A Single Center, Pilot, Open Trial of the Cefaly® Device in the Treatment of Patients With Fibromyalgia.
Phase: NA
Conditions: Fibromyalgia
Sponsor: Cefaly Technology

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A single center, pilot, open trial of the CEFALY® device 
in the treatment of patients with fibromyalgia  
PROTOCOL 
 
 
INVESTIGATOR 
Lesley M. Arnold, M.D. 
University of Cincinnati College of Medicine 
260 Stetson Street, Suite 3200 
Cincinnati, Ohio 45219  
USA 
 
 
PROMOTER 
Pierre Rigaux, M.D. 
Cefaly Technology 
ZI des Hauts Sarts, 4ème Avenue 5 
4040 Herstal (Liège) 
BELGIUM 
 
 
 
 
 
Study Number: 50212 

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Signature 
Investigator 
Name 
Date 
Signature 
Lesley M. Arnold 
 
 
 
 
 
Promoter 
Name 
Date 
Signature 
Pierre Rigaux 
 
 
 
 
 
 
 
 

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Table of contents 
Investigator ..................................................................................................................................................................... 2 
Promoter ......................................................................................................................................................................... 2 
1. 
Rationale ................................................................................................................................................................. 5 
2. 
Study objective ...................................................................................................................................................... 6 
3. 
Study outcomes ..................................................................................................................................................... 7 
4. 
Study design ........................................................................................................................................................... 8 
4.1. 
General description ....................................................................................................................................... 8 
4.2. 
Experimental protocol ................................................................................................................................... 8 
4.2.1. 
Screening visit .......................................................................................................................................... 8 
4.2.2. 
Baseline visit (enrollment visit)............................................................................................................... 8 
4.2.3. 
Treatment period – intermediate and final visits............................................................................... 8 
5. 
Subjects .................................................................................................................................................................10 
5.1. 
Inclusion criteria ............................................................................................................................................10 
5.2. 
Exclusion criteria ...........................................................................................................................................10 
6. 
Medical device and treatment ........................................................................................................................11 
6.1. 
Device description .......................................................................................................................................11 
6.2. 
Device technology ......................................................................................................................................12 
6.3. 
Mechanism of action ..................................................................................................................................13 
6.4. 
Use during the trial........................................................................................................................................13 
6.5. 
Medication during the trial .........................................................................................................................13 
6.6. 
Device provisioning ......................................................................................................................................14 
7. 
Practical study modalities ..................................................................................................................................15 
7.1. 
Measures ........................................................................................................................................................15 
7.2. 
Calendar ........................................................................................................................................................16 
8. 
Data management and statistics ....................................................................................................................17 
8.1. 
Data management .....................................................................................................................................17 
8.2. 
Statistics ..........................................................................................................................................................17 
8.2.1. 
Sample size ............................................................................................................................................17 
8.2.2. 
Statistical methods ...............................................................................................................................17 
9. 
Management of adverse events .....................................................................................................................18 
9.1. 
Definition ........................................................................................................................................................18 
9.2. 
Gradation ......................................................................................................................................................18 
9.3. 
Causality ........................................................................................................................................................18 
9.4. 
Expected AE ..................................................................................................................................................18 
9.5. 
AE collection .................................................................................................................................................19 
9.6. 
Investigator's responsibility with respect to a SAE. ..................................................................................19 

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9.6.1. 
SAE Notification.....................................................................................................................................19 
9.6.2. 
Modalities of notification to the promoter .......................................................................................20 
9.6.3. 
Monitoring ..............................................................................................................................................20 
9.6.4. 
Notification period ...............................................................................................................................20 
9.7. 
Notification of pregnancy to the promoter ............................................................................................20 
9.8. 
Notification by the promoter to the authorities ......................................................................................20 
10. 
List of Annexes ...................................................................................................................................................22 
References....................................................................................................................................................................23 
 

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1. Rationale 
Fibromyalgia (FM) is a chronic pain syndrome with characteristic symptoms of fatigue, sleep 
disturbance, mood problems and cognitive complaints. Recent research suggests that the central 
nervous system (CNS) plays a major role in these symptoms in part through central sensitization [1,2]. 
Current medications for the treatment of FM have limited efficacy and are associated with side effects 
for most patients. Furthermore, polypharmacy is common in patients with FM, which potentially 
increases the side effect burden of treatment. e-TNS (external trigeminal nerve stimulation) with the 
CEFALY® device produces a sedative effect [3] and has proven its efficacy as a prophylactic treatment 
for episodic migraine [4,5]. The device is FDA-approved for the prevention of frequent episodic migraine 
and is very safe, with less than 5% of reported adverse events that are all minor and fully reversible. 
Besides its indication for migraine, e-TNS CEFALY® device shows several actions on the CNS that could 
support its use in FM: it produces a sedative effect during the session, pilot trials reported improvement in 
depression [6], and migraine patients frequently report improved sleep and less fatigue. Therefore e-TNS 
with CEFALY® might help to improve symptoms of FM and make available a new valuable therapeutic 
treatment for FM. 
Prior to conducting a randomized sham controlled clinical trial to investigate the efficacy and safety of 
e-TNS with the CEFALY® device in FM, a pilot open trial is needed to collect preliminary data on efficacy 
and safety and to establish the group sizes for the subsequent controlled trials. 
 

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2. Study objective 
The main objective of this clinical pilot trial is to evaluate the use of the CEFALY® neurostimulator as a 
therapeutic treatment for FM.  
 
 

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3. Study outcomes  
Primary outcomes: 
• 
Mean pain intensity between baseline and 12 weeks endpoint 
• 
Fibromyalgia Impact Questionnaire-revised (FIQR) total score between baseline and 12 weeks 
endpoint 
Secondary outcomes: 
• 
Mean pain intensity between baseline and 4 weeks visit 
• 
FIQR total score between baseline and 4 weeks visit 
• 
Patient Global Impression of Change (PGIC) at 4 weeks visit and at 12 weeks endpoint 
• 
EQ-5D-3L between baseline and 4 weeks visit; and between baseline and 12 weeks endpoint 
• 
Patient Reported Outcomes Measurement Information System (PROMIS) measures for 
depression, fatigue and sleep between baseline and 4 weeks visit; and between baseline and 
12 weeks endpoint 
• 
Multiple Ability Self-report Questionnaire (MASQ) between baseline and 4 weeks visit; and 
between baseline and 12 weeks endpoint 
Exploratory outcomes: 
• 
FM30 (≥30% responder rate) i.e. meeting the following criteria: 
- 
≥30% reduction in pain (FIQR) 
- 
≥10% improvement in physical function  
- 
≥30% improvement in 2 of the following symptoms: (with FIQR) fatigue, sleep, 
depression, anxiety, (with MASQ) cognition 
• 
FM20 (≥20% responder rate) 
- 
≥20% reduction is pain (FIQR) 
- 
≥10% improvement in physical function  
- 
≥20% improvement in 2 of the following symptoms: (with FIQ) fatigue, sleep, depression, 
anxiety, (with MASQ) cognition 
 
 
 

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4. Study design 
4.1. 
General description 
This study is a clinical study with the following characteristics: 
• 
Single center 
• 
Prospective 
• 
Open 
4.2. 
Experimental protocol 
Patient diagnosed with FM will be screened for study eligibility.  Eligible patients will be scheduled for the 
baseline visit (enrollment visit) that will take place within a maximum of 4 weeks after the screening visit. 
At the baseline visit, the patients will be given a CEFALY® device together with the necessary 
accessories for a 12-week treatment period. Outcome measures will be administered at the baseline 
visit, after 4 weeks of treatment and at the end of the 12-week treatment period.  The overall study flow 
is illustrated in Figure 1. 
4.2.1. 
Screening visit  
The patients will be evaluated for study eligibility at the screening visit (Visit 1). They will receive study 
information and consent documents, and they have to sign these documents before study procedures 
are initiated. Then the investigator will verify that the patient meets all inclusion criteria and none of the 
exclusion criteria. If this is the case, the patient will be tested for tolerance to the neurostimulation 
(nociceptive threshold test). If the patient passes this test, he/she will continue in the study. 
4.2.2. 
Baseline visit (enrollment visit) 
The baseline visit (Visit 2) is scheduled within 4 weeks following the screening visit. If the patient still meets 
the inclusion criteria regarding the pain intensity, he/she will complete the baseline questionnaires.  The 
patient will receive a CEFALY® device together with the necessary accessories for a 12-week treatment 
period. 
4.2.3. 
Treatment period – intermediate and final visits 
During 12 weeks, patients will apply the CEFALY® twice a day, roughly at the same time of the day 
everyday (morning and evening) for a complete treatment session of 20 minutes. Compliance will be 
analyzed afterwards using a built-in recording system. An intermediate visit will be scheduled after 4 
weeks of treatment (between minimum 4 weeks and maximum 6 weeks) (Visit 3). The patient will 
complete the visit questionnaires to assess efficacy of the treatment, and report possible side effects 
and adverse events regardless of possible relationship to the device. A final visit will occur after the 12 
weeks of treatment (between minimum 12 weeks and maximum 14 weeks) (Visit 4) to collect the 

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CEFALY® device and complete visit questionnaires to assess efficacy as well as possible side effects and 
adverse events reported regardless of possible relationship to the CEFALY® device.  
 
 
Figure 1 - Study flowchart 

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5. Subjects 
The study will include 50 men or women. 
5.1. 
Inclusion criteria 
The following inclusion criteria apply: 
1. 
Aged from18 to 65 years 
2. 
Diagnosed with FM according to the 2010 ACR Preliminary Diagnostic Criteria for Fibromyalgia 
[7] 
3. 
Having a minimum pain score of at least 4 on the 0-10 FIQR pain scale at screening and 
baseline. 
5.2. 
Exclusion criteria 
The following exclusion criteria apply: 
1. 
Women: Pregnant, lactating or <6 months post partum 
2. 
Episodic or Chronic Migraine according to the diagnostic criteria listed in ICHD-III beta (2013) 
section 1, migraine 1, having two or more attacks per month.  
3. 
Change in any medication acting on the central nervous system (CNS) within 28 days before 
start of the study or during the study 
4. 
Severe depression i.e. having a Beck Depression Inventory-Fast Screen (BDI-FS) score >12 
5. 
Botox injection within 4 months before baseline or during the study. 
6. 
Psychiatric disorders that could interfere with study participation: bipolar disorder, psychotic 
disorders and dementia. 
7. 
Suicidal behavior and/or ideation i.e. having a Columbia Suicide Severity Rating Scale (C-SSRS) 
score ³ 4 during the preceding 2 years 
8. 
Patients currently taking any opioid medication 
9. 
Patients currently taking medically prescribed marijuana 
10. Current or history during the preceding year of alcohol or substance abuse including marijuana 
11. Intolerance to supraorbital neurostimulation that makes the treatment not applicable (test of 
nociceptive threshold with specific Cefaly program) 
12. Widespread rheumatic diseases (other than FM), evidence of inflammatory rheumatic disease  
13. Any unstable medical condition in the judgment of the investigator that would interfere with 
study participation or study assessments.  
14. Implanted active metal or electrical devices in the head 
15. Cardiac pacemaker or implanted or wearable defibrillator  
 

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6. Medical device and treatment 
6.1. 
Device description 
The CEFALY® is a small, portable product, which is meant to be worn on the forehead by attachment to 
a self-adhesive electrode. Two 1.5V AAA batteries provide power to the CEFALY® device.  The CEFALY® 
generates very precise electrical impulses that permit stimulation of the nerve fibers. The device acts by 
stimulation of the upper branch of the trigeminal nerve.  
The device has been approved by the FDA as a class II therapeutic device indicated for the 
prophylactic treatment of episodic migraine in patients 18 years of age or older. 
The CEFALY® device (Figure 2) is comprised of the following specifications: 
• 
Dimensions: 163 mm x 170 mm x 40 mm. 
• 
Weight: 30 g. 
 
Figure 2 - CEFALY® device 
The device is connected to the body via a self-adhesive electrode (Figure 3) applied on the forehead. 
The patient may use the device through sessions of 20 minutes. The CEFALY® electrode is 94 mm long 
and 30 mm high. It makes the interface between the device and the skin. It’s a multiuse electrode 
designed to be used 20 times. 

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Figure 3 - CEFALY® electrode 
6.2. 
Device technology 
The CEFALY® is an external cranial neurostimulator designed for supraorbital neurostimulation (also 
known as external trigeminal nerve stimulation: e-TNS). Trigeminal nerve stimulation induces a sedative 
effect on the central nervous system. 
The CEFALY® generates electrical impulses that are transmitted transcutaneously via a bipolar self-
adhesive electrode placed on the forehead. 
The CEFALY® operates on direct electrical energy, which is output from two 1.5V AAA batteries. 
The CEFALY® delivers electrical energy in the form of rectangular biphasic pulses. The intensity is 
increasing linearly to reach a maximum of 16 mA after 14 minutes (and then stays constant for 6 
minutes). The pulse frequency is 60 Hz. The pulse width is 250 µs. 
If the user feels that the intensity becomes too high, a simple pressure on the button will stabilize the 
intensity for the rest of the session. 
The supraorbital electrode is designed in order to cover both sides of the supratrochlearis and 
supraorbitalis nerves, which are branches of the trigeminal nerve (Figure 4).  
The electrical impulses generated by the CEFALY® device are transmitted transcutaneously via the 
supraorbital electrode to excite (trigger action potentials) the supratrochlearis and supraorbitalis nerves.  
Supratrochlearis and supraorbitalis (or supratrochlear and supraorbital) nerves belong to the upper 
branch of the trigeminal nerve (V1). Therefore the supraorbital neurostimulation is also known as 
external trigeminal nerve stimulation.  
 

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Figure 4 - The electrode placed on the forehead covers the supratrochlearis and supraorbitalis nerves 
6.3. 
Mechanism of action 
CEFALY® device generates electrical impulses. Electrical impulses get out of the device via 2 metallic 
contacts. Contacts are in connection with 2 conductive areas on the self-adhesive electrode. The self-
adhesive electrode is applied on the forehead. Therefore electrical impulses generated by the 
CEFALY® device are running through the metallic contacts then through the electrode in order to carry 
out excitation on the nerve fibers just located under the forehead skin i.e. supratrochlearis and 
supraorbitalis (or supratrochlear and supraorbital) nerves which belong to the trigeminal nerve. 
Consequently electrical impulses generated by the CEFALY® trigger signals (action potentials) on 
supratrochlear and supraorbital nerves or trigeminal nerve. Repetitive excitation of trigeminal nerve is a 
neuromodulation of the trigeminal system. Neuromodulation of the trigeminal system induces a sedative 
effect on the central nervous system and a trigeminal nociceptive threshold modification. 
6.4. 
Use during the trial 
The CEFALY® will be used twice a day by the patient. The patients should have at least two sessions of 
stimulation per day, roughly at the same time of the day everyday (morning and evening). A complete 
treatment session lasts 20 minutes. The patient should therefore use the device 40 minutes a day.  
The device contains a system that records the usage statistics (compliance). For each patient it will be 
possible to know how much time the device has been activated and at what intensity on average the 
patient has been stimulated. 
6.5. 
Medication during the trial 
• 
Medication acting on the CNS: cannot be changed within 28 days before start of the study or 
during the study. 
• 
Botox injection: no injection within 4 months before start of the study or during the study 

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• 
Opioid medication: forbidden 
• 
Marijuana: forbidden 
6.6. 
Device provisioning 
The promoter will deliver the devices directly to the investigators.  
The patient will receive the device at the baseline visit and will return it at the end of the 12-week 
treatment period during the final visit. 
 
 

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7. Practical study modalities 
7.1. 
Measures 
The outcome measures taken in the study are all based on self-assessment questionnaires. The following 
will be used: 
• 
FIQR: evaluation of the impact and the severity of FM symptoms. 
• 
EQ-5D-3L: evaluation of the general quality of life. 
• 
PROMIS for depression, fatigue, and sleep. 
• 
MASQ: assessment of the self-perception of cognitive difficulties. 
• 
PGIC: assessment of the patient perception of change induced by the treatment. 
In order to evaluate the modification of pain level from baseline to 4-week treatment and to 12-week 
treatment, the item of the FIQR related to pain will be used, i.e. numeric rating scale (NRS) scoring the 
pain between 0 and 10. 
During the screening visit, the following tests will be performed to evaluate the exclusion criteria 4 and 7, 
respectively: 
• 
Beck Depression Inventory-Fast Screen (BDI-FS); 
• 
Columbia Suicide Severity Rating Scale (C-SSRS). 
The following table depicts at which visit the various questionnaires are completed. 
 
 
Visit 1 
Screening 
 
Visit 2 
Baseline 
 
Visit 3 
Intermediate assessment 
(4-week treatment) 
Visit 4 
Final assessment 
(12-week treatment) 
FIQR 
l(*) 
l 
l 
l 
EQ-5D-3L 
 
l 
l 
l 
PROMIS 
 
l 
l 
l 
MASQ 
 
l 
l 
l 
PGIC 
 
 
l 
l 
BDI-FS 
l 
 
 
 
C-SSRS 
l 
 
 
 
(*) Only the item of the FIQR related to pain. 

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7.2. 
Calendar 
The study is foreseen to start in September / October 2015 and to be finished by May 31 2016. 
 
 

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8. Data management and statistics 
8.1. 
Data management 
The data will be included in the case report form (CRF) that will be provided to the promoter 
anonymously, using a numbering system. 
8.2. 
Statistics 
8.2.1. 
Sample size 
The number of subjects to recruit in the study (50 patients) is estimated to be sufficient for analysis. 
8.2.2. 
Statistical methods 
• 
All relevant general, safety and efficacy data will be descriptively summarized at each time 
point. 
• 
Continuous data will be summarized by the number of subjects (N), the arithmetic mean, the 
standard deviation, the coefficient of variation as a percentage (CV%), the median, the inter-
quartile range, the minimum and the maximum value. 
• 
Categorical data will be summarized by absolute (N) and relative (%) frequency tables. 
• 
Where considered as relevant, the study data will also be graphically depicted. 
• 
Results analysis will be carry out on a per protocol basis, i.e. on ³50% compliant patients; sub-
analysis will be performed as well on an intention to treat basis, i.e. including all subjects who 
used the study device at least once. For each patient, the average outcome will be calculated 
before and after the treatment period on all data available, without any imputation of missing 
data. 
 
 

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9. Management of adverse events 
9.1. 
Definition 
Adverse Event (AE) 
An adverse event (AE) is defined as any unfavorable and unintended sign, symptom or disease, 
regardless of whether it is considered related to the medical device or procedure that occurs during 
the course of the study. 
In all cases, etiology will have to be researched and identified as soon as possible.   
Serious Adverse Event  (SAE) 
A serious adverse event (SAE) is defined as any untoward medical occurrence that results in death, is 
life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. 
The investigator is responsible of transmission of SAE to the promoter and the promoter is responsible of 
transmission of the SAE declaration to the authorities. 
9.2. 
Gradation 
Adverse events should be categorized by the investigator according to severity: 
• 
Mild: perception of sign or symptom, but easily tolerated. 
• 
Moderate: cumbersome enough to impact subject activities. 
• 
Severe: modifying considerably patient activities, or impairing, or constituting a threat for the life 
of the patient.  
9.3. 
Causality 
Main factors to take into account to determine the causality are: 
• 
Events chronology, 
• 
AE evolution when the product is not used anymore or used again, 
• 
Existence of another etiology that could explain the AE, 
• 
Existence of similar published or known AE. 
9.4. 
Expected AE 
The expected AEs of the CEFALY® are: 

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• 
Reversible skin irritation at the place of electrode 
• 
Allergic reaction to the gel of the electrode (1 out of 1000) 
• 
Headache after the session (0.52%) 
• 
Feeling of fatigue 
9.5. 
AE collection 
The patients are instructed to report all AEs to the investigator. AEs will be registered daily by the subject 
in the corresponding form. This form will be returned by the subject at the intermediate visit and at the 
end of the study and will be analyzed by the investigator who will document it in the CRF. 
All AEs will be collected in the CRF, specifying: 
• 
Their nature 
• 
Start date and duration 
• 
Causality (according to investigator's opinion) 
• 
Countermeasures and results 
If the AE is a SAE, the promoter should be notified as soon as possible.  
9.6. 
Investigator's responsibility with respect to a SAE. 
9.6.1. 
SAE Notification  
Each SAE will be described on the specific form with as much detail as possible. The information to be 
communicated to the promoter are: 
• 
Patient identification 
• 
AE severity 
• 
Start and end date 
• 
Detailed description  
• 
AE evolution 
• 
Current diseases and relevant medical history of the patient 
• 
Patient received treatments 
• 
Causality link with the device under test  
The investigator should also join to the AE report, each time it is possible: 
• 
A copy of the hospitalization report 
• 
A copy of all complementary exam results performed, including relevant negative results and 
joining the laboratory reference values 
• 
Or any other document that he/she found useful and relevant 
• 
Possibly, a copy of the autopsy report  

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All documents will be made anonymous and will bear the identification number of the subject. 
9.6.2. 
Modalities of notification to the promoter 
All SAE, no matter its causality relationship with the device under test, should be declared by the 
investigator: 
• 
To promoter (represented by the CEO) 
• 
As fast as possible 
• 
By e-mail: the specific form 
9.6.3. 
Monitoring    
The monitoring is ensured until total recovery, stabilization or death of the patient, on common decision 
of the monitor and the investigator. Related costs are covered by the promoter. 
9.6.4. 
Notification period 
It is the investigator responsibility to notify the promoter about any SAE occurring: 
• 
During the whole study period 
• 
At any time, after the end of the study if the investigator thinks this could be related to the 
device under test during the study (if no other cause than the research could reasonably 
explain it). 
9.7. 
Notification of pregnancy to the promoter 
The CEFALY® device is perfectly safe for pregnant women. However, pregnancy causes many 
physiologic changes that can interfere with the FM assessment.  
If a pregnancy is suspected during the study, the subject should notify the result of the pregnancy test. If 
the pregnancy is confirmed, it is a drop out and the subject's data are excluded from the analysis. 
9.8. 
Notification by the promoter to the authorities 
In case the promoter is notified of an unexpected AE, he will report it directly to the national competent 
authority (FDA) and to the relevant Investigational Review Board. 
Similarly, if a new fact relevant to the study or to the device appears that could impact the safety of the 
subjects participating to the study, the promoter takes the appropriate emergency measures. The 
promoter also notifies both the FDA and the IRB of this new fact and of the taken measures. 
 

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The delay to inform the authorities will be 7 days in case of death or life threatening AE, and 15 days in 
case of other unexpected AE or new fact. An extra delay of 8 days is foreseen to provide a follow-up 
report. 
If necessary, the investigator will ask the subjects participating to the study to confirm their consent 
based on the updated information. 
 
 

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10. 
List of Annexes 
CRF  
AE reporting form  
Informed consent 
Instruction sheet for the nociceptive threshold test 
Patient questionnaires (FIQR, EQ-5D-3L, PROMIS depression, fatigue and sleep, MASQ and PGIC) 
 
 
 

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References 
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Clauw DJ, Arnold LM, McCarberg BH. The science of fibromyalgia. Mayo Clin Proc 2011;86:907-
911;  
2. 
Cagnie B, Coppieters I, Denecker S, et al. Central sensitization in fibromyalgia? A systematic 
review on structural and functional brain MRI. Semin Arthritis Rheum 2014;44:68-75. 
3. 
Piquet M1, Balestra C, Sava SL, Schoenen JE. Supraorbital transcutaneous neurostimulation has 
sedative effects in healthy subjects. BMC Neurol. 2011 Oct 28;11:135. doi: 10.1186/1471-2377-11-135.  
4. 
Schoenen, J. et al. Migraine prevention with a supraorbital transcutaneous stimulator: a 
randomized controlled trial. Neurology 80, 697–704 (2013). 
5. 
Magis, D., Sava, S., d’ Elia, T. S., Baschi, R. & Schoenen, J. Safety and patients’ satisfaction of 
transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a 
survey of 2,313 headache sufferers in the general population. J Headache Pain 14, 95 (2013). 
6. 
Schrader LM. Trigeminal nerve stimulation in major depressive disorder: first proof of concept in 
an open pilot trial. Epilepsy Behav. 2011 Nov;22(3):475-8. doi: 10.1016/j.yebeh.2011.06.026. Epub 2011 
Aug 4.  
7. 
Wolfe F, Clauw DJ, Fitzcharles MA, et al. Fibromyalgia criteria and severity scales for clinical and 
epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. J 
Rheumatol. 2011;38:1113-1122.