, 21-Feb-2018 
Final 3.0, 14-Mar-2018 
Final 4.0, 06-Mar-2019 
Final 5.0, 27-Nov-2019 
Final 6.0-FIN, 05-Nov-2020 

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This clinical investigation plan must be kept strictly confidential. Disclosure of the contents (in 
whole or part) to third parties is permissible only with written consent of Chordate Medical AB.  

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Revision chronology 
• Original version: Version 1.0, dated 02-Nov-2017 
• Version 2.0, dated 21-Feb-2018 
The following changes were included in Version 2.0 compared to Version 1.0: 
o The coordinating investigator was replaced. 
• Version 3.0, dated 14-Mar-2018 
The following changes were included in Version 3.0 compared to Version 2.0 
o The assessment of the migraine disability assessment score (MIDAS) was 
removed; 
o The reporting processes of serious adverse events, pregnancies, and device 
deficiencies were changed from eCRF-based reporting to paper-based reporting 
and additional clarifications were added; 
o The documentation of headache and migraine days in the eCRF was clarified; 
o The pregnancy testing at Visit V1, V2, V3, V4, V5, V6, and V7 were removed; 
o The visiting and delivery address of Chordate changed starting on 01-Apr-2018 
and was updated accordingly. 
• Version 4.0, dated 06-Mar-2019 
The following changes were included in Version 4.0 compared to Version 3.0 
o The study design was changed to a 2-stage group-sequential design with one 
interim analysis that allows the premature termination of the study due to 
efficacy or futility or adaption of the sample size (described in detail in newly 
added Section 13.3; Sections 3 and 11.3.5 were updated accordingly); 
o Because of the newly introduced 2-stage group-sequential design, the sample 
size calculation was updated (Section 13.5) and the number of subjects to be 
enrolled was increased from previously 140 to 148 subjects (Sections 3, 11.3.1, 
and 11.3.5 were updated accordingly);  
o Another secondary performance endpoint was added (Sections 3 and 11.1.2): 
Mean change from Baseline in monthly headache days (mild, moderate and 
severe intensity) in 4-week performance assessment period (V3 to V7), and its 
analysis described in Sections 3 and 13.2. 
• Version 5.0, dated -2019 
The following changes were included in Version 5.0 compared to Version 4.0 
o Finland was added as second study country; 

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o Addresses and names of involved sites were added; 
o The documentation processes of patient data were changed from eCRF-based 
reporting to paper-based reporting 
• Version 6.0-FIN, dated 05-Nov-2020 
The following changes were included in Version 6.0-FIN compared to Version 5.0 
o Addition of optional SARS-CoV-2 Test at treatment visits 
• Version 7.0, dated 14-Jun-2021 
The following changes were included in Version 7.0 compared to Version 6.0-FIN  
o Safety part of the protocol was adapted according to EN ISO 14155:2020 and 
Regulation (EU) 2017/745 
• Version 7.0, dated 14-Jun-2021 
The following changes were included in Version 7.0 compared to Version 5.0  
o Safety part of the protocol was adapted according to EN ISO 14155:2020 and 
Regulation (EU) 2017/745 
o Addition of optional SARS-CoV-2 Test at treatment visits 
 
 

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Statement of compliance  
This clinical investigation will be conducted in compliance with the clinical investigation plan 
(CIP) and the following regulatory requirements:  
• International Standard ISO 14155:2011: Clinical investigation of medical devices for 
human subjects - Good clinical practice (GCP) 
• Declaration of Helsinki adopted by the 18th World Medical Assembly in Helsinki, Finland, 
in 1964, in its currently acknowledged revision 
• Applicable sections of the national medical device law 
By acting in accordance with this CIP, the investigators and the study site personnel fulfil the 
requirements of the International Standard ISO 14155:2011. 
The clinical investigation will not commence until a favorable opinion from the respective 
ethics committees (ECs) and an authorization from the competent authority (CA) has been 
received. All additional requirements imposed by the ECs and/or the CA will be followed. 
Insurance coverage as required by national legislation has been taken out for this clinical 
investigation. 

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1 
Table of contents 
 
Page 
Revision chronology ....................................................................................................... 3 
Statement of compliance ................................................................................................. 5 
1 
Table of contents .......................................................................................... 6 
2 
Abbreviations and definition of terms ....................................................... 10 
3 
Synopsis and schedule of assessments ....................................................... 12 
4 
Addresses and responsibilities ................................................................... 20 
5 
Background information and scientific rationale ....................................... 22 
6 
Identification and description of the investigational medical device ......... 24 
6.1 
Device description ..................................................................................... 24 
6.2 
Storage and operating information............................................................. 25 
6.3 
Manufacturer .............................................................................................. 25 
6.4 
Indication ................................................................................................... 26 
7 
Justification for the design of the clinical investigation ............................ 26 
7.1 
Pre-clinical experiences and biocompatibility ........................................... 26 
7.2 
Clinical experience..................................................................................... 26 
7.3 
Justification for the clinical investigation .................................................. 27 
8 
Risks and benefits of the investigational device and clinical investigation
.................................................................................................................... 28 
8.1 
Potential risks ............................................................................................. 28 
8.2 
Potential benefits ........................................................................................ 30 
8.3 
Risk benefit rationale ................................................................................. 31 
9 
Investigators and administrative structure of the clinical investigation..... 31 
10 
Objectives of the clinical investigation ...................................................... 31 
11 
Design of the clinical investigation............................................................ 32 
11.1 
General ....................................................................................................... 32 
11.1.1 
Description of the design of the clinical investigation ............................... 32 
11.1.2 
Primary and secondary endpoints .............................................................. 32 
11.1.3 
Subject identification ................................................................................. 33 
11.1.4 
Duration of the clinical investigation ......................................................... 33 
11.2 
Treatments, precautions and restrictions.................................................... 33 
11.2.1 
Investigational device ................................................................................ 33 

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11.2.2 
Precautions and restrictions ....................................................................... 34 
11.2.3 
Methods of assigning subjects to device groups ........................................ 34 
11.2.4 
Investigational medical device accountability ........................................... 35 
11.2.5 
Previous and concomitant medications and treatments ............................. 35 
11.3 
Subjects ...................................................................................................... 36 
11.3.1 
Number of subjects .................................................................................... 36 
11.3.2 
Inclusion criteria ........................................................................................ 36 
11.3.3 
Exclusion criteria ....................................................................................... 36 
11.3.4 
Subject withdrawal..................................................................................... 37 
11.3.5 
Subject enrollment, number, and duration of subject’s participation ........ 38 
11.4 
Procedures and assessments ....................................................................... 39 
11.4.1 
Diary .......................................................................................................... 39 
11.4.2 
Questionnaires............................................................................................ 39 
11.4.2.1 
Headache impact test ................................................................................. 39 
11.4.2.2 
MSQ ........................................................................................................... 39 
11.4.3 
Patient global impression of severity ......................................................... 39 
11.4.4 
Physical examination ................................................................................. 39 
11.4.5 
Other assessments ...................................................................................... 40 
11.4.6 
Factors that may compromise the outcome ............................................... 40 
11.4.7 
Appropriateness of measurements ............................................................. 41 
11.5 
Schedule of the clinical investigation ........................................................ 41 
11.5.1 
Screening.................................................................................................... 41 
11.5.2 
Treatment ................................................................................................... 42 
11.5.3 
Follow-up (Day 70 ± 3 days) ..................................................................... 43 
11.5.4 
Early termination ....................................................................................... 43 
11.5.5 
Medical care upon termination of the clinical investigation ...................... 43 
11.6 
Clinical monitoring .................................................................................... 43 
11.7 
Training of staff ......................................................................................... 44 
12 
Adverse events, adverse device effects, and device deficiencies .............. 44 
12.1 
Definitions of adverse events and adverse device effects .......................... 44 
12.2 
Reporting of adverse events ....................................................................... 45 
12.2.1 
Methods for eliciting adverse events ......................................................... 45 
12.2.2 
Recording of adverse events ...................................................................... 46 
12.3 
Assessment of adverse events .................................................................... 46 

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12.4 
Reporting of serious adverse events .......................................................... 48 
12.5 
Follow-up of adverse events ...................................................................... 50 
12.6 
Pregnancy ................................................................................................... 50 
12.7 
Foreseeable adverse events and anticipated adverse device effects .......... 50 
12.8 
Device deficiencies .................................................................................... 50 
12.8.1 
Definition of a device deficiency ............................................................... 50 
12.8.2 
Recording and reporting of product deficiencies ....................................... 50 
12.8.3 
Handling of deficient medical devices ....................................................... 51 
13 
Statistical considerations ............................................................................ 51 
13.1 
Analysis sets............................................................................................... 51 
13.2 
Statistical analyses ..................................................................................... 52 
13.3 
Interim analysis .......................................................................................... 55 
13.4 
Blind data review meeting ......................................................................... 56 
13.5 
Sample size calculation .............................................................................. 56 
14 
Data handling and record keeping ............................................................. 57 
14.1 
Case report forms and data collection ........................................................ 57 
14.2 
Subject records and source data ................................................................. 58 
14.3 
Data management procedures .................................................................... 58 
14.4 
Data retention ............................................................................................. 59 
14.5 
Report of the clinical investigation ............................................................ 59 
15 
Ethical and regulatory considerations ........................................................ 59 
15.1 
Good Clinical Practice ............................................................................... 59 
15.2 
Ethics Committee ....................................................................................... 60 
15.3 
Regulatory requirements ............................................................................ 60 
15.4 
Insurance .................................................................................................... 60 
15.5 
Informed consent process .......................................................................... 60 
15.6 
Subject confidentiality ............................................................................... 61 
16 
Amendments to and deviations from the CIP ............................................ 61 
16.1 
Amendments .............................................................................................. 61 
16.2 
Deviations .................................................................................................. 62 
17 
Suspension or premature termination of the clinical investigation ............ 62 
18 
Unblinding ................................................................................................. 63 
19 
Publication policy ...................................................................................... 63 
20 
Approval and signatures ............................................................................ 64 

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21 
References .................................................................................................. 66 

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2 
Abbreviations and definition of terms 
 
ADE 
Adverse device effect 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ASADE 
Anticipated serious adverse device effect 
BDRM 
Blind data review meeting 
CA 
Competent authority 
CGRP 
Calcitonin gene-related peptide 
CIP 
Clinical investigation plan 
CRO 
Contract research organization 
CSF 
Cerebrospinal fluid 
DMC 
Data monitoring committee 
EC 
Ethics committee 
eCRF 
Electronic case report form 
pCRF 
Paper case report form 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
GWAS 
Genome-wide association studies 
HIT-6 
Headache impact test-6 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICHD 
International Classification of Headache Disorders 
ID 
Identification 
IFU 
Instructions for Use 
IHS 
International Headache Society 
KOS 
Kinetic oscillation stimulation  
MDD 
Medical Device Directive 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSQ 
Migraine-specific quality of life questionnaire 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
PACAP-38 
Pituitary adenylate cyclase-activating peptide 
PGI-S 
Patient global impression of severity 
PP 
Per protocol 
PPS 
Per protocol set 
PT 
Preferred term 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 

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SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SDV 
Source data verification 
SOC 
System organ class 
TCC 
Trigeminocervical complex 
US 
United States 
USADE 
Unanticipated serious adverse device effect 
V 
Visit 
 

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3 
Synopsis and schedule of assessments 
Study code  
PM007 
Title of the study 
A randomized, placebo-controlled, double-blind, multicenter study to evaluate the efficacy of 
intranasal kinetic oscillation stimulation in the preventive treatment of chronic migraine 
Principal investigators and study centers  
5 centers in Germany and max. 6 centers in Finland 
Coordinating investigator 
 Department of Systems Neuroscience, University Clinic Hamburg-
Eppendorf (UKE), Martinistrasse 52, 20246 Hamburg, Germany. 
Duration of clinical investigation (planned)  
The overall duration of the clinical investigation including enrollment and treatment of all 
subjects is anticipated to be about 3.5 years with an expected enrollment period of 
about36 months. 
The duration of the clinical investigation for each participating subject is about 14 weeks.  
Study objectives 
Primary objective: 
• To evaluate the effect of intranasal kinetic oscillation stimulation using the Chordate System 
S211 on monthly headache days with moderate to severe intensity. 
Secondary objectives: 
• To evaluate the effect of treatment with the Chordate System S211 on monthly migraine 
days, responder rate, use of abortive medication, health-related quality of life and disability, 
and patient’s global impression of severity;  
• To evaluate the incidence and severity of adverse events (AEs) and adverse device effects 
following treatment with the Chordate System S211. 
Methodology 
This is a randomized, placebo-controlled, double-blind, multicenter clinical investigation of a 
medical device. The study consists of a 4-week screening period, a 6-week treatment period (2 
weeks run-in and a 4-week observation window to assess the treatment effect), and a 4-week 
follow-up period. 
Subjects who provided written informed consent and are eligible for the study will be asked to 
complete a daily diary for 4 weeks during the screening period. In the diary the subjects will 

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record headache and migraine days, any changes in their health, and concomitant medications 
they may be using. The data collected in the diary during this screening period will be used as 
Baseline for the performance assessments. 
Subjects who completed the screening period and continue to meet the eligibility criteria after 
review of diary entries by the investigator will be randomized (stratified by medication overuse) 
in a 1:1 ratio to receive either active or placebo treatment. The subjects will receive 6 treatments 
with the Chordate System S211 at weekly intervals at the site (Day 0 to 35; treatment Visit [V] 
1 to 6) and continue to maintain a daily diary. One week after the last treatment, an end of 
treatment visit will be performed on Day 42 (V7). 
After completion of the 6-week study treatment period (V1 to V7), subjects will be followed 
up for another 4 weeks. The final visit will be performed on Day 70, 5 weeks after the last study 
treatment. During the 4-week follow-up, the subjects will continue to complete a daily diary. 
The study will be performed according to a 2-stage group-sequential design with one interim 
analysis that allows the premature termination of the study due to efficacy or futility or adaption 
of the sample size.  
Medical device and application 
Chordate System S211 consisting of the Chordate Controller, the Chordate Catheter and the 
Chordate Headband. The device stimulates the subject’s nasal mucosa by means of mechanical 
pressure and vibrations at low frequencies. The treatment time will be 10 minutes in each cavity 
(a total of 20 minutes per treatment) at 85 Hz and 80 mbar. 
Number of subjects planned 
Approximately 148 subjects will be enrolled to achieve at least 132 subjects evaluable for the 
primary performance endpoint (assuming a drop-out rate of 10%), with 66 subjects receiving 
treatment with the Chordate System S211 and 66 subjects receiving treatment with the Chordate 
System S211 in placebo mode. If, during the conduct of the study, the drop-out rate proves to 
be higher than expected (>10%), enrollment will continue until at least 132 subjects were 
assessed for the primary endpoint. A group-sequential design with one interim analysis after 
approximately 50 subjects have completed the 6-week study treatment period will be used. It 
will allow the premature termination of the study due to efficacy or futility or adaption of the 
sample size. 
Subject population 
Subjects with diagnosed chronic migraine meeting all inclusion criteria and none of the 
exclusion criteria will be eligible for the study. 

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Inclusion criteria 
1. The subject is legally competent, has been informed of the nature, the scope and the 
relevance of the study, voluntarily agrees to participation and the study’s provisions, 
and has duly signed the informed consent form; 
2. Male or female aged between 18 and 65 years (inclusive) at the time of providing 
informed consent; 
3. Diagnosed as suffering from chronic migraine with or without aura (≥15 headache 
days per month for more than 3 months before screening including at least 8 migraine 
days) according to the International Headache Society classification (International 
Classification of Headache Disorders III beta); 
4. Migraine onset before the age of 60 years; 
5. Reported history of migraine for at least 1 year before screening; 
6. Reported stable prophylactic migraine medication regimen, if any, during the 3 months 
prior to screening; 
7. Able and willing to maintain current prophylactic migraine medication regimen (no 
change in type, frequency or dose) from screening to end of follow-up; 
8. Women of childbearing potential must be willing to use highly effective contraceptive 
methods (failure rate <1% per year when used consistently and correctly) during the 
study. 
Exclusion criteria 
1. Unable to distinguish between migraine headaches and other headache types; 
2. Treatment with Botox in the head/neck area within 4 months of the screening visit, or 
planned Botox treatment during the study; 
3. Previous or ongoing treatment with an implanted stimulator or other implanted device 
in the head and/or neck; 
4. Known pronounced anterior septal deviation, or other known relevant abnormality in 
the nasal cavity, including bacterial infection and wounds; 
5. History of relevant sinus surgery, transsphenoidal surgery for pituitary or other lesions 
or cerebrospinal fluid rhinorrhea; 
6. Fitted with a pacemaker/defibrillator; 
7. Previously treated with therapeutic x-ray intervention in the facial region (that could 
have influenced the nasal mucosa); 
8. Ongoing upper respiratory infection or malignancy in the nasal cavity;  

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9. History of regular nose bleeding (epistaxis), or concomitant condition or medication 
that could cause excessive bleeding including treatment with an anticoagulant; 
10. Head injury or open wound that contraindicates use of the Chordate Headband; 
11. Known allergy to polyvinylchloride, a material used in the Chordate Catheter, or 
medicinal liquid paraffin; 
12. Concurrent condition or risk of non-compliance that, in the investigator’s opinion, may 
affect the interpretation of performance or safety data or which otherwise 
contraindicates participation in a clinical investigation; 
13. Pregnant and lactating women; 
14. Participation in a clinical investigation within 3 months of enrolment or planned 
participation at any time during this clinical investigation; 
15. Previous participation in this study; 
16. Employees of the study site or the sponsor directly involved with the conduct of the 
study, or immediate family members of any such individuals; 
Previous and concomitant treatments 
Subjects using a stable regimen of prophylactic migraine medication will be required to 
maintain this regimen from screening to end of follow-up and no new prophylactic treatment 
may be initiated during that time. Subjects on unstable dose(s) of prophylactic migraine 
medication(s) 3 months prior to screening will not be enrolled. 
Subjects can use their regular acute (abortive) migraine medication, when necessary, during the 
course of the clinical investigation. However, all such use must be documented in the study 
specific diary. 
Criteria for evaluation 
Performance endpoints 
Primary performance endpoint: 
• Mean change from Baseline (4-week screening period) in monthly headache days with 
moderate to severe intensity in 4-week performance assessment period (V3 to V7). 
Secondary performance endpoints: 
• Mean change from Baseline in monthly headache days with moderate to severe intensity in 
follow-up period; 
• Mean change from Baseline in monthly migraine days; 
• Mean change from Baseline in monthly headache days (mild, moderate and severe 
intensity) in 4-week performance assessment period (V3 to V7); 

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• Proportion of subjects with 30% or greater reduction in headache days of moderate to severe 
intensity; 
• Proportion of subjects with 50% or greater reduction of headache days of moderate to severe 
intensity; 
• Change in the use of acute (abortive) medication; 
• Change in migraine-specific quality of life questionnaire (MSQ), headache impact test-6 
(HIT-6), and patient global impression of severity (PGI-S). 
Safety endpoint: 
• Frequency, severity, device-relationship, and outcome of AEs. 
Statistical methods 
Primary performance analysis 
The primary endpoint will be analyzed by an analysis of covariance with treatment, baseline 
number of headache days, and medication overuse as independent variables with the following 
null hypothesis: 
H0: μactive = μplacebo 
versus 
H1: μactive ≠ μplacebo 
where μ is the mean change from Baseline (4-week screening period) in monthly headache days 
with moderate to severe intensity in 4-week performance assessment period (V3 to V7). If the 
data is not normally distributed, the van Elteren test will be used with medication overuse as 
strata. In addition, the number of monthly headache days and change from Baseline will be 
presented by descriptive statistics. A group-sequential design with O´Brien & Fleming alpha 
spending function with one interim analysis that allows the premature termination of the study 
due to efficacy or futility or adaption of the sample size will be used.  
Secondary performance and safety analyses  
All statistical tests for secondary performance endpoints are considered exploratory and no 
adjustment for multiplicity is made. All secondary endpoints will be evaluated for the 
performance assessment period and the follow-up period. 
The mean change from Baseline in monthly headache days with moderate to severe intensity in 
the follow-up period, the mean change from Baseline in monthly migraine days (counting 
migraine days instead of headache days), and the mean change from Baseline in monthly 
headache days (mild, moderate and severe intensity) in 4-week performance assessment period 
(V3 to V7) will be analyzed as the primary performance endpoint.  
 

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The proportion of subjects with 30% or greater or 50% or greater reduction in headache days 
of moderate to severe intensity will be analyzed descriptively using frequency tables. The active 
and placebo arm will be compared using a Chi-square test. In case of a low number of subjects 
per group, the Fisher’s exact test will be used. 
The change in the monthly use of abortive medication will be presented by descriptive statistics. 
The change in MSQ, HIT-6 and PGI-S will be presented by descriptive statistics. The change 
from Baseline will be tested using a Wilcoxon rank sum test. 
Safety analyses 
AEs will be presented by descriptive statistics showing the number and proportion of subjects 
with at least one AE overall and by system organ class and preferred term. 

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Schedule of assessments 
 
Screening 
Visit 1 
(V1) 
Visit 2 
(V2) 
Visit 3 
(V3) 
Visit 4 
(V4) 
Visit 5 
(V5) 
Visit 6 
(V6) 
Visit 7  
(V7) 
FUP 
 
D -28 ±3d 
D0 
D7 ±3d 
D14 ±3d 
D21 ±3d 
D28 ±3d 
D35 ±3d 
D42 ±3d 
D70 ±3d 
 
W-4 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W10 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
Medical and surgical history 
X 
X 
Physical examination 
X 
Prior and concomitant medication 
X 
X 
X 
X  
X  
X  
X  
X  
X  
Urine pregnancy test 
X 
 
 
 
 
 
 
  
X  
Randomization 
X 
HIT-6 
X 
X 
X  
 
X 
X  
MSQ 
X 
X 
X 
 
X 
X  
PGI-S 
X 
X 
 
X 
 
 
 
X 
X 
Treatment with Chordate System 
 
X 
X 
X 
X 
X 
X 
 
  
Documentation of adverse events 
Xa 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 Testb 
 
X 
X 
X  
X  
X  
X  
 
 
Reported in paper diary by subject 
Headache / migraine days 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Medications 
X 
X 
X 
X 
X 
X 
X 
X  
X 
a Adverse events will be documented during and after the first treatment with the Chordate System. Any changes in health prior to first treatment will be documented as medical 
history.  b if required by site policy. 
D = Day, d = days, FUP = Follow-up, HIT-6 = Headache Impact Test, MSQ = Migraine Specific Quality of life questionnaire, PGI-S = Patient Global Impression of Severity, 
V = Visit, W = Week. 
 

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Flow chart 
 
 

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4 
Addresses and responsibilities 
 
Sponsor 
 
Chordate Medical AB 
Clinical Research Director:  
Jan Hermansson 
Phone: +46 708467054 
 
 
Norgegatan 2 
 
164 32 Kista, Sweden 
 
 
 
Visiting and delivery address from 01-Apr-2018: 
 
 
Chordate Medical AB 
 
 
 
c/o Regus 
 
 
 
Kistagången 20B 
 
 
 
164 40 Kista, Sweden 
 
 
Contract 
Research 
Organization 
FGK Clinical Research GmbH 
Project Manager 
 
 
Medical Monitor 
 
 
 
Heimeranstr. 35 
80339 Munich, Germany 
 
 
  
 
  
 
Coordinating investigator 
(Leiter der Klinischen 
Prüfung, according to 
German Medical Device 
Law) 
Department of Systems 
Neuroscience 
University Clinic Hamburg-
Eppendorf (UKE) 
 
Phone: 
 
Martinistrasse 52 
 
20246 Hamburg, Germany 
 
Center 01 
Department of Systems 
Neuroscience, University 
Clinic Hamburg-Eppendorf 
(UKE), Martinistrasse 52, 
20246 Hamburg, Germany 
, 
neurologist 
Center 02 
Migräne-Klinik Königstein 
Verwaltungsgesellschaft 
mbH, Ölmühlweg 31, 61462 
Königstein / Ts., Germany 
 
, neurologist 

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Center 03 
Closed 
 
Center 04 
Neurologie- & 
Kopfschmerzzentrum, 
Leopoldstr. 59/II, 80802 
München, Germany 
, neurologist 
Center 05 
Universitätsmedizin 
Rostock, Zentrum für 
Nervenheilkunde, Klinik 
und Poliklinik für 
Neurologie, Gehlsheimer 
Str. 20, 18147 Rostock, 
Germany 
, 
neurologist 
Center 06 
LEWIS Neurologie, 
Rotebühlstrasse 80 70178 
Stuttgart, Germany 
, neurologist 
Center 81 
Suomen Terveystalo Turku, 
Humalistonkatu 9-11, 20100 
Turku, Finland 
, neurologist 
Center 82 
Terveystalo Tampere, 
Rautatienkatu 27, 33100 
Tampere,  Finland 
, 
neurologist 
Center 83 
Terveystalo Ruoholahti, 
Porkkalankatu 22, 00180 
Helsinki, Finland 
, 
neurologist 
Center 84 
Helsingin päänsärkykeskus / 
Aava Itäkeskus, Itäkatu 7, 
00930 Helsinki, Finland 
, neurologist 
 
 
 
 
 

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5 
Background information and scientific rationale 
Migraine is a chronic neurovascular disorder characterized by episodes of head pain that may 
be severe [1]. Associated features such as nausea, vomiting, and sensitivity to light, sound or 
movements are characteristic. Attacks usually last 4 to 72 hours when untreated. Approximately 
30% of patients with migraine have an aura with focal neurological symptoms, usually visual, 
preceding the headache. The one-year prevalence is 11% in the United States (US) and Western 
Europe and the disorder is more common in women. At least 10% of patients have weekly 
attacks and the degree of disability during an attack is considered comparable with having 
quadriplegia.  
Chronic migraine is defined as headache on ≥15 days/month out of which the headache must 
fulfill the International Headache Society (IHS) criteria for migraine on at least 8 days/month. 
The distinction between episodic (<15 headache days) and chronic (≥15 headache days) has 
been made as it is assumed that migraine occurring at a high frequency may involve additional 
pathophysiological features (e.g. a higher degree of neuronal sensitization) that may offer 
additional treatment targets. This assumption is supported by the observation that certain 
treatments (e.g. onabotulinumtoxin A) have only been proven effective in one of the two 
conditions.  
The pathophysiology is incompletely understood. It is thought that an abnormal activation of 
the hypothalamus and the trigeminocervical complex form the basis of the severe attacks. The 
hypothalamus may play a significant role in the initiation of an attack as an abnormal activation 
can already be observed in the 1-2 days preceding the headache, causing the premonitory 
symptoms (yawning, mood changes etc.) of the attack, and lasting throughout the attack into 
the postdrome phase. With the initiation of the headache an activation of the trigeminocervical 
complex (TCC) within the brainstem as well as other key structures which include the thalamus 
and inhibitory areas such as the periaqueductal gray become involved [2].  
During neuronal activation neuromodulatory peptides such as calcitonin gene-related peptide 
(CGRP) and pituitary adenylate cyclase-activating peptide (PACAP-38) are released and 
increase nociceptive neuronal activity. These neuropeptides also induce dilation of cranial 
blood vessels, but the clinical relevance of this vascular response appears to play a minor role 
for the induction and maintenance of migraine attacks. However, the exact mechanism of the 
generation of pain is not known.  
The higher prevalence in women compared to men has been linked to modulating effects of the 
sex hormones estrogen and progesterone [3]. A special form is menstrually-related migraine 
which is likely related to falling levels of sex hormones.  
There is a certain degree of inheritance where the risk of developing migraine is about 80% if 
both parents suffer from migraine, and 60% if one parent has migraine. Genome-wide 
association studies (GWAS) have identified four new genetic variants associated with migraine 
[4]. These variants are linked to either neurotransmitter disturbances or pain related pathways 

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but these variants only confer a small to moderate change in risk for migraine, which concurs 
with migraine being a heterogeneous disorder. 
The pharmacological treatment options of acute migraine attacks include non-specific 
analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and specific treatment with 
serotonin (5-HT1B/1D) receptor agonists (triptans) which are effective exclusively in migraine 
and cluster headache. Triptans act by reducing nociceptive neuronal activity in the TCC and 
other key regions within the affected pain pathway. The molecular mechanism behind this effect 
involves, among others, the inhibition of a release of activating neurotransmitters including 
glutamate and CGRP. Triptans are widely used in the treatment of acute migraine but only on 
average 29% of patients are free of pain 2 hours after dosing, and 20% are sustained pain free 
(pain free at 2 hours and no headache recurrence or use of rescue medication 2-24 hours post 
dose).  
For the preventive treatment of migraine, a number of substances have been shown to 
effectively reduce the number of headache days in a given month. None of the substances 
currently in use for the preventive treatment have been developed for this purpose. These 
include betablockers (mainly metoprolol, propranolol and bisoprolol), calcium antagonists 
(flunarizine), anticonvulsants (topiramate and valproate) and antidepressants (amitriptyline). 
For the preventive treatment of chronic migraine onabotulinumtoxin A has been proven 
effective in reducing the number of headache days per month. Nevertheless, despite an efficacy 
in the overall number of patients, responder rates are far from being satisfactory leaving 
millions of migraineurs without an adequate treatment.  
Transcutaneous vagus nerve stimulation is approved for cluster headache in the US. It is 
administered by transcutaneous stimulation in the neck or in the ear. Anecdotal observations in 
few patients suggest that the stimulation may reduce migraine frequency and intensity [5, 6]. A 
randomized, sham-controlled clinical trial has been conducted but results were not published. 
Thus, migraine is a complex disorder for which the underlying causes and the pathophysiology 
are only partially known. There are many potential targets for pharmacologic and non-
pharmacologic treatments where neuronal stimulation by electric currents has shown promise 
in smaller studies. 
In summary, pharmacologic treatments have not yet provided a complete solution to the 
treatment of migraine as not all patients respond, many patients suffer from substantial side 
effects, many of the used substances have a potential for unwanted drug-drug interactions, 
treatment is often limited or not possible when certain preexisting comorbidities exist and 
finally, most substances are not suitable for children or pregnant women. Therefore, there is 
still an unmet need for safe and effective migraine treatment. 
The Chordate System is a medical device system that is used to administer kinetic oscillation 
stimulation (KOS) in the nasal cavity, which has obtained a CE certification in May 2021. The 
mechanism of action is believed to be that the mechanical stimulation by modulating activity 

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in the sphenopalatine ganglion has a rebalancing effect on the autonomic nervous system such 
that acute migraine attacks can be aborted or diminished. Exploratory treatment of patients with 
migraine demonstrated reduction in migraine pain intensity and attack frequency.    
6 
Identification and description of the investigational medical 
device 
6.1 
Device description  
The investigational medical device system is the Chordate System S211, which is used to 
stimulate human tissue inside the nasal cavities by means of kinetic oscillations at low 
frequencies.  
It consists of a base unit (Chordate Controller 1002630), an associated catheter (Catheter 
1001245), and a headband (Headband 1001152). The Chordate Controller is an active 
therapeutic device intended to administer energy. The system is intended to be used by 
healthcare professionals in a clinical environment, including doctors, nurses and assistant 
nurses, trained in the use of the device system.  
The Chordate Controller is intended to create air 
mediated oscillations with controlled pressure and 
frequency for a predetermined treatment time. 
It consists of a pneumatic module with a pneumatic 
pressure and oscillation part (including pumps, valves, 
tubing etc.) and a printed circuit board assembly with an 
electronic microcontroller part (MCU, motor drives, 
pressure gauge etc.), and a user control panel (touch 
screen).  
The system is factory pre-set with parameters for treatment 
of migraine. 
The user is asked to enter a 4-digit randomization number. 
The controller contains an internal programmable database, 
defining if a specific randomization number shall result in 
normal (active) treatment, or placebo treatment (no 
vibrations). 
 
The balloon part of the catheter is inserted into the nasal 
cavity of the subject. When started, the catheter is inflated 
and transmits kinetic oscillations to the mucous membrane 
of the nasal cavity. To prevent cross contamination, the 
catheter is for single-subject treatment and discarded after 
treatment completion. 
 

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The headband is intended to fixate the catheter during 
treatment; however, its use is optional. To reduce the risk 
of contamination between subjects, disposable hair nets 
will be used. 
 
 
Additionally, medicinal liquid paraffin and protective hair nets (CE-marked product for medical 
usage) will be required.  
All investigators will be thoroughly trained including practical exercises how to use the 
Chordate System. Traceability will be ensured by lot numbers. 
For more information please refer to the Investigator’s Brochure (IB) and Instructions for Use 
(IFU). 
6.2 
Storage and operating information 
Operating temperature: 
+15°C to +30°C 
Controller and headband storage 
and transportation temperature: 
-20°C to +50°C 
Catheter storage and transportation 
temperature: 
+5°C to +40°C 
Humidity (all conditions): 
20% to 80% RH non-condensing 
Operating altitude: 
-300 m to 2500 m 
Controller input mains: 
100-240 V ~, 50/60 Hz, 115VA; Protective ground 
Classification: 
Controller and catheter: Medical Device Directive 
(MDD) Class IIa 
Headband: MDD Class I 
6.3 
Manufacturer 
Chordate Medical AB 
Norgegatan 2 
164 32 Kista, Sweden 
Telephone: +46 (0)8400 11586 
Visiting and delivery address from 01-Apr-2018: 
Chordate Medical AB 

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c/o Regus 
Kistagången 20B 
164 40 Kista, Sweden 
 
6.4 
Indication 
In this clinical investigation, the Chordate System S211 is intended to be used for the treatment 
of adult subjects (18 to 65 years) with chronic migraine. 
7 
Justification for the design of the clinical investigation 
7.1 
Pre-clinical experiences and biocompatibility 
Pre-clinical investigations in animals have not been conducted since there is no appropriate 
animal model for this treatment. 
The subject is not in contact with the Chordate Controller and no biocompatibility evaluation 
is needed. The only parts in contact with the subject are the balloon part of the catheter and the 
consumables; medicinal liquid paraffin and the hair net positioned under the head band. For the 
latter, CE-marked products for medical use will be used. 
The balloon in the catheter is made from protective gloves (polyvinylchloride) that are 
CE-marked according to the Medical Device Directive class I and apply to EN 455-1-4. The 
balloon is in contact with the subject’s mucosal membrane in the nasal cavity for transient use. 
The material (polyvinylchloride) is well known and data regarding the biocompatibility are 
given by the manufacturer. There are no biocompatibility issues during the transient use of the 
catheter. 
7.2 
Clinical experience 
The Chordate System S211 is not yet CE-marked for migraine. However, promising results 
with predecessor Chordate System models were reported in early clinical studies. 
The Chordate System is CE-marked for rhinitis. Two double-blind controlled clinical trials 
including 80 subjects with non-allergic rhinitis and rhinitis medicamentosa showed efficacy on 
nasal obstruction, secretion, and for some subjects itching [7]. 
One safety and tolerability study (PS002) with the Chordate System in 12 healthy subjects 
showed that the treatment was safe and well tolerated. 
A double-blind study (PR003) in 207 patients with non-allergic rhinitis demonstrated that the 
Chordate system was more efficacious than placebo in reducing the weekly mean Total 
Vasomotor Rhinitis Symptom Score. There were no safety concerns. One serious adverse event 
(SAE) i.e. stroke two weeks after treatment has been reported but was judged to be not 
associated with study treatment. 

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So far, 2 studies with the Chordate System were performed in migraine patients (PM004 and 
PM005). Both studies were randomized, placebo-controlled, double-blind, multicenter studies 
to evaluate the performance and safety of the Chordate System. 
Study PM004 investigated the effect of the Chordate System on acute migraine. In total, 
51 patients with acute migraine attacks of moderate to severe intensity were enrolled. No 
statistically significant effects of the Chordate System on acute migraine headache pain and 
migraine features (pain-free rate, sustained pain free rate, time to meaningful relief, migraine 
associated symptoms, migraine derived disabilities, or global impression) were shown. A total 
of 42.3% in the active group and 32.0% in the placebo group showed headache relief. Rescue 
medication was taken by 57.7% subjects in the active group and 64.0% in the placebo group at 
24 hours after treatment. A slightly higher proportion of patients with meaningful pain relief 
was observed in the active group compared with the placebo group. 
Study PM005 investigated the potential prophylactic effect of 2 treatments with the Chordate 
System at an interval of 2 weeks. A total of 78 subjects were included in the performance 
analysis. There was no statistically significant effect on migraine frequency (days) during the 
complete 3 months after treatment. However, the Chordate system showed a close to significant 
(p=0.0515) effect on migraine frequency (days) 2 months after treatment. 
In both migraine studies, treatment with the Chordate System was generally well tolerated. Mild 
transient effects on nasal and tear secretion, paresthesia of the lip, burning sensations and slight 
discomfort and pain were observed. 
For more information please see the IB. 
7.3 
Justification for the clinical investigation 
Migraine is a common neurological syndrome that affects approximately 10-20% of the 
population. The pathophysiological mechanisms leading to migraine are still poorly 
understood. Despite recent progress in pharmaceutical interventions to treat and prevent 
migraine attacks, the efficacy of these drugs is poor. In addition, for certain patients these drugs 
have many side effects, resulting in a large proportion of patients discontinuing the drugs. Thus, 
new treatment approaches are urgently needed. A drug-free approach like the Chordate System 
may provide a novel effective treatment and preventive measure with fewer adverse events 
(AEs).  
The aim of this clinical investigation is to investigate the potential prophylactic effect of 
Chordate System treatment on migraine headache. 
A randomized double-blind study with a placebo control was deemed appropriate to control for 
all potential influences. The concurrent placebo control group will be drawn from the same 
subject population as the active group. Random treatment assignment and double blinding will 
be used to minimize the chance of selection bias and to ensure that the active and control groups 

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will be similar at the start of the study and will be treated similarly during the course of the 
study. 
8 
Risks and benefits of the investigational device and clinical 
investigation 
8.1 
Potential risks 
A risk analysis for the Chordate System S211 showed that the system is free from unacceptable 
and undesirable risks.  
Results of the risk assessment are provided within the IB. For this study, eligibility criteria have 
been incorporated to avoid identified potential safety issues. The risks and mitigation 
procedures established are summarized below. 
 

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Potential risk 
Mitigation 
Hypersensitivity to polyvinylchloride or medicinal 
liquid paraffin. 
Subjects with allergies to the materials of either 
device will be excluded. 
Risks relating to biocompatibility with the Headband 
(allergic reaction, cross-contamination between 
subjects and risk of hair becoming caught in device). 
A fresh hair net will be used for each subject. 
Potential for risk of overtreatment and damage to 
nasal mucosa. 
Treatment has been confined to a maximum of 
20 minutes. 
Small amounts of blood have occasionally been 
observed on the protective glove. 
Subjects with a history of nose bleeds (epistaxis) and 
concomitant conditions that could cause excessive 
bleeding have been excluded. Treatment will be 
halted if a subject experiences a nose bleed during 
treatment. 
In subjects with a pronounced anterior septal 
deviation, the balloon may be difficult to insert and 
the treatment be painful on the narrow side. 
Subjects with a pronounced deviation will be 
excluded from the study. 
Possible risk of complications in subjects with an 
implantable stimulator.  
Subjects with any active implantable devices in the 
head and/or neck, will be excluded. 
Subjects who have received radiation to the face or 
previous sinus surgery may have scarring and more 
fragile tissues which may increase the risk of 
bleedings and tissue damage during treatment. 
Subjects with radiation to the face or who have 
undergone previous sinus surgery will be excluded. 
Ongoing infection or malignancy of the nasal passage 
may prevent a therapeutic effect and increase the risk 
of complications during therapy.  
Subjects who have been diagnosed with nasal 
malignancy will be excluded from the study. Subjects 
with an ongoing nasal infection will be excluded from 
treatment. 
 
Although there are no anticipated risks to mother or fetus, women who are pregnant or at risk 
of being pregnant at the time of treatment will also be excluded.  
The following device-related effects were observed during treatment with the Chordate System. 
These effects are not serious, but could be perceived as disturbing.  

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The following adverse device effects (ADE) are anticipated during the insertion of the catheter 
in the nasal cavity: 
• Slight discomfort 
• Slight pain 
• Mild burning sensation 
• Sneezing 
• Increased tear secretion 
The following ADEs are considered anticipated during treatment with the Chordate System: 
• Sneezing 
• Increased nasal secretion 
• Increased tear secretion 
• Paresthesia of the lip 
• Slight pain 
• Slight discomfort 
• Mild burning sensation 
• Minor epistaxis (at withdrawal of catheter) 
All these effects are short-lasting and cease within a few minutes after treatment completion. 
As these are anticipated effects, if symptoms are mild, these should not be reported as an AE 
or ADE. However, if these are moderate or severe, these must be reported as AE or ADE. 
8.2 
Potential benefits 
Anecdotal evidence has pointed to a potentially positive effect of treatment with the Chordate 
System on migraine frequency. 
A recent randomized, placebo-controlled, double-blind pilot study to investigate the potential 
prophylactic effect of 2 treatments with the Chordate System S200 at an interval of 2 weeks did 
not show a statistically significant effect on migraine frequency (days) during the complete 3 
months after treatment; however, a close-to-significant effect on migraine frequency (days) was 
observed 2 months after treatment. 
The anticipated benefits of treatment within this clinical investigation include: 
• Reduced frequency and/or severity of migraine attacks, which in addition to improving 
subject’s quality of life, could also potentially reduce the amount of medication(s) required 
and associated risks related to these.  

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• Potential improvement of the situation for patients who cannot currently tolerate other 
pharmaceutical treatments due to drug interactions or comorbidities.  
• For subjects not already keeping a migraine diary, collecting diary data for the clinical 
investigation may help in their migraine diagnosis and ongoing care. 
8.3 
Risk benefit rationale 
No hazards were found to present unacceptable risk levels when some risks are reduced further 
by proper use, handling and maintenance of the system. All users of the investigational device 
will be trained prior to administering treatment. 
There are no residual risks of the device used in this clinical investigation that have not been 
controlled within the IFU. 
Beyond the application of the medical device system under investigation, the 
protocol-mandated measures imposed to the subjects virtually are associated with no additional 
risks. 
In conclusion, the possible benefits of the clinical investigation justify the potential risks. 
9 
Investigators and administrative structure of the clinical 
investigation 
The study is planned to be conducted at 5 centers in Germany and max. 6 centers in Finland 
under the supervision of Prof. Dr. med. Arne May (coordinating investigator). 
The sponsor (Chordate Medical AB) will be responsible for the overall administration of the 
clinical investigation. FGK Clinical Research GmbH (in the following referred to as sponsor’s 
representative), a contract research organization, will be responsible for project management, 
site monitoring, medical monitoring, handling and reporting of SAEs, serious adverse device 
effects (SADE), and device deficiencies and regulatory submissions. 
Addresses and telephone numbers of the main responsible persons are provided in Section 4. 
The study is supported by the Swedish Governmental Agency for Innovation Systems 
(http://www.vinnova.se/en/). 
10 
Objectives of the clinical investigation 
Primary objective: 
• To evaluate the effect of intranasal KOS using the Chordate System S211 on monthly 
headache days with moderate to severe intensity. 

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Secondary objectives: 
• To evaluate the effect of treatment with the Chordate System S211 on monthly migraine 
days, responder rate, use of abortive medication, health-related quality of life and disability, 
and patient’s global impression of severity;  
• To evaluate the incidence and severity of AEs and ADEs following treatment with the 
Chordate System S211. 
11 
Design of the clinical investigation 
11.1 
General 
11.1.1 
Description of the design of the clinical investigation 
This is a randomized, placebo-controlled, double-blind, multicenter clinical investigation of a 
medical device. The study consists of a 4-week screening period, a 6-week treatment period (2 
weeks run-in and a 4-week observation window to assess the treatment effect), and a 4-week 
follow-up period. 
Subjects who provided written informed consent and are eligible for the study will be asked to 
complete a daily diary for 4 weeks during the screening period. In the diary the subjects will 
record headache and migraine days, any changes in their health, and concomitant medications 
they may be using. The data collected in the diary during this screening period will be used as 
Baseline for the performance assessments. 
Subjects who completed the screening period and continue to meet the eligibility criteria after 
review of diary entries by the investigator will be randomized (stratified by medication overuse) 
in a 1:1 ratio to receive either active or placebo treatment. The subjects will receive 6 treatments 
with the Chordate System S211 at weekly intervals at the site (Day 0 to 35; treatment Visit [V] 
1 to 6) and continue to maintain a daily diary. One week after the last treatment, an end of 
treatment visit will be performed on Day 42 (V7). 
After completion of the 6-week study treatment period (V1 to V7), subjects will be followed-up 
for another 4 weeks. The final visit will be performed on Day 70, 5 weeks after the last study 
treatment. During the 4-week follow-up, the subjects will continue to complete a daily diary. 
11.1.2 
Primary and secondary endpoints 
Performance endpoints 
Primary performance endpoint: 
• Mean change from Baseline (4-week screening period) in monthly headache days with 
moderate to severe intensity in 4-week performance assessment period (V3 to V7). 
Secondary performance endpoints: 

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• Mean change from Baseline in monthly headache days with moderate to severe intensity in 
follow-up period; 
• Mean change from Baseline in monthly migraine days; 
• Mean change from Baseline in monthly headache days (mild, moderate and severe 
intensity) in 4-week performance assessment period (V3 to V7); 
• Proportion of subjects with 30% or greater reduction in headache days of moderate to severe 
intensity; 
• Proportion of subjects with 50% or greater reduction of headache days of moderate to severe 
intensity; 
• Change in the use of acute (abortive) medication; 
• Change in migraine-specific quality of life questionnaire (MSQ), headache impact test-6 
(HIT-6), and patient global impression of severity (PGI-S). 
Safety endpoint 
• Frequency, severity, device-relationship, and outcome of AEs. 
All performance measurements used in this study are established migraine evaluations that have 
been validated as reliable and relevant. The measures of safety used in this study are routine 
clinical procedures.  
11.1.3 
Subject identification 
Subjects will be assigned a unique 4-digit number, with the first 2 digits identifying the site and 
the last 2 digits identifying the subject, e.g. 01-01. At each site the investigator will assign 
numbers to subjects in ascending order e.g. 01, 02, 03 etc. 
11.1.4 
Duration of the clinical investigation 
The overall duration of the clinical investigation including enrollment and treatment of all 
subjects is anticipated to be 1.5 years with an expected enrollment period of about 9 months. 
The duration of the clinical investigation for each participating subject is about 14 weeks. 
11.2 
Treatments, precautions and restrictions 
11.2.1 
Investigational device 
Packaging and labeling 
The investigational device will be labeled according to applicable guidelines and national legal 
requirements.  

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Treatment settings and protocol 
The investigational device will only be used as part of the clinical investigation. Treatment with 
the device will be in compliance with the clinical investigation plan (CIP) and manufacturer’s 
IFU. Devices will be supplied to the site with pre-set pressure/frequency to be used for the 
clinical investigation. Any deviation from the prescribed technique and timing as described in 
the IFU will be recorded as a deviation. A comment explaining the deviation must be given 
within the paper case report form (pCRF). 
The investigator will enter a 4-digit randomization number. The controller contains an internal 
programmable database, defining if a specific randomization number shall result in normal 
(active) treatment or placebo treatment (no oscillations). 
Treatment time will be 10 minutes in each cavity (a total of 20 minutes per treatment) at 85 Hz 
and 80 mbar. Subjects should be in an upright position. First, the headband will be placed on 
the subject’s head. The catheter’s balloon part will be dipped in liquid paraffin and inserted into 
the subject’s nostril (start on any side). The headband’s fixation arm and catheter will be 
connected such that the catheter is kept in the correct position. For a detailed description please 
see the IFU. 
The pre-set frequency (85 Hz) and pressure (80 mbar) will be used in the treatment of all 
subjects. All subjects should receive the pre-set 10 minutes of continuous treatment time per 
nostril. Once one nostril has been treated, the investigator will treat the other nostril with a 
minimum of delay. 
11.2.2 
Precautions and restrictions 
Treatment with the Chordate System may not be performed in subjects with a body temperature 
>38.5°C.  
11.2.3 
Methods of assigning subjects to device groups 
Subjects will be randomly assigned in a 1:1 ratio to active or placebo treatment by means of a 
computer-generated randomization list. Randomization will be stratified by medication overuse 
(yes/no) at V1.  
Medication overuse is defined as regular overuse for >3 months of one or more acute 
symptomatic drugs (according to the IHS classification): 
• Ergotamine, triptans, opioids or combination analgesic medications on ≥10 days per month 
on a regular basis for >3 months; 
• Simple analgesics or any combination of ergotamine, triptans, analgesics or opioids on 
≥15 days per month on a regular basis for >3 months without overuse (≥10 days) of any 
single class alone. 

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The Chordate System S211 can deliver normal (active) treatment or placebo treatment. The 
user will enter the randomization number assigned to the patient before start of treatment, and 
based on a hidden randomization table; the controller will either deliver active or placebo 
treatment.  
The controller acts in one of two modes: 
• Active treatment: The controller creates air-mediated kinetic oscillations with regulated 
pressure and frequency during a preset treatment time. 
• Placebo treatment: Placebo treatment is similar to active treatment, but with no oscillations. 
It is difficult to discern any difference between active and placebo treatment. 
11.2.4 
Investigational medical device accountability 
Shipment, receipt, and return of all clinical investigational devices will be tracked and 
documented by the monitor and investigator. Product name, amount, lot numbers, and expiry 
dates will be documented for investigational devices provided to each investigational site. The 
disposition of devices (used, not used, or returned) will be recorded. When the treatment period 
is complete or at the latest during the site close out visit, the monitor will ensure that all 
investigational devices are returned to the sponsor. As the treatment is administered by the 
investigator only, compliance will be controlled by the device accountability log. Single use 
products, i.e. hair nets and catheters, will be disposed at the sites according to local routine. 
11.2.5 
Previous and concomitant medications and treatments 
Subjects must be on a stable prophylactic migraine medication regimen, if any, during the 
3 months prior to screening and maintain this regimen (no change in type, frequency or dose) 
from screening to end of follow-up. No new prophylactic migraine medication may be initiated. 
Treatment with Botox is not allowed during the study (from screening to end of follow-up). 
Medication, which is considered necessary for the subject’s safety and well-being, may be given 
at the discretion of the investigator at any time. 
Subjects can use their regular acute migraine medication, when necessary, during the course of 
the clinical investigation. However, all such use and any changes must be documented in the 
diary by the subjects. 
The diary will be used to collect data about the use of concomitant medication in combination 
with discussions with the subject and medical record review. The site will record all 
concomitant medications in the appropriate sections of the pCRF. 
Subjects will not be included in the investigation if they have previously been implanted with 
a stimulator or any implantable device in the head and/or neck or a pacemaker/ defibrillator, or 
if they have previously undergone sinus surgery or received treatment with therapeutic x-ray 
intervention in the facial region.  

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11.3 
Subjects 
11.3.1 
Number of subjects 
Approximately 148 subjects will be enrolled in order to achieve at least 132 subjects evaluable 
for the primary performance endpoint. If during the conduct of the study the drop-out rate 
proves to be higher than expected (>10%), enrollment will continue until at least 132 subjects 
were assessed for the primary endpoint. 
11.3.2 
Inclusion criteria 
1. The subject is legally competent, has been informed of the nature, the scope and the 
relevance of the study, voluntarily agrees to participation and the study’s provisions, 
and has duly signed the informed consent form (ICF); 
2. Male or female aged between 18 and 65 years (inclusive) at the time of providing 
informed consent; 
3. Diagnosed as suffering from chronic migraine with or without aura (≥15 headache 
days per month for more than 3 months before screening including at least 8 migraine 
days) according to the IHS classification (International Classification of Headache 
Disorders [ICHD]-III beta); 
4. Migraine onset before the age of 60 years; 
5. Reported history of migraine for at least 1 year before screening; 
6. Reported stable prophylactic migraine medication regimen, if any, during the 3 months 
prior to screening; 
7. Able and willing to maintain current prophylactic migraine medication regimen (no 
change in type, frequency or dose) from screening to end of follow-up; 
8. Women of childbearing potential must be willing to use highly effective contraceptive 
methods (failure rate <1% per year when used consistently and correctly) during the 
study. 
11.3.3 
Exclusion criteria 
To enter the trial, to receive treatment and continue in the clinical investigation subjects must 
not meet any of the exclusion criteria as indicated below. 
1. Unable to distinguish between migraine headaches and other headache types; 
2. Treatment with Botox in the head/neck area within 4 months of the screening visit, or 
planned Botox treatment during the study; 
3. Previous or ongoing treatment with an implanted stimulator or other implanted device 
in the head and/or neck; 

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4. Known pronounced anterior septal deviation, or other known relevant abnormality in 
the nasal cavity, including bacterial infection and wounds; 
5. History of relevant sinus surgery, transsphenoidal surgery for pituitary or other lesions 
or cerebrospinal fluid (CSF) rhinorrhea; 
6. Fitted with a pacemaker/defibrillator; 
7. Previously treated with therapeutic x-ray intervention in the facial region (that could 
have influenced the nasal mucosa); 
8. Ongoing upper respiratory infection or malignancy in the nasal cavity;  
9. History of regular nose bleeding (epistaxis), or concomitant condition or medication 
that could cause excessive bleeding including treatment with an anticoagulant; 
10. Head injury or open wound that contraindicates use of the Chordate Headband; 
11. Known allergy to polyvinylchloride, a material used in the Chordate Catheter, or 
medicinal liquid paraffin; 
12. Concurrent condition or risk of non-compliance that, in the investigator’s opinion, may 
affect the interpretation of performance or safety data or which otherwise 
contraindicates participation in a clinical investigation; 
13. Pregnant and lactating women; 
14. Participation in a clinical investigation within 3 months of enrolment or planned 
participation at any time during this clinical investigation; 
15. Previous participation in this study; 
16. Employees of the study site or the sponsor directly involved with the conduct of the 
study, or immediate family members of any such individuals. 
11.3.4 
Subject withdrawal  
Subjects are free to discontinue participation in the clinical investigation at any time, without 
prejudice to further treatment. Subjects who discontinue the clinical investigation should 
always be asked about the reason(s) for their discontinuation and about the presence of any AEs 
or ADEs and, if possible, be assessed by the investigator. 
Subjects may be withdrawn from investigation treatment and assessments at any time, if 
deemed necessary by the principal investigator or sponsor.  
In case of withdrawal of consent or withdrawal of the subject from the clinical investigation, 
AEs will be followed up by the investigator according to Section 12.5. 
Subjects who are prematurely withdrawn from the study and have received at least 1 study 
treatment will be asked to undergo a final examination to monitor the subject’s safety and 
document any AEs. 

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Subjects may be discontinued for the following reasons: 
• Subject’s request; 
• Ineligibility including the development of any undercurrent illness(es), infections or 
condition(s) before treatment that might interfere with the subject’s participation in the 
clinical investigation; 
• AE(s), which in the opinion of the investigator may jeopardize the subject’s health or 
compromise the study objectives (a corresponding AE pCRF page must always be 
completed); 
• Poor compliance and/or disregarding the investigator’s instructions; 
• Major CIP violation; 
• Any problem (not covered by the other categories) deemed by the investigator and/or the 
sponsor to be sufficient to cause discontinuation. 
Every effort should be made to follow-up all subjects in accordance with this CIP. Prior to 
withdrawal for loss to follow-up, the investigator will try to contact the subject on 3 separate 
occasions and document each attempt in the subject medical records. 
In case of early withdrawal, reasons, circumstances and findings should be fully described on 
the End of Study page in the pCRF respecting the subject’s rights. 
11.3.5 
Subject enrollment, number, and duration of subject’s participation 
Subjects who have signed the ICF will be considered enrolled. Enrolled subjects who have 
completed the 4-week screening phase and comply with respective eligibility criteria, will be 
randomized. 
Randomized subjects will undergo a 6-week treatment period including 6 weekly treatments 
with the Chordate System S211 and a subsequent 4-week follow-up period. 
Approximately 148 subjects will be randomized to achieve 132 evaluable subjects (see sample 
size calculation Section 13.5). A group-sequential design with one interim analysis after 
approximately 50 subjects have completed the 6-week treatment period will be used. It will 
allow the premature termination of the study due to efficacy or futility or adaption of the sample 
size. If during the conduct of the study the drop-out rate proves to be higher than expected 
(>10%), enrollment will continue until at least 132 subjects were assessed for the primary 
endpoint. 

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11.4 
Procedures and assessments 
11.4.1 
Diary 
Subjects will be instructed to complete a paper diary each day from screening up to the follow-
up visit. The following information will be recorded: 
• Use and changes of concomitant medication (type, dose and dosing schedule); 
• AEs; 
• Headache and migraine days.  
11.4.2 
Questionnaires 
During the study subjects will be asked to complete 2 self-administered questionnaires. 
11.4.2.1 
Headache impact test 
The HIT-6 is a 6-item questionnaire that evaluates the extent of disability a subject experiences 
due to headache by measuring the subject’s level of pain, social functioning, role functioning, 
vitality, cognitive functioning, and psychological distress. 
11.4.2.2 
MSQ 
The MSQ is a 14-item, self-administered questionnaire that assesses the impact of migraine on 
health-related quality of life during the past 4 weeks. It includes 3 dimensions: role function-
restrictive, role function-preventive, and emotional function. 
11.4.3 
Patient global impression of severity 
The PGI-S is a 1-item questionnaire to assess the subject’s impression of disease severity. The 
subjects will rate the severity of their condition on a scale from 1 to 4: 
• 1: normal 
• 2: mild 
• 3: moderate 
• 4: severe 
11.4.4 
Physical examination 
A complete physical examination will be performed at screening including the following 
organs/body systems: general condition; skin; ears/nose/throat; head/thyroid; cardiovascular; 
respiratory; gastrointestinal; lymphatic; musculoskeletal; neurological; genitourinary; 
endocrine; others (e.g. allergies). Abnormalities will be recorded in the source data and 
transferred in the pCRF. 

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11.4.5 
Other assessments 
• Demography: age, sex, race, height, weight, body mass index.  
• Medical and surgical history: from subject interview and medical records covering 
relevant past medical history. Presence of allergies and pronounced septal deviation will be 
recorded separately. 
The following information will be documented separately in regard to migraine history: 
o Migraine onset; 
o Average headache days per month; 
o Average migraine days per month; 
• Concomitant medications will be recorded in the pCRF. Variables are as follows: type of 
medication; route; dose; unit; regimen; start date; end date (with a yes/no question for 
’ongoing’); reason taken.  
• Urine pregnancy test: urine pregnancy tests will be performed in women of childbearing 
potential at the times specified in the schedule of assessments (Section 3).  
11.4.6 
Factors that may compromise the outcome 
Specific subject characteristics have been included with the aim of reducing variables that could 
influence treatment outcomes and interpretation of these. The rationale for individual subject 
characteristics to be included in the clinical investigation is detailed below. 
• Diagnosis of chronic migraine with or without aura according to IHS classification (ICHD-
III Beta): this is a chronic migraine study and it is important to ensure that only subjects 
with the target indication are enrolled. 
• Male or female: although females experience more migraines that males, it is important to 
study outcomes in both genders. 
• Age 18 to 65 years: this clinical investigation is an adult migraine study. Age above 65 years 
is associated with higher comorbidity and concomitant medications, which can confound 
interpretation of treatment effects. 
• Age of migraine onset before 60 years: late onset of migraine is very rare and often mimics 
other diseases. Treatment response in these subjects may be atypical and confound results. 
• History of migraine for at least one year: this is required in order to diagnose migraine more 
accurately. The migraine does not need to be in its chronic form for the complete year; 
however, to meet the criteria for chronic migraine (see first bullet point), subjects must have 
≥15 headache days per month (of which at least 8 days fulfill the IHS criteria for migraine) 
for more than 3 months before screening. 

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11.4.7 
Appropriateness of measurements 
The use of simple subject diaries to record migraine details is recommended by the IHS and 
necessary to gather treatment outcome data.  
Migraine pain and associated symptoms impact on subjects’ daily functioning and quality of 
life. The performance endpoints, and associated variables and measurements, are consequently 
subject self-reported and reflect these elements. 
The HIT-6 and MSQ are well-established measures for the evaluation of headache-related 
disability in migraine patients. The PGI-S is a widely used instrument determining the subject’s 
impression of disease severity. 
A combination of AE review and ad hoc subject AE reporting (via the diary) should ensure an 
accurate representation of AEs occurring during the clinical investigation. 
11.5 
Schedule of the clinical investigation 
The schedule of assessments is provided in Section 3.  
11.5.1 
Screening 
After written informed consent is obtained, the following assessments will be performed and 
information will be recorded in the pCRF: 
• Check of inclusion and exclusion criteria; 
• Documentation of demographics and medical and surgical history; 
• Physical examination; 
• Documentation of prior and concomitant medication; 
• Urine pregnancy test in women of childbearing potential; 
• Completion of questionnaires (HIT-6, MSQ); 
• Assessment of PGI-S. 
A paper diary will be handed out to the subjects to be completed during the 28-day screening 
phase. 
Where a subject fails to fulfill the inclusion and exclusion criteria, this will be documented and 
the signed consent form retained by the principal investigator. The subject will not be advanced 
any further into this clinical investigation and an End of Study pCRF page will be completed. 
 
 

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11.5.2 
Treatment 
Visit 1 (Day 0) 
 Prior to any study related assessment the investigator will do a SARS-CoV-2 test, if required 
by site policy. If the test result is positive the patient will be asked to take the measures, which 
the authorities require in this case. The patient may come back to the site and continue the study 
after these requirements are fulfilled and a negative test result is present.  
Afterwards the investigator will discuss with the subject any changes in their health during the 
screening phase and any changes in their medication or any new concomitant medication they 
may have used. The investigator will also review the subject’s paper diary entries and ensure 
that the diary has been completed accurately. Additionally, the following assessments will be 
performed: 
• Completion of questionnaires (HIT-6, MSQ); 
• Assessment of PGI-S. 
Subjects who continue to meet all inclusion criteria and none of the exclusion criteria will be 
randomized to 1 of the 2 study treatments.  
Randomized subjects will be treated as described in Section 11.2.1 and detailed in the IFU. Any 
AEs or device defects occurring during or after treatment will be documented in the pCRF. 
Visits 2, 3, 4, 5, and 6 (Day 7, 14, 21, 28, and 35 [± 3 days each]) 
At each visit, subjects will receive study treatment as described in Section 11.2.1 and detailed 
in the IFU.  
At Visit 3 additionally the following assessments will be performed: 
• Completion of questionnaires (HIT-6, MSQ); 
• Assessment of PGI-S. 
The subjects will be asked about any AEs and changes in concomitant medication since the last 
visit and any new or changed information will be documented in the pCRF. 
Visit 7 (Day 42 ± 3 days) 
The following assessments will be performed:  
• Documentation of AEs; 
• Documentation of changes in concomitant medication; 
• Completion of questionnaires (HIT-6, MSQ); 
• Assessment of PGI-S. 

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11.5.3 
Follow-up (Day 70 ± 3 days) 
Five weeks after the last study treatment, subjects will be asked to return to the site. The 
following assessments will be performed: 
• Urine pregnancy test in women of childbearing potential. 
• Documentation of AEs; 
• Documentation of changes in concomitant medication; 
• Completion of questionnaires (HIT-6, MSQ); 
• Assessment of PGI-S. 
The investigator will complete the End of Study page in the pCRF. 
11.5.4 
Early termination 
In case a subject prematurely discontinues the clinical investigation (for reasons see 
Section 11.3.4), the End of Study page in the pCRF will be completed. 
In case of early withdrawal, reasons, circumstances and findings should be fully described on 
the End of Study page in the pCRF respecting the subject’s rights.  
11.5.5 
Medical care upon termination of the clinical investigation 
After the final visit subjects will not receive any further study-specific treatment. They will be 
treated according to the investigator’s discretion. 
11.6 
Clinical monitoring 
The monitor will be responsible for ensuring that the investigators are aware of their 
responsibilities and for securing investigator compliance with the CIP, the signed agreement, 
EN ISO 14155:2020 and any conditions of approval imposed by the reviewing ethics committee 
(EC), component authority (CA) and/or local institution. During the clinical investigation, the 
monitor will have regular contacts with the investigation site. These contacts will include visits 
by the monitor to confirm that the facilities remain adequate to specified standards and that the 
investigation team is carrying out the procedures stated in the CIP. All data must be accurately 
recorded in the pCRF and source data verification will be performed by the monitor, to verify 
clinical investigation compliance and the accuracy of recorded data. The investigator must 
permit the monitor to visit the site at regular intervals and the pCRFs and other records must be 
accessible during the visits. The planned extent of source data verification (SDV) is detailed in 
the monitoring plan. The monitor or other sponsor personnel will be available between visits if 
the investigator or other staff at the site needs information and/or advice. 
Authorized representatives of the sponsor and/or regulatory agencies may visit the site to 
perform audits/inspections, including SDV. The investigator will permit authorized inspectors 

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to inspect all facilities and records relating to the clinical investigation and aid the inspector to 
perform the audit in a timely fashion. It is the joint responsibility of both the sponsor and the 
investigator to ensure that the clinical investigation has been conducted in line with all 
applicable regulations.  
11.7 
Training of staff 
All study site personnel should be present at the site initiation visit, during which the sponsor 
and/or the contract research organization (CRO) who was trained in advance by the sponsor 
and acting on his behalf will provide documented training on use of the device, the pCRF and 
clinical investigation conduct. It is the responsibility of the investigator to train any member of 
the research team who was not present at the site initiation visit or joined the clinical 
investigation at a later date on the study procedures before undertaking any clinical 
investigation responsibilities. 
A Study Personnel and Authorization Log will be completed to indicate which activities the 
investigator has authorized to be performed by each research team member. This must be 
updated before a new or existing team member undertakes any new responsibility. 
The investigator will ensure that appropriate training relevant to the clinical investigation is 
given to the medical, nursing and other staff involved and that new relevant information for this 
clinical investigation is forwarded to the staff involved. 
12 
Adverse events, adverse device effects, and device deficiencies 
12.1 
Definitions of adverse events and adverse device effects 
Adverse event 
An AE is defined as any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons. For subjects this definition includes events whether or not related to the investigational 
medical device or comparator and those events related to the procedures involved (any 
procedure in this CIP). For users or other persons this definition is restricted to events related 
to the investigational medical device.  
The definition of AE in this study does not include adverse experiences observed by the patient 
or in the patient before the investigational medical device application. Those adverse 
experiences occurring after provision of informed consent and prior to application of the 
investigational medical device will be recorded as part of the medical history. However, if the 
condition deteriorates at any time from date of administration of the investigational medical 
device during the study it should be recorded and reported as an AE. 
The definition of an AE in this study does not include anticipated device effects of mild 
character (sneezing, increased nasal secretion, increased tear secretion, paresthesia of the lip, 

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slight pain, slight discomfort, mild burning sensation, minor epistaxis [at withdrawal of 
catheter]). A list of anticipated device effects is also provided in Section 8.1. However, increase 
in severity from mild of the anticipated device effects listed above will constitute an AE. Any 
hospitalization due to the above-mentioned conditions will constitute an SAE.  
The definition of an AE in this study does also not include migraine-associated symptoms 
(nausea, photophobia, phonophobia and vomiting), clinical disability and headache if they 
remain within the same severity and frequency observed by the patient before the study device 
use. Any hospitalization due to the above-mentioned conditions will constitute a SAE.  
Adverse device effect  
An ADE is defined as an AE that is related to the use of the investigational medical device. 
This includes any AE resulting from insufficiencies or inadequacies in the instructions for use, 
the deployment, the implantation, the installation, the operation, or any malfunction of the 
investigational medical device. In addition, this includes any event that is a result of a use error 
or intentional misuse. 
Serious adverse event  
An SAE is defined as any adverse event that led to any of the following: (a) death, (b) serious 
deterioration in the health of the subject, that resulted in any of the following: (i) life-threatening 
illness or injury, (ii) permanent impairment of a body structure or a body function, (iii) 
hospitalization or prolongation of patient hospitalization, (iv) medical or surgical intervention 
to prevent life-threatening illness or injury or permanent impairment to a body structure or a 
body function, (v) chronic disease, (c) fetal distress, fetal death or a congenital physical or 
mental impairment or birth defect 
Serious adverse device effect 
An SADE is defined as an ADE that has resulted in any of the consequences characteristic of 
an SAE. 
Unanticipated serious adverse device effect  
An unanticipated SADE (USADE) is defined as an SADE which by its nature, incidence, 
severity or outcome has not been identified in the current version of the risk analysis report. 
An anticipated serious adverse device effect (ASADE) is an effect which by nature, incidence, 
severity or outcome has been identified in the risk analysis report. There are no ASADEs for 
this clinical investigation. 
12.2 
Reporting of adverse events 
12.2.1 
Methods for eliciting adverse events 
All subjects will be carefully monitored for the occurrence of AEs during the clinical 
investigation period from first treatment to the completion of follow-up. At clinical 

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investigation visits, the investigators will collect AE information using non-leading questions 
such as “have you experienced any new health problems or worsening of existing conditions?”. 
Events directly observed or spontaneously volunteered by subjects will also be recorded. In 
addition, subjects will be asked to contact the investigator if they feel unwell at any time 
between treatment and the end of their study participation. 
12.2.2 
Recording of adverse events 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single AE whenever possible. The investigator must record all AEs 
on the AE page of the pCRF.  
All SAEs must be reported to the sponsor’s representative within 24 hours of the first awareness 
of the event on the paper SAE Report Form by fax (see Section 12.4). 
Complete description of all AEs must also be available in the source documents. 
Records in the pCRF should include the following information: 
• Event term (diagnosis); 
• Start date (and time, if relevant); 
• End date (and time, if relevant); 
• Continuing yes/no 
• Severity; 
• Action taken regarding the medical device; 
• Action taken regarding the procedure (none, aborted or temporarily interrupted); 
• Opinion on causality (to device or procedure) and if applicable details of the device the AE 
is related to (Chordate Controller, Chordate Catheter, Chordate Headband); 
• Seriousness; 
• Outcome. 
Changes in the assessment of relationship to the investigational medical device or procedure 
should be clearly documented. 
Any medication necessary for the treatment of an AE must be recorded on the Concomitant 
Medication page of the pCRF.  
12.3 
Assessment of adverse events 
All AEs will be assessed in terms of seriousness (yes, no), severity, outcome, relationship to 
the investigational medical device, and relationship to study procedures.  

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Adverse event assigned causality (device-related or procedure-related) 
Causality will initially be assessed by the investigator as: 
• Related: There is reasonable temporal relation between the AE and the investigational 
medical device application, AND: 
There is no other explanation for the AE or the AE follows a known or expected response 
pattern to the investigational medical device application. 
• Not related: There is an evident other explanation for the AE. 
Adverse event severity 
Severity describes the intensity of an event and will be assessed as: 
• Mild: The AE does not interfere in a significant manner with the subject’s normal 
functioning level. It may be an annoyance. 
• Moderate: Events that cause sufficient discomfort to interfere with daily activity and/or 
require a simple dose of medication, e.g. minor analgesics or antiemetics; interferes to some 
extent with the subject’s usual function. 
• Severe: Events that incapacitate and prevent usual activity or require complex medication 
or hospitalization; interferes significantly with the subject’s usual function. 
Worsening changes in severity grade will constitute a new entry in the pCRF. It is expected that 
the stop date of the original AE will be the same as the start date of the new entry when there 
is a worsening in severity grade. 
Intermittent AEs will only be recorded once, as long as the severity or seriousness does not 
change and ‘intermittent’ is added to the verbatim text of the AE term. If however, the AE 
changes from intermittent to continual, the original event should be closed out and reopened as 
a new AE. 
Adverse event outcome 
The outcome of an AE will be assessed as follows: 
• Resolved: 
the subject has returned to his/her previous health status 
observed at Baseline with no subsequent problems. 
• Resolved 
with sequelae: 
as a result of the AE, the subject suffered persistent and 
significant disability/incapacity (e.g. became blind, deaf or 
paralyzed). 
• Ongoing: 
the subject has not yet recovered to his previous health status 
observed at Baseline and continues to be followed for the AE 

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• Death due to this 
event: 
 
• Death due to other 
event: 
the subject died due to the event. If the subject died due to other 
circumstances than the event, the outcome should be stated as 
death due to other event. 
 
the subject died due to other event  
• Lost to follow-up: 
if information on the outcome of an AE cannot be obtained after 
at least 3 attempts to contact a subject over the course of a 
1-month period 
12.4 
Reporting of serious adverse events 
All SAEs will be subject to expedited reporting to the sponsor and must be reported to the 
sponsor’s representative within 24 hours of the first awareness of the event, regardless of the 
time that may have elapsed from the time the event occurred and regardless whether or not they 
are considered causally related to the investigational medical device. The investigator must 
complete the study-specific paper SAE Report Form provided by the sponsor’s representative, 
verify the accuracy of the information recorded on the SAE pages with the corresponding source 
documents, then sign and date the SAE Report Form and send it including additional 
information immediately, not later than 3 calendar days by email to: 
 
 
 
 
Email: 
 
 
or, in case sending an email is not possible, please fax to 
. 
 
The initial report should contain as much information as possible, but as a minimum the 
following information will be entered: 
• Subject identification; 
• Initial or follow-up report; 
• Medical device information (device identification; date of procedure); 
• Description of event (diagnosis); 
• Date of onset (and time of onset if on the day of treatment); 
• Name of the investigator; 
• Causality assessment (relationship to investigational device and relationship to clinical 
investigation procedure); 

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• Seriousness classification and criteria; 
• Severity. 
The investigator should also complete missing or requested information and submit follow-up 
reports until the SAE has resolved or, in the case of permanent impairment, until the SAE has 
stabilized. Any additional information requested by the sponsor or sponsor’s representative 
must be provided by the investigator without delay.  
Any serious adverse event that has a causal relationship with the investigational device, the 
comparator or the investigation procedure or where such causal relationship is reasonably 
possible; or any device deficiency that might have led to a serious adverse event if appropriate 
action had not been taken, intervention had not occurred, or circumstances had been less 
fortunate and any new findings in relation to any event described before will be reported to all 
Member States in which the clinical investigation is being conducted, as required by applicable 
EU [10] and national law, by the sponsor or sponsor’s representative without undue delay 
All SAEs for which a causal relationship between the SAE and the investigational medical 
device, diagnostic or therapeutic procedures performed as part of the clinical trial or other 
conditions of the trial conduct cannot be excluded and which indicates an imminent risk of 
death, serious injury, or serious illness and that requires prompt remedial action for other 
patients/subjects, users or other persons or a new finding to it will be reported by the sponsor 
or sponsor’s representative immediately,  but no later than 2 calendar days  from the sponsor’s 
or sponsor’s representative’s awareness of the new reportable event or of new information in 
relation with the already reported event to the all national CAs where the clinical investigation 
is conducted. 
Any other SAEs for which a causal relationship between the SAE and the investigational 
medical device, a comparator device, diagnostic or therapeutic procedures performed as part of 
the clinical trial or other conditions of the trial conduct cannot be excluded or a new finding 
to it will be reported by the sponsor or sponsor’s representative immediately, but no later than 
7 calendar days from sponsor’s or sponsor’s representative’s awareness of the new reportable 
event or of new information in relation with the already reported event to all national CAs where 
the clinical investigation is being conducted. 
. 
 
SAE EMERGENCY CONTACT DETAILS 
Medical Monitor: 
 
Phone: 
 
Email: 
 

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12.5 
Follow-up of adverse events 
All subjects who have been exposed to the investigational medical device will be evaluated for 
AEs. All AEs will be evaluated beginning with onset, and must be followed up until the last 
day of the clinical investigation at the site, until recovery or normalization of changed 
laboratory parameters, or until the investigator determines that the subject’s condition is stable, 
whichever occurs first. All SAEs judged to be related to the investigational medical device must 
be followed by the investigator until the subject has recovered, recovered with sequelae, died, 
or until the investigator determines that the subject’s condition is stable, whichever occurs first. 
The investigator will take all appropriate and necessary therapeutic measures required for 
resolution of the AE, if applicable. 
12.6 
Pregnancy 
Subjects who become pregnant during the study should discontinue the study immediately. 
Pregnancies occurring during a subject's participation in the clinical investigation are subject to 
the same reporting timelines towards FGK as SAEs (i.e. within 24 hours after being made aware 
of the pregnancy) by use of a study-specific paper Pregnancy Report Form provided by FGK 
via email (
).  
Whenever possible, the pregnancy should be followed up to determine the outcome by use of 
the study-specific paper Pregnancy Outcome Report Form provided by the sponsor’s 
representative, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or new-born 
complications. 
Pregnancy follow-up should be recorded and include an assessment of the possible relationship 
to the investigational device of any pregnancy outcome. 
12.7 
Foreseeable adverse events and anticipated adverse device effects 
For a list of foreseeable AEs and anticipated ADEs please refer to Section 8.1. 
12.8 
Device deficiencies 
12.8.1 
Definition of a device deficiency 
A device deficiency is defined as any inadequacy in the identity, quality, durability, reliability, 
safety or performance of an investigational device, including malfunction, use errors or 
inadequacy in information supplied by the manufacturer..  
12.8.2 
Recording and reporting of product deficiencies 
The investigator will notify the sponsor or within 24 hours from the site becoming aware of a 
device deficiency by completing the study-specific paper Device Deficiency Report Form 
provided by the sponsor’s representative via email (s
). 

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Where a device deficiency causes an AE, the AE page of the pCRF must be completed.  
Any device deficiency that may have led to an SAE if  
a) suitable action had not been taken,  
b) intervention had not been made or  
c) if circumstances had been less fortunate,  
has to be reported as an SAE using the same methods and timelines outlined in Section 12.4. 
12.8.3 
Handling of deficient medical devices 
Any medical device alleged to be deficient must not be used by the investigator and has to be 
returned to the manufacturer. 
13 
Statistical considerations 
This section briefly summarizes the planned statistical analyses. The statistical analyses will be 
described in detail in a statistical analysis plan (SAP). 
The assessments done before start of treatment will serve as baseline evaluations. Generally, a 
baseline measurement refers to the last non-missing assessment made before treatment start. 
Continuous data are presented with the number of observations, mean value, standard deviation, 
minimum, Q1, median, Q3, and maximum value. Categorical data are presented as counts and 
percentages. 
13.1 
Analysis sets 
The statistical analyses will be based on the following sets: 
Safety analysis set (SAF) 
The SAF will include all subjects who will be treated with the investigational medical device 
at least once, irrespective of the duration of use. Subjects will be analyzed as treated. 
Full analysis set (FAS) 
The FAS serves as the primary performance analysis set. Subjects will be analyzed as 
randomized. 
The FAS will include subjects which fulfil the following criteria:  
• Included in the SAF 
• Having baseline and any post baseline data of any performance endpoint (primary 
performance endpoint or any of the secondary endpoints) 

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Per protocol (PP) analysis set  
The PP analysis set will include all subjects in the FAS without any major protocol deviations. 
Subjects will be analyzed as treated. 
The PP set (PPS) will include subjects who fulfil the following criteria: 
• Included in the FAS. 
• Do not have any other major protocol violations which will affect the assessment of 
efficacy. An example of a major protocol violation is a subject who terminates the study 
participation before the primary endpoint follow-up or violation of the inclusion/exclusion 
criteria. 
• Have no imputation for the primary performance endpoint (i.e. completed the diary for 
28 days after V3). 
• Have full duration of study treatment. 
13.2 
Statistical analyses  
The primary efficacy analysis will be based on the FAS. A sensitivity analysis of the primary 
endpoint will be performed using the PPS. All secondary efficacy outcomes will be analyzed 
using the FAS. Safety analyses will be based on the SAF. 
The investigator will review the patient’s diary and enter the number of days with headache and 
the number of days with migraine in the pCRF. This information will be available for the 
baseline period, the performance assessment period and the follow-up period.   
In case a patient should have documented less than 28 days per period (but has a compliance of 
at least 80%), the number of headache days per period is derived as follows: 
Number of headache days = (Number of headache days x 28) / Number of days observed 
If a patient has a diary compliance of less than 80%, this period will not be used for statistical 
analysis of this endpoint.  
For example, if a patient documented 24 days for one period only, and documented 6 days 
with headache, the derived number of headache days in this period is calculated to (6 x 
28) / 24 = 7.Primary performance endpoint 
Mean change from Baseline (4-week screening period) in monthly headache days with 
moderate to severe intensity in 4-week performance assessment period (V3 to V7). 
The primary null hypothesis to be tested is  
H0: μactive = μplacebo 
vs 
H1: μactive ≠ μplacebo 
where μ is the mean change from Baseline (4-week screening period) in monthly headache days 
with moderate to severe intensity in 4-week performance assessment period (V3 to V7). 

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If the data is normally distributed an analysis of covariance (ANCOVA) with treatment, 
baseline number of headache days, medication overuse as independent variables will be 
calculated to test above null hypothesis. 
If the data is not normally distributed the van Elteren test will be used with medication overuse 
as strata to test above null hypothesis. In addition, the number of monthly headache days and 
change from Baseline will be presented by descriptive statistics. 
Normality of data cannot be assumed, if at least one of the following items can be demonstrated 
on the residuals, as determined when applying the ANCOVA as described above: 
• p-value using Shapiro-Wilk test on normality < 0.2 
• Visual check of the QQ-plot shows: plotted points do not approximately lie on the diagonal 
line y = x 
Secondary performance endpoints 
All statistical tests for secondary performance endpoints are considered exploratory and no 
adjustment for multiplicity is made.  
All secondary endpoints will be evaluated for the performance assessment period and the 
follow-up period.  
Mean change from Baseline in monthly headache days with moderate to severe intensity 
in follow-up period 
The mean change from Baseline in monthly headache days in follow-up period will be similarly 
analyzed as the primary performance endpoint for the performance assessment period. The 
analysis for the performance assessment period is covered by the primary analysis. 
Mean change from Baseline in monthly migraine days  
The mean change from Baseline in monthly migraine days will be similarly analyzed as the 
primary performance endpoint; however, the number of migraine days instead of number of 
headache days will be counted.  
Mean change from Baseline in monthly headache days (mild, moderate and severe 
intensity) in 4-week performance assessment period (V3 to V7) 
The mean change from Baseline in monthly headache days with mild to severe intensity will 
be similarly analyzed as the primary performance endpoint; however, the number of headache 
days with mild intensity will be included.  

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Proportion of subjects with 30% or greater reduction in headache days of moderate to 
severe intensity 
The proportion of subjects with 30% or greater reduction from baseline period to performance 
assessment period will be presented descriptively using frequency tables.  
Additionally, active and placebo treatment arms will be compared using a Chi-square test. In 
case of a low number of subjects per group, the Fisher’s exact test will be used. 
Proportion of subjects with 50% or greater reduction of headache days of moderate to 
severe intensity 
The proportion of subjects with 50% or greater reduction from baseline period to performance 
assessment period will be presented descriptively using frequency tables.  
Additionally, active and placebo treatment arms will be compared using a Chi-square test. In 
case of a low number of subjects per group, the Fisher’s exact test will be used. 
Change in the use of abortive medication 
The change from Baseline in monthly use of abortive medication will be presented by 
descriptive statistics. 
Headache impact test 
The total HIT-6 score and change from Baseline will be presented by descriptive statistics. The 
number and percentage of patients in each category will be presented for each of the 6 items. 
The total HIT-6 score change from Baseline will be tested using a Wilcoxon rank sum test. 
MSQ 
The 3 dimensions of the MSQ will be presented by descriptive statistics for absolute values and 
changes from Baseline. The changes from Baseline will be tested using a Wilcoxon rank sum 
test for each of the 3 dimensions. 
Patient global impression of severity 
The score will be presented descriptively using frequency tables. The change from Baseline 
will be assessed with a shift table of baseline versus post-baseline assessments.   
Furthermore, the change from Baseline in severity scale will be calculated and tested using a 
Wilcoxon rank sum test.  
Safety endpoints 
Safety variables will be analyzed based on the SAF. Adverse events will be coded by the 
Medical Dictionary for Regulatory Activities (MedDRA). Incidences of AEs will be 
summarized by preferred term (PT) and system organ class (SOC). Adverse events (SOC and 
PTs) will be summarized also by intensity, relationship to the medical device or procedure, and 
seriousness. The analysis will be based on treatment emergent AEs, i.e. AEs which started after 
first treatment. All AEs will be listed.  

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Demographic and Other Baseline Characteristics 
Subject disposition, demographics, and other baseline data will be presented using summary 
statistics. 
13.3 
Interim analysis  
One interim analysis will be conducted based on the primary efficacy variable (Mean change 
from Baseline in monthly headache days with moderate to severe intensity in 4-week 
performance assessment period) according to an adaptive 2-stage group-sequential design with 
possible sample size adaption after the interim analysis. The interim analysis includes also the 
possibility to stop for efficacy and to stop for futility (using a non-binding futility rule). For 
assessing futility, the following secondary efficacy endpoints will be considered: 
- 
Mean change from Baseline in monthly migraine days in 4-week performance 
assessment period (V3 to V7) 
- 
Mean change from Baseline in monthly headache days (mild, moderate and severe 
intensity) in 4-week performance assessment period (V3 to V7) 
- 
Change in the use of abortive medication 
- 
HIT-6 score 
An alpha spending function of the O´Brien & Fleming type is chosen for the determination of 
critical values. 
The interim analysis is planned when the first approximately 50 subjects completed the 6-week 
treatment period (Visit 7).  
The interim analysis will be performed and assessed by an independent data monitoring 
committee (DMC). The DMC will operate in adherence to pre-defined rules as written down in 
the DMC Charter and will consist of a statistician and two medical experts. Only the DMC will 
have access to unblinded efficacy data.  
Based on the analysis results of the primary efficacy variable, the DMC statistician may 
recommend a stop of the study due to efficacy or futility or an adaption of the sample size and 
submit his/her proposal to the sponsor (Chordate Medical AB) who is responsible for taking 
the appropriate actions. One action could be to involve the two other DMC members in the 
decision making. In this case the DMC statistician would provide all analysis results of the 
interim analysis (primary and secondary efficacy endpoints) to the other two DMC members. 
The DMC would provide its proposal to the sponsor (Chordate Medical AB) who is finally 
responsible for taking the appropriate actions.    
The sample size re-estimation will use the primarily assumed number of subjects in case a lower 
re-estimation will result.  
The DMC Charter details further aspects of the conduct and decision strategies of the interim 
analysis. 

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13.4 
Blind data review meeting 
A blind data review meeting (BDRM) will be conducted prior to data base lock based on clean 
data to verify the number of subjects allocated to the analysis sets, and to identify and classify 
the CIP deviation observed within the clinical investigation. 
13.5 
Sample size calculation 
For the fixed sample size approach approximately 140 subjects should be enrolled in order to 
achieve at least 128 subjects evaluable for the primary performance endpoint. If during the 
conduct of the study the drop-out rate proves to be higher than expected (>10%), enrolment 
would continue until at least 128 subjects were assessed for the primary endpoint. 
The fixed sample size estimation delivered 128 subjects (64 per group) to be sufficient to detect 
a difference in means between the treatment groups of the primary performance endpoint of 3 
days (e.g. by assuming a change in monthly headache days in the placebo group of 2, and in the 
active group of 5) and assuming that the common standard deviation is 6 using a 2-group t-test 
with a 0.05 two-sided significance level and a power of 80%. 
As one interim analysis with the possibility to stop for efficacy or to stop for (a non-binding) 
futility shall be introduced, the sample size has to be revisited. An alpha spending function of 
the O’Brien Fleming type is applied having 2 analysis stages (one interim stage and one final 
analysis stage). The interim analysis will be performed after approximately 50 subjects 
(approximately 40% of fixed sample size) have completed the 6-week treatment period (Visit 
7) (unequal spaced analyses stages). The final analysis will be performed after N=132 subjects 
are assessable. With respect to a drop-out rate of 10% 148 patients have to be enrolled. 
The calculation of critical values for the interim analysis was performed using SAS 9.4/ PROC 
SEQDESIGN. A group-sequential design using an O`Brien & Fleming alpha spending function 
with two stages (information fraction at stage 1 is 40%, an overall significance level alpha of 
0.05 and beta of 0.2) has been considered. The table below shows boundaries to be met at the 
interim and final analysis for claiming efficacy or stop for (non-binding) futility at pre-specified 
information levels. Actual boundaries will be calculated with respect to the available 
information fraction levels at each stage of analysis.  
Boundary Information (p-Value Scale) 
Nonbinding Beta Boundary, Null Reference = 0 
_Stage_ 
 
Alternative 
Boundary Values 
Information Level 
Reference 
Lower 
Upper 
Proportion 
Actual 
N 
Lower 
Upper 
Alpha 
Beta 
Beta 
Alpha 
1 
0.4000 
0.364624 
52.50584 
-1.81152 
1.81152 
0.0003942 
0.39397 
0.60603 
0.99961 
2 
1.0000 
0.91156 
131.2646 
-2.86427 
2.86427 
0.02487 
0.02487 
0.97513 
0.97513 
 

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Sample Sizes (N) 
Two-Sample Z Test for Mean Difference 
_Stage_ 
Fractional N 
Ceiling N 
N 
N(Grp 1) 
N(Grp 2) 
Information 
N 
N(Grp 1) 
N(Grp 2) 
Information 
1 
52.51 
26.25 
26.25 
0.3646 
54 
27 
27 
0.3750 
2 
131.26 
65.63 
65.63 
0.9116 
132 
66 
66 
0.9167 
14 
Data handling and record keeping 
14.1 
Case report forms and data collection 
Case report forms 
The clinical investigation data will be collected via pCRF completed by the site’s responsible 
persons and finally approved by the principal investigator. The CRF pages will consist of one 
original and two copies of each page using “No Carbon Required” (NCR) paper.  
The site will archive one copy of the completed CRF with the investigator file. Completed CRF 
originals (i.e. the top page of the NCR paper) will be transferred to the data management of the 
sponsor’s designee and one copy will be sent to the sponsor’s designee project management 
 
Data entering into the pCRF 
All data must be entered in English. The pCRFs should always reflect the latest observations 
on the subject’s participation in the trial. Therefore, the pCRFs should be completed as soon as 
possible during or after the subject’s visit. It is the investigators’ obligation to assure 
documentation of all relevant data in the patient’s file, such as medical history, concomitant 
diseases, date of clinical trial enrolment, visit dates, results of examinations, administrations of 
medication, and AEs. The investigator must verify that all data entries in the pCRFs are accurate 
and correct. If some assessments are not done, or if certain information is not available, not 
applicable or unknown, the investigator should indicate this in the pCRFs. The investigator will 
be required to sign and date the clinical data. 
The query process 
The monitor will review the pCRFs and evaluate them for completeness and consistency. Each 
pCRFs will be compared with the respective source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections, and alterations are to be made by 
the investigator or authorized designee. Any CRF corrections should be made in a way that 
does not obliterate the original entry. Investigators or designees must sign with their initials and 
date all corrections. 
Any change or addition after separation of the NCR sets must be made using Data Clarification 
Forms (DCFs). 

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The investigator or designee has to carefully answer all queries issued on DCFs. Corrections 
necessary after the CRF has been collected from the site must be documented in a DCF. A copy 
of the DCF must be retained with the respective CRF at the site.  
 
 
14.2 
Subject records and source data 
The data reported in the pCRF shall be derived from source documents and consistent with 
these. Certain data may be recorded directly in the pCRF, which will then be considered as 
source data. Source documents are all documents used by the investigator or hospital that relate 
to the subject’s medical history, that verify the existence of the subject, the inclusion and 
exclusion criteria, and all records covering the subject’s participation in the clinical 
investigation. They include laboratory notes, memoranda, material dispensing records, subject 
files, etc. The origin of source data in the clinical investigation will be further specified in a 
separate document (“Origin of Source Data”).  
It is the responsibility of the investigator and all responsible personnel at site to maintain source 
documents and to record essential information in the medical records in accordance with 
national regulations and requirements: 
• Study code; 
• Subject screening number and subject number; 
• Confirmation and date that informed consent for participating in the study was obtained; 
• Diagnosis; 
• All visits during the clinical investigation period; 
• All AEs/ADEs; 
• Treatments and medications. 
The investigator is responsible for ensuring the accuracy, completeness, legibility and 
timeliness of the data recorded in the pCRF. The investigator must submit a completed pCRF 
for each subject who signed the consent form. Any supportive documentation submitted with 
the pCRF, such as laboratory or hospital records, should be clearly identified with the clinical 
investigation ID and subject number. Any personal information, including subject name, should 
be removed or rendered illegible to preserve individual confidentiality. 
14.3 
Data management procedures  
Details on data handling will be described in the Data Management Plan (DMP). The sponsor’s 
designee will handle the data cleaning process, including logical check, medical checks, and 
query processes. Computerized validation check programs on completeness, correctness, 

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plausibility (such as range checks, cross-checks) will verify the data according to the Data 
Validation Plan (DVP). All identified discrepancies will be queried using DCFs and will be 
addressed to the investigator. The database will be soft locked when it is considered complete 
and accurate (i.e. all CRF pages entered, all data cleaning activities performed). The database 
will be hard locked after all the changes following the DRM have been done and the database 
is considered complete and accurate. All changes will be tracked (audit trail). Sponsor approval 
prior to database hard lock is mandatory. 
14.4 
Data retention 
The investigator shall retain all study records during the clinical investigation and for the period 
required by the applicable regulatory requirements or for at least 15 years after the premature 
termination or completion of the clinical investigation, whichever is the longer. However, the 
investigator should contact the sponsor prior to destruction of any records or reports pertaining 
to the clinical investigation in order to ensure they no longer need to be retained. 
The investigator must take measures to prevent accidental or premature destruction of these 
documents. Included in records to be retained are the subjects’ medical records, signed CIP, 
signed consent forms, EC approval letters, product accountability records, correspondence 
concerning the clinical investigation and any other documents to identify the subjects (including 
the Subject Identification Log). 
The medical files of study subjects must be retained in accordance with local legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
14.5 
Report of the clinical investigation 
A final report of the clinical investigation (a “Clinical Investigation Report”) will be completed, 
even if the clinical investigation is prematurely terminated. The report will be prepared by FGK 
according to ISO 14155:2011.  
The report will be submitted to regulatory authorities and ECs, as appropriate, within the 
timeframes defined per national regulation or by the EC. 
15 
Ethical and regulatory considerations 
15.1 
Good Clinical Practice  
The investigator will ensure that this study is conducted in full conformity with the currently 
acknowledged revision of the Declaration of Helsinki. By acting in accordance with this CIP 
the study site fulfills the requirements of the International Standard ISO 14155:2011 (Clinical 
investigation of medical devices for human subjects - Good clinical practice [GCP]). 

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15.2 
Ethics Committee 
Before the initiation of the clinical investigation, the final CIP, any amendments if applicable, 
the subject information sheet and consent form, as well as any additional documents which are 
required by national regulations and the EC will be submitted to the competent EC for review. 
A favorable opinion for the clinical investigation must be obtained from the EC before any 
subject is enrolled at a center.  
If appropriate, any additional requirements imposed by the EC will be followed. Amendments 
to the study documents will be notified to, or approved by, the EC before implementation, if 
applicable.  
15.3 
Regulatory requirements 
This clinical investigation will be submitted for authorization to the CA as required by national 
law. The clinical investigation will not be initiated until written authorization for the conduct 
of the clinical investigation, has been received from the CA. Amendments to the clinical 
investigation will also be submitted for authorization to the CA as applicable. 
15.4 
Insurance 
Insurance coverage for damages emerging from the clinical investigation will be provided 
according to applicable legal requirements. In addition, the sponsor has taken out insurance 
coverage for the subjects’ travelling from their homes/places of work to the site and back. 
During the informed consent procedure, the investigator must inform the subject accordingly. 
Insurance details will be provided to the subject within the subject information sheet.  
15.5 
Informed consent process 
Before any clinical study-related activities are performed, the investigator (or authorized 
designee) must review the ICF and explain the clinical investigation to potential study subjects. 
The investigator must ensure that the subject is fully informed about the aims, procedures, 
potential risks, any discomforts, and expected benefits of the clinical investigation. Before 
consenting, the subject must be left with ample time to consider and ask questions. It must be 
emphasized that participation is voluntary and that the subject has the right to withdraw from 
the clinical investigation at any time without prejudice. The subjects must then sign and date 
the ICF prior to the conduct of any study procedures. The investigator must sign and date the 
ICF as well. 
Subjects will be informed that there is a chance they may not receive the treatment due to either 
not meeting the eligibility criteria or the target number of subjects to be randomized into the 
clinical investigation having been met. 
A copy of the subject information and ICF will be given to the subjects for their records. The 
rights and welfare of the study subjects will be protected by emphasizing to them that the quality 

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of their medical care will not be adversely affected if they decline to participate in this clinical 
investigation. 
If amendments to the final CIP affect the subject’s participation in the clinical investigation 
(e.g. a change in any procedure), the subject information and ICF must be updated to 
incorporate this modification, and subjects must agree to sign the amended form indicating that 
they re-consent to participate in the clinical investigation. 
15.6 
Subject confidentiality 
The study CIP, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the clinical investigation or the data will be released to 
any unauthorized third party without prior written approval of the sponsor. 
Personal subject data will be kept confidential in compliance with the European Data Protection 
Directive [8] or the EU General Data Protection Regulation 2016/679 [9], as applicable, and 
other applicable international and national requirements.  
The investigator must ensure that the pseudonymization (coding) of study subjects will be 
maintained and that their identities are protected from unauthorized parties. On pCRFs, 
compensation documentation, or any other documents submitted to the sponsor or sponsor's 
representative, subjects must be identified only by their identification codes; it is not allowed 
to use their names, addresses, telephone numbers, or similar information. The investigator will 
keep the original of the Subject Identification Log (including complete name and date of birth 
of each subject) in his/her file. The investigator must maintain these documents in strict 
confidence. 
To allow compliance with GCP, all subjects will be asked for consent regarding the access to 
their personal clinical study-related data for monitoring, audits, and inspections as well as 
regarding transmission and storage of their pseudonymous data; a respective statement will be 
part of the ICF. Professionals getting access to source data for monitoring, audits and 
inspections are bound to preserve strict confidentiality. 
16 
Amendments to and deviations from the CIP 
16.1 
Amendments 
Any change to the CIP concerning the purpose of the study, the study design or the subject’s 
eligibility can only be made in form of a written amendment to the CIP. Such amendments have 
to be discussed and signed by the sponsor, the coordinating investigator, and the principal 
investigator(s) before implementation (see also Section 15.2). 
Amendments that might have an impact on study procedures to be performed and/or the 
well-being of the subject require a further ICF that is to be signed by all subjects enrolled in the 
clinical investigation who are affected by the amendment. 

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The sponsor or sponsor’s representative will distribute CIP amendments to the investigators. 
16.2 
Deviations 
A CIP deviation is a failure to follow, intentionally or unintentionally, the requirements of the 
CIP. As required by national regulation or guidelines, requests for deviations and reports of 
deviations will be provided to the EC if the deviation affects subject’s rights, safety and well-
being, or the scientific integrity of the clinical investigation. 
Under emergency circumstances deviations from the CIP may proceed without prior approval 
by the sponsor and favorable opinion of the EC if the rights, safety and well-being of human 
subjects need to be protected. Such deviations will be documented and reported to the sponsor 
and the EC as soon as possible in accordance with national regulations. 
Where the monitor or sponsor identifies that the investigator is out of compliance, this will be 
notified to the investigator in writing, with a request to correct the source of the deviation 
immediately. Corrective action will be implemented to avoid repeated non-compliance, which 
will usually include re-training and may include terminating the clinical investigation at the 
site. Depending on the nature of such deviations, they will either be recorded by the investigator 
on the paper deviation form or completed by the monitor via the paper deviation form and 
signed by the investigator. 
All CIP deviations will be listed and if the subjects concerned will be evaluable for analysis 
will be discussed in a data review meeting prior to the statistical analysis. 
The sponsor is responsible for analyzing deviations and assessing their significance. Corrective 
action will be implemented to avoid repeated deviations, which may include suspending the 
clinical investigation and/or amending the CIP. 
17 
Suspension or premature termination of the clinical 
investigation 
The sponsor reserves the right to terminate or suspend the clinical investigation for any reason 
(e.g. safety reasons, new data on the risk/benefit assessment, ethical or administrative reasons). 
Written notice, outlining the reasons for the termination, will be submitted to the investigators 
in advance of such termination. The sponsor will provide instructions if assessments beyond 
the regular per protocol procedures should be necessary. 
The sponsor may suspend enrollment or terminate the study at a specific site for reasons 
including, but not limited to, inadequate data collection, low subject enrollment rate, 
achievement of the total subject number, or non-compliance with the CIP or other clinical 
research requirements. 

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A principal investigator, EC, or regulatory authority (if applicable) may also suspend or 
prematurely terminate the clinical investigation at the investigational sites for which they are 
responsible.  
In terminating the clinical investigation, the sponsor and the investigator(s) will assure that 
adequate consideration is given to the protection of subjects’ interests. 
If the clinical investigation is prematurely terminated, the sponsor or its representative will 
promptly inform the CA of the termination and its reason(s); the investigator or the sponsor (or 
representative) will promptly inform the EC, as specified in applicable regulations. 
Permission to resume the clinical investigation after a temporary halt will be obtained from the 
CA and EC prior to implementation. The investigators will not resume the clinical investigation 
until the sponsor instructs them to do so and has confirmed that the necessary approvals are in 
place. 
In case a patient was treated with the investigational device when the clinical investigation is 
suspended or prematurely terminated, every effort should be made to arrange for a final 
examination of such patient. Further medical care will be according to standard care at that site. 
18 
Unblinding 
The premature breaking of the blinding code should be restricted to emergency cases in which 
knowledge of the administered treatment is necessary, e.g. after occurrence of SADEs or in 
case of detected pregnancy which has existed during treatment with the medical device but had 
not been detected prior treatment. Whenever possible, the medical monitor or sponsor should 
be contacted before breaking the blinded emergency code. Should any code be broken, the 
respective patient will be withdrawn from further participation in the study and a written 
explanation must be given by the investigator; the sponsor must be notified immediately. 
19 
Publication policy 
It is the sponsor’s intention that the results of the clinical investigation will be submitted jointly 
for publication including at least one publication in a scientific journal. Details of the 
publication policy and related sponsor, trust and investigator responsibilities are included in the 
Clinical Investigation Agreement. 
This clinical investigation will be registered on ClinicalTrials.gov before enrolment of the first 
subject. 

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20 
Approval and signatures 
 
Clinical investigational plan approval 
 
Clinical investigational plan agreed to by sponsor:
 
 
 
 
 
 
Sponsor’s signatory name (print) 
 
 
 
 
 
 
 
Sponsor’s signatory signature 
 
Date 
 
 
Clinical investigational plan agreed to by coordinating investigator:
 
 
 
 
 
 
Coordinating investigator name (print) 
 
 
 
 
 
 
 
Coordinating investigator signature 
 
Date 
 
 

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Principal investigator agreement page for the clinical investigational plan 
I agree: 
• To assume responsibility for the proper conduct of the clinical investigation at this site, and 
to conduct the study in compliance with this CIP, any future amendments, and with any 
other study conduct procedures provided by the sponsor or authorized representatives. 
• Not to implement any deviations from or changes to the CIP (including CIP amendments) 
without agreement from the sponsor and prior review and favorable opinion from the Ethics 
Committee and approval from the Competent Authority, if applicable, except where 
necessary to eliminate an immediate hazard to the subject(s), or for administrative aspects 
of the clinical investigation (where permitted by all applicable regulatory requirements). 
• That I am familiar with the appropriate use of the investigational medical device as 
described in this CIP and any other information provided by the sponsor including, but not 
limited to, the current Investigator’s Brochure or equivalent document provided by the 
sponsor. 
• To ensure that all persons assisting me with the clinical investigations are adequately 
informed about the investigational medical device and of their study-related duties and 
functions. 
• That I have been informed that certain regulatory authorities require the sponsor to obtain 
and supply details about the investigator’s ownership interest in the sponsor or the study 
product, and more generally about his/her financial ties with the sponsor. The sponsor will 
use and disclose the information solely for the purpose of complying with regulatory 
requirements. 
 
 
 
 
Principal investigator name (print) 
 
 
 
 
 
 
 
Principal investigator signature 
 
Date 
 
 

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Final 7.0, 14-Jun-2021 
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21 
References 
1. Goadsby PJ, Lipton RB, Ferrari MD. Migraine – current understanding and treatment. 
N Engl J Med 2002;346:257-70. 
2. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. 
Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017 
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3. Silberstein SD. Sex hormones and headache. Rev Neurol (Paris). 2000;156 Suppl 
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4. Schürks M. Genetics of migraine in the age of genome-wide association studies. J 
Headache Pain. 2012;13(1):1-9.  
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headaches. Cephalalgia. 2005;25(2):82-6. 
6. Hord ED, Evans MS, Mueed S, Adamolekun B, Naritoku DK. The effect of vagus 
nerve stimulation on migraines. J Pain. 2003;4(9):530-4. 
7. Juto JE, Axelsson, M. Kinetic oscillation stimulation as treatment of non-allergic 
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995L0046:en:HTML . 
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2016 on the protection of natural persons with regard to the processing of personal data 
and on the free movement of such data, and repealing Directive 95/46/EC (General 
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content/EN/TXT/HTML/?uri=CELEX:32016R0679 
10. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 
2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 
178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 
90/385/EEC 
and 
93/42/EEC. 
Available 
from: 
https://eur-
lex.europa.eu/eli/reg/2017/745/oj