Pilot Clinical Investigation Evaluating the Safety and Performance of RGn550 in Treating Sportspeople Suffering From Acute Concussion Syndrome - A Prospective, Comparative, Randomized, Simple-blinded, Monocentric Investigation [RGncon Investigation]
Phase: NA
Conditions: Acute Concussion Syndrome
Sponsor: REGEnLIFE SAS

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RGnCON INVESTIGATION 
Pilot clinical investigation evaluating the safety and 
performance of RGn550 in treating sportspeople 
suffering from acute concussion syndrome 
A prospective, comparative, randomized, simple-blinded, 
monocentric investigation 
 
CLINICAL INVESTIGATION PLAN 
Version 2.0 - 11 August 2022 
Written by 
 
 
N° ID-RCB: 2022-A01319-34 
 
 
Sponsor: 
REGEnLIFE 
1 Ter Rue de la Garrigue  
ZA Bosc Bat Hélios 
34130 Mudaison 
France  
 
 
Contract Research Organization: 
 
  
 
 
 
 
 
Version without personal nor confidential data 
 

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1. APPROVAL FORM 
Sponsor: REGEnLIFE 
1 Ter Rue de la Garrigue  
ZA Bosc Bat Hélios 
34130 Mudaison - France 
 
 
 
Date:  
Signature:  
 
 
 
 
 
Date:  
Signature:  
 
 
 
 
 
 
 
 
 
 
 
 
Date:  
Signature:  
 
 
 
 
 
Date:  
Signature:  
 
 
 
  
 
Date:  
Signature:  
 
 
 
 
 
Date:  
Signature:  
 
 
Investigators 
 
 
 
 
 
 
 
Date:  
Signature:  
 
 
 
 
 
 
 
Date:  
Signature:  
 
 
Laboratory 
 
 
 

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2. INVESTIGATOR SIGNATURE PAGE 
Having read this Clinical Investigation Plan, I hereby agree to conduct this investigation in compliance 
with the plan requirements and all applicable laws and regulations. 
Clinical Investigation Title: 
“RGnCON INVESTIGATION - Pilot clinical investigation evaluating the safety and performance of 
RGn550 in treating sportspeople suffering from acute concussion syndrome - A prospective, 
comparative, randomized, simple-blinded, monocentric investigation” 
Clinical Investigation Plan Version:  
Version 2.0 - 11 August 2022 
Principal Investigator 
 
Name: 
 
Date: 
 
Signature: 
 
 
 
 
 

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3. TABLE OF CONTENTS 
1. 
APPROVAL FORM .................................................................................................................................. 2 
2. 
INVESTIGATOR SIGNATURE PAGE .......................................................................................................... 3 
3. 
TABLE OF CONTENTS ............................................................................................................................. 4 
4. 
LIST OF FIGURES .................................................................................................................................... 6 
5. 
LIST OF TABLES ...................................................................................................................................... 7 
6. 
VERSION HISTORY ................................................................................................................................. 8 
7. 
ABBREVIATIONS .................................................................................................................................... 9 
8. 
SYNOPSIS ............................................................................................................................................ 11 
9. 
CLINICAL INVESTIGATION PLAN ........................................................................................................... 17 
9.1. 
INVESTIGATIONAL MEDICAL DEVICE ............................................................................................................. 17 
9.1.1. 
Identification ............................................................................................................................... 17 
9.1.2. 
Description .................................................................................................................................. 17 
9.1.3. 
Indications ................................................................................................................................... 19 
9.1.4. 
Contraindications ........................................................................................................................ 19 
9.1.5. 
Use .............................................................................................................................................. 19 
9.1.6. 
Training or Experience Needed to Use the Device ...................................................................... 20 
9.1.7. 
Specific Medical or Surgical Procedures Involved in the Use of the Device ................................. 20 
9.2. 
BACKGROUND, RATIONALE AND JUSTIFICATION OF THE CLINICAL INVESTIGATION DESIGN ....................................... 21 
9.2.1. 
Background ................................................................................................................................. 21 
9.2.2. 
Rationale ..................................................................................................................................... 26 
9.2.3. 
Justification of the Clinical Investigation Design ......................................................................... 30 
9.2.4. 
Investigation Classification per European Regulation 2017/745 ................................................ 31 
9.3. 
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE, CLINICAL PROCEDURE AND CLINICAL INVESTIGATION ............. 31 
9.3.1. 
Anticipated Clinical Benefits ....................................................................................................... 31 
9.3.2. 
Anticipated Adverse Device Effects ............................................................................................. 31 
9.3.3. 
Risks Associated with the Participation in the Clinical Investigation .......................................... 32 
9.3.4. 
Possible Interactions with Concomitant Treatments .................................................................. 32 
9.3.5. 
Steps Taken to Control or Mitigate Risks and Benefit-Risk Ratio Rationale ................................ 32 
9.4. 
CLINICAL INVESTIGATION OBJECTIVES AND HYPOTHESES ................................................................................... 34 
9.4.1. 
Primary Objective ........................................................................................................................ 34 
9.4.2. 
Secondary Objectives .................................................................................................................. 34 
9.5. 
CLINICAL INVESTIGATION DESIGN ................................................................................................................. 35 
9.5.1. 
Investigational Medical Devices .................................................................................................. 35 
9.5.2. 
Investigation Population ............................................................................................................. 35 
9.5.3. 
Conduct ....................................................................................................................................... 36 
9.5.4. 
Endpoints .................................................................................................................................... 38 
9.5.5. 
Description of Visits, Procedures and Data to Collect ................................................................. 40 
9.5.6. 
Monitoring .................................................................................................................................. 47 
9.6. 
STATISTICAL CONSIDERATIONS .................................................................................................................... 48 
9.6.1. 
Sample Size Justification ............................................................................................................. 48 
9.6.2. 
Analysis Population ..................................................................................................................... 48 
9.6.3. 
Statistical Analysis ...................................................................................................................... 48 
9.6.4. 
Timing of Analyses ...................................................................................................................... 50 
9.7. 
DATA MANAGEMENT ................................................................................................................................ 51 
9.8. 
CLINICAL INVESTIGATION PLAN AMENDMENTS ............................................................................................... 53 
9.9. 
CLINICAL INVESTIGATION PLAN DEVIATIONS ................................................................................................... 54 
9.10. 
INVESTIGATIONAL MEDICAL DEVICE ACCOUNTABILITY ...................................................................................... 55 

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9.11. 
STATEMENTS OF COMPLIANCE .................................................................................................................... 56 
9.11.1. 
Regulatory and Ethical Considerations ....................................................................................... 56 
9.11.2. 
Financing, Contract and Insurance ............................................................................................. 56 
9.11.3. 
Roles and Responsibilities ........................................................................................................... 56 
9.12. 
INFORMED CONSENT PROCESS .................................................................................................................... 58 
9.13. 
SAFETY RECORDING AND REPORTING ............................................................................................................ 59 
9.13.1. 
Definitions within the Context of this Investigation .................................................................... 59 
9.13.2. 
Definitions within the Context of Materiovigilance .................................................................... 60 
9.13.3. 
Safety Reporting to Sponsor ....................................................................................................... 60 
9.13.4. 
Safety Reporting to Authorities ................................................................................................... 61 
9.13.5. 
Anticipated Adverse Device Effects ............................................................................................. 61 
9.13.6. 
Data Safety Monitoring Board .................................................................................................... 62 
9.14. 
VULNERABLE POPULATION ......................................................................................................................... 63 
9.15. 
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL INVESTIGATION ...................................................... 64 
9.15.1. 
Suspension or Premature Termination of the Clinical Investigation ........................................... 64 
9.15.2. 
Site Close-Out .............................................................................................................................. 64 
9.15.3. 
Investigator Participation Discontinuation ................................................................................. 64 
9.16. 
RESULTS AND PUBLICATION POLICY .............................................................................................................. 65 
9.17. 
PROVISIONAL TIMELINES ............................................................................................................................ 66 
10. 
BIBLIOGRAPHY ................................................................................................................................ 67 
11. 
DOCUMENT REFERENCES ................................................................................................................ 70 
12. 
APPENDICES .................................................................................................................................... 71 
12.1. 
HEAD IMPACT ASSESSMENT - FORM 3 .......................................................................................................... 72 
12.2. 
TRAIL MAKING TEST .................................................................................................................................. 80 
12.2.1. 
Part A .......................................................................................................................................... 80 
12.2.2. 
Part B .......................................................................................................................................... 81 
12.3. 
SCAT5 SYMPTOM EVALUATION TOOL .......................................................................................................... 82 
 
 

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4. LIST OF FIGURES 
Figure 1: Schematic representation of RGn550 .................................................................................... 17 
Figure 2: Schematic representation of RGn550’s control box .............................................................. 17 
Figure 3: Schematic representation of RGn550’s splitter ..................................................................... 18 
Figure 4: Schematic representation of RGn550’s helmet ..................................................................... 18 
Figure 5: Schematic representation of RGn550’s modules ................................................................... 18 
Figure 6: Schematic representation and picture of RGn550’s lenses ................................................... 19 
Figure 7: Physiopathology of concussion [5] ......................................................................................... 23 
Figure 8: Horizontal orientation of the Maddox rod to identify horizontal deviation (BI: Base In, BO: 
Base Out) [38] ........................................................................................................................................ 42 
Figure 9: Vertical orientation of the Maddox rod to identify vertical deviation (BD: Base Down, BU: 
Base Up, LH: Left Hyperphoria, Rh: Right hypophoria, RH: Right Hyperphoria) [38] ............................ 42 
Figure 10: Picture of KFORCE Plates ...................................................................................................... 43 
 

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5. LIST OF TABLES 
Table 1: Parameters of RGn550’s lighting sources ................................................................................ 18 
Table 2: Schedule of procedures and evaluations ................................................................................ 46 
Table 3: Timeframes for safety reporting to authorities ....................................................................... 61 
Table 4: Anticipated RGn550's ADEs ..................................................................................................... 61 
 

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6. VERSION HISTORY 
Version 
Date 
Author 
Description of main modifications – 
amendments 
1.0 
17 June 2022 
 
Initial version of the Clinical Investigation Plan 
2.0 
11 August 2022 
 
Update of the Clinical Investigation Plan to 
address Ethics Committee’s comments: 
• 
Description of patient’s usual care pathway 
and link with investigation information and 
inclusion process (section 9.5.3.1) 
• 
Addition of a pregnancy test for women of 
childbearing potential (sections 8, 9.5.5.1 
and 9.5.5.5). 
 
 
 
 

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7. ABBREVIATIONS  
Abbreviation 
Description 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale-cognitive subscale 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ANSM 
Agence Nationale de Sécurité des Médicaments et produits de santé - 
French National Agency for the Safety of Medicines and health products 
ATC 
Anatomical Therapeutic Chemical 
ASADE 
Anticipated Serious Adverse Device Effect 
BD 
Base Down 
BI 
Base In 
BO 
Base Out 
BU 
Base Up 
CIP 
Clinical Investigation Plan 
CNIL 
Commission Nationale de l'Informatique et des Libertés - French National 
Commission on Informatics and Freedoms  
DD 
Device Deficiency 
eCRF 
electronic Case Report Form 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFAP 
Glial Fibrillary Acidic Protein 
HIA3 
Head Injury Assessment - Form 3 
IEC 
International Electrotechnical Commission 
IFU 
Instruction For Use 
IL 
InterLeukin 
ISO 
International Organization for Standardization 
IWRS 
Interactive Web Response System 
LED 
Light Emitting Diode 
LH 
Left Hyperphoria 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not Applicable 

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Abbreviation 
Description 
NPC 
Near Point of Convergence 
PBM 
PhotoBioModulation 
PT 
Preferred term 
Rh 
Right hypophoria 
RH 
Right Hyperphoria 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SCAT5 
Sport Concussion Assessment Tool - 5th edition 
SMS 
Static Magnetic Stimulation 
SOC 
System Organ Classes 
TBI 
Traumatic Brain Injury 
TMT A&B 
Trail Making Test part A and B 
UCH-L1 
Ubiquitin C-terminal Hydrolase-L1 
USADE 
Unanticipated Serious Adverse Device Effect 
WHO 
World Health Organization 
 

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8. SYNOPSIS 
Title 
Pilot clinical investigation evaluating the safety and performance of RGn550 
in treating sportspeople suffering from acute concussion syndrome 
(RGnCON) 
ID-RCB Number 
2022-A01319-34 
Investigational Medical 
Device 
RGn550 is a reusable non-invasive class IIa electromedical device that is 
manufactured by REGEnLIFE and not CE-marked yet.  
The device combines two technologies: 
• 
PhotoBioModulation (PBM), which involves exposure to directional low-
power and high-fluence monochromatic or quasi-monochromatic light 
from the red to near-infrared wavelengths (λ = 600-1,100 nm) using 
lasers and Light Emitting Diodes (LEDs) 
• 
Static Magnetic Stimulation (SMS), which consists in the application of a 
static magnetic field using a neodymium magnet. 
  
 
 
 
 
 
 
 
 
 
  
 
 
The device is intended, on medical opinion, to treat acute concussion 
syndrome (inferior or equal to 72h). It is intended for use by physicians and 
nurses trained in the use of RGn550 on adult patients. The treatment area is 
the head. 
Investigation Rationale 
Considering: 
• 
The promising results of transcranial PBM in concussion that were 
published in the literature, 
• 
The effect of a previous version of the device on neuroinflammation 
demonstrated pre-clinically and the fact that a neuroinflammatory 
response is involved in concussion’s physiopathology, 
• 
The good safety results obtained in Alzheimer’s Disease (AD) patients in 
the pilot clinical investigation on a previous version of the device, 
REGEnLIFE wishes to conduct a pilot clinical investigation on RGn550 to 
evaluate its safety and explore its performance in treating patients with 
acute concussion syndrome. 
Overall Design  
RGnCON is a prospective, comparative, randomized, simple-blinded, 
monocentric, pilot clinical investigation.  
It involves two parallel groups differing in terms of treatment frequency: half 
of the patients will be treated with 5 Hz, the other half with 10 Hz. 
Objectives  
Primary objective:  
• 
To evaluate the incidence of RGn550’s Adverse Device Effects (ADEs) in 
acute concussion syndrome, when used to deliver, either at a frequency 

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of 5 or 10 Hz, two 20-min treatment sessions at 1 week apart. 
Secondary objectives: 
• 
To evaluate the incidence of RGn550’s ADEs per severity, Adverse Events 
(AEs) and Device Deficiencies (DDs) 
• 
To evaluate the effect of RGn550, after the first and second treatment 
sessions and then 45 days after the second treatment session, on: 
o Automated oculomotor and oculopostural functions 
o Balance function 
o Executive function 
• 
To assess the effect of RGn550 on concussion syndrome symptoms 7 
days after the first treatment session as well as 7 and 45 days after the 
second treatment session  
• 
To evaluate the effect of RGn550 on blood markers that are involved in 
the pathogenesis of concussion 45 days after the second treatment 
session. 
Investigation 
Population 
Adult sportspeople with acute concussion syndrome resulting from sport 
practice who can participate in a clinical investigation per the law and are 
able to meet treatment sessions and complete requested assessments will 
be included. 
Inclusion criteria: 
• 
Male or female aged at least 18 years old  
• 
Suffering from concussion syndrome resulting from a shock that 
occurred during sport practice less than 72h ago, as confirmed by 
neurological examination via the Head Injury Assessment - Form 3 
(HIA3) tool 
• 
Affiliated to French social security 
• 
Who provided a dated and signed informed consent form. 
Non-inclusion criteria: 
• 
Patient protected by a French legal measure (“sauvegarde de justice”, 
“tutelle” or “curatelle”) 
• 
Patient not able to express his/her consent 
• 
Patient deprived of liberty or hospitalized without consent  
• 
Woman who is pregnant or breastfeeding, or who plans to become 
pregnant or breastfeeding during the investigation, or who has the 
capacity to conceive but is not using a reliable contraceptive method as 
deemed by the investigator 
• 
Patient living in a medical facility 
• 
Patient who experienced a surgery at the treatment application area 
(head) within 3 months prior to inclusion 
• 
Patient with skin lesions on the treatment application area (head) 
• 
Patient with a short-term life-threatening pathology (e.g., evolving 
cancer; non-stable heart failure; severe hepatic, renal or respiratory 
failure, etc.) 
• 
Patient diagnosed with a heart attack within 3 months prior to inclusion 
• 
Patient implanted with ferromagnetic material  
• 
Patient implanted with a pacemaker 
• 
Patient with a risk of epileptic seizure or other non-degenerative central 

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nervous system diseases 
• 
Patient with major physical or neurosensorial disorders that may 
interfere with assessments 
• 
Patient with chronic psychosis or psychotic episodes 
• 
Patient addicted to alcohol or drugs 
• 
Patient treated with antidepressant or benzodiazepine 
• 
Patient who participated to another investigation/study involving the 
use of an investigational medical device/drug within the 30 days prior 
inclusion 
• 
Patient not able to meet treatment sessions as deemed by the 
investigator 
• 
Patient not able to complete requested investigation assessments as 
deemed by the investigator. 
Investigation Conduct 
Three onsite visits will be performed at the following timepoints: 
• 
Day 0 (D0): Inclusion, randomization (to the 5 Hz or 10Hz treatment 
group) and first treatment session 
• 
Day 7 (D7): Second treatment session 
• 
Day 52 (D52): Evaluation 45 days after the last treatment session. 
In addition, at Day 14 (D14), the patient will be asked to remotely assess 
his/her concussion syndrome symptoms. 
The overall investigation duration, which corresponds to the inclusion period 
and the follow-up period, will be of 6 months approximately (4 months of 
inclusion and 52 days of follow-up). 
Endpoints 
Primary endpoint:  
• 
Incidence of RGn550’s ADEs throughout the investigation 
Secondary endpoints: 
• 
Incidence of RGn550’s ADEs per severity (mild, moderate and severe) 
throughout the investigation 
• 
Incidence of RGn550’s AEs throughout the investigation 
• 
Incidence of RGn550’s DDs throughout the investigation 
• 
Evolution, before and after treatment session at D0 and D7 and then at 
D52, of: 
o Automated oculomotor and oculopostural functions, as assessed 
through: 
▪ 
Convergence, evaluated with the measure of the Near 
Point of Convergence (NPC) 
▪ 
Deviations, evaluated with the cover test and Maddox 
rod test 
o Balance function, as assessed through the following static 
stabilometric parameters: 
▪ 
Statokinesigram area 
▪ 
Left/right distribution  
• 
Evolution, before treatment session at D0 and after treatment session at 
D7 of executive function, as assessed with the Trail Making Test part A 
and B (TMT A&B) 
• 
Evolution of concussion syndrome symptoms as assessed by the patient 

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with the Sport Concussion Assessment Tool – 5th edition (SCAT5) 
symptom evaluation tool at D0 before treatment, D7 before treatment, 
D14 and D52 
• 
Evolution from D0 before treatment to D52 of the concentration of the 
following blood markers: 
o Anti-inflammatory 
cytokines 
InterLeukin 
(IL)-1 
receptor 
antagonist, IL-4, IL-6, IL-10, IL-11 and IL-13  
o S100 calcium binding protein B (S100B) 
o Glial Fibrillary Acidic Protein (GFAP) 
o Ubiquitin C-terminal Hydrolase-L1 (UCH-L1). 
Sample Size 
Justification 
It is planned to include 50 patients in this investigation. For such a sample 
size, the probability of observing at least one ADE will be 0.87 considering a 
probability of ADE of 0.04. 
Statistical Analysis 
All analyses will be performed in the Full Analysis Set (FAS), which will 
comprise all included patients who have been treated at least once with 
RGn550 device. Patients will be assigned to the treatment group as treated. 
The global significance level (type I error rate) will be set at α = 0.05 (two-
sided). Adjustment for multiplicity in not applicable for the primary endpoint 
and no adjustment for multiplicity is planned for secondary endpoints. 
Primary endpoint analysis 
The proportion of subjects with at least one ADE will be calculated along 
with the 95% exact Clopper-Pearson confidence interval in the FAS, by 
treatment groups and overall. 
Secondary endpoints analysis 
For ADEs per severity, a descriptive analysis with 95% exact Clopper-Pearson 
confidence interval of mild, moderate and severe ADEs will be provided in 
the FAS, by treatment groups and overall. 
All AEs will be described in the FAS, for each System Organ Class (SOC) and 
Preferred Term (PT) class using MedDRA (Medical Dictionary for Regulatory 
Activities) terminology, by treatment groups and overall. 
All DDs will be described in the FAS, by treatment groups and overall. 
The secondary performance analyses will be performed in the FAS by 
treatment groups, excluding data that would be collected after the following 
intercurrent event: treatment group switch during follow-up. 
Imputation of missing data will be handled by the mixed model (details will 
be provided in the Statistical Analysis Plan). 
A sensitivity analysis will be conducted on the secondary performance 
endpoints in the FAS without excluding any data collected after intercurrent 
events.  
Provisional timelines 
• 
Regulatory submission: June 2022 
• 
Site initiation: August-September 2022 
• 
Patient recruitment: September 2022 (first patient first visit) - December 
2022 (last patient first visit) 
• 
Last visit last patient: February 2023 
• 
Database lock: March-April 2023 

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• 
Statistical analysis and clinical investigation report: May-July 2023 

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D0 
D7 
D14 
(remote) 
D52 
 
Before treatment 
After treatment 
Before treatment 
After treatment 
Patient 
information 
/ 
Informed 
consent  
X 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
Pregnancy 
test 
for 
women 
of 
childbearing potential 
X 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
Demographic and clinical data 
X 
 
 
 
 
 
NPC 
X 
X 
X 
X 
 
X 
Cover test 
X 
X 
X 
X 
 
X 
Maddox rod test 
X 
X 
X 
X 
 
X 
Stabilometric test 
X 
X 
X 
X 
 
X 
TMT A&B 
X 
 
 
X 
 
 
SCAT5 symptom evaluation tool 
X 
 
X 
 
X 
X 
Blood sampling 
X 
 
 
 
 
X 
20-min treatment session 
X 
X 
 
 
Collection of AEs and DDs that 
previously occurred 
 
X 
X 
X 
 
X 
 
 
 
 

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9. CLINICAL INVESTIGATION PLAN 
9.1. 
Investigational Medical Device 
9.1.1. Identification 
RGn550 is a reusable non-invasive class IIa electromedical device that is manufactured by REGEnLIFE 
and not CE-marked yet.  
The current valid versions of RGn550’s: 
• 
Instructions for Use (IFU) is version 1 dated 07 April 2022 
• 
Investigator brochure is version 1 dated 02 June 2022. 
9.1.2. Description 
A summarized description of RGn550 is provided below. For further details on the device, please 
refer to the IFU or investigator brochure. 
9.1.2.1. Overall Description 
RGn550 combines two technologies: 
• 
PhotoBioModulation (PBM), which involves exposure to directional low-power and high-fluence 
monochromatic or quasi-monochromatic light from the red to near-infrared wavelengths (λ = 
600-1,100 nm) using lasers and Light Emitting Diodes (LEDs) 
• 
Static Magnetic Stimulation (SMS), which consists in the application of a static magnetic field 
using a neodymium magnet. 
Further information on these two technologies is provided in section 9.2.1.2. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 

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Half aperture angle (°) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.1.6. Training or Experience Needed to Use the Device 
As mentioned in RGn550’s investigator brochure: 
A 2-hour theoretical and practical training, provided by REGEnLIFE’s staff at the time RGn550 is 
delivered to the users, is required before using RGn550.  
9.1.7. Specific Medical or Surgical Procedures Involved in the Use of the Device 
No specific medical nor surgical procedures are involved in the use of RGn550. 
 
 

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9.2. 
Background, Rationale and Justification of the Clinical Investigation Design 
9.2.1. Background 
9.2.1.1. Concussion  
9.2.1.1.1. 
Definition  
Concussion is characterized by an immediate, transient and spontaneously reversible alteration of 
mental function, ranging from confusion to loss of consciousness, as a result of direct or indirect 
trauma with impulsive force to the head [1].  
The following consensus definition was reached during the 5th international conference on 
concussion in sport held in Berlin in 2017 [2]:  
Concussion is a traumatic brain injury induced by biomechanical forces. There are several 
common features that clinically define the nature of a concussive head injury: 
• 
Concussion may be caused either by a direct blow to the head, face, neck or elsewhere on 
the body with an impulsive force transmitted to the head. 
• 
Concussion typically results in the rapid onset of short-lived impairment of neurological 
function that resolves spontaneously. However, in some cases, signs and symptoms evolve 
over several minutes to hours. 
• 
Concussion may result in neuropathological changes, but the acute clinical signs and 
symptoms largely reflect a functional disturbance rather than a structural injury and, as such, 
no abnormality is seen on standard structural neuroimaging studies. 
• 
Concussion results in a range of clinical signs and symptoms that may or may not involve loss 
of consciousness. Resolution of the clinical and cognitive features typically follows a 
sequential course. However, in some cases symptoms may be prolonged. 
The clinical signs and symptoms cannot be explained by drug, alcohol, or medication use, other 
injuries (such as cervical injuries, peripheral vestibular dysfunction, etc.) or other comorbidities 
(e.g., psychological factors or coexisting medical conditions). 
It should be noted that the terms “mild Traumatic Brain Injury (TBI)” and “concussion” are often used 
interchangeably. In the broadest clinical sense, concussion is often defined as representing the 
immediate and transient symptoms of TBI. One key unresolved issue is whether concussion is part of 
TBI spectrum associated with lesser degrees of diffuse structural changes than are seen in severe TBI, 
or whether the concussive injury is the result of reversible physiological changes [2]. The term 
“concussion” is used throughout this document. 
9.2.1.1.2. 
Physiopathology 
As stated above, the concussion may be caused either by a direct blow to the head, face, neck or 
elsewhere on the body with an “impulsive” force transmitted to the head [2]. This blow can be 
received in various situations including falls, traffic accidents and sport practice [3, 4]. Sports at risk 
include hockey, American football, team sports, boxing and winter sports [1]. 
The pathogenesis of concussion has not been fully elucidated yet, but it is becoming increasingly 
clear that biomechanical forces lead to an energy crisis, neuroinflammation, cerebral blood flow 
changes, and pathological cascades, as detailed below and summarized in Figure 7 [5]: 
• 
Biomechanical forces generate disruptions of neuronal cell membranes and axonal stretching, 
triggering indiscriminate flux of ions through previously regulated ion channels. This ions 

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imbalance causes neuronal depolarization, near-complete loss of electrochemical energy, and 
neuronal swelling. 
• 
The adenosine triphosphate-dependent Na+/K+ pumps attempt to restore ionic homeostasis, 
and hyperglycolysis rapidly depletes energy stores, resulting in lactic acid buildup, and ultimately, 
the development of cerebral edema. In addition to the ionic flux, there is a hyperacute release of 
glutamate, the brain's primary excitatory neurotransmitter. Excessive glutamate receptor binding 
can activate calcium-dependent proteases and phospholipases, uncouple mitochondrial 
adenosine triphosphate synthesis, promote oxidative stress produce reactive oxygen species, 
deplete glutathione levels, and increase cellular energy demands. 
• 
Concussion-induced disruption of the blood-brain barrier exacerbates the neuroinflammatory 
response mediated by immune cells, microglia, cytokines, and other inflammatory mediators. 
Blood-brain barrier dysfunction contributes to oxidative stress, inflammation, brain swelling, 
increased intracranial pressure, and ischemia. 
• 
Shearing forces from a direct blow to the head or acceleration-deceleration transmitted through 
the neck interrupt axonal transport resulting in accumulation of transported materials in injured 
regions. Axonal dysregulation and accumulation of transport products lead to axonal swelling, 
secondary disconnection, and Wallerian degeneration (an active, cell-autonomous death 
pathway as a consequence of the axonal transport system's inability to deliver essential 
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Figure 7: Physiopathology of concussion [5] 
9.2.1.1.3. 
Symptoms  
In the acute phase, concussion is an evolving injury with rapidly changing clinical signs and symptoms 
[2]. 
These symptoms can be categorized into [1–3, 6, 7]:  
• 
Somatic symptoms, such as:  
o Headache 
o Vision changes including blurred vision, light sensitivity, difficulty reading and 
convergence dysfunction 
o Coordination disorders 
o Disturbance in balance 
o Insomnia 
o Somnolence 
o Drowsiness 

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• 
Cognitive impairment, such as: 
o Feeling like in a fog 
o Disorientation 
o Difficulty concentrating 
o Slowed reaction time 
o Loss of consciousness 
o Amnesia 
o Neurological deficit 
• 
Emotional / behavioral changes such as: 
o Irritability 
o Lability 
Altogether, this set of symptoms is called concussion syndrome [1, 6]. 
In adults, symptoms typically resolve in 10 to 14 days [2]. However, some may linger for weeks. 
Persistent post-concussion syndrome occurs when symptoms persist beyond 3 months [6]. 
Of note, well-trained and well-prepared sportspersons are thought to heal more rapidly [1, 4]. 
9.2.1.1.4. 
Complications 
Although the short-term vital prognosis is very good (mortality < 1%), the functional prognosis in the 
mid- and long-term is more uncertain. Indeed, approximately 10-20% of the patients will have long-
lasting effects [3]. 
The literature on neurobehavioral sequelae and long-term consequences of exposure to recurrent 
head trauma is inconsistent. However, reported potential long-term problems include [1, 2]: 
• 
Cognitive impairment 
• 
Depression 
• 
Chronic traumatic encephalopathy (although a cause-and-effect relationship has not yet been 
demonstrated between chronic traumatic encephalopathy and concussion). 
Of note, well-trained and well-prepared sportsperson are thought to have less complications. 
Interestingly, concussions have been reported to be more severe in sportswomen than sportsmen 
[1]. 
9.2.1.1.5. 
Management 
Most consensus and agreement statements for managing concussion recommend that patients rest 
until they become symptom-free. Accordingly, prescribed rest is one of the most widely used 
interventions. The basis for recommending physical and cognitive rest is that rest may ease 
discomfort during the acute recovery period by mitigating concussion symptoms and/or that rest 
may promote recovery by minimizing brain energy demands following concussion. After a brief 
period of rest during the acute phase (24–48 hours) after injury, patients can be encouraged to 
become gradually and progressively more active while staying below their cognitive and physical 
symptom-exacerbation thresholds (i.e., activity level should not bring on or worsen their symptoms). 
It is reasonable for athletes to avoid vigorous exertion while they are recovering. The exact amount 
and duration of rest is not yet well defined in the literature and requires further study [2]. 
No pharmacological therapies are available specifically for concussion; therefore, medications for 
symptom management can be used (e.g., nonsteroidal anti-inflammatory drugs or amitriptyline for 
headaches, sleep aids, anxiolytics) [8]. 

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Sunglasses can be used in case of photophobia, and earplugs or noise-canceling headphones can be 
used in case of phonophobia [8].  
9.2.1.1.6. 
Epidemiology and Burden 
Epidemiological data suggest that 50 to 60 million people suffer from craniocerebral trauma in the 
world every year, including 60% to 95% of concussions. Men are more affected than women, with an 
overall relative risk close to 2 [3]. 
In France, there is a high prevalence of concussion: about 150,000 cases per year [3]. 
Of note, the OMS highlights that the incidence of concussions caused by rugby, American football, 
soccer and hockey are similar (from 0.6 to 0.8/1,000 athlete-game-hour) while, for combat sports, it 
is higher (e.g., 7-15/athlete-exposition in taekwondo) [4]. 
Due to its frequency and the significant risk of an unfavorable evolution (10-20% of cases), the 
concussion is considered a public health problem [3]. 
9.2.1.2. Photobiomodulation and Static Magnetic Stimulation 
9.2.1.2.1. 
Photobiomodulation 
PBM is a technique that was discovered more than 50 years ago, and that involves exposure to 
directional low-power and high-fluence monochromatic or quasi-monochromatic light from the red 
to near-infrared wavelengths (λ = 600-1,100 nm) using lasers or LEDs [9–11]. 
Of note, PBM also used to be called “low-level laser therapy” but the term “photobiomodulation” 
was chosen in 2015 as standard because the term “low” was deemed too vague and lasers are not 
absolutely required [9]. 
Photons generated by the lasers or LEDs are absorbed by molecules present in the cells, called 
photoacceptors. The molecule targeted by the light reaches an electronically excited state that 
temporarily changes its conformation and function, thereby triggering signaling pathways that affect 
cellular metabolism [9–11]. PBM is thought to stimulate healing, reduce inflammation, relieve pain, 
and prevent tissue from dying [9]. 
Transcranial PBM has been widely used in conditions such as wound healing, musculoskeletal pain, 
and arthritis, and is currently being tested for applications in aging-related neurocognitive decline, 
depression, and anxiety as well as various neurological disorders, including concussion [12].  
In vivo studies have provided promising findings on the effects of transcranial PBM in concussion. 
Indeed, in animal models, transcranial PBM has been shown to: 
- 
Reduce levels of pro-inflammatory cytokines [13, 14]  
- 
Decrease levels of pro-apoptotic markers [15] 
- 
Reduce the size of brain injury [16] 
- 
Decrease neurological severity [17, 18] 
- 
Improve neurological performance [16] 
- 
Improve behavioral performance [15, 19]. 
Transcranial PBM was also evaluated across various devices at various parameters and treatment 
durations through several clinical investigations involving people with concussion or TBI, as fully 
described in the investigator brochure. Overall, transcranial PBM improved cognition, sleep disorders 
and quality of life and decreased headache, depression, anxiety and insomnia in these investigations. 
No side effects related to PBM were evidenced. However, since none of these investigations were 

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controlled nor randomized, there is a risk that such results were obtained because of coincidence 
only. Controlled randomized clinical investigations are necessary to reach conclusions [20]. 
9.2.1.2.2. 
Static Magnetic Stimulation 
SMS is a non-invasive stimulation technique that consists of the application of a static magnetic field 
using a cylindrical neodymium magnet [21, 22]. 
Static magnetic fields have a constant intensity and direction over time, along with a frequency of 
0 Hz. They are different from electromagnetic fields, which vary over time and are associated with 
induced electric currents [22, 23]. 
Non-invasive brain stimulation techniques, such as SMS, are becoming increasingly popular for 
treating a variety of neurological and neuropsychiatric disorders [22].  
At the cellular level, transcranial SMS is thought to act primarily at the synapse and alter the function 
of membrane phospholipids and ion channels [22, 23]. It induces changes in voltage-gated calcium 
channels, intracellular calcium flow, and membrane depolarization [23]. 
At the systems level, transcranial SMS was demonstrated through clinical investigations to modulate 
membrane excitability for up to a few minutes after the end of stimulation: 
• 
Application over the motor cortex was demonstrated to: 
o Reduce motor cortex excitability [21, 22, 24] 
o Reduce somatosensory cortex excitability (N33 component) [21] 
o Modulate intracortical excitability: enhanced facilitation and decreased inhibition [24]. 
• 
Application over the sensorimotor cortex was shown to reduce the somatosensory cortex 
excitability (N20 component) [21] and alter normal somatosensory processing [23] 
• 
Finally, application over the visual cortex increases alpha oscillations and slows visual search 
abilities [21]. 
Although conventional non-invasive brain stimulation techniques have some undesirable side effects, 
such as itching, tingling, headache, and discomfort, these are not observed with transcranial SMS 
[21]. 
9.2.2. Rationale 
Pre-clinical and clinical investigations were conducted by REGEnLIFE on the previous versions of 
RGn550 device (RGn500 and RGn530). Although some of these investigations relate to Alzheimer’s 
Disease (AD) rather than concussion syndrome, they are presented below to: 
• 
Testify that the device was previously used in animal models and humans  
• 
Demonstrate that the device’s use was safe 
• 
Picture what could be the device performance in concussion syndrome, especially considering its 
effect on inflammation. 
All these investigations are summarized below. For further details, please refer to RGn550’s 
investigator brochure. 
9.2.2.1. Pre-Clinical Investigation on RGn500 in Alzheimer’s Disease 
RGn500 was the first device used in a pre-clinical investigation involving animal models.  
 
 
 
 
 

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A pre-clinical investigation in an animal model of AD was conducted to evaluate RGn500’s effects in 
a functional context [25].  
The amyloid β 25-35 mouse model of AD was used: male Swiss mice were intracerebroventricularly 
injected with amyloid β 25-35 peptide. This model was chosen since it has been described as 
reproducing some of the features of AD. Indeed, this model has been repeatedly shown to result in 
neuroinflammation and reactive gliosis, pro-apoptotic caspases activity enhancement, oxidative 
stress, endogenously produced amyloid protein deposition, tau protein hyperphosphorylation, and 
increase of kinases, a reduction in the number of neurons measured in hippocampal pyramidal cell 
layers, loss of cholinergic neurons, and memory deficits. 
 
 
Results showed a neuroprotective effect when treatment was applied both on the head and the 
abdomen. Protection was statistically significantly demonstrated through: 
• 
Memory restoration 
• 
Normalization of key markers of AD (amyloid β 1-42, pTau) 
• 
Reduction of oxidative stress (lipid peroxidation) 
• 
Normalization of apoptosis (Bax/Bcl2) 
• 
Decrease in neuroinflammation.  
When the treatment was localized only on the head or abdomen, RGn500 failed to yield beneficial 
effects. 
 
 
Although this rodent model was far from reproducing the complexity of the physiopathological 
characteristics of AD dementia in humans, these results on RGn500 were promising, especially 
considering the extremely severe phenotype of amyloid β 25-35 mouse model of AD. 
9.2.2.2. Pre-Clinical Investigations on RGn530 in Alzheimer’s Disease 
Following the preclinical investigation on RGn500, a new version of the device was created: RGn530.  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  

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Two pre-clinical investigations were conducted on RGn530 using the amyloid β 25-35 mouse model 
of AD. 
 
 
 
 
 
 
 
 
. Results showed that, depending on the parameters used, RGn530 
treatment significantly: 
• 
Alleviated memory deficits (spatial working memory, contextual long-term memory) 
• 
Reduced oxidative stress (lipid peroxidation) 
• 
Decreased key markers of AD (amyloid β 1-42, pTau) 
• 
Decreased neuroinflammation (TNFα). 
 
 
  
In the second pre-clinical investigation, 
 
 
 
 Results showed full and highly significant reversal of memory 
deficits. No effects on the locomotor activity were observed. 
9.2.2.3. Pre-Clinical Investigations to Validate RGn530’s Security 
Additional pre-clinical investigations were conducted on RGn530 to validate its security. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
. 
9.2.2.4. Pilot Clinical Investigation on RGn530 in Alzheimer’s Disease 
Following pre-clinical investigations on RGn530, the clinical safety and performance of the device on 
cognition in mild-to-moderate AD was evaluated for the first time in a pilot clinical investigation 
 
 
  
 
 
 
 
 
 
 
 

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In conclusion, this investigation proved RGn530 treatment feasibility and safety in mild-to-moderate 
AD patients. Although no statistically significant difference in ADAS-cog score after 8 weeks of 
treatment was observed, results evidenced encouraging performance trends to be evaluated in 
investigations with a larger sample size. Of note, statistical power was reduced due to the premature 
end of the investigation associated with the COVID-19 pandemic 
9.2.2.5. RGn550 
Considering: 
• 
The promising results of transcranial PBM in concussion that were published in the literature 
• 
The effect of RGn500 on neuroinflammation demonstrated in the above-described pre-clinical 
investigation and the fact that a neuroinflammatory response is involved in concussion’s 
physiopathology 
• 
The good safety results obtained in AD patients in the pilot clinical investigation on RGn530 

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REGEnLIFE decided to create a new version of the device, named RGn550, designed to be used in 
concussion syndrome.  
 
 
 
 
 
 
 
 
 
  
Of note, REGEnLIFE reviewed the differences between RGn530 and RGn550 and investigated their 
impact to determine whether pre-clinical investigations that validate RGn530’s security 
 
 can validate RGn550’s security as well. In this impact analysis 
 
, REGEnLIFE concluded that these pre-clinical investigations indeed validate 
RGn550’s security. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
In this context, REGEnLIFE wants to conduct a pilot clinical investigation on RGn550 to evaluate its 
safety and explore its performance in treating patients with acute concussion syndrome.  
9.2.3. Justification of the Clinical Investigation Design 
RGnCON is a prospective, comparative, randomized, simple-blinded, monocentric, pilot clinical 
investigation: 
• 
A prospective design has been chosen since no data on the use of RGn550 in sportspeople 
suffering from acute concussion syndrome were previously collected. 
• 
This investigation is comparative. It involves two parallel groups differing in terms of treatment 
frequency: half of the patients will be treated with 5 Hz, the other half with 10 Hz. This will allow 
to determine which frequency is optimal for the patient both in terms of safety and 
performance. 
• 
Patients will be assigned to one of these two groups through randomization (1:1 ratio).  
• 
Patients will not be aware of the group they were assigned to (simple blinded). 
• 
A monocentric design has been chosen because RGnCON is a pilot investigation. 
Various methodological aspects will prevent investigation bias: 
• 
The presence of two groups will allow to take into consideration all confounding factors, apart 
from placebo effect. 
• 
The unpredictable randomization will spread all known and unknown confounding factors (apart 
from placebo effect) within the two groups, resulting in comparable groups, and will prevent 
selection bias. 

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• 
Patients will be stratified based on gender (male/female) and concussion history (history/no 
history of concussion within 6 months prior to inclusion) as such parameters are known to 
influence current concussion symptoms and complications. 
• 
The analysis will be performed in the Full Analysis Set (FAS) population without methods to 
replace missing data. However, some of the used models take into consideration missing data. 
Of note, the following bias will remain present: 
• 
The follow-up bias and evaluation bias since investigators will not be blinded 
• 
The site effect since only one site will be recruited. 
Nevertheless, the primary purpose of this investigation is to evaluate, for the first time, the safety of 
RGn550 in sportspeople suffering from acute concussion syndrome and explore its performance in 
this population. In case this investigation demonstrates RGn550’s safety in this population, further 
investigation(s), using a double-blinding design versus sham, and involving more sites, will be 
conducted to demonstrate RGn550’s safety and performance. 
9.2.4. Investigation Classification per European Regulation 2017/745 
According to European Regulation 2017/745, RGnCON is a clinical investigation conducted to 
establish the conformity of a non-CE marked non-invasive class IIa medical device, referred to in 
Articles 62 and 70.7 a) of the Regulation (case 1 per the French National Competent Authority 
(ANSM) classification). 
9.3. 
Benefits and Risks of the Investigational Device, Clinical Procedure and Clinical 
Investigation 
9.3.1. Anticipated Clinical Benefits 
The potential clinical benefits anticipated to result from the use of RGn550 in patients with acute 
concussion syndrome are: 
• 
Improvement of automated oculomotor / oculopostural functions,  
• 
Improvement of balance function, 
• 
Improvement of executive function, 
• 
Decrease of concussion syndrome symptoms 
• 
Reduction of neuroinflammation. 
These potential benefits are investigated in RGnCON. 
9.3.2. Anticipated Adverse Device Effects 
The following Adverse Device Effects (ADEs) were observed during the pilot investigation on RGn530 
(previous version of the device) and are thus considered as anticipated ADEs of RGn550: 
 
  
 
 
Per RGn550’s investigator brochure, the ADEs anticipated to result from the use of RGn550 are: 
 
 
 
 
 
 

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No severe ADEs are expected. 
9.3.3. Risks Associated with the Participation in the Clinical Investigation 
Compared to standard clinical practice, additional risks associated with the participation in RGnCON 
are risks related to: 
• 
The use of RGn550 
Anticipated ADEs of RGn550 are described above (section 9.3.2). 
Moreover, as mentioned in RGn550’s investigator brochure, a risk management process specific 
to RGn550 was put in place by REGEnLIFE in accordance with NF EN ISO 14971-2019.  
 
• 
The automated oculomotor/oculopostural tests and the TMT A & B 
Identified risks related to the conduct of such tests are symptoms such as fatigue, headache and 
dizziness, which are related to the fact that treated patients have a concussion. These symptoms 
remain acceptable as they are usual symptoms of concussions, expected to remain minor within 
this context. 
 
• 
The stabilometric test 
The only risk that has been identified as related to the use of the stabilometry platform is a risk 
of stumble/fall of the patient. However, this risk remains very unlikely considering the reduced 
height of the platform and the fact that investigators, which are healthcare professionals, will 
help and support patients during the whole stabilometric process.  
 
• 
The blood sampling procedure  
Risks related to the blood sampling procedure are pain, hematoma at the puncture site, lack of 
blood reflux, reflex syncope as well as contamination by hepatitis C, C or HIV for the person 
performing the sampling. These risks are mitigated by the fact that a nurse will be perform the 
sampling. 
No risks were identified as being related to the use of the Sport Concussion Assessment Tool – 5th 
edition (SCAT5) symptom evaluation tool. 
9.3.4. Possible Interactions with Concomitant Treatments 
As mentioned in the IFU, RGn550 should not be used in: 
• 
Patients with recent major surgery at the treatment application area (head) within 3 months 
• 
Patients with ferromagnetic material 
• 
Patient with a pacemaker. 
No interactions with pharmacological treatments are mentioned in the IFU. 
9.3.5. Steps Taken to Control or Mitigate Risks and Benefit-Risk Ratio Rationale 
All risks identified during RGn550’s risk analysis were mitigated as far as possible. It was concluded 
that anticipated benefits outweigh residual risks and the overall residual risk is acceptable. 

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Risks related to investigation procedures mentioned in section 9.3.3 are mitigated by the fact that 
healthcare professionals will help and support patients during the whole investigation. Investigators 
will conduct all evaluations while a nurse will perform the blood sampling. 
A risk analysis specific to RGnCON will be put in place. This risk analysis will take into consideration 
any risks associated with each step of the investigation. Associated documentation will describe all 
steps taken to control and mitigate these risks. 
 

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9.4. 
Clinical Investigation Objectives and Hypotheses  
As a pilot investigation, the objective of RGnCON is to demonstrate RGn550’s safety and explore its 
performance in treating adult sportspeople with acute concussion syndrome. 
9.4.1. Primary Objective  
The primary objective of this investigation is to evaluate the incidence of RGn550’s ADEs in acute 
concussion syndrome, when used to deliver, either at a frequency of 5 or 10 Hz, two 20-min 
treatment sessions at 1 week apart. 
9.4.2. Secondary Objectives 
The secondary objectives of this investigation relate to both the safety and performance of RGn550 
in acute concussion syndrome, when used to deliver, either at a frequency of 5 Hz or 10 Hz, two 20-
min treatment sessions at 1 week apart.  
These objectives are: 
• 
To evaluate the incidence of RGn550’s ADEs per severity, AEs and Device Deficiencies (DDs)  
 
• 
To evaluate the effect of RGn550, after the first and second treatment sessions and then 45 days 
after the second treatment session, on: 
o Automated oculomotor and oculopostural functions 
o Balance function 
o Executive function 
 
• 
To assess the effect of RGn550 on concussion syndrome symptoms 7 days after the first 
treatment session as well as 7 and 45 days after the second treatment session  
 
• 
To evaluate the effect of RGn550 on blood markers that are involved in the pathogenesis of 
concussion 45 days after the second treatment session. 
These secondary objectives have been chosen as they will allow to evaluate RGn550’s safety and 
determine whether: 
• 
RGn550 could improve important functions that are impacted in acute concussion syndrome, i.e., 
automated oculomotor/oculopostural, balance and executive functions 
• 
RGn550 could decrease acute concussion syndrome symptoms 
• 
RGn550 could impact the concentration of blood markers involved in acute concussion syndrome 
 
 

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9.5. 
Clinical Investigation Design 
9.5.1. Investigational Medical Devices 
Two RGn550 devices producing a 5 Hz frequency and two producing a 10 Hz frequency will be 
provided by REGEnLIFE to the investigational site. Provided devices will be tracked, during and after 
the investigation, with assigned serial numbers. 
The principal investigator will be trained in the use of RGn550 by REGEnLIFE before the inclusion of 
the first patient.  
Each patient will be treated with the same device throughout the investigation. For a given patient, 
the other device of the same type (5 Hz or 10 Hz) may only be used in case of malfunction of the 
initial device. 
To maintain simple blinding, the devices will be visually identified as follows: 
• 
The RGn550 devices producing a 5 Hz frequency will be labeled as: Device A1 and Device A2 
• 
The RGn550 device producing a 10 Hz frequency will be labeled as: Device B1 and Device B2. 
To track the use of the devices, the principal investigator will mention in the electronic Case Report 
Form (eCRF) which RGn550 device was used at each treatment session of each patient. In parallel, he 
will fulfil a treatment sheet associated with the device in question and write down the number of the 
treated patient, date of treatment, number of treatment session and duration of treatment.  
The maximal overall exposure of patients to RGn550 will be of 1 week, since the second, and last, 
treatment session is planned at Day 7. Exposure during a treatment session will be of 20 min. 
9.5.2. Investigation Population  
Adult sportspeople with acute concussion syndrome resulting from sport practice who can 
participate in a clinical investigation per the law and are able to meet treatment sessions and 
complete requested assessments will be included. 
9.5.2.1. Inclusion Criteria 
• 
Male or female aged at least 18 years old  
• 
Suffering from concussion syndrome resulting from a shock that occurred during sport practice 
less than 72h ago, as confirmed by neurological examination via the Head Injury Assessment - 
Form 3 (HIA3) tool 
• 
Affiliated to French social security 
• 
Who provided a dated and signed informed consent form. 
9.5.2.2. Non-Inclusion Criteria 
• 
Patient protected by a French legal measure (“sauvegarde de justice”, “tutelle” or “curatelle”) 
• 
Patient not able to express his/her consent 
• 
Patient deprived of liberty or hospitalized without consent  
• 
Woman who is pregnant or breastfeeding, or who plans to become pregnant or breastfeeding 
during the investigation, or who has the capacity to conceive but is not using a reliable 
contraceptive method as deemed by the investigator 
• 
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• 
Patient who experienced a surgery at the treatment application area (head) within 3 months 
prior to inclusion 
• 
Patient with skin lesions on the treatment application area (head) 
• 
Patient with a short-term life-threatening pathology (e.g., evolving cancer; non-stable heart 
failure; severe hepatic, renal or respiratory failure, etc.) 
• 
Patient diagnosed with a heart attack within 3 months prior to inclusion 
• 
Patient implanted with ferromagnetic material  
• 
Patient implanted with a pacemaker 
• 
Patient with a risk of epileptic seizure or other non-degenerative central nervous system diseases 
• 
Patient with major physical or neurosensorial disorders that may interfere with assessments 
• 
Patient with chronic psychosis or psychotic episodes 
• 
Patient addicted to alcohol or drugs 
• 
Patient treated with antidepressant or benzodiazepine 
• 
Patient who participated to another investigation/study involving the use of an investigational 
medical device/drug within the 30 days prior inclusion 
• 
Patient not able to meet treatment sessions as deemed by the investigator 
• 
Patient not able to complete requested investigation assessments as deemed by the investigator. 
9.5.3. Conduct 
9.5.3.1. Patient Inclusion 
It is planned to include 50 patients in this investigation (refer to section 9.6.1 for sample size 
justification).  
Based on this number and considering that the site estimated that it would be able to include 
approximately 3 patients per week, a 4-month inclusion period is planned: from September 2022 to 
December 2022.  
The recruited site will be the Hôpital européen Georges-Pompidou located in Paris. The principal 
investigator will be a neurologist specialized in sport concussions and the coinvestigator will be a 
sport physician and posturologist. 
In current clinical practice, following a shock, a sportsperson with obvious signs of concussion is 
examined by a physician within 72 hours after the shock to establish the diagnosis of concussion. For 
example, in the context of professional rugby, the French federation's regulation requires to follow 
HIA protocol immediately after the shock and the appearance of such signs. This protocol, composed 
of three steps, is performed by a physician within 48 hours after the shock: 
• 
Step 1: Assessment during the match using HIA1  
• 
Step 2: Post-match assessment, the same day, using HIA2 
• 
Step 3: 36-48 hours post-injury assessment using HIA3. 
The subjects of RGnCON investigation will be identified among sportspersons examined by the 
principal investigator within 72 hours after the shock. They will be included if they meet eligibility 
criteria and agree to participate in the investigation. Of note, HIA3 is mentioned in the eligibility 
criteria as the diagnostic tool for concussion. Indeed, as the principal investigator is the referring 
neurologist for a lot of rugby clubs and several sports federations, it is expected that most subjects 
will be professional rugby players for whom this protocol is implemented in current clinical practice. 
Nevertheless, subjects practicing other sports may be included as well if they have a diagnosis of 
concussion confirmed by the HIA3, meet the eligibility criteria and agree to participate. 

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All potential subjects will be informed about the investigation as soon as possible after the shock in 
order to give them adequate time to think about the investigation and their potential participation. 
During the consultation with the principal investigator, all the information will be reexplained to the 
patients, who will then be able to ask the investigator any questions they may have. After that, 
patients will have as much time as needed to provide an answer regarding their participation. If the 
answer is provided within 72 hours after the shock, then the patient will be included. 
9.5.3.2. Visits 
Three onsite visits will be performed at the following timepoints: 
• 
Day 0 (D0): Inclusion, randomization (to the 5 Hz or 10Hz treatment group) and first treatment 
session 
• 
Day 7 (D7): Second treatment session 
• 
Day 52 (D52): Evaluation 45 days after the last treatment session. 
In addition, at Day 14 (D14), the patient will be asked to remotely assess his/her concussion 
syndrome symptoms. 
9.5.3.3. Investigation Duration 
The investigation duration per subject will be of 52 days. 
The overall investigation duration, which corresponds to the inclusion period and the follow-up 
period, will thus be of 6 months approximately (4 months of inclusion and 52 days of follow-up).  
9.5.3.4. Prohibited/Restricted Treatments 
Other treatments involving PBM or magnetic fields will be prohibited during the investigation in 
order to evaluate RGn550’s effects only. 
The following pharmacological treatments will be prohibited as well as during the investigation in 
order to evaluate RGn550’s effects only: benzodiazepine and antidepressants. 
In addition, any patients who have a head surgery or get implanted with ferromagnetic material or a 
pacemaker between the first and second RGn550 treatment sessions will not undergo the second 
treatment session because RGn550 is contraindicated in these conditions.  
Of note, the same will apply to patients who meet other contraindications between the two 
treatment sessions, i.e.: 
• 
Patients with skin lesions on the head 
• 
Patients with short-term life-threatening pathologies (e.g., evolving cancer, non-stable heart 
failure, severe hepatic, renal or respiratory failure, etc.) 
• 
Patients with a heart attack  
• 
Patients with a risk of epileptic seizure 
• 
Pregnant women. 
9.5.3.5. End of Investigation 
The end of the investigation is defined as the completion of the last patient last visit. The last patient 
last visit will occur when the last patient either completes the 52-day follow-up visit or prematurely 
terminate the investigation. 
A patient may prematurely terminate the investigation for the following reasons: 
• 
Screen failure 

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• 
Withdrawal 
• 
Lost to follow-up 
• 
Death. 
For each patient, an end-of-investigation form will be filled in within the eCRF by the investigator, 
whether or not they have completed the investigation. In case of premature termination, the date 
and reason will be collected.  
Screen failure 
A screen failure occurs when a patient was included while he/she has one or several non-inclusion 
criteria and/or does not have one or several inclusion criteria. 
In that case, the investigators must ensure that the reason for screen failure is adequately 
documented in the patient’s medical file and the eCRF. 
Withdrawal 
Patients may voluntarily withdraw from the investigation at any time. A patient may also be 
withdrawn from the investigation at the investigators’ discretion.  
In case of withdrawal, the investigators must ensure that the date and reason for the withdrawal is 
adequately documented in the patient’s medical file and the eCRF. 
Data from all patients who left the investigation prematurely will be analyzed until the date of 
withdrawal. 
Lost to Follow-Up 
When investigators do not have any news from a patient, they will make at least three attempts to 
contact the patient as well as the patient’s general practitioner and/or a family member if known. If 
all these attempts fail, the investigators can then declare the patient as “lost to follow-up”. In that 
case, every effort will be made to obtain necessary information to complete the eCRF. 
Each attempt should be documented in the patient’s medical file with the date, description of the 
three unsuccessful contacts along with the contact method (e.g., telephone, letter with 
acknowledgement of receipt). 
Of note, to prevent lost-of follow-up patients, automatic alerts will be sent via emails to the site to 
remind them of upcoming visits with their patients. 
Data from patients who were lost to follow-up will be analyzed until the date of loss to follow-up. 
Death 
Should it be discovered that the patient is dead, an investigation regarding the cause of death will be 
conducted by the investigator. The date and cause of death will be recorded in the eCRF and the 
patient’s medical file.  
Data from dead patients will be analyzed until the date of death. 
9.5.4. Endpoints 
9.5.4.1. Primary Endpoint 
The primary endpoint of this investigation is the incidence of RGn550’s ADEs throughout the 
investigation. 

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9.5.4.2. Secondary Endpoints 
The secondary endpoints are: 
• 
The incidence of RGn550’s ADEs per severity throughout the investigation: 
o Incidence of mild ADEs 
o Incidence of moderate ADEs 
o Incidence of severe ADEs 
• 
The incidence of RGn550’s AEs throughout the investigation 
 
• 
The incidence of RGn550’s DDs throughout the investigation. 
 
• 
The evolution, before and after treatment session at D0 and D7 and then at D52, of: 
o Automated oculomotor and oculopostural functions, as assessed through: 
▪ 
Convergence, evaluated with the measure of the Near Point of Convergence 
(NPC)  
▪ 
Deviations, evaluated with the cover test and Maddox rod test 
o Balance function, as assessed through the following static stabilometric parameters: 
▪ 
Statokinesigram area 
▪ 
Left/right distribution  
 
• 
The evolution, before treatment session at D0 and after treatment session at D7 of executive 
function, as assessed with the TMT A&B 
 
• 
The evolution of concussion syndrome symptoms as assessed by the patient with the SCAT5 
symptom evaluation tool at D0 before treatment, D7 before treatment, D14 and D52 
 
• 
The evolution from D0 before treatment to D52 of the concentration of the following blood 
markers: 
o Anti-inflammatory cytokines InterLeukin (IL)-1 receptor antagonist, IL-4, IL-6, IL-10, IL-11 
and IL-13 
o S100 calcium binding protein B (S100B) 
o Glial Fibrillary Acidic Protein (GFAP) 
o Ubiquitin C-terminal Hydrolase-L1 (UCH-L1). 
These secondary endpoints have been chosen since: 
• 
Convergence insufficiency is an emerging oculomotor-related outcome after a sport-related 
concussion [26] and the NPC is one of the primary diagnostic tests used to assess convergence 
insufficiency. Of note, convergence insufficiency rate following concussion was reported to range 
from 42% to 55% [7]. 
• 
The cover and Maddox rod tests are recognized tests to assess ocular deviations [27, 28]. In 
particular, the Maddox rod test has been used for more than a century in ophthalmology [28]. 
• 
Stabilometry is an objective and reproducible method for the recording and evaluation of 
balance function, in particular following neurologic impairment [29]. Of note, the 
statokinesigram area is chosen as it is a parameter that might evolve with concussion evolution 
[30] while the left/right distribution is added as an exploratory parameter. 
• 
The TMT A&B is a recognized test to evaluate executive function [31]. Of note, in the pilot clinical 
investigation on RGn530 in AD, the TMT B completion time decreased from baseline to W8 in 
RGn530 group while it increased in the sham group. 

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• 
The SCAT5 is a standardized tool for evaluating concussions designed for use by physicians and 
licensed healthcare professionals [32]. 
• 
Anti-inflammatory cytokines, whose major ones are IL-1, IL-4, IL-6, IL-10, IL-11 and IL-13 [33], are 
released as part of the neuroimmune response to concussion [34]. 
• 
S100B, GFAP and UCH-L1 are regarded as biomarkers of acute brain injury [35]. 
9.5.5. Description of Visits, Procedures and Data to Collect 
Data will be collected at D0, D7, D14 and D52. 
The principal investigator will perform the informed consent process, apply treatment and conduct 
all evaluations apart from the oculomotor/oculopostural and stabilometric tests that will be 
conducted by the coinvestigator. 
9.5.5.1. Inclusion, Randomization and First Treatment Session Visit (D0) 
During this visit, the principal investigator will offer patients who meets eligibility criteria to 
participate in the investigation. In particular, to be included, patients must have a diagnosis of 
concussion confirmed via the HIA3 tool. This tool is the third, and last, stage of the head injury 
assessment protocol. It is to be performed after two night’s rest (36-48 hours post-head impact 
event) to further assess clinical progress and identify a late diagnosis of concussion [36]. The French 
version of this tool, presented in Appendix 12.1 [36], will be used during this investigation. 
Of note, women of childbearing potential will undergo a pregnancy test to ensure they are not 
pregnant and thereby meet the corresponding eligibility criteria. 
The principal investigator will thus inform the patients and obtain their consent as described in 
section 9.12. 
The investigators will then collect the following data:  
• 
Eligibility criteria 
• 
Demographic and clinical data 
Data such as gender, age, sport practiced, concussion history and concomitant treatments will be 
collected, along with parameters that are known to influence oculomotor/oculopostural or 
stabilometric tests such as: 
o For oculomotor/oculopostural tests: 
▪ 
Regular orthoptic rehabilitation sessions  
o For stabilometric test: 
▪ 
Surgery of the lower limbs within 6 months prior to inclusion. 
The investigators will also perform the following tests: 
• 
NPC 
The NPC is the closest point in space where the patient’s eyes can converge [7, 26]. 
An objective measurement of the NPC will be performed in line with previous literature. The 
measurement will be conducted with a fixation stick placed at 30-40 cm of the patient’s eye 
within the median plan. The patient will keep its glasses on in case he/she has glasses. The 
patient will be asked to “focus on the object with both eyes”. The object will then be moved by 
the investigator closer to the patient’s eyes until the patient sees two distinct images or until the 
investigator observes an outward deviation of one eye. The distance from this point to the lateral 
canthus will then be measured using a ruler [26]. 

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The measure will be performed three consecutive times and the mean of these three 
measurements will be calculated. 
In accordance with previous literature, a NPC ≤5 cm will be considered normal while a NPC >5 cm 
will be considered abnormal [37]. 
 
• 
Cover test 
There are different variants of the cover test. The unilateral cover test will be used, which 
consists into covering one eye, horizontally moving a target 5 cm in front of the non-covered eye, 
and then uncovering the covered eye and observing its movements. If it moves to regain fixation, 
the patient exhibits deviation. If the covered eye moves to recover fixation (restitution 
movement), the test is positive. The patient will keep its glasses on in case he/she has glasses. 
The result will be measured qualitatively by the co-investigator using the following four 
categories: 
o Normal fixation = 0  
o Light restitution movement = 1 
o Important restitution movement = 2 
o Deviated eye without restitution movement = 3. 
The test will then be repeated on the other eye. 
 
• 
Maddox Rod test 
This test will be performed with a pen torch and a red Maddox rod consisting of 17 biconvex 
cylinders that have enough convergence to transform the image of a white light point into a red 
line perpendicular to the cylinder axis [28]. During this test, the patient will keep its glasses on in 
case he/she has glasses. 
The Maddox rod will be placed in front of one eye with the cylinders first oriented horizontally. 
The fixed light point will be placed at least 3 meters from the patient, at the height of his/her 
eyes, and will be focused on the midline of the patient’s face. The patient will indicate where the 
vertical red line is positioned relative to the white point. If the white light and vertical red line are 
not overlapping, there is a horizontal deviation (see Figure 8). In case a deviation is identified, 
prisms will be held in front of the Maddox rod until the line is centered on the light. The value of 
the prism will quantify the deviation [38]. The horizontal deviation will be measured on one eye 
only. 
Then, the Maddox rod will be placed in front of the same eye with the cylinders oriented 
vertically. If the white light and vertical red streak are not overlapping, there is a vertical 
deviation (see Figure 9). Similarly, in case of deviation, prisms will be used to quantify it [38]. The 
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Figure 8: Horizontal orientation of the Maddox rod to identify horizontal deviation (BI: Base In, BO: 
Base Out) [38] 
 
Figure 9: Vertical orientation of the Maddox rod to identify vertical deviation (BD: Base Down, BU: 
Base Up, LH: Left Hyperphoria, Rh: Right hypophoria, RH: Right Hyperphoria) [38] 
 
• 
Static stabilometric test 
Static stabilometric parameters are measured with the use of a stabilometric platform equipped 
with sensors that monitor the evolution in time of the patient’s center of pressure and its 
movements relative to the center of the platform. The signal is digitalized, evaluated by special 
computer program and results are visualized on the monitor and recorded [29]. 
The patient will be asked to stand on KFORCE Plates (a stabilometric platform manufactured by 
KINVENT HELLAS, see Figure 10) either barefoot or with his/her shoes and orthopedic inserts in 
case the patient has inserts. A 30 s-record will be performed, two times consecutively: one time 
with the patient’s eyes open and one time with the patients’ eyes closed. 
Following these two records, the two values of the following parameters will be collected, and 
their mean will be calculated: 
o The statokinesigram area 

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The statokinesigram is the projection onto a 2-dimensional space of the trajectory of the 
patient’s center of pressure [39]. Its area is measured in mm2. The larger the area is, the 
higher the patient’s imbalance is. 
o The left/right distribution 
The left/right distribution comprises two percentages representing the patient’s body 
weight distribution on his/her left versus right foot. If 50% is obtained for each foot, the 
patient is stable. 
 
Figure 10: Picture of KFORCE Plates 
 
• 
TMT A&B 
The TMT is an executive function test reflecting various cognitive processes such as selective 
attention, motor activity and flexibility. In Part A, the subject is instructed to trace a line that 
connects circled numbers in consecutive order (see Appendix 12.2.1). In Part B, the subject is 
asked to trace a line that connects circled numbers and circled letters in consecutive order while 
alternating between numbers and letters (see Appendix 12.2.2). The time to perform the task, 
number of correct moves and number of errors are collected [31].  
Following this, the patient will evaluate his/her symptoms using the SCAT5 symptom evaluation 
tool. The patient will rate the intensity of every symptom from 0 (none) to 6 (severe) using a form. 
This will allow to calculate the total number of symptoms (out of 22) and the symptom severity score 
(out of 132) (see Appendix 12.3). 
A blood sample will also be obtained from the patients by a nurse. The blood sample analysis will be 
performed by Montpellier Neuroscience Institute (Institut de Neuroscience de Montpellier) following 
the institute standard practice. 
During the visit, the patients will be randomized in a 1:1 ratio to the 5 Hz group or 10 Hz group using 
the centralized Interactive Web Response System (IWRS) incorporated into the eCRF. A block 
randomization method will be used. Only patients will be blinded to their assigned treatment. 
Depending on their assigned group, the patients will then be treated with one of the 5 Hz RGn550 
devices or one of the 10 Hz RGn550 devices for 20 min. To perform the treatment, the principal 
investigator will follow the below instructions: 
• 
Make the patient comfortable. 
• 
Install the helmet on the patient's head, taking care not to bump it with the modules. 
• 
Lightly tighten the soft helmet holding wire and check the positions of the modules. Each module 
can be moved slightly to adjust its position. 
• 
On the control unit, in the menu on the left, choose the option 'Program' and choose the 
proposed treatment 
• 
Finally press the red arrow to start the treatment. 
A countdown is displayed on the screen indicating the time remaining until the end of the treatment 
session. At each treatment session, the principal investigator will fulfil a treatment sheet associated 
with the used device and mention the number of the treated patient, date of treatment, number of 

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treatment session and duration of treatment. To stop the treatment, the principal investigator will 
press the red button with a cross inside that is displayed on the screen (a confirmation message will 
be displayed to avoid any manipulation error). 
Following treatment, the investigators will: 
• 
Perform the following tests following the methodology described above:  
o NPC 
o Cover test 
o Maddox rod test 
o Static stabilometric test 
• 
Collect any AEs and DDs that occurred during the visit. 
9.5.5.2. Second Treatment Session Visit (D7) 
This visit will occur at D7 and will correspond to the second treatment session. 
Before treatment, the investigators will collect any AEs that occurred since the last visit. 
Following that, they will check that: 
• 
Patients did not have a second concussion between the first and second treatment sessions, as 
this could impact the performance evaluations 
• 
Patients did not become contraindicated to RGn550 treatment between the first and second 
treatment sessions 
If that’s the case, the second treatment session will not be performed nor any of the remaining 
performance evaluations described below.  
If applicable, before treatment: 
• 
The investigators will perform the following tests following the methodology described above:  
o NPC 
o Cover test 
o Maddox rod test 
o Static stabilometric test 
• 
The patient will be asked to evaluate the intensity of his/her symptoms using the SCAT5 
symptom evaluation tool. 
The patients will then be treated for 20 min, as per their assigned group and using the same RGn550 
device that was used at D0.  
Following treatment, the investigators will: 
• 
Perform the following tests: 
o NPC 
o Cover test 
o Maddox rod test 
o Static stabilometric test 
o TMT A&B 
• 
Collect any AEs and DDs that occurred during the visit. 
• 
Give the patient a SCAT5 symptom evaluation tool form for remote completion by the patient at 
D14. 

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9.5.5.3. Remote Visit (D14) 
Seven days after the second treatment session, the investigators will call the patients to remind 
them to complete the SCAT5 symptom evaluation tool and bring the form with them during their 
next visit at D52. 
9.5.5.4. Follow-up Visit (D52) 
During this visit, which will occur 45 days after the second treatment session, no treatment will be 
performed. 
The investigators will: 
• 
Collect the SCAT5 symptom evaluation tool form that was completed by the patient at D14 
• 
Collect any AEs that occurred since the last visit  
• 
Check that, between the first and second treatment sessions, patients did not have a second 
concussion. If that’s the case, remaining performance evaluations won’t be performed. 
• 
If applicable, perform the following tests:  
o NPC 
o Cover test 
o Maddox rod test 
o Static stabilometric test 
The patient will be asked to evaluate the intensity of his/her symptoms using the SCAT5 symptom 
evaluation tool. 
Finally, a blood sample will be obtained by the nurse. 
Once all these evaluations have been conducted and all the required data have been collected, a 
treatment session may be offered to patients who did not become contraindicated to RGn550 
treatment after the second treatment session. 
Patients who became contraindicated to RGn550 treatment or had a second concussion between the 
first and second treatment session will not come on site for this visit since no further performance 
evaluations will be performed for these patients. However, the principal investigator will call them on 
D52 to collect any AEs that occurred since the last visit. 
9.5.5.5. Schedule 
Table 2 below summarizes procedures and evaluations to perform at each visit. 

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Table 2: Schedule of procedures and evaluations 
 
 
D0 
D7 
D14 
(remote) 
D52 
 
Before treatment 
After treatment 
Before treatment 
After treatment 
Patient 
information 
/ 
Informed 
consent  
X 
 
 
 
 
 
Eligibility criteria  
X 
 
 
 
 
 
Pregnancy 
test 
for 
women 
of 
childbearing potential 
X 
 
 
 
 
 
Randomization  
X 
 
 
 
 
 
Demographic and clinical data 
X 
 
 
 
 
 
NPC 
X 
X 
X 
X 
 
X 
Cover test 
X 
X 
X 
X 
 
X 
Maddox rod test 
X 
X 
X 
X 
 
X 
Stabilometric test 
X 
X 
X 
X 
 
X 
TMT A&B 
X 
 
 
X 
 
 
SCAT5 symptom evaluation tool 
X 
 
X 
 
X 
X 
Blood sampling 
X 
 
 
 
 
X 
20-min treatment session 
X 
X 
 
 
Collection of AEs and DDs that 
previously occurred 
 
X 
X 
X 
 
X 

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9.5.6. Monitoring  
Monitoring activities will be performed by 
 
During the investigation, 
 monitors will perform: 
• 
Source data verification during on-site monitoring visits to confirm that data entered into the 
eCRF by authorized site personnel are complete, accurate, and verifiable based on source 
documents. During these visits, the monitors will also check that the informed consent process 
was performed as planned in section 9.12.  
• 
Source data review during remote monitoring (through telephone and/or email) to confirm that 
data entered into the eCRF by authorized site personnel are complete and consistent. These 
remote monitoring will also allow to check the inclusion progress, data entry progress and collect 
any missing documents from the site. 
The monitors will ensure that the investigation is conducted according to this Clinical Investigation 
Plan (CIP), the Good Clinical Practice (GCP) and applicable laws and regulations. 
Monitoring will be performed according to the process defined in the Clinical Monitoring Plan, which 
will notably describe the extent and frequency of monitoring. 
Source documents are paper or electronic documents in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies of transcriptions that are certified after 
verification as being accurate and complete, microfiche, photographic negatives, microfilm or 
magnetic media, X rays, patient files, and records kept at pharmacies, laboratories, and medico 
technical departments involved in a clinical investigation. Source documents will be saved after the 
end of the investigation during 15 years by the investigators or site.  
The investigators and site must provide authorized personnel (monitors, sponsor, regulatory 
authorities, Ethics Committee) direct access to applicable source documents for investigation-related 
monitoring, sponsor audits, health authorities inspections and Ethics Committee review. 
 
 

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9.6. 
Statistical Considerations 
9.6.1. Sample Size Justification 
For a sample size of 50 patients, the probability of observing at least one ADE will be 0.87 considering 
a probability of ADE of 0.04. The sample size calculation was performed with SAS® v9.4. 
9.6.2. Analysis Population 
All analyses will be performed in the Full Analysis Set (FAS), which will comprise all included patients 
who have been treated at least once with RGn550 device. Patients will be assigned to the treatment 
group as treated. 
9.6.3. Statistical Analysis 
Full details related to statistical analysis will be provided in the Statistical Analysis Plan.  
The statistical analysis will be performed using SAS® Viya v9.4 (or a more recent version). 
The global significance level (type I error rate) will be set at α = 0.05 (two-sided). Adjustment for 
multiplicity in not applicable for the primary endpoint and no adjustment for multiplicity is planned 
for secondary endpoints. 
Continuous data will be described by the number of missing data, number of data analyzed, mean, 
standard deviation, median, Q1, Q3, minimum, maximum. 
Categorical data will be described by the number of missing data, frequencies and percentages of 
patients in each modality. The percentage of patients will be calculated once missing data are 
excluded from the denominator. 
9.6.3.1. Primary Endpoint Analysis 
The proportion of subjects with at least one ADE will be calculated along with the 95% exact Clopper-
Pearson confidence interval in the FAS, by treatment groups and overall. 
Of note, a lost to follow-up rate of 10% is anticipated. If this rate is higher, an analysis of the primary 
endpoint using percentage of patient-years will be considered in the Statistical Analysis Plan. 
9.6.3.2. Secondary Endpoints Analysis 
ADEs per severity 
A descriptive analysis with 95% exact Clopper-Pearson confidence interval of mild, moderate and 
severe ADEs will be provided in the FAS, by treatment groups and overall. 
AEs 
All AEs will be described in the FAS, for each System Organ Class (SOC) and Preferred Term (PT) class 
using MedDRA (Medical Dictionary for Regulatory Activities) terminology, by treatment groups and 
overall. 
DDs 
All DDs will be described in the FAS, by treatment groups and overall. 

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Secondary performance analyses 
The secondary performance analyses will be performed in the FAS by treatment groups, excluding 
data that would be collected after the following intercurrent event: treatment group switch during 
follow-up. 
Imputation of missing data will be handled by the mixed model (details will be provided in the 
Statistical Analysis Plan). 
The analyses will be performed as follows: 
• 
For the evolution of the below parameters, the following timepoints will be compared: (D0 after 
treatment - D0 before treatment, D7 before treatment - D0 before treatment, D7 after treatment 
- D0 before treatment, and D52 – D0 before treatment) and a mixed effect regression model will 
be used with a patient random effect. Group effects (5 Hz vs 10Hz), period effects (D0 before, D0 
after, D7 before, D7 after and D52) and the group-by-period interaction will be added as fixed 
effects. The stratification variables will be added in the model as covariates. 
o Automated oculomotor and oculopostural functions: 
▪ 
Convergence, evaluated with the Near Point of Convergence (NPC) (>5 cm vs 
≤5 cm) 
▪ 
Deviation as evaluated with the cover test (normal fixation or light restitution 
movement or important restitution movement or deviated eye without 
restitution movement) 
▪ 
Horizontal deviation as evaluated with the Maddox rod test (orthophoria or 
exophoria or esophoria and measure in diopter) 
▪ 
Vertical deviation of the right eye as evaluated with the Maddox rod test 
(orthophoria or hypophoria or hyperphoria and measure in diopter) 
▪ 
Vertical deviation of the left eye as evaluated with the Maddox rod test 
(orthophoria or hypophoria or hyperphoria and measure in diopter) 
o Balance function: 
▪ 
Statokinesigram area (m²) 
▪ 
Difference between left distribution and right distribution (%) 
 
• 
For the evolution of executive function, the following timepoints will be compared: (D0 before 
treatment – D7 after treatment) and a mixed effect regression model will be used with a patient 
random effect. Group effects (5 Hz vs 10Hz), period effects and group-by-period interaction will 
be added as fixed effects. The stratification variables will be added in the model as covariates. 
▪ 
TMT A: time (s) 
▪ 
TMT A: number of errors 
▪ 
TMT B: time (s) 
▪ 
TMT B: number of errors 
▪ 
TMT B-A: time (s) 
▪ 
TMT B-A: number of errors 
 
• 
For concussion syndrome symptoms (SCAT5): For the analysis at D0 before treatment, D7 before 
treatment, D14 and D52, a mixed linear regression model will be used with a patient random 
effect. Group effects (5 Hz vs 10Hz), period effects and group-by-period interaction will be added 
as fixed effects. The stratification variables will be added in the model as covariates. This model 
will be run for: 
o The total number of symptoms (score from 0 to 22) 
o The symptom severity (score from 0 to 132) 

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• 
A description analyses of blood markers at each time point and the change from baseline to each 
time point will be assessed by groups and overall. 
Sensitivity analysis: 
A sensitivity analysis will be conducted on the secondary performance endpoints in the FAS without 
excluding any data that would be collected after intercurrent events.  
Of note, data of patients with a second concussion that occurred after RGn550 first treatment 
session will be considered before the onset of the concussion. Similarly, data of patients with a 
contraindication to RGn550 that occurred after RGn550 first treatment session will be considered 
before the onset of the contraindication. 
This sensitivity analysis will be performed only if the proportion of excluded patients exceeds 10% (at 
least 5 patients excluded). 
9.6.4. Timing of Analyses 
There will be only one final analysis at the end of the investigation. 
 
 

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9.7. 
Data Management 
Data management activities will be performed by 
 
The randomization will be managed centrally using an IWRS. It will be handled in a non-blinded 
manner since only patients will be blinded to their assigned treatment. 
Data will be collected by investigators using an electronic Case Report Form (eCRF) that is compliant 
with Food and Drug Administration 21 CFR Part 11 regulation.  
A clinical database will be created specifically for the investigation, tested and validated before any 
data has been entered into the eCRF. 
In accordance with current laws and regulation, data confidentiality will be ensured using 
appropriate security means: 
• 
Patients will be identified in the eCRF and clinical database by a numeric identifier. Only the site 
will maintain a confidential list of included patients linking patients’ identifier to their identity. 
• 
No nominative data will be collected.  
• 
Data hosting will be managed by a company certified as a health data company and as ISO 27001, 
ensuring strong security and confidentiality measures, as well as an IT infrastructure designed for 
Certified Health Data Hosting. 
Two types of queries can be issued within the eCRF: 
• 
Automatic queries which are automatic consistency checks set up in the eCRF that relate to data 
format, missing data, outliers and inter-field inconsistencies. These will guide the investigators 
during data entry and inform them that corrections might be needed. 
• 
Manual queries which are queries issued by monitors during on-site monitoring visits and remote 
monitoring or by data managers or the project manager following data review meetings and 
reconciliations. 
Both automatic and manual queries will be visible by the site which will be able to either confirm the 
entered data if correct or modify them if not.  
To ensure data traceability, all data entries and modifications as well as all queries will be tracked in 
the eCRF audit trail. The following information will appear in the audit trail: date of entry, 
modification, or query; name of the person who entered or modified the data or issued the query; 
data in question. 
 will code safety events in accordance with MedDRA terminology and medicinal treatments in 
accordance with the World Health Organization’s (WHO) medicinal product reference list, which uses 
the "Anatomical Therapeutic Chemical" (ATC) classification system. 
A data review meeting will be held at the end of the investigation to ensure that the database is 
clean. This meeting may rely on specific listings such as the list of pending queries. Decisions on 
inconsistent data remaining at the end of investigation will be taken at this meeting with REGEnLIFE. 
Following regular or final quality control, the principal investigator will be asked to sign off the eCRF 
forms to attest the accuracy of entered data. The database will then be locked. 
All data will be stored until final report or results publication. They will then be archived on 
informatic support, transmitted to the responsible of treatment for a retention period in accordance 
with regulation. 
A Data Management Plan will be prepared by 
 and submitted to REGEnLIFE for approval. This 
plan will describe all data management tasks to realize during the investigation and how to realize 

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them (e.g., database cleaning, database lock etc.). The investigation will be conducted in accordance 
with this Data Management Plan. 
 
 

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9.8. 
Clinical Investigation Plan Amendments 
Any amendments to this CIP will be prepared by 
 validated by REGEnLIFE, and submitted for 
evaluation to the Ethics Committee in accordance with the regulation.  
The investigators will be notified by 
 or REGEnLIFE of any relevant modifications. 
 
 

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9.9. 
Clinical Investigation Plan Deviations 
The investigators should strictly follow this CIP. 
An investigation deviation may occur when the investigators or any other member of the 
investigation team fails to conduct the investigation in compliance with the CIP, GCP and the 
applicable regulation. Such deviations may include lack of documentation of patient information and 
informed consent, deviations in safety reporting as well as deviations in data recording and archiving. 
 will document any deviations that occur at the site. REGEnLIFE will be informed within 72h 
following the deviation. If needed, reasonable corrective and preventive actions will be undertaken 
to avoid any subsequent deviations. 
 
 

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9.10. Investigational Medical Device Accountability 
As previously mentioned, two RGn550 devices producing a 5Hz frequency and two producing a 10 Hz 
frequency will be provided by REGEnLIFE to the site. These devices will be returned to REGEnLIFE at 
the end of the investigation. 
REGEnLIFE will keep records of the physical location of all investigational devices from shipment to 
return. 
The site will keep records of receipt and return of devices. These will include: 
• 
Date of receipt 
• 
Identification (reference number) 
• 
Expiry date 
• 
Date of return. 
 
 

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9.11. Statements of Compliance  
9.11.1. Regulatory and Ethical Considerations 
The investigation will be conducted in accordance with this CIP, applicable laws and regulations 
(including European Regulation 2017/745) and ISO 14155:2020 as well as with recognized ethical 
principles described in the declaration of Helsinki, ISO 14155:2020 standard and applicable laws and 
regulations.  
The investigation will only start once the submission dossier is validated by the French National 
Agency for the Safety of Medicines and health products (Agence Nationale de Sécurité des 
Médicaments et produits de santé (ANSM)) and the Ethics Committee’s approval is obtained. Any 
additional requirements imposed by the Ethics Committee will be followed.  
Since patient personal data will be collected and processed during this investigation, compliance to 
MR001 or authorization from the French authority of data protection (CNIL: Commission Nationale 
de l'Informatique et des Libertés) is required. REGEnLIFE has a declaration of compliance with MR001. 
In addition, the processing of personal data will comply with the European General Data Protection 
Regulation (GDPR) 2016/679. 
All information and data concerning patients or their participation in this investigation will be 
considered confidential and, to the extent permitted by the applicable laws and regulations, will not 
be made publicly available. Data will be collected and retained in a pseudo-anonymized format, with 
no identifying values that might link the data to an individual participant of the investigation. Patient 
names will not be communicated to REGEnLIFE. 
Since the clinical part of EUDAMED database is not available yet, the investigation will be registered 
on a publicly available database. Registration on EUDAMED will be made once available (if available 
during the investigation). 
9.11.2. Financing, Contract and Insurance 
REGEnLIFE will finance this clinical investigation. 
A financial convention will be put in place with the site. 
A specific insurance to the investigation has been subscribed by REGEnLIFE. 
9.11.3. Roles and Responsibilities 
Each member of the investigation team will comply with their respective following roles and 
responsibilities. 
9.11.3.1. 
Contract Research Organization 
 is the Contract Research Organization that performs the following activities on behalf of 
REGEnLIFE: 
• 
Investigation preparation, including writing of this CIP 
• 
Regulatory submission 
• 
Project management 
• 
Site management 
• 
Data management 

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• 
Statistical analyses 
• 
Writing of Clinical Investigation Report. 
9.11.3.2. 
Principal Investigator 
The role of the principal investigator is to implement, oversee the management of the day-to-day 
conduct of the clinical investigation as well as ensure data integrity and the rights, safety, and 
wellbeing of the patients involved in the clinical investigation. 
Responsibilities of the principal investigator are to: 
• 
Provide an up-to-date signed and dated copy of his/her curriculum vitae describing his/her 
experience, qualification and training 
• 
Ensure adequate training and qualifications of the investigation site team and maintain oversight 
of its activities 
• 
Explain the investigation to the patient in local language using non-technical terms to ensure 
proper understanding and provide the patient with ample time to read and understand the 
patient information sheet and to consider participation 
• 
Provide the patient with a copy of the signed and dated patient information and informed 
consent sheet and document the process of patient’s informed consent obtention in the 
patient’s medical file 
• 
Ensure that the anonymity of the patients is strictly maintained and that their identity is 
protected against unauthorized parties 
• 
Conduct the investigation as per this CIP 
• 
Collect and report the necessary data in the eCRF and ensure their quality 
• 
Perform safety reporting, as described in section 9.13 
• 
Report any deviations to this CIP, the applicable laws and regulations to REGEnLIFE 
• 
Permit authorized representatives of the sponsor, regulatory agencies, and Ethics Committee 
direct access to review the patient’s original medical file for verification of investigation-related 
procedures and data  
• 
Ensure medical care of the patients 
• 
After the end of the investigation, maintain and archive for 15 years the investigation site file, 
which will contain at a minimum the CIP and any amendments, the favorable opinion from the 
Ethics Committee, the list of included patients, any relevant correspondence, as well any other 
appropriate documents.  
 
 

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9.12. Informed Consent Process 
All applicable laws, regulations, and Ethics Committee requirements must be followed during the 
informed consent process. 
As previously mentioned, the participating site will offer investigation participation to patients 
meeting the eligibility criteria.  
The principal investigator will explain to the patient: 
• 
The nature, objectives, benefits, implications, risks and inconveniences of the clinical 
investigation 
• 
The patient's rights and guarantees regarding their protection, in particular their right to refuse 
to participate in and the right to withdraw from the clinical investigation at any time without any 
resulting detriment and without having to provide any justification 
• 
The conditions under which the clinical investigations will be conducted, including the expected 
duration of patient’s participation 
• 
The possible treatment alternatives, including the follow-up measures if the participation of the 
subject in the clinical investigation is discontinued.  
The patient will be provided with the current patient information sheet and informed consent form 
to read. The principal investigator will verify that the patient has understood the information and any 
questions that may arise will be addressed. Moreover, adequate time will be given for the patient to 
consider their decision to participate in the clinical investigation. 
To participate in the investigation, the patient and the principal investigator must sign and date the 
informed consent form. The principal investigator will provide patients with a copy of their signed 
informed consent form and retain the original version in the investigation site file. 
The informed consent process and patient participation to the investigation will be documented in 
the patient medical file. 
In case of new information available during the investigation or modification in the investigation 
procedure, the patient will be informed accordingly. An updated patient information sheet will be 
given to the patient and the informed consent form will be resigned and dated. 
 
 

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9.13. Safety Recording and Reporting 
9.13.1. Definitions within the Context of this Investigation 
9.13.1.1. 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or any untoward clinical signs, 
including an abnormal laboratory finding, in subjects, users or other persons, in the context of 
investigation, whether or not related to the investigational medical devices (Regulation 2017/745). 
Relevant notes from ISO 14155:2020 standard: 
• 
This definition includes events related to the procedures involved.  
• 
For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices. 
9.13.1.2. 
Serious Adverse Event (SAE)  
Any AE that led to any to any of the following (Regulation 2017/745): 
• 
Death 
• 
Serious deterioration in the health of the subject resulting in any of the following: 
o Life-threatening illness or injury 
o Permanent impairment of a body structure or a body function  
o Hospitalization or prolongation of patient hospitalization,  
o Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function  
o Chronic disease 
• 
Fetal distress, fetal death, or a congenital physical or mental impairment or birth defect. 
Relevant note from ISO 14155:2020 standard: Planned hospitalization for a pre-existing condition, or 
a procedure required by the CIP, without serious deterioration in health, is not considered a SAE.  
9.13.1.3. 
Adverse Device Effect (ADE) 
AE related to the use of an investigational medical device (ISO 14155:2020 standard). 
Relevant notes from ISO 14155:2020 standard: 
• 
This definition includes AEs resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, operation, or any malfunction of the investigational 
medical devices.  
• 
This includes any event resulting from use error or from intentional misuse of the investigational 
medical device.  
9.13.1.4. 
Serious Adverse Device Effect (SADE)  
ADE that has resulted in any of the consequences characteristic of a SAE (ISO 14155:2020 standard). 
9.13.1.5. 
Unanticipated Serious Adverse Device Effect (USADE)  
SADE which by its nature, incidence, severity or outcome has not been identified in the current risk 
assessment (ISO 14155:2020 standard).  
Relevant note from ISO 14155:2020 standard: Anticipated SADE (ASADE) is an effect which by its 
nature, incidence, severity or outcome has been previously identified in the risk assessment. 

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9.13.1.6. 
Device Deficiency (DD)  
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 (Regulation 2017/745). 
9.13.2. Definitions within the Context of Materiovigilance  
9.13.2.1. 
Incident 
Any malfunction or deterioration in the characteristics or performance of a device made available on 
the market, including use-error due to ergonomic features, as well as any inadequacy in the 
information supplied by the manufacturer and any undesirable side-effect (Regulation 2017/745). 
9.13.2.2. 
Serious Incident  
Any incident that directly or indirectly led, might have led or might lead to any of the following 
(Regulation 2017/745): 
• 
The death of a patient, user or other person 
• 
The temporary or permanent serious deterioration of a patient's, user's or other person's state of 
health 
• 
A serious public health threat. 
9.13.2.3. 
Serious Public Health Threat 
An event which could result in imminent risk of death, serious deterioration in a person's state of 
health, or serious illness, that may require prompt remedial action, and that may cause significant 
morbidity or mortality in humans, or that is unusual or unexpected for the given place and time 
(Regulation 2017/745). 
9.13.3. Safety Reporting to Sponsor 
Per Article 80 of the European Regulation 2017/745, the following events shall be recorded: 
• 
Any AE of a type identified in the CIP as being critical to the evaluation of the results of that 
clinical investigation 
• 
Any SAEs 
• 
Any DD that might have led to a SAE if appropriate action had not been taken intervention had 
not occurred, or circumstances had been less fortunate 
• 
Any new findings in relation to the above events. 
The following events that occur in patients included in RGnCON from inclusion to the end of the 52-
day follow-up period will thus be recorded: 
• 
All AEs, including SAEs 
• 
All DDs  
• 
Any new findings in relation to AEs and DDs. 
AEs will be reported using the Adverse Event form of the eCRF while DDs will be reported using the 
Device Deficiency form. The date of the event, its severity, causality, treatment and resolution will 
notably be collected. 
These events will be reported immediately to REGEnLIFE and no later than 3 calendar days after the 
investigator becomes aware of the event.  

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If needed, the investigations site team or 
 can contact REGEnLIFE’s materiovigilance department 
via email (gchampleboux@regenlife.com) or phone (+33 6 49 81 34 54). 
9.13.4. Safety Reporting to Authorities 
Per Article 80 of the European Regulation 2017/745, the following events shall be reported to 
authorities: 
• 
Any SAE that has a causal relationship with the investigational device, the comparator or the 
investigation procedure or where such causal relationship is reasonably possible 
• 
Any DD that might have led to a SAE if appropriate action had not been taken, intervention had 
not occurred, or circumstances had been less fortunate 
• 
Any new findings in relation to the above events. 
The Medical Device Coordination Group 2021-1 guideline states that, since EUDAMED clinical 
modules are not operational yet, national provisions apply for safety reporting to authorities. 
REGEnLIFE will thus report the above-listed events to the ANSM via the following email address: 
EC.DMCOS@ansm.sante.fr. 
Timeframes for safety reporting to the ANSM are described in Table 3 below. 
Table 3: Timeframes for safety reporting to authorities 
Type of event 
Timeframe  
• 
All SAEs or DDs mentioned at the beginning of 
section 9.13.4 that led to death or a risk of 
imminent death, serious injury or disease and that 
require prompt corrective action for patients, users 
or others 
• 
Any new information related to such events 
Immediately and no later than 2 calendar 
days after REGEnLIFE becomes aware of 
the event or new information related to an 
already-reported event 
• 
Other SAEs or DDs mentioned at the beginning of 
section 9.13.4 
• 
Any new information related to such events 
Immediately and no later than 7 calendar 
days after REGEnLIFE becomes aware of 
the event or new information related to an 
already-reported event 
9.13.5. Anticipated Adverse Device Effects 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9.13.6. Data Safety Monitoring Board 
There is no Data Safety Monitoring Board for this investigation. 
 
 

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9.14. Vulnerable Population 
There will not be any vulnerable patients included in this investigation. 
 
 

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9.15. Suspension or Premature Termination of the Clinical Investigation 
9.15.1. Suspension or Premature Termination of the Clinical Investigation 
REGEnLIFE has the right to suspend or terminate this investigation at any time. Reasons for 
suspending or terminating the investigation may include but are not limited to the incidence or 
severity of ADEs or DDs resulting in an unexpected, significant, or unacceptable risk to participants, 
and unsatisfactory patient enrollment.  
In this case, the investigators will be informed, with the reason for investigation suspension or early 
termination. Notification of suspension or termination will occur no later than five business days 
after REGEnLIFE’s decision. Moreover, REGEnLIFE will send a report outlining the circumstances to 
the Ethics Committee and all investigators. The investigators should continue to follow their patients 
as standard of care at their institution, but data collection will be stopped. 
A suspended or terminated investigation may not be reinitiated without approval of the reviewing 
Ethics Committee, where applicable.  
9.15.2. Site Close-Out 
REGEnLIFE reserves the right to close the site at any stage, upon giving reasonable written notice to 
the investigators. Reasons for closing the site may include, but are not limited to excessively slow 
recruitment, major deviations to regulations or to GCP by the site, inaccurate or incomplete data 
recording and no investigation activity (i.e., all patients have completed the investigation and all 
obligations have been fulfilled).  
A closed site may not be reinitiated without giving reasonable proof to REGEnLIFE that sufficient 
preventive and corrective actions have been implemented to resolve root causes of the problem.  
9.15.3. Investigator Participation Discontinuation 
Likewise, the investigators may discontinue participation upon giving reasonable written notice. In 
this case, the investigators shall return relevant documents to REGEnLIFE.  
At the end of the investigation, or at premature site closure, routine close-out activities will be 
conducted to ensure site records are complete, investigation data are complete and accurate, 
arrangements are made for record retention, and Ethics Committee is notified. 
 
 

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9.16. Results and Publication Policy 
As previously mentioned, since registration on EUDAMED database is not available yet, the 
investigation will be registered on a publicly available database. Registration on EUDAMED will be 
performed once available (if available during the investigation). 
A Clinical Investigation Report will be written. Results of the investigation will be communicated to 
the investigators and made available on the publicly available database. 
The investigation results will be submitted for publication in an appropriate peer reviewed journal.  
If the investigators wish to publish data from this investigation (poster, abstract, article, etc.), they 
must first seek approval from REGEnLIFE. 
 
 

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9.17. Provisional Timelines 
• 
Regulatory submission: June 2022 
• 
Site initiation: August-September 2022 
• 
Patient recruitment: September 2022 (first patient first visit) - December 2022 (last patient first 
visit) 
• 
Last visit last patient: February 2023 
• 
Database lock: March-April 2023 
• 
Statistical analysis and clinical investigation report: May-July 2023 
 

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[27]  Mestre C, Otero C, Díaz-Doutón F, et al. An automated and objective cover test to measure 
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the brain injury. Prague Med Rep 2006; 107: 433–442. 
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11. DOCUMENT REFERENCES  
RGn550 IFU: Instructions for Use RGn550 version 1 dated 07 April 2022 
RGn550 investigator brochure: RGn550 Brochure Investigateur version 1.0 dated 02 June 2022 

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12. APPENDICES 
All tools provided below are provided in French considering that the investigation will be conducted 
in 
France.

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12.1. Head Impact Assessment - Form 3  
 

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12.2. Trail Making Test  
12.2.1. Part A 
 
 
 

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12.2.2. Part B 
 
 
 

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12.3. SCAT5 Symptom Evaluation Tool